Evolution by Natural Selection is a Evolution by Natural Selection is a SelfSelfish Processish Process

Things (units) that survive & reproduce relatively more of self become relatively more common over time.

An important way to increase survival & reproduction is to form cooperative coalitionsform cooperative coalitions.

In evolutionary theory, the main mechanisms that underpin cooperation (by stabilizing against cheating) are reciprocityreciprocity and kin selectionkin selection.

By helping kin, a ‘unit’ helps reproduce copies of shared genes (replicators).By helping kin, a ‘unit’ helps reproduce copies of shared genes (replicators).

In diploid sexual species, full siblings share 1/2 of their genes by common descent.

All the cells within a bodycells within a body (vehicle) that descend from a fertilized egg are a clonea clone and share all genes (except for mutations, ex cancers) & kinship = 1; this makes for a very cooperative coalition - a bodya very cooperative coalition - a body.Most cells in a clonal body don’t reproduce across generations; they increase copies of shared genes in their ‘close kin’ - the gametes.

It is the job of the immune system It is the job of the immune system to stabilize this big cooperative coalition of cellsto stabilize this big cooperative coalition of cells by making sure everyone is on the same team - the ‘self team.’ by making sure everyone is on the same team - the ‘self team.’

Other Myeloid Myeloid stem cells develop into phagocytes … neutrophils neutrophils – fast & briefMonocytesMonocytes become big persistent macrophagesmacrophages

Myeloid Myeloid stem cells develop into granule-containing inflammatory cells:Basophils Basophils – release histamines, prostaglandinsChemokines, pyrogens, etc. Eosinophils & Eosinophils & Natural Killer cellsNatural Killer cells– ‘bombs’

Cells of the Immune SystemCells of the Immune System

Fig 43.1: An overview of defenses

LymphoidLymphoid stem cells develop into lymphocytes. … two major classes are B cellsB cells and T cellsT cells.

(antigen-independent)

Beyond their role as a physical barrier, the skin & mucous membranesskin & mucous membranes counter pathogens with chemical defenses.

MucusMucus is also rich in phagocytes and IgA antibodies Mucus traps microbes and other particles that contact it. In the trachea, ciliated epithelial cells sweep out mucus with its trapped microbes, preventing them from entering the lungs.

Most microbes in food or water or swallowed mucus are destroyed by the highly acidic environment of the stomach. However, Hepatitis A virus is one of many pathogens that survives gastric acidity and enters to the body via the digestive tract.

In humans, for example, secretions from sebaceous and sweat glands give the skin a pHpH ranging from 3 to 5; acidic enough to prevent colonization by many microbes. (Normal skin bacteria are adapted to acidic, relatively dry env.) Microbial colonization is also inhibited by the washing action of saliva, tears, and mucous secretions. These secretions contain antimicrobial proteins, like the enzyme lysozymelysozyme, which digests peptidoglycan (fig 27.5) in the cell walls of many bacteria.

(antigen-independent)

(antigen-independent)Microbes that penetrate the first line of defense, face the internal nonspecific defense: phagocytosisphagocytosis, ingestion by certain types of white cells.

Phagocytic neutrophilsneutrophils constitute 60-70% of all leukocytes. Damaged cells release chemical signals that attract neutrophils {proinflammatory cytokines like interleukin-8 (Il-8) – aka chemokines}. The neutrophils enter the infected tissue, engulfing and destroying microbes.http://www.cat.cc.md.us/courses/bio141/lecguide/unit1/bacpath/cytogn.html#neutLipopolysaccharide LPS (aka endotoxin) from the gram-negative bacterial cell wall binds to LPS receptors on monocytes, macrophages and neutrophils. The binding of LPS to the LPS (CD14) receptor and Il-8 to Il-8 receptors on neutrophils stimulates them to release proteases and toxic oxygen radicals for extracellular killing.

All components of the non-specific immune system are modulated by products of the specific immune system, such as interleukins, interferon-gamma, antibody, etc

(antigen-independent)

Phagocytic Monocytes Monocytes (5% of leukocytes) circulate in the blood for only a few hours, then migrate into tissues, developing into large macrophages ("big eaters") = MacrophagesMacrophages, the largest phagocytic cells.

Fig 43.3  Phagocytosis: This micrograph shows fibril-like pseudopodia of a macrophage attaching to rod-shaped bacteria, which will be ingested and destroyed.

A macrophagemacrophage engulfs a microbe in a vacuole that fuses with a lysosome (Fig 7.14). The lysosome has two ways of killing the trapped microbe: 1) w/ toxic forms of oxygen like superoxide anion and nitric oxide, 2) w/ lysosomal enzymes, including lysozyme.

