Basic immunology

Historically, the immune system was divided into two basic branches: humoral immunity and cellular immunity. In fact, the immune response is an active interplay of both humoral and cellular immunity, along with cytokines (Table 10-1) made by a multitude of cells including lymphocytes, Langerhans' cells, macrophages, and keratinocytes.

Table For Basic Immunology
Table 10-1 T-Cell Cytokines

Humoral Immunity

Humoral immunity is mediated by antibodies produced by B lymphocytes. When activated by antigen, antigen-presenting cells, and helper T lymphocytes, the B lymphocytes differentiate into plasma cells, which produce antibodies. Antibodies can specifically bind their appropriate antigen with high affinity. These antibodies can be divided into five classes: immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin D (IgD), and immunoglobulin E (IgE, reagin). IgA is the principal antibody secreted at mucosal surfaces. These antibodies, with varying degrees of efficiency, can fix (activate) complement (IgG, IgM), aid macrophages in cytotoxicity or cell killing and phagocytosis (IgG), and trigger release of immunoreactive substances from mast cells (IgE).

Complement System

The complement system is a complex set of proteins that, when activated, can lyse cells and aid in phagocytosis by macrophages, cause mast cells to release histamines, and be chemotactic for neutrophils. Activation of complement occurs as a cascade of factors, resulting in amplification. Complement can be activated by antibodies and immune complexes through the classic pathway. The sequence of activation of factors in the classic complement pathway is C1qrs, C2, C4, C3, C5, C6, C7, C8, C9. Complement can also be activated by bacteria, fungi, and endotoxins through the alternate pathway by activation of properdin. This results in cleavage and activation of C3. C5a is produced by cleavage of C5 during activation and is an "anaphylatoxin" that induces histamine release, vascular permeability, and chemotaxis of inflammatory cells. The final components of complement form a complex (C5b6789) that can lyse cells.

Cellular Immunity

Cellular immunity involves T lymphocytes (T cells), antigen-presenting cells, and natural killer (NK) cells. T cells are subdivided into CD4+ and CD8+ cells. The CD4+ T cells act as helper cells both in the production of antibodies and CD8+ T-cell responses. CD8+ T cells can kill target cells with specific antigens (cytotoxicity). CD8+ T cells may also suppress immune responses (suppressor cells). Both CD4+ and CD8+ T-cells produce hormones termed interleukins, which mediate many of their effects. CD4+ cells generally produce greater amounts of those interleukins that promote T-cell proliferation, and B-cell antibody production, hence providing help. Production of antibodies by B cells is generally dependent upon such help from T cells. Therefore, the separation of immune responses into humoral and cellular is artificial.

Antigen Presentation

T cells cannot see antigen without the aid of antigen-presenting cells. Antigen-presenting cells include macrophages and dendritic antigen-presenting cells, such as the Langerhans' cells of the skin. Langerhans' cells are the primary antigen-presenting cell of the epidermis and are central to epidermal T cell-mediated reactions such as allergic contact dermatitis. Presentation of antigens to T cells generally requires that protein antigens are first degraded to peptides and presented by special antigen-presenting molecules. Antigens that derive from inside the cells are generally presented on major histocompatibility complex (MHC) class I molecules ( e.g., HLA-A, B, C), to CD8+ T cells. Examples of internal antigens are viral antigens, tumor-associated antigens, and transplantation antigens. CD8+ cyto-toxic cells are thus positioned to recognize and kill these cells.

Extracellular antigens are phagocytosed by the antigen presenting cells and presented on MHC class II molecules ( e.g. HLA-DR, DP, DQ) to CD4+ T cells. Examples of extracellular antigens are bacteria, toxins, and vaccines. The CD4+ cells are thus positioned to help in the production of antibodies to these proteins.

Interleukins, Interferons, and Cytokines

Many of the effects of T cells are mediated by hormones that go by the names of cytokines (IabJ.e...,..1..,0.-.1), interleukins, or interferons. Interleukin 2 (IL-2) is the principal growth factor of T cells. Production of IL-2 by CD4+ cells is closely regulated and is one of the major controls in the immune response. Cytokines are divided into TH1 cytokines, which promote cellular immunity, and TH2 cytokines, which promote antibody production, especially IgE. Both TH1 and TH2 cytokines are made by CD4+ cells, which may differentiate into TH1 and TH2 CD4+ cells. Classic TH1 cytokines are interferon-g, interleukin 2 (IL-2), and tumor necrosis factor-a. TH2 cytokines include IL-4, IL-5, and IL-10.

immunity and Skin Disease

Response to an antigen (either foreign or self) is divided into four types according to the Gel and Coombs classification. Type I is anaphylaxis or immediate hypersensitivity, which is an IgE-mediated response. Type II involves binding antibodies to cell membranes. Type III is mediated by circulating immune complexes that fix complement to induce inflammation. Type IV is cell-mediated or delayed hypersensitivity. Although this classification is useful, many conditions are a combination of these types.

immune-mediated skin conditions

ATOPIC DISEASE AND ATOPIC ECZEMA Atopic conditions include asthma, allergic rhinitis, urticaria, and atopic dermatitis. These conditions are generally associated with elevated serum IgE levels and serum IgE responses to allergens. The role of IgE and exogenous antigens in atopic dermatitis is extremely controversial (see Chap 9). Candidate antigens include food, animal dander, inhalants, Staphylococcus aureus, and house dust mite. Atopic diseases are believed to result from a predominance of TH2 CD4+ immune responses. TH2 T cells produce cytokines (e.g., IL-4, IL-5) which favor the production of IgE.

