Aging of the Immune System

Dr. Hal SternbergBioTime, Inc.Berkeley, CA

Evidence for Decline in Immune Function with Aging

Aged Individuals have:1) Increased incidence of INFECTIONS:

For example: pneumonia, influenza, tuberculosis, meningitis, urinary tract infections

2) Increased incidence of AUTOIMMUNE

DISEASE:For example: rheumatoid arthritis, lupus, hepatitis, thyroiditis (graves-hyper/hashimotos-hypo), multiple sclerosis

(Predisposition toward these diseases is related to Human Leukocyte Antigens HLA genes)

Aged Individuals have:

3) Increased CANCER INCIDENCE: For Example: prostate, breast, lung, throat/neck/head, stomach/colon/bladder, skin, leukemia, pancreatic

4) TOLERANCE to organ transplants: Kidneys, skin, bone marrow, heart (valves), liver,

pancreas, lungs

Evidence for Decline in Immune Function with Aging

Function of Immune System is PROTECTION

against:1. Bacteria2. Virus3. Fungus/ multicellular parasites4. Cancer5. Toxins 6. ( 5,000

daltons--protein/lipid/CHO/nucleic acids)

Tissues and Organs Important for Immune Function

•Cells derived from stem cells: liver, bone marrow

• Cells are stored, multiply, interact, and mature in: thymus,

spleen, lymph nodes, blood

•Transport: lymphatic vessels

Accessory Organs

•Appendix, tonsils, intestines

Cell Types

1. Lymphocytes: derived in bone marrow from stem cells 10^12A) T cells: stored & mature in thymus-migrate throughout the body-Killer Cells Perform lysis (infected cells)Cell mediated immune response

-Helper CellsEnhance T killer or B cell

activity -Supressor CellsReduce/suppress immune

activityMay help prevent auto immune

disease

B)B-Cells: stored and mature in spleen

• secrete highly specific Ab to bind foreign substance (antigen: Ag), form Ab-Ag complex

• responsible for humoral response• perform antigen processing and presentation

• differentiate into plasma cells (large Ab secretion)

Lymphocytes (cont.)

2.Neutrophils- found throughout body, in blood-phagocytosis of Ab-Ag CX

3.Macrophages- throughout body, blood, lymphatics-phagocytose non-specifically (non Ab coated Ag)-phagocytose specifically Ab-Ag CX-have large number of lysosomes (degradative enzyme)-perform Ag processing and presentation-present Ag to T helper cell-secrete lymphokines/ cytokines to stimulate T helper

cells and immune activity

4. Natural Killer Cells-in blood throughout body-destroy cancer cells-stimulated by interferons

Bacterial

Infection

MacrophageBacte

ria

ComplementSeries of enzymes which are

sequentially activated and result in lysis of cell membrane of infected

cell at bacteriumPermeablizes membrane leaky

Complement binding and activation

~35 enzymes and factors involved in cascade

Viral Infection

5 classes of Ig

IgG: 150,000 m.w.most abundant in blood, cross

placental barrier,fix complement, induce

macrophage engulfment

IgA: associated with mucus and secretory glands, respiratory tract, intestines, saliva, tears, milk

variable size

IgM: 900,000 m.w.2nd most abundant , fix

complement,induce macrophage engulfment,

primary immune response

5 Classes of Ig

IgD: Low level in blood, surface receptor on B- cell

IgE: Binds receptor on mast cells (basophils)

secretes histamine, role in allergic

reactions

Increased histamine leads to vasodilation, which leads to increase blood vessel permeability. This induces lymphocyte immigration swelling and redness.

Thymus Involution

Repertoire of lymphocytes shift with aging (membrane

components shift)

Cortex

Experimental Evidence for Age Related Decrease in Immune

Function

Dependent on T & B cell function

Sheep RBC (Antigen) 1st into human

In vitro

B-Cell MitogenesisStrain dependent, mitogen dependent,

etc.

Mitogen•Lipopolysac.•PHA

Table 15-2: Some Aging Related Effects on B-

Cells• Decreased number of circulating and peripheral blood B cells

• Alteration in B-cell repertoire (diversity)

• Decreased generation of primary and secondary memory B cells

• General decline in lymphoproliferative capacity

Table 15-14: Some Aging-Related Effects on T-cells

•General decline in cell mediated immunological function•T-cell population is hyporesponsive•Decrease responsiveness in T-cell repertoire (i.e. diversity of CD8+ T-cells)•Decline in new T-cell production•Increase in proportion of memory and activated T-cells while naïve T-cells decrease •Diminished functional capacity of naïve T-cells (decreased proliferation, survival, and IL-2 production)•Senescent T-cells accumulate due to defects in apoptosis•Increased proportion of thymocytes with immature phenotype•Shift in lymphocyte population from T-cells to NK/T cells (cell expressing both T-cell receptor and NK cell receptors)

