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Immunity

When your Friend turns to Foe

Fellowship in Anti-Aging MedicineModule 4

Did You Know, Immune Dysregulation is Found in:

Alzheimer’s DiseaseSchizophreniaHeart DiseaseSpontaneous AbortionsDepressionHyperhomocysteinaemia

And more…

The Gut Regulates Systemic Immunity

The proper functioning of the gut environment is essential for systemic immunityAntigen Presenting Cells (APC) such as M cells, B cells, endothelial cells, macrophages and dendritic cells dictate the immune response in the gut.These cells send messages (cytokines) to the systemic immune system, which then dictates its responseImproving gut flora can normalise immunity.

The Gut Directs Immunity

“First, the cells of the gut itself produce TGF-b, vasoactive intestinal peptide (which controls the secretory piece of IgA), and other immunologically relevant molecules.”

Oral Alpan, Gregory Rudomen and Polly Matzinger. The Role of Dendritic Cells, B Cells, and M Cells in Gut-Oriented Immune Responses. The Journal of Immunology, 2001, 166:4843-4852.


“Second, the luminal side of the intestinal epithelium contains a set of specialized Ag (antigen) -handling cells called M (microfold) cells. These cells overlay intestinal lymphoid follicles and Peyer’s patches, sending down long protrusions that form pockets in which T cells, B cells, and macrophages can be found.”

Oral Alpan, Gregory Rudomen and Polly Matzinger. The Role of Dendritic Cells, B Cells, and M Cells in Gut-Oriented Immune Responses. The Journal of Immunology, 2001, 166: 4843-4852.


“M cells can take up and transport Ags such as ferritin and pathogens such as Salmonella and HIV by active transport. By their Ag handling, or perhaps by the secretion of specialized cytokines, the M cells might influence the effector class of local immune responses.”


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“Third, in contrast to other lymph nodes, B cells far outnumber all other lymphoid cells in the Peyer’spatches. They might therefore serve as a specialized set of APCs to induce tolerance or to drive immune responses toward particular effectorclasses.”


Gut M Cells Passage Antigens“After the uptake of antigens through M cells, the

antigens are processed and presented by professional APCs. A major APC population in the subepithelial (dome) region of PPs is characterised as DCs.”

Hideki Iijima1, Ichiro Takahashi1 and Hiroshi Kiyono1,2* Mucosal immune network in the gut for the control of infectious diseases. Rev. Med. Virol. 2001; 11: 117–133.

Spahn TW, Kucharzik T. Modulating the intestinal immune system: the role of lymphotoxin and GALT organs. Gut. 2004 Mar;53(3):456-65.

How The Gut Regulates Immunity

“The gut is believed to be central in the development of counter-regulatory immune function. The gastrointestinal tract and associated mucosal immune system is an IL-10 and TGF dominant environment, promoting mucosal immune responses and systemic immune tolerance.”

SL Prescott New concepts of cytokines in asthma: Is the Th2/Th1 paradigm out the window? Journal of Paediatrics and Child Health

Volume 39 Issue 8 Page 575 - November 2003

How The Gut Regulates Immunity

“It is of note that germ-free animals that do not achieve normal gut colonization have profound disorders of immune tolerance including both autoimmunity and allergy.”

SL Prescott New concepts of cytokines in asthma: Is the Th2/Th1 paradigm out thewindow? Journal of Paediatrics and Child Health


Systemic Immunity: Review

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Review: Leukocytes

The leukocytes are subdivided into granulocytes(containing large granules in the cytoplasm) and agranulocytes (without granules). The granulocytes consist of neutrophils (55–70%), eosinophils (1–3%), and basophils (0.5–1.0%). The agranulocytes are lymphocytes (consisting of B cells and T cells) and monocytes. Lymphocytes circulate in the blood and lymph systems, and make their home in the lymphoid organs.

Review: Innate Immunity

The innate immunity system is what we are born with and it is nonspecific; all antigens are attacked pretty much equally. It is genetically based and we pass it on to our offspring.


Each of the cells in the innate immune system bind to antigen using pattern-recognition receptors. These receptors are encoded in the germ line of each person. This immunity is passed from generation to generation. Over the course of human development these receptors for pathogen-associated molecular patterns have evolved via natural selection to be specific to certain characteristics of broad classes of infectious organisms.


There are several hundred of these receptors and they recognize patterns of bacterial lipopolysaccharide, peptidoglycan, bacterial DNA, dsRNA, and other substances. Clearly, they are set to target both Gram-negative and Gram-positive bacteria.

Review: (Innate) Phagocytosis

A phagocyte is a cell that attracts (by chemotaxis), adheres to, engulfs, and ingests foreign bodies. Promonocytes are made in the bone marrow, after which they are released into the blood and called circulating monocytes, which eventually mature into macrophages, meaning "big eaters”.

Review: Adaptive or Acquired Immunity

B cells are produced in the stem cells of the bone marrow; they produce antibody and oversee humoral immunity. T cells are nonantibody-producing lymphocytes which are also produced in the bone marrow but sensitized in the thymusand constitute the basis of cell-mediated immunity. Parts of the immune system are changeable and can adapt to better attack the invading antigen. There are two fundamental adaptive mechanisms: cell-mediated immunity and humoral immunity.

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Review: T-Cells

Cytotoxic or killer T cells (CD8+) do their work by releasing lymphotoxins, which cause cell lysis. Helper T cells (CD4+) serve as managers, directing the immune response. They secrete chemicals called lymphokines that stimulate cytotoxic T cells and B cells to grow and divide, attract neutrophils, and enhance the ability of macrophages to engulf and destroy microbes.

Review: T-Cells

Suppressor T cells inhibit the production of cytotoxic T cells once they are unneeded, lest they cause more damage than necessary. Memory T cells are programmed to recognize and respond to a pathogen once it has invaded and been repelled.

Review: B-Cells

An immunocompetent but as yet immature B-lymphocyte is stimulated to maturity when an antigen binds to its surface receptors and there is a T helper cell nearby (to release a cytokine). Most of the family of clones become plasma cells. These cells, after an initial lag, produce highly specific antibodies at a rate of as many as 2000 molecules per second for four to five days. The other B cells become long-lived memory cells.

Review: Antibodies

Antibodies are soluble proteins secreted by the plasma offspring (clones) of primed B cells. The antibodies inactivate antigens by, (a) complement fixation (proteins attach to antigen surface and cause holes to form, i.e., cell lysis), (b) neutralization (binding to specific sites to prevent attachment—this is the same as taking their parking space), (c) agglutination(clumping), (d) precipitation (forcing insolubility and settling out of solution), and other more arcane methods.

Review: Macrophage

Once a macrophage phagocytizes a cell, it places some of its proteins, called epitopes, on its surface—much like a fighter plane displaying its hits. These surface markers serve as an alarm to other immune cells that then infer the form of the invader. All cells that do this are called antigen presenting cells (APCs).

Review: Macrophages

The non-fixed or wandering macrophages roam the blood vessels and can even leave them to go to an infection site where they destroy dead tissue and pathogens. Emigration by squeezing through the capillary walls to the tissue is called diapedesis or extravasation. The presence of histamines at the infection site attract the cells to their source.

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Review: NK Cells

Natural killer cells move in the blood and lymph to lyse (cause to burst) cancer cells and virus-infected body cells. They are large granular lymphocytes that attach to the glycoproteins on the surfaces of infected cells and kill them.

Review: Complement System

The complement system is a major triggered enzyme plasma system. It coats microbes with molecules that make them more susceptible to engulfment by phagocytes. Vascular permeability mediators increase the permeability of the capillaries to allow more plasma and complement fluid to flow to the site of infection.

Review: Eosinophils

Eosinophils are attracted to cells coated with complement C3B, where they release major basic protein (MBP), cationic protein, perforins, and oxygen metabolites, all of which work together to burn holes in cells and helminths(worms). About 13% of the WBCs are eosinophils. Their lifespan is about 8–12 days. Neutrophils, eosinophils, and macrophages are all phagocytes.

Review: Dendritic cells

Dendritic cells are covered with a maze of membranous processes that look like nerve cell dendrites. Most of them are highly efficient antigen presenting cells. There are four basic types: Langerhans cells, interstitial dendritic cells, interdigitating dendritic cells, and circulating dendritic cells.

IL-10 is King! “Although initially classified as a Th2 cytokine, IL-10

is produced by a much wider range of cell types (dendritic cells, monocytes, macrophages, CD4+ and CD8+ T cells, natural killer cells, neutrophils and epithelial cells), and is now viewed more as a potent immunoregulatory cytokine. It plays an important role modulating and dampening excessive immune responses across the whole immune system.”


Volume 39 Issue 8 75 - November 2003

IL-10 is King! “IL-10 is also produced by a recently described T-

cell subset; the CD4+ CD25 + regulatory T cell. Interleukin-10 inhibits T-cell activation, immunoglobulin (Ig)E production, eosinophilrecruitment and many other aspects of allergic inflammation.”



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Corticosteroids Increase IL-10“Of note, inhaled corticosteroids increase IL-10

responses by alveolar macrophages, suggesting that this may contribute to the anti-inflammatory action of these medications.”

“Both IL-10 and TGF gene polymorphisms have been noted in association with asthma and atopy.”



Th1/Th2 Paradigm“In the current research literature Th1 cells (now

sometimes called "Type 1 immunity") and Th2 cells ("Type 2 immunity") are invoked to rationalize virtually all the known patterns of immune response.”

Parris Kidd Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alternative Medicine Review, August 2003 v8 i3 p223(24)

Th1/Th2: The Two Generals of Immunity

The Two General and their Troops

Th1IL-1IL-2IL-8IL-12INF-g

InflammatoryIL-1bIL-6TNF-a

Th2IL-4IL-5IL-13

Anti-inflammatory (Balancing)IL-10TGF-b

Th1/Th2 Beneficial Roles“Th1 cells are hypothesized to lead the attack

against intracellular pathogens such as viruses, raise the classic delayed-type hypersensitivity (DTH) skin response to viral and bacterial antigens, and fight cancer cells. Th2 cells are believed to emphasize protection against extracellular pathogens such as multicellularparasites.”


Th1/Th2 Negative Roles“On the negative side, the Th1 pathway is often

portrayed as being the more aggressive of the two, and apparently, when it is overreactive, can generate organ-specific autoimmune disease (e.g., arthritis, multiple sclerosis, type 1 diabetes). The Th2 pathway is seen as underlying allergy and related IgE-based disease, and predisposing to systemic autoimmune disease.”


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LONG, KURT Z. PHD; SANTOS, JOSE IGNACIO MD Vitamins and the regulation of the immune response. Pediatr Infect Dis J. Volume 18(3) March 1999 pp 283-290.

Th1/Th2 Paradigm: APCs“Curiously, published studies on Th1/Th2

dominance often downplay the dendritic cells (DCs), monocyte-macrophages, and other antigen-presenting cells (APCs). Judging from the current body of knowledge, these cells are just as strongly qualified to supervise immunity.”


DC’s in the Gut Dictate T-Helper Response

The kinds of immune responses evoked by each DC activation in the gut are distinct:

The generation of Th2 cells for the induction of an IgA response, the induction of Th3/Tr1 cells for oral tolerance and the generation of Th1 cells for antimicrobial immune responses.


Normal Immune/Gut Relations and Oral Tolerance

Under normal conditions, the gut has several mechanisms that control allergies and immune over reactions to certain foods. At a high dose of foods, the immune system undergoes deletion, which reduces the immune response. When a low dose is introduced, IL-10 and TGF-b is released also down regulating the immune system. Hideki Iijima1, Ichiro Takahashi1 and Hiroshi Kiyono1,2* Mucosal immune network in the

gut for the control of infectious diseases. Rev. Med. Virol. 2001; 11: 117–133.

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Th1/Th2 Cell Interactions and Oral Tolerance


T-helper Cell Interactions

Building a Th1 Response: Microbe Attack Th1 Cell Production

“A DC or related APC exposed to an intracellular pathogen (or perhaps a cell wall antigen or other smaller fragment of the organism) will likely become type- 1 biased. It promptly migrates to a nearby lymph node and begins to secrete IL-12.”


Th1 Cell Production“As this cytokine builds in concentration it begins to

influence naive T cells to eventually become Th1 cells. Natural killer (NK) cells also respond to the IL-12 environment and proceed to release IFN-gamma, which reinforces the APC's production of IL- 12 and also helps drive the naive T-cell commitment process.”


Th1 Cell Production“As they attain maturity, Th1 cells also produce

IFN-gamma, which (together with the NK cells) stimulates the APC and naive T cells to polarize into more Th1 cells, in a self-reinforcing "autocrine" loop.”


