The environment contains thousands of pathogenic microorganisms — viruses, bacteria, fungi, and parasites. Ordinarily, we protect ourselves from infectious organisms and other harmful invaders through an elaborate network of safeguards — the host defense system. Understanding how this system functions provides the framework for studying various immune disorders.
The host defense system includes physical and chemical barriers to infection, the inflammatory response, and the immune response. Physical barriers, such as the skin and mucous membranes, prevent invasion by most organisms. Those organisms that penetrate this first line of defense simultaneously trigger the inflammatory and immune responses. Both responses involve cells derived from a hematopoietic stem cell in the bone marrow.
Chemical barriers include lysozymes (found in body secretions, such as tears, mucus, and saliva) and hydrochloric acid (found in the stomach). Lysozymes destroy bacteria by removing cell walls. Hydrochloric acid breaks down food and mucus that contains pathogens.
The inflammatory response involves polymorphonuclear leukocytes, basophils, mast cells, platelets and, to some extent, monocytes and macrophages.
The immune response primarily involves the interaction of lymphocytes (T and B), macrophages, and macrophage-like cells and their products. These cells may be circulating or may be localized in the immune system's tissues and organs, including the thymus, lymph nodes, spleen, and tonsils. The thymus participates in the maturation of T lymphocytes (cell-mediated immunity); here these cells are “educated” to differentiate “self” from “nonself.” In contrast, B lymphocytes (humoral immunity) mature in the bone marrow. The key humoral effector mechanism is the production of immunoglobulin by B cells and the subsequent activation of the complement cascade. The lymph nodes, spleen, liver, and intestinal lymphoid tissue help remove and destroy circulating antigens in the blood and lymph.
An antigen is any substance that can induce an immune response. T and B lymphocytes have specific receptors that respond to specific antigen molecular shapes (epitopes). In B cells, this receptor is an immunoglobulin (Ig) (antibody) cell: IgD or IgM, sometimes referred to as a surface immunoglobulin. The T-cell antigen receptor recognizes antigens only in association with specific cell surface molecules known as the major histocompatibility complex (MHC). (See The major histocompatibility complex, page 342.) MHC molecules, which differ among individuals, identify substances as self or nonself. Slightly different antigen receptors can recognize a phenomenal number of distinct antigens, which are coded by distinct, variable region genes.
Groups, or clones, of lymphocytes exist with identical receptors for a specific antigen. The clone of a lymphocyte rapidly proliferates when exposed to the specific antigen. Some lymphocytes further differentiate, and others become memory cells, which allow a more rapid response — the memory or anamnestic response — to subsequent challenge by the antigen.
Many factors influence antigenicity. Among them are the antigen’s physical and chemical characteristics, its relative foreignness, and the individual’s genetic makeup, particularly the MHC molecules. Most antigens are large molecules, such as proteins or polysaccharides. (Smaller molecules such as drugs that aren’t antigenic by themselves are known as haptens. These haptens can bind with larger molecules, or carriers, and become antigenic or immunogenic.) The antigen’s relative foreignness influences the immune response’s intensity. For example, little or no immune response may follow transfusion of serum proteins between humans; however, a vigorous immune response (serum sickness) commonly follows transfusion of horse serum proteins to a human. Genetic makeup may also determine why some individuals respond to certain antigens, whereas others don’t. The genes responsible for this phenomenon encode the MHC molecules.
B lymphocytes and their products, immunoglobulins, contribute to humoral immunity. The binding of soluble antigen with B-cell antigen receptors initiates the humoral immune response. The activated B cells differentiate into plasma cells that secrete immunoglobulins or antibodies. This response is regulated by T lymphocytes and their products, lymphokines. These lymphokines, which include interleukin (IL)-2, IL-4, IL-5, and interferon 8, are important in determining the class of immunoglobulins made by B cells.
The immunoglobulins secreted by plasma cells are four-chain molecules with two heavy (H) and two light (L) chains. (See Structure of the immunoglobulin molecule.) Each chain has a variable (V) region and one or more constant (C) regions, which are coded by separate genes. The V regions of both L and H chains participate in the binding of antigens. The C regions of the H chain provide a binding site for crystallizable fragment (Fc) receptors on cells and govern other mechanisms.
Any clone of B cells has one antigen specificity determined by the V regions of its L and H chains. However, the clone can change the class of immunoglobulin that it makes by changing the association between its V region genes and H chain C region genes (a process known as isotype switching). For example, a clone of B cells genetically preprogrammed to recognize tetanus toxoid initially will make an IgM antibody against tetanus toxoid and later an IgG or other antibody against it.
