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31 The Immune Response: Chemical Mediators, B- and T-Cell Biology, and Immune Disorders

 

CHAPTER OVERVIEW

This chapter continues the discussion of the immune system with a description of the chemical mediators involved in the immune response and of the biology of T and B cells. The chapter also describes disorders of the immune system, including hypersensitivities as well as genetic and induced disorders. Finally, problems associated with the immune system, such as transplant rejection and blood transfusion reactions, are discussed.

 

CHAPTER OBJECTIVES

After reading this chapter you should be able to:

! discuss the various cytokines involved in the immune response and the roles that they play

! discuss the origins, development, and activities of B and T cells

! discuss superantigens

! discuss the four types of hypersensitivities (allergies) and the roles of the various immune system components in mediating these hypersensitivities

! discuss autoimmune diseases and immune deficiencies

! describe the role of the immune system in transplant rejection and blood transfusion reactions

! discuss cell-associated differentiation antigens (CDs) and their functions as cell surface receptors

 

CHAPTER OUTLINE

I. Cytokines

A. Cytokines are glycoproteins released by one cell population that acts as an intercellular mediator

1. MonokinesCreleased from mononuclear phagocytes

2. LymphokinesCrelapsed from T lymphocytes

3. InterleukinsCreleased from a leukocyte and act on another leukocyte

4. Colony stimulating factors (CSFs)Ceffect is to stimulate growth and differentiation of immature leukocytes in the bone marrow

B. Cytokines can affect various cell populations

1. Autocrine functionCaffect the same cell responsible for its production

2. Paracrine functionCaffect nearby cells

3. Endocrine functionCdistributed by circulatory system to target cells

C. Exert their effects by binding to cell-surface receptors called cell association differentiation antigens (CDs); possible effects include

1. Stimulation of cell division

2. Stimulation of cell differentiation

3. Inhibition of cell division

4. ApoptosisCprogrammed cell death

5. Stimulation of chemotaxis

6. ChemokinesisCdirect cell movement

D. Mediators of Natural or Nonspecific Immunity

1. Interferon-I (IFN-I)Cwhen secreted by infected macrophages and monocytes, it protects neighboring cells that have not yet been infected; also increases Fc receptors on macrophages and activates the lytic activity of NK cells

2. Interferon-J (IFN-J)Cproduced by fibroblasts and other cells; activates an antiviral state, modulates antibody production, induces NK activity, modulates cytotoxic T-cell activity and regulates production of cytokines and other molecules in certain cells

3. Tumor Necrosis Factor-I (TNF-I)Cmediates host response to gram-negative bacteria and modulates the inflammatory response; also acts as an endogenous pyrogen and is cytotoxic for tumor cells

4. Interleukin-1 (IL-1)Cproduced by a variety of cells; modulates CD4+ cell proliferation in the immune response and mediates production of other cytokines involved in the inflammatory response

5. ChemokinesClow molecular weight, proinflammatory, paracrine cytokines

E. Activators of Effector Cells

1. Interferon-K (IFN-K)Cproduced by TH1, TC, and NK cells and functions in amplifying the activation of T-helper cells and other activities

2. Migration inhibition factor (MIF)Cinhibits the migration of macrophages away from the site of infection

F. Mediators of Mature Cell Activation, Growth, and DifferentiationCInterleukin-2 (IL-2)C produced by T4 cells and stimulate T and B cell proliferation; successfully used as therapeutic agent against certain cancers

G. Mediators of Immature Cell Growth and Differentiation

1. Interleukin-3 (IL-3)Cstimulates hematopoiesis

2. CSFsCstimulate differentiation of various leukocytes

H. Interleukins 8 through 16Cmediate various body responses to infections (see Table 31.5)

II. B-Cell Biology

A. Cells differentiate in bone marrow and lymphoid tissue

B. Have IgM and IgD on surfaceCboth function as transmembrane B cell antigen receptors (BCRs)

C. Activated by antigen binding (clonally specific) or by mitogens (nonspecific)

D. T-dependent antigen triggeringCcauses production of IgG, IgA, and IgE

1. A macrophage ingests the antigen or antigen-bearing organism

2. The antigen is processed and appears on the surface of the antigen-presenting macrophage

3. A T-helper cell is signaled by this complex and by IL-1

4. The T cell divides and produces IL-2, which stimulates more T-cell division

5 These T cells bind to B cells presenting the appropriate antigen on their surface

6. These T cells secrete B-cell growth factor (BCGF), which causes B cells to divide

7. These T cells also secrete B-cell differentiation factor (BCDF), which causes the B cells to differentiate into plasma cells and produce antibodies

8. B cells recognize antigen through BCRs; those that are stimulated differentiate into plasma cells and secrete antibody

E. T-independent antigen triggering causes production of IgM; used for polymeric antigens with a large number of identical epitopes; antibodies have low affinity and never switch to high-affinity IgG or other isotypes