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Building a Th2 Response: Parasite Attack Th2 Cell Production

“Like the Th1 cells, the emergence of Th2 cells is also dependent on their cytokine environment. Their maturation is likely initiated by the cytokine IL-6 from an APC, but also driving their maturation is IL-4 released by NK cells, mast cells, and eosinophils.”


Th2 Cell Production“As the Th2 cells mature they also produce IL-4,

which together with the other participating cell types generates an autocrine loop to the naive T cells to make more Th2 cells.”


Hormones and Immunity Oestrogen Increases Th2

“Estrogen appears to play a central role in the immune response and immune-mediated diseases. Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset during the postpartum period.”

Salem ML Estrogen, A Double-Edged Sword: Modulation of TH1- and TH2-Mediated Inflammations by Differential Regulation of TH1/TH2 Cytokine Production. Curr

Drug Targets Inflamm Allergy. 2004 Mar;3(1):97-104.

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Oestrogen Increases Th2

“Recent evidence indicates that estrogens inhibit the production of TH1 proinflammatory cytokines, such as IL-12, TNF-alpha and IFN-gamma, whereas they stimulate the production of TH2 anti-inflammatory cytokines, such as IL-10, IL-4, and TGF-beta. This can explain why estrogen suppresses and potentiates TH1- and TH2-mediated diseases, respectively.”



Oestrogen Increases Th2

“We hypothesize that exacerbation or suppression of inflammatory diseases by estrogen is mediated by skewing TH1-type to TH2-type response. This view represents a novel mechanism for the modulatory effect of estrogen on certain inflammatory diseases that can lead to beneficial or detrimental impacts depending on the type of immune involved.”



DHEA and Cortisol Increases Th2

“Of importance may be the finding of a positive correlation between DHEA and IL-4 (TH2 cytokine), together with a relatively high negative correlation between cortisol and IL-10 (also TH2 cytokine).”

Sterzl I, Hampl R, Hill M, Hrda P, Matucha P. Immunomodulatory cytokines in human seminal plasma correlate with immunomodulatory steroids. Steroids. 2003 Oct;68(9):725-31.

Progesterone Induces a Th2 Shift

“The pregnancy-related hormone progesterone induces Th2 immunity; on the other hand, relaxininduces Th1 immunity. Preeclamptic placentas produce more progesterone than do normal placentas.”

Shigeru Saito, and Masatoshi Sakai. Th1/Th2 balance in preeclampsia. Journal of Reproductive Immunology. Volume 59, Issue 2 , August 2003, Pages 161-173

7-OH-DHEA Increases Th1

“On the other hand, 7-OH-DHEA showed a positive correlation with IFN-g (TH1 cytokine), thus confirming the fact that from the point of view of their immunomodulatory role, the 7-hydroxyepimers of DHEA differ markedly in their effects.”

Sterzl I, Hampl R, Hill M, Hrda P, Matucha P. Immunomodulatory cytokines in human seminal plasma correlate with immunomodulatory steroids. Steroids. 2003 Oct;68(9):725-31.

Low Testosterone/DHEA in RA (Th1 Excess)

“Low plasma and synovial fluid testosterone concentrations are observed in male RA patients; low plasma DHEAS levels are mainly observed in female RA patients.”

Cutolo M, Giusti M, Foppiani L, Seriolo B, Briata M, Bisso A, Faelli F, Felli L, Prete C, Pizzorni C, Sulli A. The hypothalamic-pituitary-adrenocortical and gonadal axis function in rheumatoid arthritis. Z Rheumatol. 2000;59 Suppl 2:II/65-9.

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Low Oestrogen/Progesterone Promote RA (Th1 Excess)

“The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity).”

Cutolo M, Giusti M, Foppiani L, Seriolo B, Briata M, Bisso A, Faelli F, Felli L, Prete C, Pizzorni C, Sulli A. The hypothalamic-pituitary-adrenocortical and gonadal axis function in rheumatoid arthritis. Z Rheumatol. 2000;59 Suppl 2:II/65-9.

Low Androgens are Observed in RA

“In particular, low levels of gonadal and adrenal androgens (testosterone and DHT, DHEA and DHEAS) and a reduced androgen:estrogen ratio have been detected in body fluids (i.e., blood, synovial fluid, smears, saliva) of male and female RA patients.”

Cutolo M. Sex hormone adjuvant therapy in rheumatoid arthritis. Rheum Dis Clin North Am. 2000 Nov;26(4):881-95.


“Sex hormones might exert their immune-modulating effects, at least in RA synovitis, because synovial macrophages, monocytes, and lymphocytes possess functional androgen and estrogen receptors and may metabolize gonadalhormones.”



“Recent studies have shown positive effects of androgen replacement therapy at least in male RA patients, particularly as adjuvant treatment.”



“The androgen replacement obtained directly (i.e., testosterone, DHT, DHEAS) or indirectly (i.e., antiestrogens) may represent a valuable concomitant or adjuvant treatment to be associated with other disease-modifying antirheumatic drugs (i.e., MTX, NSAIDS) in the management of RA.”


HRT (E2) Induces a Th1 Shift, Which is Atherogenic

“Surprisingly, E2 induces an inflammatory-immune response towards a T helper cell (Th1) profile with increasing interferon-gamma production that could destabilize atheromatous plaques, and could account for the increase in the frequency of cardiovascular events in women undergoing HRT.”

Arnal JF, Gourdy P, Elhage R, Garmy-Susini B, Delmas E, Brouchet L, Castano C, Barreira Y, Couloumiers JC, Prats H, Prats AC, Bayard F. Estrogens and atherosclerosis. Eur J Endocrinol. 2004 Feb;150(2):113-7.

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Pregnancy and Immunity Th2 During Pregnancy“The first-born child, as opposed to subsequent

children, and perhaps male fetuses more so than female fetuses, are foreign to the mother's innate immune response. To prevent T helper type 1 (Th1)-mediated rejection, the inherent ability of the mother's and fetus's immune systems to mount a protective Th2 response promotes successful pregnancy.”

Varner AE. The increase in allergic respiratory diseases: survival of the fittest? Chest.

2002 Apr;121(4):1308-16.

Allergies are Less Common in Premature Inflants

“The onset of labor is associated with an increase in cyclo-oxygenase-2 production of prostaglandin [E.sub.2]. Th2 cytokines inhibit cyclooxygenase-2 activity and permit the pregnancy to continue until term. Observations confirm atopy to be less common in premature infants as opposed to infants born at term or later.”


2002 Apr;121(4):1308-16.

Pregnancy is a Th2 ‘Condition’

“Interleukin (IL)-18 acts in synergy with IL-12 to promote development of T helper 1 (Th1) responses. On the other hand, IL-18 alone has the capacity to induce Th2 responses.”

Sakai M, Shiozaki A, Sasaki Y, Yoneda S, Saito S. The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients.

J Reprod Immunol. 2004 Apr;61(2):133-43.

Pregnancy is a Th2 ‘Condition’

“These results suggest that elevated IL-18 secretion and decreased IL-12 secretion by PBMC may induce Th2 dominance in normal pregnancy, while elevated secretion of both IL-18 and IL-12 by PBMC may cause Th1 dominance in severe pre-eclampsia.”

Sakai M, Shiozaki A, Sasaki Y, Yoneda S, Saito S. The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients.

J Reprod Immunol. 2004 Apr;61(2):133-43.

Pregnancy and Th1/Th2 Balance

“To explain why fetuses are not rejected by the maternal system, Wegnamm et al. proposed that of the cytokines produced by T cells, type-2 T helper (Th2) cytokines predominate during pregnancy and suppress Th-1 type immune reaction by cytotoxic T cells that might attack fetuses and trophoblasts.”


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Pregnancy Improves RA

“Pregnancy improves the symptoms of RA in 75 percent of patients, leading to a significant resolution of inflammation and sufficient symptom relief to enable patients to taper off or even stop medications. In fact, the positive effect of pregnancy alone has been deemed greater than the benefit of some of the newer therapeutic agents.”


The Consequence of Th2 Pregnancy

“The consequence of protection of the pregnancy by regulation of maternal Th-1/Th-2 balance is that the fetus is also exposed to a high concentration of Th-2 and T regulatory cytokines. These are present in the placenta, together with maternal IgE and allergens which have reached the amniotic fluid via the maternal circulation, leading to the potential for fetal allergic sensitisation, particularly as a consequence of swallowing and the generation of gut priming of the immune response.”

J O Warner. The early life origins of asthma and related allergic disordersArch. Dis. Child., Feb 2004; 89: 97 - 102.

Allergies Run In the Family

“In addition to differences in IgE levels in amniotic fluid of atopic mothers, there are also higher levels of IL-10. This regulatory cytokine will suppress both Th-1 and Th-2 cells.


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“A number of factors counter-balance the drive to a fully committed Th-2 response to allergens in the fetus. These include the fetal generation of IFN-g and a maternal supply of soluble CD14 which, in combination with endotoxin, will lead to stimulation of IL-12 and, therefore, IFN-production. Maternal lgG antibody which is actively transported across the placenta may block fetal allergen sensitisation.”



“This is consistent with the finding that infants born to atopic mothers have not only significantly lower levels of Th-1 cytokines such as IFN-g from stimulated cord blood mononuclear cells, but also reduced levels of Th-2 cytokines such as IL-13. However, the balance is still biased towards greater suppression of Th-1 than Th-2 activity.


Infants are Born Th2 Dominant

“Forty-five healthy term neonates, 25 of the neonates' mothers and 27 healthy adults (controls) participated in the study. Cytokine concentrations were measured in blood samples from the umbilical cord, from the neonates on the 1st and 5th day after birth, from mothers and from controls.”

Protonotariou E, Malamitsi-Puchner A, Rizos D, Sarandakou A, Makrakis E, Salamolekis E. Alterations in Thl/Th2 cytokine concentrations in early neonatal life. J Matern Fetal Neonatal Med. 2003 Dec;14(6):407-10.


“IFN-g concentrations were significantly lower in the umbilical cord, compared to concentrations in the controls (p < 0.04), and increased significantly from the umbilical cord to levels in neonates on day 5 (p < 0.03). In mothers and the umbilical cord, IFN-gconcentrations were dependent on the mode of delivery, being higher after vaginal delivery than after elective Cesarean section.”



“IL-4 concentrations in the umbilical cord for 1-day and 5-day neonates were significantly elevated compared to those in mothers (p < 0.001; p < 0.0007; p < 0.0001, respectively) and controls (p < 0.05; p < 0.01; p < 0.006, respectively).”



“These findings promote a role for Th2-mediated responses in the age-dependent reduction of intestinal helminth infections in humans.”

Turner JD, Faulkner H, Kamgno J, Cormont F, Van Snick J, Else KJ, Grencis RK, Behnke JM, Boussinesq M, Bradley JE. Th2 cytokines are associated with reduced worm burdens in a human intestinal helminth infection. J Infect Dis. 2003 Dec1;188(11):1768-75. Epub 2003 Nov 14.

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We Needs More Bugs! The ‘Hygiene Hypothesis’

“Numerous studies have suggested that there is an inverse relation between early exposure to microbial products and a reduced risk of developing allergy and allergic disease. As all babies are born with a weakly Th-2 biased immune response, there must be a rapid down-regulation postnatally.”


The ‘Hygiene Hypothesis’

“Supporting the hygiene hypothesis, Ball et al and Illiet al presented data suggesting that frequent respiratory infections early in life prevent the development of atopy and allergic respiratory disease.”


2002 Apr;121(4):1308-16.

Infections Reduce Allergy

“Exposure to microbial products has been suggested as one important event achieving this effect. A number of studies have shown an inverse relation between the prevalence of atopy and tuberculin responsiveness, hepatitis A, and measles infection in early childhood.”


RAW Milk Reduces Allergy

“It has been suggested that the much lower prevalence of allergy and asthma among the children of farmers who have been born on farms and have been exposed to raw and sometimes unpasteurised milk, which obviously has a higher microbial load, particularly of lactobacilli, is consistent with the gut flora hypothesis.”


‘Natural’ Diets Reduce Allergy

“The anthroposophic lifestyle, which avoids immunisations and antibiotics but includes consumption of a diet of fermented vegetables rich in lactobacilli, is associated with significantly less atopy and skin test positivity in childhood.”