Table 15-13 Aging-Related Shifts in Antibodies

General decrease in humoral responsiveness:Decline in high affinity protective antibody production

Increased auto-antibodies:Organ specific and non-organ specific antibodies directed to self

Increased serum levels of IgG (i.e. IgG1 and IgG3) and IgA; IgM levels remain unchanged

Table 15-16 Influence of Aging on Macrophages

and Granulocytes

General functional impairment of macrophages and granulocytes

GM-CSF is unable to activate granulocytes from elderly subjects (e.g.: superoxide production and cytotoxic abilities)

Polymorphonuclear neutrophils appear to possess higher levels of surface markers CD15 and CD11b and lesser vesicles containing CD69 which lead to the impairment observed to destroy a bacteria

In elderly subjects the monocyte phenotype shifts (i.e. expansion of CD14dim and CD16 bright subpopulations which have features in common with mature tissue macrophages)

Macrophages of aged mice may produce less IFN-, less nitric oxide synthetase, and hydrogen peroxide.

Table 15-15 Aging-Related Changes in Natural Killer (NK) Cells

General decline in cell function

Good correlation between mortality risk and NK cell number

Increased in proportion of cells with high NK activity (i.e. CD16+, CD57-)

Progressive increase in percentage of NK cells

Impairment of cytotoxic capacity per NK cell

Increase in NK cells having surface molecule CD56

dim subset

Table 15-10 Some Aging-Related Shifts in Cytokines•Increased proinflammatory cytokines IL-1, IL-6, TNF-•Increased cytokine production imbalance•Decreased IL-2 production•Increased production of IL-8, which can recruit macrophages and may lead to pulmonary inflammation•Increase in dysfunctional IL-8•Decreased secretion of IFN- (interferon) •Altered cytokine responsiveness of NK cells, which have decreased functional abilities•Increased levels of IL-10 and IL-12 upregulated by Antigen Processing Cells

Table 15-17 Major Diseases Associated with Aging in Immune Function

Increased tumor incidence and cancer

Increased incidence of infectious diseases caused by:

E. ColiStreptococcus pneumoniaMycobacterium tuberculosisPseudomonas aeruginosaHerpes virusGastroenteritis, bronchitis, and

influenza

Reappearance of latent viral infection

Autoimmune diseases and inflammatory reactions:ArthritisDiabetesOsteoporosis

Dementia

Table 15-9 Hallmarks of ImmunosenescenceAtrophy of the thymus: decreased size decreased cellularity (fewer thymocytes and epithelial cells) morphologic disorganization

Decline in the production of new cells from the bone marrow

Decline in the number of cells exported by the thymus gland

Decline in responsiveness to vaccines

Reduction in formation and reactivity of germinal center nodules in lymph nodes where B-cells proliferate

Decreased immune surveillance by T lymphocytes and NK cells

TABLE 15.6 - CHEMICAL MEDIATORS OR MODULATORS

CYTOKINES - influence proliferation, differentiation, and survival of lymphoid cells; has numerous actions on other body cells, compromises the following:

Interleukin (IL): family, 16 different proteins from IL1 and up; numerous effects on lymphocytes and other cells with IL receptors

Tumor Necrosis Factor (TNF): 1) TNF- cytotoxic against malignant and inflammatory cells; produced primarily by macrophages, 2) TNF- cytotoxic against malignant cells; enhances phagocytosis; produced primarily by T cells

Interferon (IFN): 1) IFN-,: produced by many cells; antiviral actions, 2) IFN-:synthesized by activated NK and T cells; involved in activation of macrophages and inflammation

Colony Stimulating Factor (CSF): glycoprotein regulating white blood cell production, activity, and

survival

Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF): regulates hematopoiesis, affects phagocyte function and angiogenesis

15-11 Additional Aging-Related Shifts in Immune Functions

Altered membrane fluidityIncreased apoptosis perhaps due to decline in CD28 expression and IL-2 productionCD20 overexpression on lymphocytesIncreased CAMs expression on lymphocytesOld cells may have greater levels of messenger RNA for 3 mitotic inhibitorsDecrease number of HLA class I and II antigenic sites on lymphocytesIncrease in activated T-cell expressing DR moleculesDecreased proportion of T, B, and NK cells expressing CD62L and increased density per cell of this adhesion receptor expressionUpregulation of L-selectin per T-cellShift in lymphocyte population to contain more CD3-NK cells and CD3+CD56+ T-cellsCD3 downregulation and CD50 upregulation on T-cells affecting activation and proliferationIncreased T-cell death by fas/fas-ligand mediated response in presence of IL-2 Heightened density of CD5 on B-cellsDecreased number of monocytes with LFA-1Decreased ability of dendritic cells to stimulate T-cell secretion of IFN- and IL2