Immune-Mediated Tissue Injury (Hypersensitivity Reactions)
Hypersensitivity is synonymous with immune-mediated tissue injury. Hypersensitivity reactions occur in several forms and give rise to numerous conditions including allergies, autoimmune disease, allograft rejection, granulomatous inflammation, and a variety of acute or chronic inflammatory disorders (vasculitis, glomerulonephritis, arthritis, pneumonitis, encephalitis, etc.). While hypersensitivity is usually detrimental, in some cases it represents a normal response to a pathogen (e.g., the granulomatous inflammation of tuberculosis).
Several years ago, Gell and Coombs divided hypersensitivity states into four basic types (1), and this classification remains useful today (Table 1). Type I hypersensitivity reactions result from IgE-dependent degranulation of mast cells or basophils. Type II, or "cytotoxic" hypersensitivity, results from the binding of IgG or IgM antibodies to cell membranes or fixed tissue antigens, causing activation of the complement system. Type III, or "immune-complex" hypersensitivity, results from the formation of immune complexes that precipitate in tissues (or form in situ), also with activation of complement. Type IV, or "cell-mediated" reactions, can be subdivided into two basic types: type IV-A is synonymous with delayed-type hypersensitivity (DTH) and usually occurs in response to soluble antigens; type IV-B results from the direct killing of target cells by cytotoxic T lymphocytes (CTL). Stimulation of cells by anti-receptor autoantibodies (such as the anti-TSH receptor antibodies of Graves' disease) has been designated as type V hypersensitivity by some authors. In addition, there are syndromes caused by massive cytokine release that are not usually referred to as hypersensitivity reactions, although (in accord with the definition) they should be included in that category. Examples are anti-CD3 mAb therapy, superantigen- (superAg) induced diseases (toxic shock syndrome, scalded skin syndrome), and shock caused by endotoxins (gram negative septicemia).
Despite the occurrence of tissue injury, it should be understood that hypersensitivity mechanisms evolved as a means of fighting infectious agents. The mechanisms underlying these hypersensitivity states will be described and some clinical examples will be mentioned. In particular, the important role of cytokines, which is an area where considerable progress has occurred in recent years, will be emphasized.
- Coombs RRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell PGH, Coombs RRA, Lachmann PJ, editors. Clinical Aspects of Immunology, 3rd ed. Oxford: Blackwell Scientific, 1975:761-781.
- Sutton BJ, Gould HJ. The human IgE network. Nature 1993;366:421-428.
- Plaut M, Zimmerman EM. Allergy and mechanisms of hypersensitivity. In: Paul WE, editor. Fundamental Immunology. New York: Raven Press, 1993:1399-1425.
- Lictenstein LM. Allergy and immune system. Scientific American 1993;269:117-124.
- Borish L, Joseph B. Inflammation and allergic response. Medical Clinics of North America 1992;76:765- 776.
- Bochner BS, Undern BJ, Lichtenstein LM. Immunological aspects of allergic asthma. Annual Review of Immunology 1994;12:295-335.
- Beasley CR, Robinson C, Featherstone RL, et al. 9-alpha, 11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways. Journal of Clinical Investigation 1987;79:978-983.
- Kniker WT. Anaphylaxis in children and adults. In:Bierman CW, Pearlman DS, editors. Allergic Diseases from Infancy to Adulthood. Philadelphia: WB Saunders Co., 1988:667-677.
- Frew AJ, Kay AB. Eosinophils and T-lymphocytes in late-phase allergic reactions. Journal of Allergy and Clinical Immunology 1990;85:533-539.
- Sparholt SH, Georgsen J, Madsen HO, Svendsen UG, Schou C. Association between HLA-DRB3 0101 and immunoglobulin-E responsiveness to Bet v I. Human Immunology 1994;39:76-78.
- Male D. Hypersensitivity-type II. In: Roitt I, Brostoff J, Male D, editors. Immunology. St. Louis: The C.V. Mosby Co., 1994.
- Bruijn JA, Hoedemaeker PJ, Fleuren GJ. Pathogenesis of anti-basement membrane glomerulopathy and immune complex glomerulonephritis: dichotomy dissolved. Laboratory Investigation 1989;61:480-488.