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Antibiotics, Maternal Allergy and Vaccines Increase Allergy

“Logistic regression analysis identified three statistically significant predictors of subsequent atopic disease: maternal atopy (1.97, 95% CI 1.46 to 2.66, p<0.0001), immunisation with whole-cell pertussis vaccine (1.76, 95% CI 1.39 to 2.23, p<0.0001), and treatment with oral antibiotics in the first two years of life (2.07, 95% CI 1.64 to 2.60, p<0.0001).”

Farooqi IS, Hopkin JM. Early infection and atopic disorder. Thorax 1998;53:927–32.

Th1 Excess is Bad in Pregnancy

Preeclampsia is Th1 Dominant

“Recent data demonstrate that up-regulation of Th1 responses occurs not only in peripheral blood but also at the fetomaternal interface in preeclampticpatients.”


Pregnancy Loss Corresponds With a Th1 Excess

“Cytokines are critical immunoregulatory molecules, responsible for determining the nature of an immune response. It has been proposed that Th2/Th3 immune reactions support normal pregnancy, while Th1 immunity is considered detrimental to the fetus.”

Costeas PA, Koumouli A, Giantsiou-Kyriakou A, Papaloizou A, Koumas L. Th2/Th3 cytokine genotypes are associated with pregnancy loss. Hum Immunol. 2004 Feb;65(2):135-41.


“Our results support the importance of Th2/Th3 immune responses in pregnancy loss, and suggest that an individual's immunogenetic profile indicative of imbalances in Th2/Th3 cytokines is associated with pregnancy loss.”

Costeas PA, Koumouli A, Giantsiou-Kyriakou A, Papaloizou A, Koumas L. Th2/Th3 cytokine genotypes are associated with pregnancy loss. Hum Immunol. 2004 Feb;65(2):135-41.


“Previous data on murine abortion indicate that DPP-IV may play a critical role in pregnancy failure by inducing a Th1 local response. This abortive effect may be mediated by enhancing the levels of Th1 abortogenic cytokines locally.”

Sehmsdorf US, Zenclussen AC, Arck P, Hertwig K, Joachim RA, Klapp B, Hildebrandt MO. Human miscarriage is associated with increased number of CD26 deciduallymphocytes. Scand J Immunol. 2004 Apr;59(4):400-7.

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TNF, From Th1 Cells Induce Preeclampsea

“TNF also induces activation of endothelial cells and the induction of glomerular endothelial damage.”

“TNF suppresses production of the vasodilator NO.”


Exercise and Immunity

Exercise Decreases Th1“In conclusion, the postexercise decrease in T lymphocyte number is accompanied by a more pronounced decrease in type 1 T cells, which may be linked to high plasma epinephrine. Furthermore, IL-6 may stimulate type 2 T cells, thereby maintaining a relatively unaltered percentage of these cells in the circulation.”

Steensberg A, Toft AD, Bruunsgaard H, Sandmand M, Halkjaer-Kristensen J, Pedersen BK. Strenuous exercise decreases the percentage of type 1 T cells in the circulation. J Appl Physiol. 2001 Oct;91(4):1708-12.

Exercise Decreases Th1“Exhaustive exercise causes the suppression of T lymphocyte activity while asthmatic and allergic diseases are subclinically more prevalent in athletes. One of the mechanisms behind these observations might be a lower type-1 and higher type-2 cytokine balance, which we previously demonstrated to occur after exhaustive exercise.”

Suzuki K, Nakaji S, Kurakake S, Totsuka M, Sato K, Kuriyama T, Fujimoto H, Shibusawa K, Machida K, Sugawara K. Exhaustive exercise and type-1/type-2 cytokine balance with special focus on interleukin-12 p40/p70. Exerc Immunol Rev. 2003;9:48-57.

Exercise Decreases Th1“The marathon race caused a marked increase in the plasma concentrations of IL-6 and IL-10. Their responses were correlated (r = 0.78, p < 0.01), indicating that IL-6 is an inducer of IL-10, and may partly induce the type-1 < type-2 cytokine balance.”


Exercise Decreases Th1“This may be one of the mechanisms behind several phenomena including cellular immunosuppression, an increase in the relative proportion of type-2 cytokines following exhaustive exercise, and the higher incidence of infections and allergic disorders in regularly exercising endurance athletes.”


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Intense Exercise Improves Rheumatoid Arthritis

“We undertook this randomized, controlled, multicenter trial to compare the effectiveness and safety of a 2-year intensive exercise program (Rheumatoid Arthritis Patients In Training [RAPIT]) with those of physical therapy (termed usual care [UC]).”

de Jong Z, Munneke M, Zwinderman AH, Kroon HM, Jansen A, Ronday KH, van Schaardenburg D, Dijkmans BA, Van den Ende CH, Breedveld FC, Vliet Vlieland TP, Hazes JM. Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial.Arthritis Rheum. 2003 Sep;48(9):2415-24.

Intense Exercise Improves Rheumatoid Arthritis

“CONCLUSION: A long-term high-intensity exercise program is more effective than UC in improving functional ability of RA patients. Intensive exercise does not increase radiographic damage of the large joints.”

de Jong Z, Munneke M, Zwinderman AH, Kroon HM, Jansen A, Ronday KH, van Schaardenburg D, Dijkmans BA, Van den Ende CH, Breedveld FC, Vliet Vlieland TP, Hazes JM. Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial.Arthritis Rheum. 2003 Sep;48(9):2415-24.

Exercise Induces IL-6 Release

“Cytokines such as interleukin (IL)-6 are proteins, which were originally discovered within the immune system. Recent studies, however, demonstrate that IL-6 is produced by, and released from contracting skeletal muscles during exercise.”

Steensberg A. The role of IL-6 in exercise-induced immune changes and

metabolism. Exerc Immunol Rev. 2003;9:40-7.


“IL-6 can enhance lipolysis in humans and might play a role in glucose metabolism. In addition, muscle-derived IL-6 is likely to initiate many of the exercise associated immune changes, as IL-6 can increase plasma levels of the cytokines IL-1 ra and IL-10, together with cortisol and blood neurtrophils.”

Steensberg A. The role of IL-6 in exercise-induced immune changes and metabolism.

Exerc Immunol Rev. 2003;9:40-7.


“Also, the observed shift towards Th2 lymphocyte dominance during exercise may be mediated by IL-6. Because carbohydrate ingestion during exercise has been demonstrated to blunt the IL-6 and hormonal response, it might also blunt other beneficial adaptations.”

Steensberg A. The role of IL-6 in exercise-induced immune changes and metabolism.

Exerc Immunol Rev. 2003;9:40-7.

Stress and Immunity

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Stress Effects The Immune System

“Previously, a large number of studies reported that psychological stress and psychiatric illness reduces immune responsiveness. However, it turned out that stress reduces immune responsiveness is an oversimplified statement because the interactions between central nervous system, endocrine system and the immune system are undoubtedly complex.”

Matalka KZ. Neuroendocrine and cytokines-induced responses to minutes, hours, and

days of mental stress. Neuroendocrinol Lett. 2003 Oct;24(5):283-92.


“This review shows evidence that short-time (minutes) or preparation to a written examination, in those students who are stressed, induces the production of proinflammatory cytokines which may be related to Th1 response.”




“However, longer mental stress (days) causes dysregulation in the immune function by shifting the cytokine response to Th2 response.”




“Recent evidence indicates that glucocorticoids and catecholamines, the major stress hormones, inhibit the production of proinflammatory cytokines, such as interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, whereas they stimulate the production of antiinflammatory cytokines, such as IL-10, IL-4, and transforming growth factor (TGF)-beta.”

Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatorycytokines, and autoimmunity. Ann N Y Acad Sci. 2002 Jun;966:290-303.


“Thus, systemically, an excessive immune response, through activation of the stress system, stimulates an important negative feedback mechanism, which protects the organism from an "overshoot" of proinflammatory cytokines and other products of activated macrophages with tissue-damaging potential.”

Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatorycytokines, and autoimmunity. Ann N Y Acad Sci. 2002 Jun;966:290-303.

Stress (Catecholamines) Stimulate Bacterial Growth

“The mechanisms of promoting infection in stressful situations have not been defined, but catecholamines could play a role. In the present study gram negative bacteria grown with catecholamines showed enhanced bacterial growth compared to controls.”

Sonnenfeld G, Aviles H, Belay T, Vance M, Fountain K. Stress, suspension and resistance to infection. J Gravit Physiol. 2002 Jul;9(1):P199-200.

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Stress (Catecholamines) Stimulate Bacterial Growth

“Therefore, stress-induced enhanced bacterial growth and immunosuppression could play a role in suspension-induced enhanced mortality due to infection.”

Sonnenfeld G, Aviles H, Belay T, Vance M, Fountain K. Stress, suspension and resistance to infection. J Gravit Physiol. 2002 Jul;9(1):P199-200.

Medications and Immunity

Antibiotics and ImmunityWe have shown previously that the b-lactamantibiotic benzylpenicillin (BP) conjugates to IFN-and reduces its activity in a number of in vitroassays. We also showed that BP does not bind to IL-4.

Brooks BM, Thomas AL, Coleman JW.Benzylpenicillin differentially conjugates to IFN-gamma, TNF-alpha, IL-1beta, IL-4 and IL-13 but selectively reduces IFN-gamma activity.Clin Exp Immunol. 2003 Feb;131(2):268-74.

Antibiotics and Immunity“Although generally nontoxic, b-lactams are one of the classes of drug most frequently associated with IgE-mediated allergy. Our data led us to hypothesize that selective impairment of IFN-activity by b-lactams during the early phase of an immune response may favor the generation of Th2 over Th1 responses, thus leading to IgEproduction and allergy.”Brooks BM, Thomas AL, Coleman JW.Benzylpenicillin differentially conjugates to IFN-gamma, TNF-alpha, IL-1beta, IL-4 and IL-13 but selectively reduces IFN-gamma activity.Clin Exp Immunol. 2003 Feb;131(2):268-74.

Probiotics Prevent Antibiotic Immune Suppression

“These results suggest that adequate probioticintervention after antibiotic treatment may improve the intestinal ecosystem, and thereby prevent the Th2-shifted immunity induced by neonatal antibiotic use.”

Sudo N, Yu XN, Aiba Y, Oyama N, Sonoda J, Koga Y, Kubo C. An oral introduction of intestinal bacteria prevents the development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice. Clin Exp Allergy. 2002 Jul;32(7):1112-6.

Methotrexate (MTX) Suppressers Th1

“These results indicate that MTX appears to suppress Th1 and, to a lesser extent, Th2 immune responses and its anti-arthritic effect on human rheumatoid arthritis might be at least in part explained by down-regulation of Th1 responses involved in the disease.”

Yamaki K, Uchida H, Harada Y, Li X, Yanagisawa R, Takano H, Hayashi H, Taneda S, Mori Y, Yoshino S. Effect of methotrexate on Th1 and Th2 immune responses in mice. J Pharm Pharmacol. 2003 Dec;55(12):1661-6.

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Flu Vaccine Suppresses Th1“We confirm that vaccine aggregates deviate the immune response to a greater Th2 cytokine pattern with potential implications for vaccine screening, safety, and efficacy.”

Babiuk S, Skowronski DM, De Serres G, HayGlass K, Brunham RC, Babiuk L. Aggregate content influences the Th1/Th2 immune response to influenza vaccine: evidence from a mouse model. J Med Virol. 2004 Jan;72(1):138-42.

Vaccines Induce Th2“Our results indicate early and persistent Th2 responses to the vaccine, in contrast to a more delayed and transient pattern of IFN-gamma production.”

Rowe J, Macaubas C, Monger TM, Holt BJ, Harvey J, Poolman JT, Sly PD, Holt PG. Antigen-specific responses to diphtheria-tetanus-acellular pertussis vaccine in human infants are initially Th2 polarized. Infect Immun. 2000 Jul;68(7):3873-7.

Vaccines Induce Asthma“Researchers in England note similar results in a survey of 446 children. In a group of 203 children who had not been immunized for pertussis, two percent had a diagnosis of asthma at eight years of age, compared to 11 percent of 243 who had been vaccinated for pertussis (p=0.0005).”

Odent MR, Culpin EE, Kimmel T. Pertussis vaccination and asthma: is there a link? JAMA 1994;272:592-593.

Th2 Conditions

Allergies

Common Causes of Th2 Dominance

Genetics Micro-organisms RSV Yeast/Fungi Chlamydia?

Pertussis vaccination Heavy Metals

Lead Mercury

Zinc deficiency Pollution

Alan L. Miller. The Etiologies, Pathophysiology, and Alternative/Complementary Treatment of Asthma. Alternative Medicine Review, Feb 2001 v6 i1 p20

Dust Mites Increase Th2

“The allergic response to dust mites involves an immediate hypersensitivity response, including increases in specific IgE antibodies and T-cells of the Th2 phenotype. Inhalation challenge of the allergic individual with dust mite antigen produces airway hyper-reactivity and bronchospasm, along with an eosinophil-dominated inflammatory response.”