ALLERGIC CONTACT DERMATITIS. Poison ivy is the prototypic allergic contact dermatitis. It is mediated by T-cell recognition of a small chemical (hapten) or allergen that is bound to protein and presented by epidermal Langerhans' cells. Both CD4+ and CD8+ T cells can have a role in the inflammation. Allergic contact dermatitis often presents with a linear or asymmetric distribution, matching exposure to the inciting hapten. Patch tests are used clinically to discover the cause of allergic contact dermatitis.

DRUG ERUPTIONS. Recognition of drugs by the immune system generally requires that the small chemical entities bind to protein and act as a hapten, or directly to MHC molecules. Drug eruptions take many forms, some of which are immune-mediated. Urticarial or anaphylactic reactions can be medicated by IgE degranulation of mast cells. Vasculitic reactions (e.g., palpable purpura) and serum sickness result from deposition of immune complexes and complement in vessels. There is evidence suggesting that morbilliform and bullous (blistering) drug reactions may be mediated by T lymphocytes.

ERYTHEMA MULTIFORME AND TOXIC EPIDERMAL NECROLYSIS Erythema multiforme is a severe bullous eruption, marked by necrosis of the full thickness of the epidermis. When involving more than 30% of body surface, it is called toxic epidermal necrolysis. Toxic epidermal necrolysis has a significant mortality rate. Erythema multiforme involving mucous membranes and systemic toxicity is also called Stevens Johnson syndrome. These conditions may be a continuous spectrum. It is proposed that they are mediated by T lymphocytes. Mild, recurrent erythema multiforme may result from recurrent herpes simplex infection. Severe forms are generally drug reactions.

URTICARIA. The classic type I or immediate hypersensitivity reaction can cause urticaria and also the true systemic anaphylactoid reactions, which can include bronchospasm with asthma-like reactions, laryngeal edema, convulsions, nausea, diarrhea, hypotension, and in its most exaggerated state, shock. Allergic urticaria results from IgE-mediated degranulation of mast cells.

cutaneous autoimmune conditions

AUTOIMMUNE BULLOUS ERUPTIONS. Autoantibodies against epidermal adhesion molecules can induce blisters that correspond histologically to the site of the autoantigen. Pemphigus vulgaris results from IgG directed against desmoglein III, which is associated with desmosomes. The IgG is deposited between epidermal cells and stains in an intercellular pattern on immunofluorescence. Blisters form within the epidermis of skin and mucosa. Pemphigus is a classic Gel and Coombs type II reaction, and transfer of pemphigus IgG to neonatal mice induces similar blisters and immunofluorescent findings. In contrast, bullous pemphigoid is associated with IgG against proteins associated with hemidesmosomes. Immunofluorescence shows a linear band of IgG at the dermal-epidermal junction. The blisters are below the epidermis, through the lamina lucida of the basement membrane. Autoantibodies in epidermolysis bullosa acquisita are directed against type VII collagen, which is present in the anchoring filaments below the basement membrane. Blisters are below the basement membrane, which results in scarring. Dermatitis herpetiformis differs in that immune complexes containing IgA are deposited in the dermal papillae. This is associated with micropustules of neutrophils and clefts below the epidermis, resulting in extremely pruritic grouped vesicles. Table 10-2 contains a partial list of autoimmune blistering diseases, which are also discussed in Chapter 22..

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Table 10-2 Bullous Skin Diseases Associated With Autoimmunity*

ALOPECIA AREATA. This condition results in loss of hair in circular patches. It may extend to the entire scalp or all body hair. Histology demonstrates an infiltrate of T cells around affected hair follicles. Both autoantibodies and autoreactive T cells have been demonstrated. It is possible to transfer alopecia areata to human scalp on immunosuppressed mice by injection of T cells.

VITILIGO. The primary defect in vitiligo is the absence of melanocytes from affected skin. This is associated with autoantibodies against melanocyte antigens.

PSORIASIS. This condition is marked by increased proliferation of epidermal keratinocytes, associated with an infiltrate of neutrophils and lymphocytes. T-lymphocyte functions are necessary to induce and maintain psoriasis lesions. Psoriasis responds to a variety of immunosuppressive treatments, including fusion toxins that specifically target only T cells. It is also possible to induce psoriasis in human skin grafted onto immunodeficient mice by transferring T cells. Bacterial superantigens, which activate T cells, may have a role in flaring psoriasis.