III. T-Cell Biology

A. T-cell antigen receptorsCclosely related to immunoglobulins, but cannot bind to free antigens; antigen is presented by an antigen-presenting cell (usually a macrophage) or a dendritic cell

B. Major histocompatibility complex (MHC) moleculesCproteins encoded by a group of genes called the major histocompatibility complex (MHC) genes; comprise three classes (also known as human leukocyte antigens (HLA))

1. Class ICmade by all cells except red blood cells; function to identify cells as Aself@; primary basis of HLA typing for organ transplant; also function to present endogenous antigens to T cells

2. Class IICproduced only by activated macrophages, mature B cells, some T cells, and certain cells of other tissues; function in T-cell recognition of presented exogenous antigens

3. Class IIICinvolved in the classical and alternate complement pathways

C. Regulator T cellsCcontrol the development of effector T cells

1. T-helper cells (TH) are needed for T-dependent antigen triggering; recognize antigen-HLA combination on antigen-presenting cells; secrete interleukin-2 (IL-2) and activate cytotoxic T (TC) cells; there are three types, each of which secretes a different mixture of cytokines

2. T-suppressor cells (TS) can be stimulated by a specific antigen to proliferate (mediated by IL-2), and to suppress immune responses; provide a negative feedback control

D. Acquired immune toleranceCnonresponse to self

1. Clonal deletionCearly in development, lymphocytes with ability to interact with self-antigens are destroyed in the thymus; mechanism is unknown

2. Functional inactivation (clonal anergy)Clymphocytes that can interact with self-antigens are present but are inhibited either by TS cells, or by their entry into an unresponsive state known as clonal anergy

E. Effector cellsCdirectly attack specific target cells

1. Cytotoxic T cells (TC) recognize infected cells with appropriate class I MHC proteins, and are stimulated by IL-2 secreted by TH cells to divide; they produce lymphokines that mediate destruction of infected cells either by cytolysis or by apoptosis (a programmed cell death); two possible mechanisms are:

a. CD95 pathwayCtransmembrane signal transductions

b. Perforin pathwayCrelease of perforins that damage the target cell

2. Delayed-hypersensitivity T cells (TDTH) are responsible for type IV delayed-type hypersensitivity via secretin of lymphokines; they also activate macrophages and inhibit their migration away from the site of an inflammation

3. Natural killer (NK) cells are nonphagocytic and granular (they may not be T cells); they do not require prior exposure to relevant antigens; they recognize cell-surface changes on virus-infected and tumor cells; they also recognize fungi, bacteria, protozoa, and helminth parasites (immune surveillance); they kill by cell-mediated lysis as follows:

a. The NK cells are activated by interferon and/or IL-2

b. They recognize class I MHC proteins on the target cell and bind to the cell

c. They insert perforin I (a pore-forming protein) into the plasma membrane of the target cell

d. They also secrete lysosomal hydrolases

e. The attacked cell thereby undergoes cytolysis

f. They also have Fc receptors that function by antibody-dependent cell-mediated cytotoxicity

IV. Superantigens

A. Bacterial proteins that stimulate the immune system more extensively than do normal antigens

B. Stimulate T cells to proliferate nonspecifically through interaction with class II MHC molecules and T-cell receptors in the absence of an antigenic peptide for which the T-cell receptor is specific

C. Cause symptoms by way of release of massive quantities of cytokines

D. Associated with various chronic diseases including rheumatic fever, arthritis, and others

V. HypersensitivitiesCexaggerated or inappropriate immune responses that result in tissue damage to the individual

A. Type I hypersensitivityCincludes allergic reactions

1. Occurs immediately following second contact with responsible antigen (allergen)

2. On first exposure, B cells form plasma cells that produce IgE instead of IgG

3. IgE binds to mast cells or basophils via Fc receptors and sensitizes them

4. Upon subsequent exposure, the allergen binds to these IgE-bearing cells; physiological mediators released by this binding cause anaphylaxisCsmooth muscle contraction, vasodilation, increased vascular permeability, and mucus secretion

5. Systemic anaphylaxis results from a massive release of these mediators, which cause respiratory impairment, lowered blood pressure, and serious circulatory shock; death can occur within a few minutes

6. Localized anaphylaxis

a. Hayfever if in upper respiratory tract

b. Bronchial asthma if in lower respiratory tract

c. Hives (skin eruptions) if food allergy

7. Desensitization to allergens involves controlled exposure to the allergen in order to stimulate IgG production; IgG molecules serve as blocking antibodies that intercept and neutralize the allergen before it can bind to the IgE-bound mast cells