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Cockroaches Increase Th2

“As with dust mites, cockroaches can be a very significant allergen source in the allergic asthmatic. It is thought that cockroach antigens (from the body and feces) pose a significant threat to individuals with asthma, and may be partially responsible for the greatly increased morbidity and mortality from asthma in inner-city residents.”


NSAID’s/Asthma Exacerbates Asthma

“Since most NSAIDs block the enzyme cyclooxygenase, it is thought this leaves more arachidonic acid to react with the other arm of the eicosanoid pathway, regulated by activity of lipoxygenase. Downstream metabolites of this pathway include the leukotrienes, very potent stimulators of inflammation and bronchial constriction.”


Depression and Asthma are Linked

“In a study of 230 patients with asthma, 45 percent scored high enough on depression ratings scales to be considered depressed. Those with more depressive symptoms reported worse health-related quality of life than asthma patients without depression.”


Allergies are Increasing“The prevalence of allergic respiratory diseases,

asthma and allergic rhinoconjunctivitis, has increased dramatically since the advent of industrialization. Many hypotheses exist to explain this phenomena: better hygiene, fewer severe infections early in life due to treatment with antibiotics and vaccinations, the loss of some protective effect found in rural lifestyle, environmental pollution, and changes in dietary habits.”


2002 Apr;121(4):1308-16.

Allergies are Increasing“All have merit and data to support their role, but the

underlying theme is that the environment is changing to promote allergic disease. One assumption in all of these theories is that the immune system of atopic individuals, characterized by the ability to produce T helper type 2 (Th2) type cytokines.”


2002 Apr;121(4):1308-16.

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Allergy is a Th2 Dominant Condition

“Compared to non-atopic individuals, atopics have higher Th2 (IL-4, IL-5, IL-13 and IL-9) peripheral blood mononuclear cell (PBMC) responses to allergens and other stimuli. Similar patterns are seen in asthmatics as a reflection of their atopic propensity.”



Allergy/Asthma is a Th1 Deficient Condition

“In a long-term follow-up study, persistent asthmatics had reduced Th1 (IFN-g) responses to house dust mite compared to adults with resolved asthma, but both groups had higher IL-5 and IL-13 responses compared to non-atopic controls.”




“Strong associations with allergic disease have also provided a strong case for a primary role of T helper type 2 (Th2) cells in the development of asthma.”




“There is a substantial body of evidence implicating most 'Th2' cytokines (interleukin (IL)-4, IL-5, IL-9, IL-13) in the expression and development of airways inflammation and hyperactivity (AHR).”




“While all of these cytokines appear to have a role, the recent literature indicates that IL-13 is especially critical and may be 'sufficient and necessary' for the development of reactive airways disease, at least in animal models.”

“IL-13 appears to act directly on airways epithelial cells to produce the pathological features of asthma.”




“IL-13 and transforming growth factor beta (TGF-b) also act synergistically on human airway fibroblasts to increase production of eotaxin-1, a powerful eosinophil chemoattractant.”



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Th1 Conditions: Causes

Weet Bix and Milk Anyone?

Diabetes Type I is a Th1 Driven Condition

“Disease pathogenesis is associated with a shift of the cytokine secretion pattern in the pancreas from Th2- (low levels of IFN-g, high levels of IL-10) to Th1- (high levels of IFN-g, low levels of IL-10) type cytokines. Genetic predisposition is a prerequisite for the development of diabetes.”

Flohe SB, Wasmuth HE, Kerad JB, Beales PE, Pozzilli P, Elliott RB, Hill JP, Scott FW, Kolb H. A wheat-based, diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice. Cytokine. 2003 Feb 7;21(3):149-54.

Diabetes Type I is Caused by Grains

“With regard to dietary antigens, it has been shown that cereal-based diets are usually associated with a higher diabetes incidence than the semi-purified diets that lack diabetes-inducing properties.”


Diabetes Type I is Caused by Grains

“The present study shows that the cytokine mRNA expression in the small intestine of diabetes prone NOD mice fed with a cereal-based diet was shifted towards a pro-inflammatory response compared to the mRNA expression in animals fed with Prosobee or Prosobee supplemented with casein.”


Grains Increase Th1 Autoimmunity

“The shift towards a pro-inflammatory cytokine milieu in the gut after feeding a cereal-based diet compared to a hypoallergenic semi-purified diet could be demonstrated as an up-regulation of the mRNA for the Th1-associated cytokines IFN and TNF-a, the inflammatory marker iNOS, and an increased ratio of Th1/Th2 cytokines (IFN/IL-10 or IFN/TGF).”



“A Th1-based cytokine response has been demonstrated in the intestinal lesions in celiac disease and certain other inflammatory bowel diseases.”


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“Hence, the strong diabetogenic effects of feeding a cereal-based diet were accompanied by a shift towards Th1-type reactivity in the gut, while this was not the case for the less diabetogenic casein fraction of cow-milk.”



“Recently, exposure of macrophages to wheat gluten was found to cause the release of pro-inflammatory cytokines suggesting that this type of antigen-presenting cell is associated with the Th1 bias in the gut after feeding a wheat-based diet.”


Cows Milk Increases Type I Diabetes

“Oral tolerance reactions are usually dependent on a T-helper (Th) 2–Th3 cytokine secretion profile. Conversely, a pro-inflammatory Th1-biased cytokine profile is related to disturbed oral tolerance mechanisms. In recent years it has become clearer that in patients with type 1 diabetes mellitus there is a systemic bias towards Th1-type immune responses.”

Hermann E. Wasmuth and Hubert Kolb Cow’s milk and immune-mediated diabetes. Proceedings of the Nutrition Society. Volume 59: Issue 4: 2000


“Two meta-analyses of the relevant studies showed a modest but significant increased risk for diabetes in children who were exposed to cow’s milk before the age of 3 months.”



“In recent years the availability of two rodent models which spontaneously develop insulin-dependent diabetes mellitus has allowed the direct testing of cow’s milk and certain constituent proteins for their diabetes-inducing potential.”



“In several studies the avoidance of intact cow’s milk proteins led to a reduced frequency of diabetes, while the addition of cow’s milk to the rodent’s diet resulted in an increased incidence of the disease.”


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“The outcome of such dietary studies is obscured by the fact that cereal-based diets appear to induce an even higher frequency of diabetes.”



“Despite these uncertainties an international multi-centre trial has been set up to test the hypothesis that the avoidance of intact cow’s milk proteins after prolonged breast-feeding in the first 9 months in genetically-predisposed infants might prevent the appearance of diabetes-associated autoantibodies or even type 1 diabetes mellitus itself.”



“An interim analysis of this primary prevention trial suggests that delayed introduction of cow’s milk products in the infant diet decreases the incidence of islet autoimmunity.”


Cows Milk Increases Type I Diabetes: Mechanisms?

“One theoretical mechanism for the link between cow’s milk exposure and autoimmune diabetes could be immunological cross reactivity (molecular mimicry) between cow’s milk proteins and autoantigens of the b-cell. Indeed, sequence homologies between cow’s milk proteins and islet autoantigens have already been identified.”



“Cow’s milk-based diets have also been implicated in the aetiology of other immune-mediated diseases in human subjects, such as multiple sclerosis, and have been shown to induce mild rheumatoid arthritis in genetically predisposed animals.”



“Furthermore, the consumption of cow’s milk has also been associated with some other neurological diseases, e.g. autism, some of which have not been proved to be immune mediated.”


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Th1 Conditions

Psoriasis is a Th1/IL-10 Deficient Disease

“IFN-gamma was markedly elevated in all sera from psoriasis patients, 33.8 +/- 1.3 pg/ml (mean +/-standard error) versus 8 +/- 1.5 pg/ml for normal controls (p < 0.01), and positively correlated with all indices of disease severity (Spearman r > 0.6).”

Jacob SE, Nassiri M, Kerdel FA, Vincek V. Simultaneous measurement of multiple Th1 and Th2 serum cytokines in psoriasis and correlation with disease severity. Mediators Inflamm. 2003 Oct;12(5):309-13.

Psoriasis is a Th1/IL-10 Deficient Disease

“Also, serum IL-10 levels were below detection levels in psoriatics compared with controls (6.4 +/- 1.3 pg/ml).”

Jacob SE, Nassiri M, Kerdel FA, Vincek V. Simultaneous measurement of multiple Th1 and Th2 serum cytokines in psoriasis and correlation with disease severity. Mediators Inflamm. 2003 Oct;12(5):309-13.

Crohn’s is a Th1 Dominant Disease

“Crohn's disease (CD) is a chronic inflammatory condition of the gastrointestinal tract, characterized by overactive T-helper (Th)1-mediated responses towards resident bacterial flora in genetically susceptible individuals.”

Bamias G, Sugawara K, Pagnini C, Cominelli F. The Th1 immune pathway as a therapeutic target in Crohn's disease. Curr Opin Investig Drugs. 2003 Nov;4(11):1279-86.

RA is Antagonised by Allergies

“These results support the concept that RA and atopy antagonize each other and that a change in the cytokine patterns of Th1 and Th2 cells could provide an indication for curative effects on RA.”

Hartung AD, Bohnert A, Hackstein H, Ohly A, Schmidt KL, Bein G. Th2-mediated atopic disease protection in Th1-mediated rheumatoid arthritis. Clin Exp Rheumatol. 2003 Jul-Aug;21(4):481-4.

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RA Sufferers Have Less Allergies

“CONCLUSIONS: Atopic disorders are decreased in RA.”

Rudwaleit M, Andermann B, Alten R, Sorensen H, Listing J, Zink A, Sieper J, Braun J. Atopic disorders in ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis. 2002 Nov;61(11):968-74.

Insomnia is a Th2 Dominant Condition

“The present results showed a link between insomnia unrelated to medical disorders and a shift in the Th1/Th2 balance toward Th2 dominance, indicating that the relationship between sleep quality and the etiology of immune-related diseases should be reconsidered.”

Sakami S, Ishikawa T, Kawakami N, Haratani T, Fukui A, Kobayashi F, Fujita O, Araki S, Kawamura N. Coemergence of insomnia and a shift in the Th1/Th2 balance toward Th2 dominance. Neuroimmunomodulation. 2002-2003;10(6):337-43.

Homocysteine? Immunity?Hyperhomocysteinemia Causes Neurodegeneration and Heart Disease

“Moderate hyperhomocysteinemia is associated with an increased risk of atherosclerosis, thrombosis and neurodegenerative diseases. Homocysteine accumulation in the blood can be due to many underlying causes, which may interact with each other, e.g. genetic disposition and B-vitamin status.”

Schroecksnadel K, Frick B, Wirleitner B, Winkler C, Schennach H, Fuchs D.Moderate hyperhomocysteinemia and immune activation.Curr Pharm Biotechnol. 2004 Feb;5(1):107-18.

Hyperhomocysteinemia: Associations with Th1

“Deficiency of these B-vitamins in parallel with moderate hyperhomocysteinemia is often found in patients with enhanced activation of the cellular immune system, like Alzheimer's disease, rheumatoid arthritis and also vascular diseases.”


Th1 Deplete B Vitamins

“On the one hand proliferation of immunocompetentcells having an enhanced demand for B-vitamins leads to the accumulation of homocysteine. On the other hand macrophages stimulated by TH1-type cytokine interferon-gamma form reactive oxygen species (ROS), which oxidize antioxidants, lipoproteins and oxidation-sensitive B-vitamins.”


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Th1 Causes Hyperhomocysteinaemia

“Thereby Th1-type immune response could contribute importantly to the development of hyperhomocysteinemia, and may also be a major determinant of disease progression.”


Atherosclerosis: an Immune Disorder?

“Studies published in 1974 already found that the WBC count was a strong predictor of infarction. The predictive value of the WBC count was similar to that of serum total cholesterol or a single determination of blood pressure.”

Michael Hoffman, Arnon Blum, , Roni Baruch, Eli Kaplan and Moshe Benjamin Leukocytes and coronary heart disease. Atherosclerosis. Volume 172, Issue 1 , January 2004, Pages 1-6


“Later on it was found that smokers with WBC counts in excess of 9000 per ml had an increased risk to develop AMI, four times greater than smokers with a leukocyte count below 6000 per ml.”



“Another study demonstrated that a total WBC count in excess of 10000 per l was associated with a risk that was approximately twice that seen when the WBC count was at or below 4000 per l. This excess risk was independent of gender, smoking history, blood pressure, and cholesterol level.”