CONNECTIVE TISSUE DISEASE. A final division of autoimmune disease is the connective tissue or collagen vascular diseases (Tibie 1.0.-3.). These include lupus erythematosus, scleroderma, and dermatomyositis. Most of these diseases are associated with autoantibodies, including antinuclear antibodies. Clinical presentation, serology, and histology are used to classify the disorders. Overlap syndromes combining one or more of these illnesses are common.

Antibody Table Dermatomyositis

Table 10-3 Autoimmune Connective Tissue Diseases in the Skin

VASCULITIS. The types of vasculitis are listed in Table 10.-4. The immune response in vasculitis is thought to be type III or immune complex disease, and this can be demonstrated by complement and immunoglobulins in vessel walls as circulating serum immune complexes. The most common clinical manifestation of all these diseases is palpable purpura, but other manifestations can include urticarial lesions, gangrene, and ischemic ulcers.

Nysphsaa Skin Disease Form

Table 10-4 Types of Vasculitis: Immune and Clinical Responses

GRAFT-VERSUS-HOST DISEASE (GVH). This condition results from transplanted T cells attacking the recipient. Target organs are skin, gut, and liver. It is manifested as a sunburn type rash, diarrhea, and elevated liver enzymes. The requirements for GVH are transferred T cells capable of attacking the host as foreign and an inability of the host to eliminate the hostile T cells. The most common setting for GVH is bone marrow transplantation, but transfusion of immunosuppressed patients with blood that has not been irradiated can have the same result. The rash of GVH can vary from macular erythema to epidermal necrosis and death.

skin disease associated with immunodeficiency

Immunodeficiency can be acquired, as in AIDS (see Chap 18) or other viral infections, or genetic. Genetic immune defects can selectively target antibody production

(e.g., agammaglobulinemias), or T-lymphocyte function (e.g., ataxia telangiectasia). Other immunodeficiencies can alter neutrophil chemotaxis, lysosomal function, or oxidative burst. Genetic deficiencies of complement components can inhibit resistance to encapsulated bacteria ( e.g., C3 deficiency) or predispose to autoimmune disease (e.g., C4). Deficiency of antibody production is correlated with infection with encapsulated bacteria, whereas deficiency of T-cell function results in viral infections. Severe combined immunodeficiency results in defects in both antibody and T-cell mediated immunity. (See Tab.Je,.1Q:5 for a list of skin diseases associated with immunodeficiency.)

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Table 10-5 Skin Diseases Associated With Immunodeficiency immunomodulation of skin disease

Most inflammatory skin disease responds to topical or systemic corticosteroids. However, long-term use of corticosteroids has significant toxicity and there are multiple nonsteroidal immunosuppressive agents used in dermatology. "Steroid sparing" agents used in the treatment of autoimmune bullous diseases include azathioprine, cyclophosphamide, dapsone, gold, and methotrexate. Immunosuppressive agents useful for psoriasis include cyclosporine A, hydroxyurea, mycophenolate mofetil, and methotrexate. Phototherapy with UVB, or psoralen plus UVA, has immunosuppressive effects. Antimalarials (e.g., hydroxychloroquine) are useful for connective tissue disease. Additional immunomodulatory therapies used in dermatology include extracoporeal photophoresis, interferons, interferon inducers, and topical nitrogen mustard. Nonsteroidal antiinflammatory agents under investigation for skin conditions include FK506 and related compounds that can have topical activity. With the use of molecular biology it has been possible to create molecules that specifically target T cells, cytokines, or antigen-presentation molecules. Several such designer molecules have show efficacy in phase I trails for psoriasis. The future promises increasingly sophisticated nonsteroidal antiinflammatory therapies.

*Associate Professor, Department of Dermatology, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York BIBLIOGRAPHY

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Del Prete G. The concept of type-1 and type-2 helper T-cells and their cytokines in humans. Int Rev Immunol 1998;16:427.

Dahl MV. Clinical immunodermatology, ed 3. New York, Mosby, 1996.

Fine JD. Management of acquired bullous skin diseases. N Engl J Med 1995;333:22.

Jennette CJ, Milling DM, Falk RJ. Vasculitis affecting the skin: A review [editorial]. Arch Dermatol 1994;13Q:899.

Johnson ML, Farmer ER. Graft-versus-host reactions in dermatology. J Am Acad Dermatol 1998;38:3.

Jordon RE. Immunologic diseases of the skin. East Norwalk, CT, Appleton & Lange, 199Q.

Kalish RS. Drug eruptions: A review of clinical and immunologic features. Adv Dermatol 1991;6:221.

Kalish RS. Antigen processing: The gateway to the immune response [review]. J Am Acad Dermatol 1995;32:64Q.

Kondo S, Sauder DN. Epidermal cytokines in allergic contact dermatitis. J Am Acad Dermatol 1995;33:786.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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