Bull Org. mond. Sante 1 1969, 41, Bull. Wld Hlth Org. 779-792

Cell-Mediated Immunological Processes in

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 of certain bacteria, such as specifically with the , 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 ". 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 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 , 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

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 of approxi- A few in vitro reactions have been studied exten- mately 70 000. These substances can be shown to sively over the past few years in relation to cell- have a direct effect on the cellsurface ofmacrophages, mediated immunity. One of these is related to the decreasing the surface electrostatic charge, increasing increased adhesiveness of macrophages following the their adhesibility both to each other and to similarly release of a soluble substance after the interaction of charged surfaces, and decreasing their permeability specifically sensitized lymphocytes with specific to certain organic chemicals with molecular weights antigen. The macrophages are grown in tissue culture from 600 to 900, such as diphosphopyridine nucleo- in small capillary tubes. Under normal conditions, tide and triphosphopyridine nucleotide. The rela- they migrate from these tubes in a fan-like manner. tionship of these changes to the development of an However, if they are in close contact with antigen and inflammation in the skin with erythema, induration specifically sensitized lymphocytes, or incubated and a mononuclear cell infiltrate is not yet completely together with the soluble substances released from clear. However, the soluble mediator can be isolated specifically sensitized lymphocytes incubated with after culture of specifically sensitized lymphocytes antigen, they fail to migrate from the tubes. For this with specific antigen and, when this is injected intra- reason, the soluble substance released by incubation dermally, it will produce an inflammatory reaction of specifically sensitized cells with antigen is referred which has many of the characteristics of a tuberculin to as the " migration inhibition factor " and the reac- reaction (Bennett & Bloom, 1968; Pick et al., 1969). tion is referred to as " inhibition of macrophage The effect of the interaction between specifically migration in vitro ". sensitized lymphocytes and antigen on the ability of The other reaction performed in tissue culture is macrophages to eliminate mycobacteria has also not more related to the changes which occur to lympho- been completely elucidated. However, Berthrong & cytes in lymph nodes following first contact with Hamilton (1959) have observed the intracellular antigen, during the development of a cell-mediated growth ofthese organisms in macrophages. Normally, immunological response. It will be remembered that tubercle bacilli multiply intracellularly and form after first contact with antigen, probably in the peri- cords which engorge the cells so that they eventually phery, lymphocytes differentiate into large cells in the burst. Macrophages from immune animals do not paracortical area of lymph nodes, prior to division allow the bacilli to grow intracellularly in this manner, into other lymphocytes. These large cells which are and they survive longer than non-immune macro- synthesizing DNA, and which can thus incorporate phages although they may have still ingested the radioactively labelled thymidine, are referred to as organisms. At the same time it has been shown that " immunoblasts ". Similar transformation of small macrophages from immune animals have a higher lymphocytes into " blast" cells can be produced in rate of dehydrogenase enzyme activity (Allison, tissue culture in vitro. However, this occurs most Zapposodi & Lurie, 1962), and an increase in frequently if the person or animal has had a previous lysosomal enzymes (acid phosphatase, /3-glucoronid- exposure to the antigen. Under these conditions, no ase and cathepsin). Lysosomes of macrophages more than 10% of the small lymphocytes are trans- from animals immune to mycobacteria are also pro- formed. There are a number of substances which will bably more fragile than normal, as indicated by the regularly transform 80%-90% of the small lympho- release of considerable amounts of lysosomal en- cytes, without any known, previous exposure zymes, especially ,B-glucoronidase, into the plasma of the individual to the substance. The substances, or following the intravenous injection of an endotoxin non-specific mitogens, include phytohaemagglutinin (Saito & Suter, 1965a, 1965b). The little work that (PHA), a similar mitogen from pokeweed (Phytolacca has been published on the phagocytosis of Myco. americana), streptolysin S and the filtrate of Staphylo- leprae by macrophages suggests, as will be discussed coccus aureus cultures. Similar transformation can be later, that in tuberculoid leprosy, where there is a obtained by treating the lymphocytes with an anti- high degree of cell-mediated immunity, macrophages immunoglobulin allotype serum. Although the can readily lyse phagocytosed Myco. leprae, whereas relationship