“Total WBC count was correlated with the risk of thrombotic cerebral infarction; patients suffering thrombotic strokes had a statistically significantly higher antecedent WBC count than did members of the cohort not experiencing ischemic events.”


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“Even when tobacco smoking was controlled/corrected for, the WBC count was found to predict coronary heart disease prevalence, risk of nonfatal MI, and risk of sudden cardiac death. In the PARIS-1 study, 2026 patients were examined 2–60 months after suffering a first AMI; the total WBC count obtained at that time was found to correlate strongly with the risk of reinfarction.”



“Recent advances in the understanding of microvascular injury, leukocyte activation, and hemorrheology make more attractive the hypothesis that WBCs are major contributors to microvascular injury and atherogenesis and that a chronic leukocytosis reflects ischemic risk in a direct rather than an indirect manner.”


Figure 1.

Immune cells are attracted to the endothelial cells in the presents of inflammation. The immune cells then cause further vascular damage via free radical attacks, ultimately leading to atherosclerosis

CRP (C-reactive protein) Causes Atherosclerosis

“CRP was shown to possess proatherogenicproperties. For example, CRP activates endothelial cells to express adhesion molecules, ICAM-1, vascular cell adhesion molecule 1, selectins, and the chemokines, monocyte chemotactic protein 1.”


CRP Causes Atherosclerosis

“CRP also induces the secretion of interleukin 6 and endothelin 1 and decreases the expression and bioavailability of endothelial nitric oxide synthase in human endothelial cells. CRP activates macrophages to express cytokine and TF and enhances the uptake of LDL.”


Th1 Excess Promotes Atherosclerosis

“Most of the activated T cells in the plaque are T helper 1 subtype (Th1), which secrete interferon-gamma (IFN-gamma), now generally accepted as a proatherogenic cytokine.”

Levy Z, Rachmani R, Trestman S, Dvir A, Shaish A, Ravid M, Harats D. Low-dose interferon-alpha accelerates atherosclerosis in an LDL receptor-deficient mouse model. Eur J Intern Med. 2003 Dec;14(8):479-483.

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Tr1 Reduces Atherosclerosis

“We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 (Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis.”

Mallat Z, Gojova A, Brun V, Esposito B, Fournier N, Cottrez F, Tedgui A, Groux H. Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2003 Sep

9;108(10):1232-7. Epub 2003 Aug 11.


“Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels (P<0.0001), a decrease in the production of interferon-gamma (P<0.001), and an increase in interleukin-10 production (P<0.001) by cultured spleen and lymph T cells compared with controls.”


9;108(10):1232-7. Epub 2003 Aug 11.


“CONCLUSIONS: Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.”


9;108(10):1232-7. Epub 2003 Aug 11.

IL-10 Reduces Th1 and Reduces Atherosclerosis

“Atherosclerosis has a close relationship to inflammation, particularly T helper type 1 lymphocyte (Th1) response. Interleukin-10 (IL-10), is thought to suppress Th1 response.”

Namiki M, Kawashima S, Yamashita T, Ozaki M, Sakoda T, Inoue N, Hirata K, Morishita R, Kaneda Y, Yokoyama M. Intramuscular gene transfer of interleukin-10 cDNA reduces atherosclerosis in apolipoprotein E-knockout mice. Atherosclerosis. 2004 Jan;172(1):21-9.


“IL-10 gene transfer significantly reduced the atherosclerotic plaque area and the macrophage infiltrated area. IL-12 and IFN-gamma mRNA expressions in spleens and plasma IFN-gamma levels were decreased by IL-10 gene transfer.”



“Therefore, IL-10 gene transfer changed the Th1 response and suppressed atherosclerotic lesion formation in apoE-KO mice. IL-10 could be a new target as a therapeutic tool for the treatment of atherosclerosis.”


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IL-10 Reduces inflammation

“Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine in Th1 cell-mediated chronic inflammatory diseases such as, e.g. Crohn's disease. Moreover, IL-10 has been shown to limit the progression of atherosclerosis, presumably by influencing endothelial cell function.”

Cattaruzza M, Slodowski W, Stojakovic M, Krzesz R, Hecker M. Interleukin-10 induction of nitric-oxide synthase expression attenuates CD40-mediated interleukin-12 synthesis in human endothelial cells. J Biol Chem. 2003 Sep 26;278(39):37874-80. Epub 2003 Jul 11.

IL-10 Induces NOS-3

“Subsequent exposure to IL-10 results in an up-regulation of both endothelial nitric-oxide synthase (NOS-3) expression and activity.”

“Increased NOS-3 expression may, thus, be one mechanism by which IL-10 exerts its anti-inflammatory effects in Th1 cell-mediated chronic inflammatory diseases”

Cattaruzza M, Slodowski W, Stojakovic M, Krzesz R, Hecker M. Interleukin-10 induction of nitric-oxide synthase expression attenuates CD40-mediated interleukin-12 synthesis in human endothelial cells. J Biol Chem. 2003 Sep 26;278(39):37874-80. Epub 2003 Jul 11.

IL-10 Deficiency Induces Atherosclerosis

“Lack of IL-10 led to increased low-density lipoprotein cholesterol whereas very-low-density lipoprotein was reduced. In parallel, T-helper 1 responses and lesion size were dramatically increased in double knockout compared with E-/-controls.”

Caligiuri G, Rudling M, Ollivier V, Jacob MP, Michel JB, Hansson GK, Nicoletti A. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med. 2003 Jan-Feb;9(1-2):10-7.


“In parallel, T-helper 1 responses and lesion size were dramatically increased in double knockout compared with E-/- controls. At 48 wk, matrix metalloproteinases and tissue factor activities were increased in lesions of double-knockout mice. Furthermore, markers of systemic coagulation were increased, and vascular thrombosis in response to i.v. thrombin occurred more frequently.”



“Our findings suggest that IL-10 deficiency plays a deleterious role in atherosclerosis. The early phase of lesion development was increased, and the proteolytic and procoagulant activity was elevated in advanced lesions. These data show that IL-10 may reduce atherogenesis and improve the stability of plaques.”


Statins are Immunomodulators

“Statins may also be potent immunomodulatory agents and be beneficial in the treatment of autoimmune diseases. Statins have already been used to reduce the rejection of human heart transplants by the immune system, and there have been reports of a protective effect of injected statins in models of brain autoimmunity similar to experimental autoimmune encephalomyelitis.”

Koh CS. Effects of atorvastatin in multiple sclerosis. Nippon Rinsho. 2003 Aug;61(8):1455-60.

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Statins are Immunomodulators

“Atorvastatin has been shown to have pleiotropicimmunomodulatory effects involving both antigen presenting cells and T cell compartment. Thus, statins may be beneficial for MS, and clinical trials of the effects of statins on MS are now in progress, hopefully in a favorable way.”

Koh CS. Effects of atorvastatin in multiple sclerosis. Nippon Rinsho. 2003 Aug;61(8):1455-60.

Statins Benefit MS

“Number and volume of Gd-enhancing lesions declined by 44%, (p<0·0001) and 41% (p=0·0018), respectively. Treatment was well tolerated. Oral simvastatin might inhibit inflammatory components of multiple sclerosis that lead to neurological disability.”

Timothy Vollmer, Lyndon Key, Valerie Durkalski, William Tyor, John Corboy, Silva Markovic-Plese, Jana Preiningerova, Marco Rizzo, Inderjit Singh. Oral simvastatintreatment in relapsing-remitting multiple sclerosis. The Lancet Volume 363, Number 9421 15 May 2004

Alzheimer’s and Immunity Alzheimer’s and ImmunityThere are close relationships between the central

nervous system (CNS) and the immune system (IS). Not only has the old paradigm of the immunological privileged site of the CNS been overcome by neuroimmunological research, the field of psychoneuro-endocrino-immunology has also shown that the activity of the immune system is influenced by the CNS and vice versa.

Markus J. Schwarz, Sonnig Chiang, Norbert Mu¨ller, and Manfred Ackenheil. T-helper-1 and T-helper-2 Responses in Psychiatric Disorders. Brain, Behavior, and Immunity 15, 340–370 (2001)

Alzheimer’s Treatment

“Recently, several groups demonstrated that immunization of APP transgenic mouse (APP/Tg) models of AD with human Aß42 peptide blocks the deposition of Aß in the central nervous system and can at least partially promote the clearance of established plaque material from the brain.”

David H. Cribbs1, Anahit Ghochikyan2, Vitaly Vasilevko2, Mike Tran1, Irina Petrushina1, Nadya Sadzikava1, Davit Babikyan2, Patrick Kesslak1, Thomas Kieber-Emmons3, Carl W. Cotman1 and Michael G. Agadjanyan2 Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with ß-amyloid. International Immunology, Vol. 15, No. 4, pp. 505-514, April 2003

Reducing Th1 Benefits Alzheimer’s

“Taken together, these results show enhanced Th2 and down-regulated Th1 immunity following immune challenge with Abeta(1-42).”

Town T, Vendrame M, Patel A, Poetter D, DelleDonne A, Mori T, Smeed R, Crawford F, Klein T, Tan J, Mullan M. Reduced Th1 and enhanced Th2 immunity after immunization with Alzheimer's beta-amyloid(1-42). J Neuroimmunol. 2002 Nov;132(1-2):49-59.

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Alzheimer’s: a Th1 Condition?

“A marked increase in IFN-g secretion by peripheral mononuclear cells and by NK cells either spontaneously or after IL-2 stimulation was found in AD patients. The release of IFN-g, the principal Th1 cytokine, in both studies appeared to be dependent upon the severity of disease.”



“Two investigations from Huberman and co-workers explored the link between IL-2 and AD and exhibited similar results. They indicated that IL-2 secretion by peripheral blood mononuclear cells was significantly elevated in AD patients, though solely in the moderately severe stage of the disease.”



“In contrast to IFN-g, IL-4 reduces the expression of CD40 on cultivated microglial cells. Moreover, IL-4 reduces the neurotoxicity of microglia through inhibition of IFN-g-mediated microglial activation, resulting in a reduced production of TNF-a and NO (nitrogen monoxide).”


Increasing Th2 May Reduce AD

“IL-10 was found to suppress Ab-induced inflammatory proteins such as IL-1 and TNF-a. Altogether, the Th2-like cytokines IL-4 and IL-10 appear to be potent in reducing the activity and neurotoxicity of microglia. Their activity might be reduced in AD patients.”


Th2 Cytokines Protect Against AD

“The typical Th2 parameters should protect from Ab-induced microglia activation and the typical Th1 cytokines seem to be crucially involved in the pathological mechanism of Alzheimer’s disease.”



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Alzheimer’s is Inflammatory

“Several data of altered serum IL-6 levels in AD seem to confirm this finding: Higher IL-6 plasma levels in AD patients than in controls have been reported and another study showed higher levels of IL-6 in severely demented patients compared to those with mild to moderate stage of disease.”


Anti-inflammatory Drugs Benefit Alzheimer’s

“There is strong evidence that conventional nonsteroidal anti-inflammatory drugs delay the onset and slow the progression of AD, suggesting that anti-inflammatory therapy may have a protective effect against AD. These data fit very well with the theory of a Th1-related immune mechanism in the development of the AD pathology.”


Schizophrenia: a Th2 Condition?

“Total serum Immunoglobulin E (IgE)—the characteristic immunoglobulin of allergic/atopic disorders—was shown to be significantly higher in schizophrenic patients with poor therapy response.”



“A similar subgroup of patients, those suffering from more pronounced negative symptoms, was described as expressing higher levels of CSF IgG(Muller & Ackenheil, 1995). McAllister et al. (1989) and Printz and colleagues (1999) reported markedly elevated levels of peripheral CD51 B cells in schizophrenic patients compared to healthy controls.”


Schizophrenia: INF-g

“Those patients who had predominantly positive symptoms of schizophrenia (delusions, hallucinations, bizarre behavior, and thought disorders) had an elevated production of IFN-g, while negative symptoms (asociality or withdrawal, flat affect, attention impairment, avolition, or apathy) were associated with decreased IFN-g production.”



“A significant decrease in the production of IL-2 by peripheral lymphocytes is one of the best replicated immunological findings in schizophrenia. Some data suggested that decreased IL-2 production is associated with acute illness in patients who produce elevated amounts of autoantibodies or in patients with later age at onset.”


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“Altogether, due to the heterogeneity of schizophrenia, most of the studies describe a subgroup of schizophrenic patients with immunological findings, indicating a shift from Th1-like cellular to Th2-like humoral immune reactivity.”