- Muller-Eberhard HJ. Molecular organization and function of the complement system. Annual Review of Biochemistry1988;57:321-347.
- DeBaets MH, Vincent A. Myasthenia gravis. In: Bona CA, Siminovitch KA, Zanetti M, Theofilopoulos AN, editors. The Molecular Pathology of Autoimmune Diseases. Switzerland: Harwood Academic Publishers, 1993:543-553.
- Theofilopoulos AN. Immune complexes in autoimmunity. In: Bona CA, Siminovitch KA, Zanetti M, Theofilopoulos AN, editors. The Molecular Pathology of Autoimmune Diseases. Switzerland: Harwood Academic Publishers, 1993:229-244.
- Barbanel C, Noel L-H. Membranous glomerulonephritis. In: Hamberger J, Crosnier J, Grunfeld J-P, editors. Nephrology. New York: John Wiley & Sons, 1979:489-505.
- Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology 1986;136:2348-2357.
- Romagnani S. Lymphokine production by human T cells in disease states. Annual Review of Immunology 1994;12:227-257.
- Del Prete G, Maggi E, Romagnani S. Human Th1 and Th2 cells: functional properties, mechanisms of regulation and role in disease. Laboraory Investigation 1994;70:299-306.
- De Maeyer E, De Maeyer-Guignard J. Interferons. In: Thomson E, editor. The Cytokine Handbook. London: Academic Press, 1994:265-288.
- Mosman TR. T lymphocyte subsets, cytokines and effector functions. Annals of the New York Academy of Sciences 1992;664:89-92.
- Sadick MO, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T-cell dependent, interferon-gamma independent mechanism. Journal of Experimental Medicine 1990;171:115-127.
- Scott P, Pearce E, Cheever AW, Coffman RL, Sher A. Role of cytokines and CD4+ T-cell subsets in the regulation of parasite immunity and disease. Immunology Review 1989;112:161-182.
- Heinzel FP, Schoenhant DS, Rerko RM, Rossea LE, Gately MK. Recombinant interleukin 12 cures mice infected with Leishmania major. Journal of Experimental Medicine 1993;177:1505-1510.
- Del Pret GF, De Carli M, Mastromauro C, et al. Purified protein-derivative of mycobacterium tuberculosis and excretory-secretory antigen(s) of toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. Journal of Clinical Investigation 1991;88:346-350.
- Robinson DS, Hamid Q, Ying S, et al. Predominant Th2-like bronchoalveolar T-lymphocyte population in atopic asthma. New England Journal of Medicine 1992;326:298-304.
- Broide DH, Lotz M, Cuomo AJ, Coburn DA, Federman EC, Wasserman ST. Cytokines in symptomatic asthma airways. Journal of Allergy and Clinical Immunology 1992;89:958-967.
- Salgame P, Yamamura M, Bloom BR, Modlin RL. Evidence for functional subsets of CD4+ and CD8+ T cells in human disease: lymphokine patterns in leprosy. Chemical Immunology 1992;54:44-59.
- Ju ST, Cui H, Panka DJ, Ettinger R, Marshak-Rothstein A. Participation of target Fas protein in apoptosis
- pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells. Proceedings of the National Academy of Sciences of the United States of America 1994;91:4185-4189.
- Ruddle NH. Tumour necrosis factor-beta, lymphotoxin-alpha. In: Thomson A, editor. The Cytokine Handbook. London: Academic Press, 1994:305-318.
- O'Garra A, Murphy K. Role of cytokines in determining T lymphocyte function. Current Opinion in Immunology 1994;6:458-466.
- Biron CA. Cytokines in the generation of immune responses to, and resolution of, virus infection. Current Opinion in Immunology 1994;6:530-538.
- Naume B, Espevik T. Immunoregulatory effects of cytokines on natural killer cells. Scandinavian Journal of Immunology 1994;40:128-134.
- Swartz LB. Mast cells: function and contents. Current Opinion of Immunology 1994;6:91-97.