Some microbes have evolved mechanisms for evading phagocytic destruction. Some bacteria have outer capsules to which a macrophage cannot attach. Others, like Mycobacterium tuberculosistuberculosis, are readily engulfed {it binds to macrophage surface receptors for the sugar mannose} but are resistant to lysosomal destruction {it can inhibit phagosome-lysosome fusion; the exact mechanism is not known} and can even reproduce inside a macrophage.

(antigen-independent)

Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins.

About 1.5% of all leukocytes are eosinophilseosinophils. Their main contribution is against larger parasitic invaders, such as the blood fluke Schistosoma mansoni.Eosinophils position themselves against the external wall of a parasite Eosinophils position themselves against the external wall of a parasite and discharge destructive enzymes from cytoplasmic granules. and discharge destructive enzymes from cytoplasmic granules. These cells have only limited phagocytic activity.

Nonspecific defense also includes natural killer (NK) cellsnatural killer (NK) cells. NK cells do not attack microorganisms directly; instead, they destroy virus-infected body cellsdestroy virus-infected body cells (as well as abnormal & cancerous cells). NK cells are not phagocytic; rather, they mount an attack on the cell's membrane, causing the cell to lyse (burst open).

www.bio.ic.ac.uk/ research/dmd/ NK cells require the order of a minute or two to survey a target cell. A lack of such accumulation of MHC I protein (HLA-C) signifies to the Natural Killer cell that something is abnormal in the cell, e.g. it is virally infected, and it should be killed.

ProstaglandinsProstaglandins: … attract neutrophils, increase platelet aggregation to help clotting. cause redness (increase vasodilation and permeability) pain (increase sensitivity of nerve endings)

Cellular Mediators of InflammationCellular Mediators of Inflammation - http://web.indstate.edu/nurs/mary/PATHOPHY.htm

Neutrophils and Monocytes are drawn by the chemotactic chemicals, Neutrophils are highly phagocytic leukocytes … contain lysosomal granules (enzymes) which digest substances that they engulf. Monocytes are large immature forms of a macrophage …

Chemical Mediators of InflammationChemical Mediators of Inflammation - http://web.indstate.edu/nurs/mary/PATHOPHY.htm

HistamineHistamine: In response to injury, granulated leukocytes known as mast cells (fixed in the body organs) and basophils (flowing in blood stream) release histamine which causes dilation of local blood vessels … bronchial constriction (smooth muscle) and mucus production,

{antihistamines fill receptor cell ‘locks’ w/o turning the key - preempt histamine keys;} Bradykinin: … which causes increases heart rate & vascular permeability … The kinins are also responsible for pain.

Leukocytes also release molecules called pyrogenspyrogens, which set the body's thermostat at a higher temperature – feverfever: phagocytized bits of bacterial pyrogens (cell wall etc) increase the production of interleukin-1interleukin-1 in phagocytes.IL-1 (endogenous pyrogen or leukocyte pyrogen) increases the local production of prostaglandinsprostaglandins in the anterior hypothalamus, increasing the temperature set-point. Fever can be reduced by aspirin which inhibits the cyclooxygenase enzyme necessary for the synthesis of prostaglandins.

Certain bacterial infections can induce an an overwhelming systemic inflammatory response known as septic shockseptic shock . Characterized by high fever and low blood pressure, septic shock is the most common cause of death in U.S. critical care units.

There are many types of interferonsinterferons, and their name derives from their function: the ability to interfere with viral infectionsinterfere with viral infections.

http://www.mnwelldir.org/docs/immune/immune1.htm

The complement systemThe complement system - later.

When a cell is attacked by a virus, though it cannot save itself, it can create an interferon that will warn other cells of an impending infection. Having been warned, the uninfected cells arm themselves with antiviral substances that keep the virus from replicating (reproducing themselves) in the uninfected cells. {the actual mechanisms are complex & not well known, see http://www.bio.indiana.edu/studies/ugrad/M430/INTERFERON.html }Some interferons act as chemokines, attracting & activating phagocytes.Interferons are not virus specific.

Lethal H5N1 influenza viruses escape host anti-viral cytokine responsesSeo SH, Hoffmann E, Webster RG NATURE MEDICINE 8 (9): 950-954 SEP 2002

This strain has a gene thatinterferes w/ interferon!interferes w/ interferon!& prevents infected cells from signaling for immune response.

Bone MarrowBone Marrow -- All the cells of the immune system are initially derived from the bone marrow … bone marrow-derived stem cells differentiate into … B cells, natural killer cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets. Immature thymocytes … leave the bone marrow and migrate into the thymus.

ThymusThymus -- The function of the thymus is to produce mature T cells. Through a maturation process sometimes referred to as thymic educationthymic education, T cells that are beneficial to the immune system are spared, while T cells that evoke a detrimental autoimmune response are eliminated. The mature T cells are then released into the bloodstream.