The five known classes of immunoglobulins — IgG, IgM, IgA, IgE, and IgD — are distinguished by the constant portions of their H chains. However, each class has a kappa or a lambda L chain, which gives rise to many subtypes. The almost limitless combinations of L and H chains give immunoglobulins their specificity.
❑ IgG, the smallest immunoglobulin, appears in all body fluids because of its ability to move across membranes as a single structural unit (a monomer). It constitutes 75% of total serum immunoglobulins and is the major antibacterial and antiviral antibody.
❑ IgM, the largest immunoglobulin, appears as a pentamer (five monomers joined by a J-chain). Unlike IgG — which is produced mainly in the secondary, or recall, response — IgM dominates in the primary, or initial, immune response. However, like IgG, IgM is involved in classic antibody reactions, including precipitation, agglutination, neutralization, and complement fixation. Because of its size, IgM can’t readily cross membrane barriers and is usually present only in the vascular system. IgM constitutes 5% to 10% of total serum immunoglobulins.
❑ IgA exists in serum primarily as a monomer; in secretory form, IgA exists almost exclusively as a dimer (two monomer molecules joined by a J-chain and a secretory component chain). As a secretory immunoglobulin, IgA defends external body surfaces and is present in colostrum, saliva, tears, nasal fluids, and respiratory, GI, and genitourinary secretions. This antibody is considered important in preventing antigenic agents from attaching to epithelial surfaces. IgA makes up 15% to 20% of total serum immunoglobulins.
❑ IgE, present in trace amounts in serum, is involved in the release of vasoactive amines stored in basophils and tissue mast cell granules. When released, these bioamines cause the allergic effects characteristic of this type of hypersensitivity (erythema, itching, smooth-muscle contraction, secretions, and swelling).
❑ IgD, present as a monomer in serum in minute amounts, is the predominant antibody found on the surface of B lymphocytes and serves mainly as an antigen receptor. It may function in controlling lymphocyte activation or suppression.
T lymphocytes and macrophages are the chief participants in cell-mediated immunity. Immature T lymphocytes are derived from the bone marrow. Upon migration to the thymus, they undergo a maturation process that is dependent upon products of the MHC, human leukocyte antigen (HLA) genes. Thus, mature T cells can distinguish between self and nonself. T cells acquire certain surface molecules, or markers; these markers combined with the T-cell antigen receptor promote the particular activation of each type of T cell. T-cell activation requires presentation of antigens in the context of a specific HLA antigen. Helper T cells require class II HLA antigens; cytotoxic T cells require class I HLA antigens. T-cell activation also involves IL-1, produced by macrophages, and IL-2, produced by T cells.
Natural killer (NK) cells are a discrete population of large lymphocytes, some of which resemble T cells. NK cells recognize surface changes on body cells infected with a virus; they then bind to and, in many cases, kill the infected cells.
Important cells of the reticuloendothelial system, macrophages influence both immune and inflammatory responses. Macrophage precursors circulate in the blood. When they collect in various tissues and organs, they differentiate into macrophages with varying characteristics. Unlike B and T lymphocytes, macrophages lack surface receptors for specific antigens; instead, they have receptors for the C region of the H chain (Fc region) of immunoglobulin, for fragments of the third component of complement (C3), and for nonimmunologic factors such as carbohydrate molecules.
One of the most important functions of macrophages is the presentation of antigen to T lymphocytes. Macrophages ingest and process antigen, then deposit it on their own surfaces in association with HLA antigen. T lymphocytes become activated upon recognizing this complex. Macrophages also function in the inflammatory response by producing IL-1, which generates fever. Additionally, macrophages synthesize complement proteins and other mediators that produce phagocytic, microbicidal, and tumoricidal effects.
Cytokines are low-molecular-weight proteins involved in communication between cells. Their purpose is to induce or regulate a variety of immune or inflammatory responses. However, disorders may occur if cytokine production or regulation is impaired. Cytokines are categorized as follows:
❑ Colony-stimulating factors function primarily as hematopoietic growth factors, guiding the division and differentiation of bone marrow stem cells. They also influence the functioning of mature lymphocytes, monocytes, macrophages, and neutrophils.
❑ Interferons act early to limit the spread of viral infections. They also inhibit tumor growth. Mainly, they determine how well tissue cells interact with cytotoxic cells and lymphocytes.
❑ Interleukins are a large group of cytokines. (Those produced primarily by T lymphocytes are called lymphokines. Those produced by mononuclear phagocytes are called monokines.) They have a variety of effects, but most direct other cells to divide and differentiate.
