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Cell-Mediated Immunologicalprocesses in Leprosy

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Cell-Mediated Immunologicalprocesses in Leprosy Bull Org. mond. Sante 1 1969, 41, Bull. Wld Hlth Org. 779-792 Cell-Mediated Immunological Processes in Leprosy J. L. TURK A large number of organisms such as viruses, protozoa, helminths, fungi and bacteria, especially mycobacteria, need cell-mediated immunological processes for their elimination. As well as being involved in protection, cell-mediated immunological processes are also involved in a number of allergic reactions to products derived from mycobacteria. Cell- mediated immunological processes can be demonstrated by a number of in vitro reactions. Leprosy can present with a wide range of different clinical patterns. The clinical spectrum ofleprosy can be shown to depend on the degree of the cell-mediated immune response of the host against Mycobacterium leprae. Thus in tuberculoid leprosy there is a high degree of cell-mediated immune response whereas in lepromatous leprosy such a response is virtually absent. There appears to be a constitutionalpredisposition to lepromatous leprosy. In addition to a specific loss of cell-mediated immune response against Myco. leprae, there is also a non-specific drop in the ability ofpatients with lepromatous leprosy to show other aspects of cell-mediated immune response, e.g., contact sensitivitjy and skin homograft rejection. There is also a relative impairment of the ability of lymphocytes to react in vitro. Lymph nodes from patients with lepromatous leprosy show a deficiency in those areas associated with the development of cell-mediated immune responses. The article includes a discussion on the possible causes of deficiencies in cell-mediated immune responses in lepromatous leprosy. THE NATURE OF THE IMMUNOLOGICAL RESPONSE ma, hay-fever, urticaria, etc.) or react with comple- ment and be deposited in the walls of blood vessels, The body can respond to an antigenic stimulus in causing vasculitis, glomerulonephritis, arthritis, 2 fundamentally different ways. The end result of uveitis, etc. The interaction between humoral anti- each is the production of a factor which will interact bodies and the antigens of certain bacteria, such as specifically with the antigen, setting off a train of pneumococci or Salmonella, may increase the phago- events leading either to the elimination of the antigen cytosis and elimination of these organisms from the from the body or the induction of an inflammatory body. However, a large number of micro-organisms reaction. In one case, the specific antigen-reacting cannot be eliminated by the action of humoral anti- factor is a serum protein, an immunoglobulin bodies alone. These organisms require the interaction molecule, which we can refer to as a " humoral of sensitized lymphocytes and macrophages for their antibody ". In the other, there is the production of elimination. It is becoming more apparent that cell- lymphocytes which have a similar property of re- mediated immune processes are necessary for the acting specifically with the antigen. The production protection of the body from viruses, protozoa, of these specifically sensitized lymphocytes is known helminths, fungi and many bacteria, including. as the " cell-mediated immune response ". Although organisms as different as the treponemata, Brucella both humoral antibody and sensitized lymphocytes and the mycobacteria. react specifically with the antigen, the subsequent The need of cell-mediated immune processes for train ofevents, which each leads to, is different. Thus, the elimination of mycobacteria has been known for humoral antibodies may react with antigen on cell many years. Much of the early work on this subject surfaces to produce anaphylactic phenomena (asth- was performed on Mycobacterium tuberculosis, and started with the observation of Koch (1891), who 1 Director, Department of Immunology, Institute of demonstrated that if virulent tubercle bacilli were Dermatology, St. John's Hospital for Diseases of the Skin, London, and Reader in Immunology, University of London, injected subcutaneously into a guinea-pig which was. England. already infected, the animal reacted against the~ 2433 779- 780 J. L. TURK organism differently from an uninfected animal. The mediated immune response (Oort & Turk, 1965). rejection of the organisms was associated with a Removal of the thymus in neonatal life depletes these massive inflammation which developed at the site areas of lymphocytes and is associated with an of injection. A similar type of inflammation could be inability to manifest such a response (Miller, 1961). induced if the guinea-pig, or a similarly infected Babies born with congenital thymic hypoplasia are human subject, was inoculated intradermally with a found to be unable to produce a cell-mediated