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 cells), 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 lymphocytes, or 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 391.) 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 (IFN) gamma, 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, page 392.) 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.

T lymphocytes, or T cells, 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 depends on the 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 gene. Helper T cells require class II HLA genes; cytotoxic T cells require class I HLA genes. 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 lymphocytes. 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 gene. 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:

The chief humoral effector of the inflammatory response, the complement system consists of more than 20 serum proteins that are synthesized primarily in the liver. 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 alternative 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. Some forms of immunodeficiency are iatrogenic. (See Iatrogenic immunodeficiency.)

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 396 and 397.)

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.

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 on 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 immunologic 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).

Asthma is a lung disease characterized by reversible obstruction or narrowing of the airways, which are typically inflamed and hyperresponsive to a variety of stimuli. It may resolve spontaneously or with treatment. Its symptoms range from mild wheezing and dyspnea to life-threatening respiratory failure. (See Determining asthma’s severity.) Symptoms of bronchial airway obstruction may persist between acute episodes.

Allergic rhinitis is a reaction to airborne (inhaled) allergens. Depending on the allergen, the resulting rhinitis and conjunctivitis may occur seasonally (hay fever) or year-round (perennial allergic rhinitis).

Atopic dermatitis is a chronic type I immediate hypersensitivity skin disorder that’s characterized by superficial skin inflammation and intense itching. Although this disorder may appear at any age, it typically begins during infancy or early childhood. It may then subside spontaneously, followed by exacerbations in late childhood, adolescence, or early adulthood. Atopic dermatitis affects 2.5% of the population.

Latex is a substance found in an increasing number of products both on the job and in the home environment. Latex allergy is a hypersensitivity reaction to products that contain natural latex, which is derived from the sap of a rubber tree, not synthetic latex. There are two types of latex allergy. A type I hypersensitivity reaction involves mast cells releasing histamine and other secretory products. This leads to vasodilation and bronchoconstriction. A type IV delayed hypersensitivity reaction occurs as a reaction to chemicals involved in processing rather than to the latex itself. Sensitized T lymphocytes are triggered, which cause other lymphocytes and mononuclear cells to proliferate, resulting in tissue inflammation.

Anaphylaxis is a dramatic, acute atopic reaction marked by the sudden onset of rapidly progressive urticaria and respiratory distress. A severe reaction may precipitate vascular collapse, leading to systemic shock and, sometimes, death.

The source of anaphylactic reactions is ingestion of or other systemic exposure to sensitizing drugs or other substances. Such substances may include animal serums, vaccines, allergen extracts, enzymes (L-asparaginase), hormones, penicillin and other antibiotics, sulfonamides, local anesthetics, salicylates, polysaccharides, diagnostic chemicals (sulfobromophthalein, sodium dehydrocholate, and radiographic contrast media), foods (especially legumes, nuts, berries, seafood, and egg albumin) and sulfitecontaining food additives, insect venom (honeybees, wasps, hornets, yellow jackets, Are ants, mosquitoes, and certain spiders) and, rarely, ruptured hydatid cyst.

A common cause of anaphylaxis is penicillin, which induces anaphylaxis in 1 to 4 of every 10,000 patients treated with it. Penicillin is most likely to induce anaphylaxis after parenteral administration or prolonged therapy and in atopic patients with an allergy to other drugs or foods. (See Preventing allergic response to penicillin, page 406) An anaphylactic reaction requires previous sensitization or exposure to the specific antigen, resulting in the production of specific immunoglobulin (lg) E antibodies by plasma cells. This antibody production takes place in the lymph nodes and is enhanced by helper T cells. IgE antibodies then bind to membrane receptors on mast cells (found throughout connective tissue) and basophils.

On re-exposure, the antigen binds to adjacent IgE antibodies or cross-linked IgE receptors, activating a series of cellular reactions that trigger degranulation—the release of powerful chemical mediators (such as histamine and eosinophil chemotactic factor of anaphylaxis) from mast cell stores. IgG or IgM enters into the reaction and activates the release of complement fractions.

At the same time, two other chemical mediators, bradykinin and leukotrienes, induce vascular collapse by stimulating contraction of certain groups of smooth muscles and by increasing vascular permeability. In turn, increased vascular permeability leads to decreased peripheral resistance and plasma leakage from the circulation to extravascular tissues, which lowers blood volume, causing hypotension, hypovolemic shock, and cardiac dysfunction. (See Understanding anaphylaxis.)

Urticaria, commonly known as hives, is an episodic, usually self-limited skin reaction characterized by local dermal wheals surrounded by an erythematous flare. Angioedema is a subcutaneous and dermal eruption that produces deeper, larger wheals (usually on the hands, feet, lips, genitals, and eyelids) and a more diffuse swelling of loose subcutaneous tissue. Urticaria and angioedema can occur simultaneously, but angioedema may last longer.

Diagnosis also requires physical assessment to rule out similar conditions as well as a complete blood count, urinalysis, erythrocyte sedimentation rate, and a chest X-ray to rule out inflammatory infections. Skin testing, an elimination diet, and a food diary (recording time and amount of food eaten and circumstances) can pinpoint provoking allergens. The food diary may also suggest other allergies. For instance, a patient allergic to fish may also be allergic to iodine contrast materials.

Recurrent angioedema without urticaria, along with a familial history, points to hereditary angioedema. (See Hereditary angioedema.) Decreased serum levels of complement 4 and complement 1 esterase inhibitors confirm this diagnosis.

Mediated by immune or nonimmune factors, a transfusion reaction accompanies or follows I.V. administration of blood components. Its severity varies from mild (fever and chills) to severe (acute renal failure or complete vascular collapse and death), depending on the amount of blood transfused, the type of reaction, and the patient’s general health.