between lymphocyte transformation with in lepromatous leprosy, where cell-mediated immu- specific antigen and cell-mediated immune response nity is deficient, the organisms are still phagocytosed or humoral antibody production is highly contro- but not lysed. Moreover, the lysis of Myco. leprae by versial, there is a direct relationship between the 782 J. L. TURK ability of lymphocytes to be transformed with PHA Thus the disease may often be considered to be and the ability of individuals to show cell-mediated "mobile ". A patient with leprosy at the tuberculoid immune phenomena. Thus an inability both to be end of the spectrum may move to a more borderline sensitized to show contact sensitivity to DNCB and condition, or a patient with borderline leprosy may to have their lymphocytes transformed with PHA move to the lepromatous end of the spectrum as a occurs in patients with congenital thymic aplasia, result of an exacerbation of the disease. Conversely, Hodgkin's disease and sarcoidosis. on sulfone therapy a patient may move from the lepromatous end of the leprosy scale towards a more borderline position, or a patient with borderline THE SPECTRUM OF CLINICAL LEPROSY leprosy may move towards a tuberculoid position. The lesions in the 2 polar forms of leprosy show It has been recognized for a considerable time that marked histological differences. In tuberculoid leprosy may present clinically in a wide variety of leprosy, the granuloma is invariably infiltrated with forms. The pleomorphism of the presentation of the a dense collection of small lymphocytes and, despite disease was first rationalized by the separation of well-developed collections of histiocytic cells (macro- those forms of the disease where the presentation was phages), Myco. leprae are not found on standard one of peripheral nerve damage from the form where methods of examination. This is in marked contrast the lesions mainly took the form of nodular deposits to the appearance in lepromatous leprosy where in the skin. The association of anaesthetic patches in small lymphocytes are absent or scanty and the the skin with a surrounding raised erythematous macrophages are packed with leprosy bacilli edge or with a large erythematous plaque led to the which may form globi. The tissues throughout the description of these lesions as " tuberculoid " owing body may be infiltrated with macrophages containing to their occasionally resembling the lesions of lupus proliferating bacilli which, it appears, cannot be vulgaris. The nodular lesions are generally referred eliminated. As with the clinical state, the histological to as " lepromatous " as they are typical of this form appearance shows a broad spectrum between the of disease. Thus leprosy has become divided into 2 polar forms, the main variable being the proportion 2 polar forms, " tuberculoid " leprosy and " lepro- of small lymphocytes present in the lesion, and the matous" leprosy. However, more recently many intensity of parasitism of the macrophages by descriptions have been made of patients who may mycobacteria. Also, in parallel with the trend show, at one and the same time, manifestations of towards the lepromatous end of the scale as the both polar forms of the disease. This form of leprosy disease worsens, lesions may show a decrease in the has been referred to as " dimorphous " or " border- number of small lymphocytes and an increase in line" leprosy. Occasionally, patients may present the number of bacilli present. Similarly with treat- with just one or more hypopigmented macules. These ment, as the clinical condition swings back towards cases may be difficult to classify into one or other of the tuberculoid end of the spectrum there will be an the more florid forms of the disease, and are referred increased infiltration with small lymphocytes as the to as " indeterminate " leprosy. However, the disease bacterial load gradually decreases. rarely stays in this form and may develop with the In an attempt to provide a scheme whereby the production of more typical tuberculoid or lepro- patient can be assigned at any time to the correct matous lesions. It is thought that the indeterminate place on the spectrum, Ridley & Jopling (1966) state is probably the earliest form of the disease and attempted to characterize a number of points on the that many patients pass through it before they leprosy spectrum, understanding, however, that the develop the typical manifestations of tuberculoid or disease in a number of patients was mobile and that lepromatous leprosy. the patients could only be assigned to one place on Thus, clinically, leprosy forms a spectrum between the scale at a particular point in time. By closely the 2 polar forms-tuberculoid and lepromatous correlating the clinical state of the patient with the leprosy-and patients may present with varying histological appearance of the lesions, Ridley & lesions depending on the degree to which tuberculoid Jopling were able to define 5 points on the spectrum. or the lepromatous elements contribute to the disease. The 2 polar forms of the disease at the tuberculoid Apart from those with the 2 polar forms, patients and lepromatous ends of the spectrum are