- Ferrick DA, Schrenzel MD, Mulvania T, Hsieh B, Ferlin WG, Lepper H. Differential production of interferon-gamma and interleukin-4 in response to Th1- and Th2-stimulating pathogens by *gamma T cells in vivo. Nature 1995;373:255-257.
- Pretolani M, Vargaftig BB. Cytokines-eosinophil interactions in experimental allergy. Annals of the New York Academy of Sciences 1994;725:247-258.
- Moqbel R. Eosinophils, cytokines, and allergic inflammation. Annals of the New York Academy of Sciences 1994;725:223-233.
- Leung DYM, Martin RJ, Szefler SJ, et al. Dysregulation in interleukin 4, interleukin 5 and interferon gamma gene expression in steroid-resistant asthma. Journal of Experimental Medicine 1995;181:33-40.
- Bloom BR, Modlin RL, Salgame P. Stigma variations: Observations on suppressor T cells and leprosy. Annual Review of Immunology 1992;10:453-488.
- Salgame P, Abrams JS, Clayberger C, Goldstein H, Modlin RL, Bloom BR. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T-cell clones. Science 1991;254:279-281.
- Sher A, Coffman RL. Regulation of immunity to parasites by T cells and T-cell derived cytokines. Annual Review of Immunology 1992;10:385-409.
- Prud'homme GJ, Kono DH, Theofilopoulos AN. Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1ß, interleukin-10, and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. Molecular Immunology. In press.
- Al-Janadi M, Al-Balla S, Al-Dollan A, Raziuddin S. Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases. Journal of Clinical Immunology 1993;13:58-67.
- Linker-Israeli M. Cytokine abnormalities in human lupus. Clinical Immunology and Immunopathology 1992;63:10-12.
- Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunology Today 1995;16:34-38.
- Olsson T. Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma. Journal of Neuroimmunology 1992;40:211-218.
- Khoury SJ, Hancock WW, Weiner HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines. Journal of Experimental Medicine 1992;176:1355-1364.
- Kennedy MK, Torrance DS, Picha KS, Mohler KM. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental allergic encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. Journal of Immunology 1992;149:2496-2505.
- Rabinovitch A. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention or immunostimulation? Diabetes 1994;43:613-621.
- Ferran C, Bach JF, Chatenoud L. In vivo T cell activation properties of anti-T cell monoclonal antibodies. Experimental Nephrology 1993;1:83-89.
- Chatenoud L. OKT3-induced cytokine-release syndrome: prevention effect of anti-tumor necrosis factor monoclonal antibody. Transplantation Proceedings 1993;1(25 Suppl):47-51.
- Kotzin, BL, Leung DY, Kappler J, Marrack P. Superantigens and their potential role in human disease. Advances in Immunology 1993;54:99-166.
- Kotzin BL. Superantigens and their role in disease. Hospital Practice 1994;29:59-70.
- Drake CG, Kotzin LL. Superantigens: Biology, immunology and potential role in disease. Journal of Clinical Immunology 1992;12:149-162.
- Scherer MT, Ignatowicz L, Winslow GM, Kappler JW, Marrack P. Superantigens: bacterial and viral proteins that manipulate the immune system. Cell 1993;9:101-128.
- Leung DY, Miessner HC, Fulton DR, Murray DL, Kotzin BL, Schlievert PM. Toxic shock syndrome toxin-secreting staphylococcus aureus in Kawasaki syndrome. Lancet 1993;342:1385-1388.
- Parrillo JE. Pathogenic mechanisms in septic shock. New England Journal of Medicine 1993;328:1471- 1480.
- Tracey KJ, Cerami A. Tumor necrosis factor (cachectin) in septic endotoxic shock. In: Neugebauer EA, Holoday JW, editors. Handbook of Mediator of Septic Shock. Boca Raton: CRC Press, 1993:291-308.
- Tracey KJ. Tumor necrosis factor-alpha. In: Thomson A, editor. The Cytokine Handbook. London: Academic Press, 1994:289-304.
- Simpson SQ, Casey LC. Role of tumor necrosis factor in sepsis and acute lung injury. Critical Care Clinics 1989;5:27-47.
Download data is not yet available.