In immature lymphocytes, genes for immunoglobulins mutate like crazy,creating zillions of mutant ‘locks,’ each w/ a different key to its ignition.

Most of these mutant immunoglobulins are ‘ignited’ by self-antigens (95%).Self-tolerance results from clonal deletionSelf-tolerance results from clonal deletion:

maturing lymphocytes that react intensely in Bone or Thymusare convinced to commit suicide (apoptosisapoptosis, Fig 21.18)

http://www.thebody.com/step/immune.html

The Organs of the Immune SystemThe Organs of the Immune System

http://www.thebody.com/step/immune.html

Cells of the Immune SystemCells of the Immune System

T-Cells are divided into two major subsets. The TThe TH H helper subset, also called CD4+ T cell coordinates immune regulation.helper subset, also called CD4+ T cell coordinates immune regulation. The main function of the TH helper cell is to augment immune responses by the secretion of {chemokines - interleukins} that activate other white blood cells.

T cells interact with cell surface glycoproteins encoded by a family of genes called the major histocompatibility complex (MHC).the major histocompatibility complex (MHC). In humans, MHC glycoproteins are known as HLA (Human Leukocyte Antigens).HLA (Human Leukocyte Antigens). Through a process known as antigen presentationantigen presentation, an MHC molecule cradles a 9 amino acid fragment of an intracellular protein antigen in its groove, carries it to the cell surface, and "presents" it to an antigen receptor on a T cell.

{see Falk et al 2002. Nature 348,248-251}(a) Class I MHC Class I MHC molecules found on almost all nucleated cells in the body present to Cytotoxic T cells (TC), which then kill the presenter.

(b) Class II MHC Class II MHC molecules are made by only a few cell types, chiefly macrophages and B cells (called antigen-presenting cells (APCs)) that ingest bacteria (and viruses) and then destroy them. Class II MHC molecules in these cells collect peptide remnants of this degradation and present them to helper T cells, which send out chemical signals that incite other cell types to fight the pathogen

MHC-dependent mate preferences in humans.Wedekind et al. 1995. Proc. Roy. Soc. Lond. B 260: 245-249.

…each female student was asked to rate the odours of six T-shirts.

They scored male body odours as more pleasant when they differed from the men in their MHC {II} than when they were more similar.

Oooohh -he smells so …

different!

http://www.thebody.com/step/immune.html

Cells of the Immune SystemCells of the Immune System

The cytotoxic TThe cytotoxic TC C killer subset or CD8+ T cell killer subset or CD8+ T cell. … directly kill certain tumor cells, viral-infected cells and sometimes parasites.

perforin, a protein that forms pores in the target cell's membrane.

http://www.thebody.com/step/immune.html

Cells of the Immune SystemCells of the Immune System

B CellsB Cells -- The major function of B lymphocytes is the production of antibodies the production of antibodies in response to foreign proteins of bacteria, viruses, and tumor cells. Antibodies are specialized proteins that specifically recognize and bind to one particular proteinrecognize and bind to one particular protein. Antibody … binding to a foreign substance or antigen, often is critical as a means of signaling other cells to engulf, kill or remove that substance from the body.

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

Antibodies {& membrane-bound receptors} Each antibody is made up of two identical heavy chains and two identical light chains, shaped to form a Y.… the tips of the Y's arms = the variable regionthe variable region = the antigen-binding site … allow the antibody to recognize a matching antigen, much as a lock matches a key. The stem of the Y links the antibody to other participants in the immune defenses. This area is identical in all antibodies of the same class …

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

Antibody GenesScientists long wondered how all the genetic information needed to make millions of different antibodies could fit in a limited number of genes. The answer is that antibody genes are pieced together from widely scattered bits of DNA, and the possible combinations are nearly endless. As this gene forms, it assembles segments that will determine the variable-V, joining-J, and constant-C segments of this antibody molecule …

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

Antibodies belong to a family of large protein molecules known as immunoglobulins.

IgGIgG, the major immunoglobulin in the bloodin the blood, is also able to enter tissue spacestissue spaces; it works efficiently to coat microorganisms, IgDIgD is inserted into the membrane of B cellsthe membrane of B cells, where it somehow regulates the cell's activation. IgEIgE is normally present in only trace amounts, but it is responsible for the symptoms of allergy {it triggers mast cells in mucous membranesin mucous membranes to release histamines}.

IgAIgA—a doublet— concentrates in body fluids such as tears, salivatears, saliva, and the secretions of the respiratory and gastrointestinal tracts {snotsnot}. It is, thus, in a position to guard the entrances to the body.

IgMIgM usually combines in star-shaped clusters. It tends to remain in the bloodstreambloodstream, where it is very effective in killing bacteria.