Markus J. Schwarz, Sonnig Chiang, Norbert Mu¨ller, and Manfred Ackenheil. T-helper-1 and T-helper-2 Responses in Psychiatric Disorders. Brain, Behavior, and Immunity 15, 340–370 (2001) Markus J. Schwarz, Sonnig Chiang, Norbert Mu¨ller, and Manfred Ackenheil. T-helper-1 and T-

helper-2 Responses in Psychiatric Disorders. Brain, Behavior, and Immunity 15, 340–370 (2001)

Major Depression (MD): a Th1 Condition?

“The essential amino acid tryptophan is the precursor of two distinct metabolism pathways, leading to the products serotonin or kynurenine. The enzyme indoleamine-2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, which is further catabolized to quinolinic acid by the enzyme kynurenine hydroxylase. Both IDO and kynurenine hydroxylase are induced by IFN-g.”


Tryptophan

Serotonin

Kynurenine

Quinolinic acid

Indoleamine-2,3-dioxygenase

Tryptophan’s Metabolic Fate During Th1 Excess

INF-g (Th1)

Anti-depressant

Kynurenine hydroxylase

Major Depression (MD): a Th1 Condition?

“An IFN-g-induced, IDO-mediated decrease of central nervous tryptophan availability may lead to a serotonergic deficiency.”



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Treatments for Immune Dysfunction

Astragalus Normalises Th1:Th2

“Levels of serum IL-4 and IL-10 in HSK patients were significantly higher and those of IL-2 and gamma-IFN were significantly lower than those in the healthy control (all P < 0.01). These parameters were significantly improved in the patients of the AM group after treatment, but with no change in patients of the ribavirin group.”

Mao SP, Cheng KL, Zhou YF. Modulatory effect of Astragalus membranaceus on Th1/Th2 cytokine in patients with herpes simplex keratitis. Zhongguo Zhong Xi Yi

Jie He Za Zhi. 2004 Feb;24(2):121-3.

Astragalus Normalises Th1:Th2 in Cancer Patients: Background

“Th2 cytokine is predominant in tumor patients and was found to be associated with tumor progression. Reversing of Th2 dominant status is thought to be a promising strategy.”

Wei H, Sun R, Xiao W, Feng J, Zhen C, Xu X, Tian Z. Traditional Chinese medicine Astragalus reverses predominance of Th2 cytokines and their up-stream transcript factors in lung cancer patients. Oncol Rep. 2003 Sep-Oct;10(5):1507-12.

Astragalus Normalises Th1:Th2 in Cancer Patients

“Astragalus (AG) was observed to reverse Th2 status of lung cancer. AG enhanced culture supernatant and gene expression levels of Th1 cytokine (IFNgamma and IL-2) and its transcript factor (T-bet), and reduced those of Th2 cytokines in cultured PBMNC of lung cancer patients.”


Astragalus Normalises Th1:Th2 in Cancer Patients

“These results demonstrated that traditional Chinese medicine AG might reverse the Th2 predominant status in lung cancer patients, which is a probable alternative therapeutic regime in future.”


Golden Seal

Is Golden Seal Good for Allergies?How Does it Work?

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Berberine Herbs Increase Th1 via IL-12

“Berberine is an alkaloid that has been isolated from Hydrastis canadensis (goldenseal), Coptischinensis (Coptis or goldenthread), Berberisaquifolium (Oregon grape), Berberis vulgaris(barberry), and Berberis aristata (tree turmeric).”

Tae S. Kim*, Bok Y. Kang*, Daeho Cho & Seung H. Kim* Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizinealkaloid, deviates CD4+ T cells from a Th2 to a Th1 response. Immunology. Volume 109 Issue 3 Page 407 - July 2003


“Interleukin-12 (IL-12), a heterodimeric cytokine secreted by macrophages and other antigen-presenting cells (APC), is critical for the development of Th1 cells and the initiation of the cell-mediated immune response.”



“Berberine has shown a number of beneficial effects including immunostimulation and macrophage activation. Recently, we reported that berberine induced the production of IL-12p40, a larger subunit of IL-12, in mouse macrophages.”



“In this study we have demonstrated that pretreatment with berberine induced IL-12 production in both macrophages and dendriticcells (DCs), and strongly enhanced IL-12 production when subsequently stimulated with either lipopolysaccharide (LPS) or heat-killed Listeria monocytogenes (HKL), two well-known inducers of IL-12 production.”


Tae S. Kim*, Bok Y. Kang*, Daeho Cho & Seung H. Kim* Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid, deviates CD4+ T cells from a Th2 to a Th1 response. Immunology. Volume 109 Issue 3 Page 407 - July 2003


“Importantly, the increased levels of IL-12 production in berberine-treated macrophages deviated CD4+ T cells from the Th2 to the Th1 pathway.”


39


Berberine Stimulates Th1 Cytokines and Reduces Th2 Cytokines


Berberine Containing Herbs Reduce Allergies

“These findings may point to a possible therapeutic use of berberine or medicinal plants containing berberine in the Th type 2 cell-mediated immune diseases such as allergic diseases.”

Polypodium leucotomosmodulates Th1/Th2 cytokines

“The percentage of inhibition was 24% for IL-2, 72% for INF-gamma and 53% for TNF-alpha. With regard to Th2 cytokines, the addition of PLE resulted in a significant increase (33%) in IL-10 production. Surprisingly, the production of the inflammatory cytokine IL-6 was completely abolished (100% inhibition) by PLE at all doses tested.”

Gonzalez S, Alcaraz MV, Cuevas J, Perez M, Jaen P, Alvarez-Mon M, VillarrubiaVG. An extract of the fern Polypodium leucotomos (Difur) modulates Th1/Th2 cytokines balance in vitro and appears to exhibit anti-angiogenic activities in vivo: pathogenic relationships and therapeutic implications. Anticancer Res. 2000 May-Jun;20(3A):1567-75.


“Taken together, these data suggest that PLE works through the induction of suppressive/anti-inflammatory cytokines such as IL-10 and/or TGF-beta which in turn appear to allow the partial deactivation of macrophages or other accessory cells.”



“These features suggest that PLE could be useful in the treatment of autoaggressive/inflammatory conditions due to an exacerbation of Th1 responses.”


Ginseng (Rg1) Induces Th2

“These results show that Rg1 induces a Th2-dominated pattern from naive CD4+ T cells upon stimulation of the CD3 complex.”

Eui-joon Lee a, Eunjung Ko b, Jinwoo Lee b, Samwoong Rho b, Seonggyu Ko c, Min-Kyu Shin b, Byung-il Min a, Moo-Chang Hong b, Si-young Kim d and HyunsuBae. Ginsenoside Rg1 enhances CD4+ T-cell activities and modulates Th1/Th2 differentiation. International Immunopharmacology. Volume 4, Issue 2 , February 2004, Pages 235-244

40

Ginseng (Rg1) Induces IL-4

Eui-joon Lee a, Eunjung Ko b, Jinwoo Lee b, Samwoong Rho b, Seonggyu Ko c, Min-KyuShin b, Byung-il Min a, Moo-Chang Hong b, Si-young Kim d and Hyunsu Bae. GinsenosideRg1 enhances CD4+ T-cell activities and modulates Th1/Th2 differentiation. International Immunopharmacology. Volume 4, Issue 2 , February 2004, Pages 235-244

Ginseng (Rg1) Induces Th2


“These results strongly suggest that Rg1 induces an immune response change from a Th1 cell-dominated pattern to a Th2 cell-dominated pattern.”

Ginseng (Rg1) Reduces INF-y


Ginseng INCRESES Th1

“In addition, ginsan induced the endogenous production of cytokines such as Il-1, Il-6, IFN-g and Il-12, which are required for hematopoietic recovery, and was able to enhance Th1 function while interfering with the Th2 response in irradiated mice.”

Song JY, Han SK, Bae KG, Lim DS, Son SJ, Jung IS, Yi SY, Yun YS. Radioprotective effects of ginsan, an immunomodulator. Radiat Res. 2003 Jun;159(6):768-74.

Lipoic Acid (a-LA) Normalises Th1/Th2 in the Brain

“T cells from mice treated with a-LA produced significantly less IFN and IL-4 than control mice. In particular, administration of a-LA almost completely abolished the production of IFN compared with animals treated with the vehicle alone (p=0.0047).”

Monica Morini, Luca Roccatagliata, Raffaella Dell'Eva, Enrico Pedemonte, Roberto Furlan, Simona Minghelli, Debora Giunti, Ulrich Pfeffer, Monica Marchese, Douglas Noonan, Gianluigi Mancardi, Adriana Albini and Antonio Uccelli. a-Lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. Journal of Neuroimmunology

Volume 148, Issues 1-2 , March 2004, Pages 146-153


“Similarly, a remarkable reduction of IL-4 levels was detected in treated animals (p=0.0331).”

“Overall, a-LA inhibits the production of IFN and IL-4 produced by MOG-specific T cells.”



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These findings further suggest that a-LA, a drug which has been safely tested in other human disorders, may be effective in the clinical management of neurological autoimmune disorders such as MS.



Vitamin D Reduces Th1

“Vitamin D, a common food additive, has been shown to prevent the induction of experimental autoimmune diseases in mice. A possible immune deviation from T(H)1 to T(H)2 responses has been postulated.”

Matheu V, Back O, Mondoc E, Issazadeh-Navikas S. Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol. 2003 Sep;112(3):585-92.

Vitamin A (RA) Decreases Th1 and Increases Th2

“In both systems, all-trans-RA at > or = 1 nMconcentrations suppressed Th1 development, but enhanced Th2 development. 9-cis-RA elicited similar effects.”

Iwata M, Eshima Y, Kagechika H. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int Immunol. 2003 Aug;15(8):1017-25.

Low Vitamin A Reduces Th2

“Previously we reported that vitamin A-deficient (-A) mice had a profound reduction in T helper 2 (Th2) cells, accounting for their depressed T-dependent antibody responses. Providing vitamin A or its active metabolites reversed this defect.”

Hoag KA, Nashold FE, Goverman J, Hayes CE. Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells. J Nutr. 2002 Dec;132(12):3736-9.

Vitamin A Increases Th2 via IL-4

“Most importantly, with the Th2 polarizing cytokine IL-4, atRA significantly increased the IL-4 secretion (fivefold) and also increased the Th2 cell frequency twofold.”

Hoag KA, Nashold FE, Goverman J, Hayes CE. Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells. J Nutr. 2002 Dec;132(12):3736-9.

Vitamin E Increases Th1 in Cancer Patients

“Short-term supplementation with high doses of dietary vitamin E leads to increased CD4:CD8 ratios and to enhanced capacity by their T cells to produce the T helper 1 cytokines interleukin 2 and IFN-gamma. In 10 of 12 patients, an increase of 10% or more (average, 22%) in the number of T cells producing interleukin 2 was seen after 2 weeks of vitamin E supplementation.”Malmberg KJ, Lenkei R, Petersson M, Ohlum T, Ichihara F, Glimelius B, Frodin

JE, Masucci G, Kiessling R. A short-term dietary supplementation of high doses of vitamin E increases T helper 1 cytokine production in patients with advanced colorectal cancer. Clin Cancer Res. 2002 Jun;8(6):1772-8.

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PGE2 Decreases Th1 in Elderly Patients

“T helper 1 (Th1) cytokines, especially interferon-gamma (IFN-gamma), play an important role in defending against influenza infection. However, there is an age-associated loss of Th1 cytokine production. Prostaglandin E2 (PGE2) production, which increases with age, can modulate the T helper cell function by suppressing Th1 cytokine production.”Han SN, Wu D, Ha WK, Beharka A, Smith DE, Bender BS, Meydani SN. Vitamin

E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus. Immunology. 2000 Aug;100(4):487-93.

Vitamin E Increases Th1 in Elderly Patients

“Following influenza infection, interleukin (IL)-2 and IFN-gamma production was significantly lower in old mice than in young mice. Vitamin E supplementation increased production of IL-2 and IFN-gamma in old mice; higher IFN-gamma production was associated with lower pulmonary viral titre.”Han SN, Wu D, Ha WK, Beharka A, Smith DE, Bender BS, Meydani SN. Vitamin

E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus. Immunology. 2000 Aug;100(4):487-93.

Vitamin E Increases Th1 in Elderly Patients

“Our results indicate that the vitamin E-induced decrease in influenza viral titre is mediated through enhancement of Th1 cytokines, which may be the result of reduced PGE2 production caused by vitamin E.”

Han SN, Wu D, Ha WK, Beharka A, Smith DE, Bender BS, Meydani SN. Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus. Immunology. 2000 Aug;100(4):487-93.