❑ Tumor necrosis factors are believed to play a major role in mediating inflammation and cytotoxic reactions (along with IL-1, IL-6, and IL-8).
❑ Transforming growth factor demonstrates both inflammatory and anti-inflammatory effects. It’s believed to be partially responsible for tissue fibrosis associated with many diseases. It demonstrates immunosuppressive effects on T cells, B cells, and NK cells.
The chief humoral effector of the inflammatory response, the complement system consists of more than 20 serum proteins. When activated, these proteins interact in a cascadelike process that has profound biological effects. Complement activation takes place through one of two pathways. In the classical pathway, binding of IgM or IgG and antigen forms antigen-antibody complexes that activate the first complement component, C1. This, in turn, activates C4, C2, and C3. In the alternate pathway, activating surfaces such as bacterial membranes directly amplify spontaneous cleavage of C3. Once C3 is activated in either pathway, activation of the terminal components — C5 to C9 — follows.
The major biological effects of complement activation include phagocyte attraction (chemotaxis) and activation, histamine release, viral neutralization, promotion of phagocytosis by opsonization, and lysis of cells and bacteria. Other mediators of inflammation derived from the kinin and coagulation pathways interact with the complement system.
Besides macrophages and complement, other key participants in the inflammatory response are the polymorphonuclear leukocytes (also known as granulocytes) — neutrophils, eosinophils, and basophils.
Neutrophils, the most numerous of these cells, derive from bone marrow and increase dramatically in number in response to infection and inflammation. Highly mobile cells, neutrophils are attracted to areas of inflammation (chemotaxis); in fact, they’re the primary constituent of pus.
Neutrophils have surface receptors for immunoglobulin and complement fragments, and they avidly ingest opsonized particles such as bacteria. Ingested organisms are then promptly killed by toxic oxygen metabolites and enzymes such as lysozyme. Unfortunately, neutrophils not only kill invading organisms but may also damage host tissues.
Also derived from bone marrow, eosinophils multiply in both allergic disorders and parasitic infestations. Although their phagocytic function isn’t clearly understood, evidence suggests that they participate in host defense against parasites. Their products may also diminish the inflammatory response in allergic disorders.
Two other types of cells that function in allergic disorders are basophils and mast cells. (Mast cells, however, aren’t blood cells.) Basophils circulate in peripheral blood, whereas mast cells accumulate in connective tissue, particularly in the lungs, intestines, and skin. Both types of cells have surface receptors for IgE. When cross-linked by an IgE-antigen complex, they release mediators characteristic of the allergic response.
Because of their complexity, the processes involved in host defense and immune response may malfunction. When the body’s defenses are exaggerated, misdirected, or either absent or depressed, the result may be a hypersensitivity disorder, autoimmunity, or immunodeficiency, respectively.
An exaggerated or inappropriate immune response may lead to various hypersensitivity disorders. Such disorders are classified as type I through type IV, although some overlap exists. (See Classification of hypersensitivity reactions, pages 346 and 347.)
In individuals with type I hypersensitivity, certain antigens (allergens) activate T cells. These, in turn, induce B-cell production of IgE, which binds to the Fc receptors on the surface of mast cells. When these cells are re-exposed to the same antigen, the antigen binds with the surface IgE, cross-links the Fc receptors, and causes mast cell degranulation with release of various mediators. (Degranulation may also be triggered by complement-derived anaphylatoxins — C3a and C5a — or by certain drugs such as morphine.)
Some of these mediators are preformed, whereas others are newly synthesized upon activation of mast cells. Preformed mediators include heparin, histamine, proteolytic and other enzymes, and chemotactic factors for eosinophils and neutrophils. Newly synthesized mediators include prostaglandins and leukotrienes. Mast cells also produce a variety of cytokines. The effects of these mediators include smooth-muscle contraction, vasodilation, bronchospasm, edema, increased vascular permeability, mucus secretion, and cellular infiltration by eosinophils and neutrophils. Among classic associated signs and symptoms are hypotension, wheezing, swelling, urticaria, and rhinorrhea.
Examples of type I hypersensitivity disorders are anaphylaxis, atopy (an allergic reaction related to genetic predisposition), hay fever (allergic rhinitis) and, in some cases, asthma.
In type II hypersensitivity, antibody is directed against cell surface antigens. (Alternately, though, antibody may be directed against small molecules adsorbed to cells or against cell surface receptors rather than against cell constituents themselves.) Type II hypersensitivity then causes tissue damage through several mechanisms. Binding of antigen and antibody activates complement, which ultimately disrupts cellular membranes.