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

ComplementComplement The complement system consists of a series of proteins that "complement" the work of antibodies in destroying bacteria. Complement proteins circulate in the blood in an inactive form. The so-called "complement cascade" is set off when the first complement molecule, C1, encounters antibody bound to antigen in an antigen-antibody complex. The end product is a cylinder that punctures the cell membranepunctures the cell membrane and, by allowing fluids and molecules to flow in and out, dooms the target cell.

The next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly.

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

Immunity: Short- and Long-Term Cell MemoryWhenever T cells and B cells are activated, some become "memory" cells"memory" cells.

Short-term immunity can be transferred passively via antibody-containing serum; similarly, infants are protected by antibodies they receive from their mothers (IgG antibodies cross the placenta, IgA antibodies are passed in breast milk).

Long-term immunity can be stimulated not only by infection but also by vaccinesvaccines made from infectious agents that have been inactivated or, more commonly, from minute portions of the microbe.

Note the use of passive immunity w/ IgG to Rh factor at 1st birth preempt Rh- mom from developing active memory & strong attack on 2nd child.

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

Disorders of the Immune System: AllergyAllergies such as hay fever and hives are related to the antibody known as IgE.

To Desensitize the person to the antigen - (allergy shots) Give repeated small doses of the antigen intramuscularly. This leads to a build up of IgGIgG, {circulating in blood & lymph} which clears out the antigen before it gets to the IgEIgE on the Mast cells. Not 100% effective, but it does help some.

The first time an allergy-prone person is exposed to an allergen—for instance, grass pollen— the individual's B cells make large amounts of grass pollen IgE antibody. These IgE molecules attach to granule-containing cells known as mast cells, which are plentiful in the lungs, skin, tongue, and linings of the nose and gastrointestinal tract. The next time that person encounters grass pollen, the IgE-primed mast cell releases {histamines} that cause the wheezing, sneezing, and other symptoms of allergy.

People w/ systemic lupus erythematosussystemic lupus erythematosus … have developed an immune response to their own DNA, and the presence of anti-DNA antibodies in their serum is one mechanism of diagnosis lupus …

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

Disorders of the Immune System: Autoimmune Disease{See: http://www.montana.edu/wwwwami/523/Reading11.htm}Sometimes the immune system's recognition apparatus breaks down, and the body begins to manufacture antibodies and T cells directed against the body's own cells and organs.

Rheumatoid ArthritisRheumatoid Arthritis: Some people produce the rheumatoid factor which is an IgM autoantibody. This auto IgM binds to the Fc part of IgG, forming immune complexes, which lodge in the joints and cause inflammation of the joint. {see Vinuesa & Goodnow 2002. Nature 416,595-598}

… type I or juvenile-onset diabetesjuvenile-onset diabetes is due to the combined attack of T cells and antibodies directed against the ß cells of the pancreas that normally produce insulin

is an immunodeficiency disorder caused by {HIV}, {HIV}, a virus that destroys helper T cells.a virus that destroys helper T cells. CD4 molecules on helper T cells enhance the binding w/ class II MHC-bearing antigen-presenting cells. HIV binds to CD4 & helper T cells are highly susceptible to infection.The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses.

Disorders of the Immune System: AIDSAIDS

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

Immunity and CancerWhen normal cells turn into cancer cells, some of the antigens on their surface change. These altered antigens flag immune defenders, including cytotoxic T cells, natural killer cells, & macrophages. According to one theory, patrolling cells of the immune system provide continuing bodywide surveillance, spying out and eliminating cells that undergo malignant transformation. Tumors develop when the surveillance system breaks down or is overwhelmed {or when the immune system is suppressed, ex by stressstress}

Social stress in laboratory rats - Behavior, immune function, and tumor metastasis.Stefanski V. PHYSIOLOGY & BEHAVIOR 73 (3): 385-391 JUN 2001Abstract:… in subdominant males after 2 days of continuous social confrontation … elevated plasma concentrations of adrenal hormones … lower numbers of blood CD4 and CD8 T cells as well as reduced activity levels of T cells and natural killer (NK) cells …A 10-fold lower tumor clearance in subdominant males demonstrates suppression of the animals' capacity to prevent metastatic development. …

Immune responses and latent herpesvirus reactivation in spaceflight.Stowe et al. Aviation Space and Environmental Medicine 72 (10): 884-891 OCT 2001.

{ Think Happy Thoughts – ‘humoral immunity’! }{ Think Happy Thoughts – ‘humoral immunity’! }

Abstract:Background: Increased frequency and severity of herpesvirus infections are common in individuals with impaired cellular immunity … This study investigated immune responses and latent herpesvirus reactivation during a 9-d spaceflight. …Conclusions: … spaceflight and associated stresses reactivate latent herpesviruses … acute changes in neuroendocrine hormones mediate these changes in part by downregulating cellular immunity. …

http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm

The Immune System and the Nervous SystemBiological links between the immune system and the nervous system exist at several levels.