Vitamin C Increases Th1“In animal studies vitamin C deficiency has been

linked to compromised immunocompetence characterized by depressed cell-mediated immunity including leukocyte phagocytosis and microbicidal activity but does not affect antibody production.”


Vitamin C and E are Low in Asthmatics

“Significantly decreased levels of vitamin C and vitamin E were found in lung lining fluid of asthmatics in a recent study, even though plasma levels were normal.”

Kelly FJ, Mudway I, Blomberg A. Altered lung antioxidant status in patients with mild asthma. Lancet 1999;354:482-483.

Vitamin C Decreases Th2“Studies of asthmatic children receiving a

supplement of ascorbic acid have found that asthmatic children receiving the supplement suffered less severe and fewer attacks of asthma during the study period. Similarly serum total IgE levels but not specific IgE levels were reduced among asthmatic children receiving ascorbate.”


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Astaxanthin Normalise Th1/Th2 Responses in Infected individuals

“Helicobacter pylori is a gram-negative bacterium affecting about half of the world population, causing chronic gastritis type B dominated by activated phagocytes. In some patients the disease evolves into gastric ulcer, duodenal ulcer, gastric cancer or MALT lymphoma.”

Bennedsen M, Wang X, Willen R, Wadstrom T, Andersen LP. Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol Lett. 1999 Dec 1;70(3):185-9.

Astaxanthin Normalise Th1/Th2 Responses in Infected individuals

“We found that treatment of H. pylori infected mice with an algal cell extract containing the antioxidant astaxanthin reduces bacterial load and gastric inflammation. These changes are associated with a shift of the T-lymphocyte response from a predominant Th1-response dominated by IFN-gamma to a Th1/Th2-response with IFN-gamma and IL-4.”Bennedsen M, Wang X, Willen R, Wadstrom T, Andersen LP. Treatment of H.

pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol Lett. 1999 Dec 1;70(3):185-9.

Beta-sitosterol (BSS) and its glycoside (BSSG) Normalise Th1/Th2 Responses

“This phytosterol complex seems to target specific T-helper lymphocytes, the Th1 and Th2 cells, helping normalize their functioning and resulting in improved T-lymphocyte and natural killer cell activity.”

Bouic PJ, Lamprecht JH. Plant sterols and sterolins: a review of their immune-modulating properties. Altern Med Rev. 1999 Jun;4(3):170-7.

Omega 6 Oils Modify Th1/Th2 Balance

“Evidence from in vitro and in vivo studies for a role of AA metabolites in immune cell development and functions shows that they can limit or regulate cellular immune reactions and can induce deviation toward a T helper (Th)2-like immune response.”

Harbige LS. Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids. 2003 Apr;38(4):323-41.


“In contrast to the effects of the oxidative metabolites of AA, the longer-chain n-6 PUFA produced by gamma-linolenic acid (18:3n-6, GLA) feeding decreases the Th2 cytokine and immunoglobulin (Ig)G1 antibody response.”



GLA can also induce T-regulatory cell activity, e.g., transforming growth factor (TGF)-beta-producing T cells; GLA feeding studies also demonstrate reduced proinflammatory interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha production.


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Omega 3 Oils Increase Th2, and Decrease Th1

“The n-3 PUFA diets decreased production of prostaglandin E2 while increasing oxidative burst and tumour necrosis factor alpha production. In addition adaptive Th1-driven responses (immunoglobulin, Ig)G2a, IgG2b, interferon-gamma:interleukin 4) were decreased, whereas Th2-driven and mucosal immune responses were increased (IgE) or unaffected (IgG1, IgA).”

Albers R, Bol M, Bleumink R, Willems A, Blonk C, Pieters R. Effects of dietary lipids on immune function in a murine sensitisation model. Br J Nutr. 2002 Sep;88(3):291-9.

B6 Increases Th1

“These studies collectively suggest that a B6 deficiency suppresses Th1-like activity and promotes Th2-like activity whereas its repletion reverses this tendency.”


Folate Increases Th1

“These findings suggest that folate may promote a Th1-like response.”


B12 Suppressers Th1

“This results indicates that B12 may suppress a Th1-like response.”


Minerals and ImmunityZinc and Immunity: Background

“Zinc plays an important role in cell-mediated immune function. Altered cellular immune response resulting from zinc deficiency leads to frequent microbial infections, thymic atrophy, decreased natural killer activity, decreased thymic hormone activity, and altered cytokine production.”

Bao B, Prasad AS, Beck FW, Godmere M. Zinc modulates mRNA levels of cytokines.

Am J Physiol Endocrinol Metab. 2003 Nov;285(5):E1095-102. Epub 2003 Jun 17.

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Zinc Boosts Th1 Cytokines

“These data demonstrate that zinc mediates positively the gene expression of IL-2 and IFN-gamma in the Th1 cell line and negatively TNF-alpha, IL-1 beta, and IL-8 in the monocyte-macrophage cell line.”

Bao B, Prasad AS, Beck FW, Godmere M. Zinc modulates mRNA levels of cytokines.

Am J Physiol Endocrinol Metab. 2003 Nov;285(5):E1095-102. Epub 2003 Jun 17.

Zinc Boosts Th1 Cytokines

“Zinc deficiency caused an imbalance between Th1 and Th2 functions, with a subsequent increased production of IL-4, IL-6, and IL-10, and decreased production of IL-2, IFN-[Gamma], and tumor necrosis factor alpha.”

Prasad AS. Zinc and immunity. Mol Cell Biochem 1998;188:63-69.

Zinc Reduces Viral Severity“Treatment of colds with zinc reduced the mean daily

clinical score and this was statistically significant on the fourth and fifth day of medication. Similarly, medication (zinc) also reduced the mean daily nasal secretion weight and total tissue count and these reductions were statistically significant on days two and six for nasal secretion weights and days four to six of medication for tissue counts when compared with placebo.”

Al-Nakib, W., et al. Prophylaxis and treatment of rhinovirus colds with zinc gluconatelozenges. J Antimicrob Chemother. 20(6):893-901, 1987.

Selenium Reduces Viral Severity

Selenium deficiency is linked to the occurrence, virulence, or disease progression of some viral infections.

Taylor, E. W., et al. Genomic structures of viral agents in relation to the biosynthesis of selenoproteins. Biol Trace Elem Res. 56:63-91, 1997.

Selenium Reduces Viral Mutations

“Because flu virus mutations create new virus strains each year, it becomes virtually impossible for the body's immune system to develop a permanent defense. However, taking adequate amounts of selenium can prevent those mutations from occurring.”

Nelson, H. K., et al. Host nutritional selenium status as a driving force for influenza virus mutations. FASEB J. 15:1481-1483, 2001.

Selenium Reduces Viral Mutations

“Influenza viruses infecting selenium-deficient mice developed 29 mutations, which led to greater virulence. In contrast, selenium-replete mice experienced no mutations in the infecting virus and had milder symptoms.”

Nelson, H. K., et al. Host nutritional selenium status as a driving force for influenza virus mutations. FASEB J. 15:1481-1483, 2001.

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Copper Enhances Th1

“Some of the recent research showed that interleukin 2 is reduced in copper deficiency and is likely the mechanism by which T cell proliferation is reduced. These results were extended to show that even in marginal deficiency, when common indexes of copper are not affected by the diet, the proliferative response and interleukin concentrations are reduced.”

Percival SS. Copper and immunity. Am J Clin Nutr. 1998 May;67(5 Suppl):1064S-1068S.

Copper Deficiency Reduces Neutrophils

“The number of neutrophils in human peripheral blood is reduced in cases of severe copper deficiency. Not only are they reduced in number, but their ability to generate superoxide anion and kill ingested microorganisms is also reduced in both overt and marginal copper deficiency.”

Percival SS. Copper and immunity. Am J Clin Nutr. 1998 May;67(5 Suppl):1064S-1068S.

Micro-organisms and T-helper Balance

Pathogenic Microbes

Klebsiella Induces a Th1 Response

“Thus our results strongly support the concept that differential modulation of DC explains the differences in the immune response to various bacterial strains and indicates that K. pneumoniae induces Th1 immune responses via DC.”

Braat H, de Jong EC, van den Brande JM, Kapsenberg ML, Peppelenbosch MP, van Tol EA, van Deventer SJ. Dichotomy between Lactobacillus rhamnosus and Klebsiella pneumoniae on dendritic cell phenotype and function. J Mol Med. 2004

Mar;82(3):197-205.

Klebsiella Induces AS, a Th1 Disease

“This suggests the involvement of outer membrane proteins of Klebsiella pneumoniae in the pathogenic mechanism of ankylosing spondylitis.”

Madhavan R, Porkodi R, Rajendran CP, Chandrasekaran AN, Umadevi KR, AlameluR. IgM, IgG, and IgA response to enterobacteria in patients with ankylosingspondylitis in southern India. Ann N Y Acad Sci. 2002 Apr;958:408-11.

Microbes and Immunity

Friendly Bacteria Reduce Th1

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Inflammatory Bowel Disease (IBD)

“In active IBD lesions, there are elevated numbers of activated macrophages and T-lymphocytes in the lamina propria. These cells are activated with an excessive production of interleukin (IL)-1, tumor necrosis factor (TNF)-a and reactive oxygen radicals.”

Pathmakanthan S, Li CK, Cowie J, Hawkey CJ. Lactobacillus plantarum 299: beneficial in vitro immunomodulation in cells extracted from inflamed human colon.J Gastroenterol Hepatol. 2004 Feb;19(2):166-73.

L. Plantarum Normalises Immunity

L. Plantarum Improves IBD

“In rats, (Colitis) attenuated by Lactobacillus plantarum. Treatment with lactobacilli also prevented the development of spontaneous colitis in interleukin (IL)-10-deficient mice and attenuated established colitis in the same knockout model.”


L. Plantarum Increases IL-10

“Lactobacillus plantarum demonstrates beneficial immunomodulatory activity by increasing IL-10 synthesis and secretion in macrophages and T-cells derived from the inflamed colon. This may provide a mechanism through which probioticbacteria ameliorate inappropriate inflammation and induce tolerance.”


L. Plantarum Increases IL-10“Importantly, mononuclear cells derived from an

inflamed colon displayed significant increases in IL-10 production after incubation with L. plantarum. This increase was not present with any other bacterial sonicate and demonstrated the ability of this probiotic to induce secretion of a downregulatory cytokine in an environment of excessive inflammation.”


L. Plantarum Reduces Colitis“Interleukin (IL)-10-deficient (IL-10-/-) mice develop

colitis under specific pathogen-free (SPF) conditions and remain disease free if kept sterile (germ free [GF]).”

Schultz M, Veltkamp C, Dieleman LA, Grenther WB, Wyrick PB, Tonkonogy SL, Sartor RB. Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient mice. Inflamm Bowel Dis. 2002 Mar;8(2):71-80.

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L. Plantarum Reduces Colitis“Treating SPF IL-10-/- mice with L. plantarum

attenuated previously established colonic inflammation as manifested by decreased mucosal IL-12, IFN-gamma, and immunoglobulin G2a levels.”


L. Plantarum Reduces Colitis“These results demonstrate that L. plantarum can

attenuate immune-mediated colitis and suggest a potential therapeutic role for this agent in clinical inflammatory bowel diseases.”


Lactobacillus rhamnosus GG Normalises Immunity

Lactobacillus rhamnosus GG Reduces Colits

“Lactobacillus rhamnosus GG (LGG) has been used in acute colitis treatment. However, it is unclear whether the LGG prevents chronic colitis. The aim of this study was to examine the prophylactic effect of LGG on animal colitis, cytokine secretion, and mucin gene expression.”

Moon G, Myung SJ, Jeong JY, Yang SK, Cho YK, Lee SM, Chang HS, Byeon JS, Lee YJ, Lee GH, Hong WS, Kim JH, Min YI, Kim JS. Prophylactic effect of Lactobacillus GG in animal colitis and its effect on cytokine secretion and mucingene expressions. Korean J Gastroenterol. 2004 Apr;43(4):234-45.

Lactobacillus rhamnosus GG Reduces Colits

“These results suggest that LGG prevents chronic murine colitis. It may be associated with cytokine modulation and competitive inhibition of pathogenic bacteria.”


LGG Reduces Arthritis“The mean number of tender and swollen joints

decreased from 8.3 to 4.6 in the Lactobacillus group and from 5.5 to 4.8 in the placebo group (p = 0.41). According to the global assessment the RA activity was reduced in 71% (LGG group) vs. 30% (controls) (p = 0.15).”