Another mechanism is mediated by various phagocytic cells with receptors for immunoglobulin (Fc region) and complement fragments. These cells envelop and destroy (phagocytose) opsonized targets, such as red blood cells, leukocytes, and platelets. Antibody against these cells may be visualized by immunofluorescence. Cytotoxic T cells and NK cells also contribute to tissue damage in type II hypersensitivity.
Examples of type II hypersensitivity include transfusion reactions, hemolytic disease of the neonate, autoimmune hemolytic anemia, Goodpasture’s syndrome, and myasthenia gravis.
In type III hypersensitivity, excessive circulating antigen-antibody complexes (immune complexes) result in the deposition of these complexes in tissue — most commonly in the kidneys, joints, skin, and blood vessels. (Normally, immune complexes are effectively cleared by the reticuloendothelial system.) These deposited immune complexes activate the complement cascade, resulting in local inflammation. They also trigger platelet release of vasoactive amines that increase vascular permeability, augmenting deposition of immune complexes in vessel walls.
Type III hypersensitivity may be associated with infections, such as hepatitis B and bacterial endocarditis; certain cancers in which a serum sickness-like syndrome may occur; and autoimmune disorders such as lupus erythematosus. This hypersensitivity reaction may also follow drug or serum therapy.
In type IV hypersensitivity, antigen is processed by macrophages and presented to T cells. The sensitized T cells then release lymphokines, which recruit and activate other lymphocytes, monocytes, macrophages, and polymorphonuclear leukocytes. The coagulation, kinin, and complement pathways also contribute to tissue damage in this type of reaction.
Examples of type IV hypersensitivity include tuberculin reactions, contact hypersensitivity, and sarcoidosis.
Autoimmunity is characterized by a misdirected immune response in which the body’s defenses become self-destructive. Autoimmune diseases aren’t transmitted from one person to another, and the causes of autoimmunity aren’t clearly understood. However, the process of autoimmunity is related to genes or a combination of genes, hormones, and environmental stimuli. Individuals with specific genes or gene combinations may be at a higher risk for developing autoimmune disorders, which may be triggered by outside stimuli, such as sun exposure, infection, drugs, or pregnancy.
Recognition of self through the MHC is of primary importance in an immune response. However, how an immune response against self is prevented and which cells are primarily responsible isn’t well understood.
Many autoimmune disorders are characterized by B-cell hyperactivity, marked by proliferation of B cells and autoantibodies and by hypergammaglobulinemia. B-cell hyperactivity is probably related to T-cell abnormalities, but the molecular basis of autoimmunity is poorly understood. Hormonal and genetic factors strongly influence the incidence of autoimmune disorders; for example, lupus erythematosus predominantly affects females of childbearing age, and certain HLA haplotypes are associated with an increased risk of specific autoimmune disorders.
Autoimmune diseases may not follow a clear pattern of symptoms; therefore, a definitive diagnosis may be delayed. Diagnosis may rely on the patient’s medical history; family history; physical examination, including signs and symptoms; and laboratory tests. Autoantibodies are usually found with such disorders as rheumatoid arthritis or systemic lupus erythematosus, but confusion may occur because individuals with these disorders may have false negative results to laboratory tests.
Treatment for autoimmune disorders focuses on relieving symptoms, preserving organ function, and providing medication that can target the immune system, such as cyclophosphamide and cyclosporine. Autoimmune and immunological disorders are being researched. Web sites for the National Institutes of Health (www.nih.gov) and other organizations offer substantial health care information relevant to both the patient and the physician.
In immunodeficiency, the immune response is absent or depressed, resulting in increased susceptibility to infection. This disorder may be primary or secondary. Primary immunodeficiency reflects a defect involving T cells, B cells, or lymphoid tissues. The National Primary Immunodeficiency Resource Center is a source of information on primary immunodeficiency syndromes.
Secondary immunodeficiency results from an underlying disease or factor that depresses or blocks the immune response. The most common forms of immunodeficiency are caused by viral infection (as in acquired immunodeficiency syndrome). Other forms are iatrogenic. (See Iatrogenic immunodeficiency, pages 348 and 349.)
Review other book chapters online related to Autoimmune uveitis:
Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: Professional Guide to Diseases (Eighth Edition) Authors: Springhouse Publisher: Lippincott Williams & Wilkins Copyright: 2005 ISBN: 1-58255-370-X 
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