B. Type II hypersensitivityCgenerally cytolytic or cytotoxic

1. IgG or IgM antibodies are directed against cell surface or tissue antigens

2. Cell destruction is mediated by lysis (complement activation) or by toxic mediators

3. Interferes with normal mechanisms for eliminating toxic materials

4. An example is a blood transfusion reaction in which donated blood cells are attacked by the recipient=s antibodies

C. Type III hypersensitivity

1. Immune complexes are usually removed by monocytes

2. Sometimes if immune complexes are not efficiently removed, they trigger complement-mediated inflammation such as

a. VasculitisCinflammation of the blood vessels

b. GlomerulonephritisCinflammation of the kidney glomerular basement membranes

c. ArthritisCinflammation of the joints

3. Groups of type III reactions

a. Persistent viral, bacterial, or protozoan infection, combined with a weak antibody response, leads to chronic immune complex formation and deposition in the tissues of the host

b. Autoimmune diseases, such as systemic lupus erythematosus, lead to the prolonged production of autoantibodies and, therefore, to chronic immune complex formation; this overloads the reticuloendothelial system, which leads to immune complex deposition in the tissues

c. Repeated inhalation of allergens can cause immune complex deposition at body surfaces (e.g., in the lungs in farmer=s lung disease)

D. Type IV hypersensitivity

1. Involves TDTH lymphocytes, which proliferate at the site of antigen processing by macrophages

2. The cytokines released by the TDTH cells attract macrophages and basophils to the area, leading to inflammatory reactions

3. Can be used diagnostically, as in the tuberculin skin test

4. Examples of type IV hypersensitivities

a. Allergic contact dermatitis (poison ivy, cosmetic allergies)

b. Some chronic diseases (leprosy, tuberculosis, leishmaniasis, candidiasis, herpes simplex lesions) involve chronic TDTH stimulation

VI. Autoimmune DiseasesCautoimmunity is characterized by the presence of autoantibodies and is a natural consequence of aging; autoimmune disease results from activation of self-reactive T and B cells that lead to tissue damage

A. More common in older individuals

B. May involve viral or bacterial infections that cause tissue damage and that thereby release abnormally large quantities of antigen and/or cause some self-proteins to alter their form so that they are no longer recognized as self

VII. Transplantation (Tissue) Rejection

A. AutograftCdonor and recipient are same individual (e.g., skin grafts)

B. IsograftCdonor and recipient are identical twins

C. AllograftCdonor and recipient are genetically different individuals of the same species

D. XenograftCdonor and recipient are different species

E. Mechanisms of tissue rejection reaction

1. Foreign MHC class II antigens may trigger TH cells to help TC cells destroy the graft; the TC cells recognize the graft as foreign by recognizing the MHC class I antigens

2. The cells may react directly with the graft, releasing cytokines that stimulate macrophages to enter the graft and destroy it

3. Graft vs. Host ReactionCimmunocompetent cells in donor tissue (e.g., bone marrow) reject the host

F. Ways to minimize rejection

1. Tissue matchingClook for the best match of MHC (particularly class I) antigens

2. Immunosuppressive drugsCthese however increase susceptibility to infections and cancer

G. Immunologically privileged site (e.g., cornea)Cnot subject to graft rejection because lymphocytes do not circulate there

VIII. ImmunodeficienciesCfailure to recognize and/or respond properly to antigens

A. Primary (congenital) immunodeficiencies result from a genetic disorder

B. Secondary (acquired) immunodeficiencies result from infection by immunosuppressive microorganisms (e.g., AIDS, chronic mucocutaneous candidiasis)

IX. Human Blood Types

A. The surface of red blood cells contains genetically determined sets of molecules

B. ABO groupingCbased on differences in glycosphingolipid molecules

1. Type AChave type A glycoprotein molecules

2. Type BChave type B glycoprotein molecules

3. Type ABChave both types

4. Type OChave neither type on their surface

C. Antibodies exist in the bloodstream to those molecules that an individual does not have, even though no prior exposure has occurred (this is different from other antibody productions); the reasons for their existence are not entirely clear, but may be the result of exposure to similar antigens that occur in the normal intestinal microbiota

D. Transfusion of the wrong type of blood will lead to agglutination, which can block blood vessels and cause serious circulation problems

E. Rh systemCbased on presence (Rh+) or absence (RhB) of the Rh or D antigen on the surface of the erythrocytes

1. Requires prior exposure for production of antibodies in RhB individuals

2. Important in transfusions, and in pregnancies if child is Rh+ and mother is RhB

a. Mother produces antibodies after birth of first Rh+ child

b. The circulating antibodies can cross placenta and agglutinate red blood cells of the next Rh+ infant, causing hemolytic disease of the newborn

c. This can be prevented by injecting the mother with anti-Rh antibodies (RhoGAM) within 72 hours of delivery of an Rh+ baby; these antibodies bind any Rh antigens in the mother=s bloodstream and thereby prevent the formation of antibodies that could harm subsequent offspring

X. Cell-Associated Differentiation Antigens (CDs)

A. Cell surface proteins that function as receptors for various cytokines

B. Specific cell types can be identified by their complement of CDs

C. Can be secreted from cells and levels in serum can be used in disease management

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