Hatakka K, Martio J, Korpela M, Herranen M, Poussa T, Laasanen T, Saxelin M, Vapaatalo H, Moilanen E, Korpela R. Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis--a pilot study. Scand J Rheumatol. 2003;32(4):211-5.

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LGG Reduces Inflammation“Additionally, TNF-alpha, IL-6 and in part IFN-

gamma cytokine secretion by PB cells following stimulation with whole stool preparations and single members of the flora was significantly decreased, whereas the IL-10 and in part IL-4 cytokine secretion was increased at the end of the study.”

Schultz M, Linde HJ, Lehn N, Zimmermann K, Grossmann J, Falk W, Scholmerich J. Immunomodulatory consequences of oral administration of Lactobacillus rhamnosus strain GG in healthy volunteers. J Dairy Res. 2003 May;70(2):165-73.

LGG Reduces Inflammation: Mechanism of Action

“Lactobacillus species may be capable of producing soluble molecules that inhibit TNF-alpha production in activated macrophages. As overproduction of pro-inflammatory cytokines, especially TNF-alpha, is implicated in pathogenesis of chronic intestinal inflammation.”

Pena JA, Versalovic J. Lactobacillus rhamnosus GG decreases TNF-alpha production in lipopolysaccharide-activated murine macrophages by a contact-independent mechanism. Cell Microbiol. 2003 Apr;5(4):277-85.

Bifidobacteria Normalises Immunity

Probiotics Reduces Colits: Recent Clinical Trial

“Thirty patients received treatment with sulphasalazine (SASP) and glucocorticoid and then were randomly administered bifid triple viable capsule (BIFICO) (1.26 g/d), or an identical placebo (starch) for 8 wk. The patients were evaluated clinically, endoscopically and histologically after 2 mo of treatment or in case of relapse of UC. ”

Cui HH, Chen CL, Wang JD, Yang YJ, Cun Y, Wu JB, Liu YH, Dan HL, Jian YT, Chen XQ. Effects of probiotic on intestinal mucosa of patients with ulcerative colitis. World J Gastroenterol. 2004 May 15;10(10):1521-5.


“Three patients (20%) in the BIFICO group had relapses during 2-mo follow-up period, compared with 14 (93.3%) in placebo group (P<0.01). The concentration of fecal lactobacilli, bifidobacteriawas significantly increased in BIFICO-treated group only (P<0.01).”



“The expressions of NF-kappaB p65 and DNA binding activity of NF-kappaB were significantly attenuated in the treatment group than that in control (P<0.05). The mRNA expression of anti-inflammatory cytokines was elevated in comparison with the control group.”


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“CONCLUSION: The probiotic could impede the activation of NF-kappaB, decrease the expressions of TNF-alpha and IL-1beta and elevate the expression of IL-10.”



“These results suggest that oral administration of this new probiotic preparation is effective in preventing flare-ups of chronic UC. It may become a prophylactic drug to decrease the relapse of UC.”


Bifidobacteria Reduces Colitis (Th1)

“Here we show that Bifidobacterium genomic DNA induced secretion of the antiinflammatoryinterleukin-10 by PBMC. Total bacterial DNA from feces collected after probiotic administration modulated the immune response by a decrease of interleukin-1 beta and an increase of interleukin-10.”

Lammers KM, Brigidi P, Vitali B, Gionchetti P, Rizzello F, Caramelli E, Matteuzzi D, Campieri M. Immunomodulatory effects of probiotic bacteria DNA: IL-1 and IL-10 response in human peripheral blood mononuclear cells. FEMS Immunol Med Microbiol. 2003 Sep 22;38(2):165-72.

Probiotics Reduces NF-kB“Probiotics can suppress interleukin-8 secretion in

intestinal epithelia when stimulated by proinflammatory cytokines, which is most likely mediated by NF-kappaB.”


Microbes and Immunity

Friendly Bacteria Reduce Th2

Lactobacilli Reduce Th2

“In a subsequent study, perinatal administration of lactobacilli halved the later development of atopic eczema during the first 2 years of life. Specific strains of the healthy gut microbiota have been shown to induce the production of IL-10 and transforming growth factor-beta, which possess an important regulative role in the development of allergic type immune response.”

Kalliomaki M, Isolauri E. Role of intestinal flora in the development of allergy.Curr Opin Allergy Clin Immunol. 2003 Feb;3(1):15-20.

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Lactobacilli Strengthen Gut Barrier Function

“Probiotics also strengthen gut defense barrier mechanisms and reduce antigen load in the gut.”

Kalliomaki M, Isolauri E. Role of intestinal flora in the development of allergy.Curr Opin Allergy Clin Immunol. 2003 Feb;3(1):15-20.

Acidophilus Yogurt Reduces Th2

Yogurt containing L. acidophilus generated trends in the increase in interferon gamma and decreased eosinophilia; however, we were unable to detect changes in clinical parameters in asthma patients in association with these modest immune changes.

Wheeler JG, Shema SJ, Bogle ML, Shirrell MA, Burks AW, Pittler A, Helm RM. Immune and clinical impact of Lactobacillus acidophilus on asthma. Ann Allergy

Asthma Immunol. 1997 Sep;79(3):229-33.

Acidophilus Yogurt Reduces Th2

“Cultured PBMC of the group fed with yoghurt released more IFNgamma and less IL-4.”

“CONCLUSION: Yoghurt feeding appears to improve or prevent allergic recurrences in rhinopatic patients.”

Aldinucci C, Bellussi L, Monciatti G, Passali GC, Salerni L, Passali D, Bocci V. Effects of dietary yoghurt on immunological and clinical parameters of rhinopathic patients. Eur J Clin Nutr. 2002 Dec;56(12):1155-61.

Lactobacillus GG Reduces Allergy

“This has led inevitably to a study employing lactobacillus GG given prenatally to mothers who had at least one first degree relative or partner with atopic disease and to their infants for the first six months of life. Atopic eczema occurred less frequently up to 2 years of age in the actively treated compared with the placebo treated infants.”


LGG Reduces Th2

“In 2 previous studies administration of the probiotic Lactobacillus rhamnosus GG to infants with AD and cow's milk allergy significantly reduced the severity of the eczema. In vitro L rhamnosus GG was shown to inhibit antigen-induced IgE production in murine lymphocytes.”

Rosenfeldt V, Benfeldt E, Nielsen SD, Michaelsen KF, Jeppesen DL, ValeriusNH, Paerregaard A. Effect of probiotic Lactobacillus strains in children with atopic dermatitis. J Allergy Clin Immunol. 2003 Feb;111(2):389-95.

LGG Reduces Eosinophils“During active treatment, sECP levels decreased

from 17.4 to 12.6 μg/L but remained stable during placebo treatment. A significant difference between the change in sECP levels during active treatment compared with the change observed during placebo treatment was demonstrated. The mean change in sECP was −6.2 μg/L (95% CI, −13.3 to 0.5 μg/L) versus 2.0 μg/L (95% CI, −0.5 to 4.6 μg/L) during placebo treatment (P = .03).”

Rosenfeldt V, Benfeldt E, Nielsen SD, Michaelsen KF, Jeppesen DL, Valerius NH, Paerregaard A. Effect of probiotic Lactobacillus strains in children with atopic dermatitis. J Allergy Clin Immunol. 2003 Feb;111(2):389-95.

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Lactococci Reduces Th2, Even if Dead

“Six strains induced the production of cytokines (IL-12, IL-6, and TNF-alpha) in macrophage-like cell line J774.1, and the highest induction was observed with Lactococcus lactis subsp. lactisG50. The cytokine induction in the J774.1 cell line was almost entirely sustained after heat-killing of the strain.”

Kimoto H, Mizumachi K, Okamoto T, Kurisaki J. New Lactococcus strain with immunomodulatory activity: enhancement of Th1-type immune response. MicrobiolImmunol. 2004;48(2):75-82.

Lactococci Increases Th1“Spleen cells from BALB/c mice fed G50 culture

produced more IL-12 and IFN-gamma and slightly less IL-4 and IL-6 than the control (i.e., without strain G50), indicating that strain G50 can enhance Th1-type immune response in vivo.”


Lactococci Decreases Th2“These results suggest that strain G50 has an

ability to suppress the Th2 response. Thus, Lactococcus lactis subsp. lactis G50 is a potential probiotic strain for the suppression of hypersensitive reactions caused by the Th2 response.”


Probiotics Normalise Immunity and Inflammation

“Lactobacillus acidophilus TMC 0356 significantly induced the production of more IL-6, IL-10, IL-12, and TNF-alpha than the other bacteria tested (p < 0.0001; ANOVA).”

Morita H, He F, Fuse T, Ouwehand AC, Hashimoto H, Hosoda M, Mizumachi K, Kurisaki J. Cytokine production by the murine macrophage cell line J774.1 after exposure to lactobacilli. Biosci Biotechnol Biochem. 2002 Sep;66(9):1963-6.

Probiotics Normalise Immunity and Inflammation

“These results suggest that lactobacilli can activate macrophages to secrete both inflammatory and anti-inflammatory cytokines. Selected strains might be used to bring about pro or antiinflammatory immune reactions.”

Morita H, He F, Fuse T, Ouwehand AC, Hashimoto H, Hosoda M, Mizumachi K, Kurisaki J. Cytokine production by the murine macrophage cell line J774.1 after exposure to lactobacilli. Biosci Biotechnol Biochem. 2002 Sep;66(9):1963-6.

Probiotics

Friendly Bacteria Reduces Infections

53

Probiotics Reduce Infections “Consumption of lactic acid bacteria (LAB) has

been suggested to confer a range of health benefits including stimulation of the immune system and increased resistance to malignancy and infectious illness.”

Sanders ME, Klaenhammer TR. Invited review: the scientific basis of Lactobacillus acidophilus NCFM functionality as a probiotic. J Dairy Sci. 2001 Feb;84(2):319-31.

LGG Reduces Nasal Infections “The results indicate that regular intake of

probiotics (LGG) can reduce Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococci, and Haemophilusinfluenzae in the upper respiratory tract. The results also indicate a linkage of the lymphoid tissue between the gut and the upper respiratory tract.”

Gluck U, Gebbers JO. Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and beta-hemolytic streptococci). Am J Clin Nutr. 2003 Feb;77(2):517-20.

LGG Reduces Nasal Infections “The results also indicate a linkage of the lymphoid

tissue between the gut and the upper respiratory tract.”

Gluck U, Gebbers JO. Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and beta-hemolytic streptococci). Am J Clin Nutr. 2003 Feb;77(2):517-20.

NCFM Acidophilus Benefits Humans

“NCFM survives gastrointestinal tract transit in both healthy and diseased populations. NCFM inhibits aberrant crypt formation in mutagenized rats, indicative of activity that could decrease the risk of colon cancer.”


NCFM Acidophilus Benefits Humans

“A blend of probiotic strains containing NCFM decreased the incidence of pediatric diarrhea. NCFM led to a significant decrease in levels of toxic amines in the blood of dialysis patients with small bowel bacterial overgrowth. At adequate daily feeding levels, NCFM may facilitate lactose digestion in lactose-intolerant subjects.”


Probiotics Increase Interferon-gamma

“Spleen cells from mice given L. rhamnosus, L. acidophilus or B. lactis also produced significantly higher amounts of interferon-gamma in response to stimulation with concanavalin A than cells from the control mice.”


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Probiotics Increase Antibodies to Microbes

“Together, these results suggest that supplementation of the diet with L. rhamnosus(HN001), L. acidophilus (HN017) or B. lactis(HN019) is able to enhance several indices of natural and acquired immunity in healthy mice.”


Acidophilus Kills Klebsiela“It has been shown that introduction of

Lactobacillus substantially decreased the level of the gut contamination by Klebsiella, prevented generalization of infection and death of animals. Significant higher levels of IgA in the blood serum, IgA and IgM in the gut content, percentage of splenocytes, expressing surface IgM and IgG were observed on the 7th day as compared with those in animals without Lactobacillus.”

Kostiuk OP, Chernyshova LI, Slukvin II. Protective effect of Lactobacillus acidophilus on development of infection, caused by Klebsiella pneumoniae. Fiziol Zh. 1993 Jul-Aug;39(4):62-8.

Acidophilus Kills Klebsiela

“A conclusion was made that introduction of Lactobacillus prevents development of the Klebsiella infection and protects the immune system from excessive antigenic action.”

Kostiuk OP, Chernyshova LI, Slukvin II. Protective effect of Lactobacillus acidophilus on development of infection, caused by Klebsiella pneumoniae. Fiziol Zh. 1993 Jul-Aug;39(4):62-8.

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