culture filtrate of the micro-organisms (the tuberculin immunological response and the paracortical areas reaction). Subsequently, it has been shown that both of their lymph nodes and the area of the white pulp the elimination of the organisms from the body and of the spleen round the central arteriole are deficient the inflammatory reaction produced by a sensitized in lymphocytes and replaced by reticulo-histiocytes. person against the organism or culture fluid are A similar appearance is found in the lymphoid tissue caused by the reaction with sensitized lymphocytes of animals treated with antilymphocyte serum (Turk and macrophages, cell-mediated immunological & Willoughby, 1967) which also prevents the develop- reactions. ment of cell-mediated immune responses. Neonatally Both the cell-mediated immune response and the thymectomized animals, babies with congenital humoral-antibody response are functions of the thymic aplasia and animals treated with antilympho- central lymphoid tissues of the body. An immunolo- cyte sera are able to produce humoral antibodies, gical response may be considered to have a number have normal levels of immunoglobulins in their of phases. There is first contact with antigen and this serum and have normal numbers of plasma cells is followed by a phase of cellular proliferation, in their lymphoid tissue. lymphocytes in the case of cell-mediated immune As well as being involved in the protection of the responses, and plasma cells for humoral-antibody body against a wide range of micro-organisms, cell- production. Cellular proliferation takes place mainly mediated immune responses are involved in a number in the lymph nodes, spleen or the lymphoid tissue of of allergic responses to substances produced by a the gut. As a result of this, either sensitized lympho- number of micro-organisms. These reactions, like the cytes or humoral antibody are present in a sufficient tuberculin reaction mentioned above, take 24-48 concentration to react with the foreign substances hours to develop and include the "reaction of <antigens) on subsequent contact. immunity " to vaccinia virus, the mumps skin test,- Production of humoral antibody takes place in the skin reactions to streptococcal antigens such as those plasma cells which are found at the cortico-medullary found in mixtures of streptokinase and streptodor- junction or in medullary cords of lymph nodes or in nase, to fungal antigens such as coccidiomycin and the red pulp of the spleen, and is usually associated histoplasmin, and to protozoal antigens such as the with the formation of germinal centres in the cortex Montenegro test for leishmaniasis. The reaction of of the lymph nodes or the splenic white pulp. The rejection of a skin homograft is another example of proliferation of lymphocytes associated with cell- a cell-mediated immune response, so also is contact mediated immune responses takes place in what is sensitivity to simple chemical agents such as 2,4- often referred to as the paracortical area of lymph dinitrochlorobenzene (DNCB) which attach readily nodes or in the area of the white pulp of the spleen to skin proteins. around the central arteriole. The paracortical area of Following contact between sensitized lymphocytes the lymph node is found situated between the true and antigen in the periphery, a soluble substance is cortex and the medulla, and between the lymph released which has a direct effect on macrophages. follicles and germinal centres (Oort & Turk, 1965). The nature of the substances on or within the Both this area and the areas of lymphocytes in the lymphocytes, with which the antigen reacts specifical- white pulp of the spleen round the central arteriole ly, is not known. However, many people feel that, have been found to be dependent on thymus integrity because the reaction resembles humoral antibody in late foetal and neonatal life (Parrott, de Sousa & reactions so closely, the reacting molecule must be East, 1966). The differentiation of lymphocytes, related in some way to an immunoglobulin molecule. probably sensitized by contact with antigen in the Thus it has been suggested that it might be a poly- periphery (Medawar, 1958), into large pyroninophilic peptide chain such as the Fd fragment of the cells (immunoblasts), which can be shown to divide immunoglobulin molecule, or some similar peptide into other small lymphocytes, takes place in the chain carrying an amino-acid sequence specific to the paracortical area of lymph nodes as part of a cell- particular antigen for which it is coded to react. CELL-MEDIATED IMMUNOLOGICAL PROCESSES IN LEPROSY 781 The soluble substances released by the incubation macrophages from patients with lepromatous leprosy of specifically sensitized lymphocytes with specific is immunologically specific (Beiguelman, 1967). antigen are in the molecular-weight range
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