referred may vary from time to time in the degree to which to as TT and LL, respectively, while the central the 2 elemeinits contribute to the disease. position, dimorphous or borderline leprosy, is re- CELL-MEDIATED IMMUNOLOGICAL PROCESSES IN LEPROSY 783 ferred to as BB. They added 2 other points, BT tion-the Mitsuda reaction-which develops 3 weeks between TT and BB, and BL between BB and LL. after inoculation. It is the Mitsuda reaction which It was recognized that patients with single-lesion TT is used by most leprologists to indicate whether a rarely, if ever, swing forward across the spectrum, patient with leprosy is at the tuberculoid end of the and patients with true polar LL also rarely swing scale. Although this reaction takes place as long back across the spectrum. However, within the as 3 weeks after inoculation, and is not a typical range BT-BL there could be considerable variation delayed hypersensitivity reaction, it is probably from year to year. In South-East Asia, lepromatous evidence of a high degree of cell-mediated immunity leprosy appears to be more labile than it is in other directed against the mycobacterial antigens. As the parts of the world and patients have a form of lepro- inoculated material is particulate, it is retained in matous leprosy which is far less stable than that the tissues for a long period and does not diffuse found in LL patients in other parts of the world, aways as rapidly as does tuberculin. However, it presenting histologically with a slightly different may be that in the form in which it is injected the picture in which the granuloma consists of undifferen- antigen is not readily available to react with the tiated histocytes, often with a fibrocytic appearance. sensitized lymphocytes of a cellkmediated immune These patients, intermediate between BL and LL process and possibly the 3-week latent period is the with a potentiality to revert to BL on treatment, are time taken for the mycobacterial antigens to be sometimes referred to as LI (Ridley & Waters, per- exposed and made available, perhaps by tissue sonal communication). It must, however, be empha- enzymes. sized that the points TT, BT, BB, BL, LI and LL The lepromin test is not in itself an indication of are arbitrary points on what is a spectrum of disease. infection with Myco. leprae, but indicates that the Patients can be at any particular time at points inter- patient has had previous contact and has been mediate between the 5 marker points, i.e., TT/BT, immunized with these antigens which are probably BT/BB, BB/BL, BL/LI or LI/LL, depending on the common to a number of mycobacteria. Normal state of their disease at that time. subjects can be immunized to produce positive lepromin tests by repeated intradermal injections of the killed antigen. However, it does indicate that THE IMPORTANCE OF THE SPECTRUM CONCEPT the patients are capable of mounting a strong cell- IN ASSESSING THE STATE OF RESISTANCE mediated immune reaction against Myco. keprae OF THE PATIENT TO HIS DISEASE associated with marked lymphocytic infiltration. A positive lepromin test and the extensive lympho- The correlation between the lepromin test and cytic infiltration in the lesions of patients with the state of clinical leprosy has been accepted for tuberculoid leprosy of the TT type indicate that these many years. Thus patients with tuberculoid leprosy patients have a high degree of cell-mediated immu- are well known to be strongly lepromin-positive, nity directed agairhst Myco. leprae. This means that while those at the lepromatous end of the scale are they have in their circulation sensitized lymphocytes lepromin-negative. The presence of a positive lepro- capable of activating macrophages and interacting min test in a patient with indeterminate leprosy would with Myco. leprae antigens. This would account indicate that he is more likely to develop tuberculoid for their lesions having the appearance of typical leprosy, whereas a negative lepromin test would cell-mediated allergic reactions (i.e., prolonged ery- indicate a considerable risk of lepromatous leprosy thema, induration and infiltration with small lympho- developing. cytes). It would also account for the fact that At this stage it is profitable to digress slightly and mycobacteria are absent from the lesions. Thus they discuss the nature and importance of the lepromin also have a high degree of cell-mediated immunity test. The antigen used is an extract of lepromatous and are capable of eliminating Myco. leprae from tissue containing particulate material, especially par- the body, although they over-react with an intense ticulate mycobacteria, as well as antigens derived allergic reaction to the antigens at the same time. from the human tissue from which the extract is In tuberculoid leprosy of the BT type lymphocytic derived. The reaction appears in 2 phases: a typical, infiltration is of the same degree as that in TT delayed hypersensitivity reaction-the Fernandez leprosy and the extent of the allergic reaction in the reaction-maximal 48-72. hours after intradermal skin is as intense. However, more than one lesion is inoculation, and a papular granulomatous reac- present and mycobacteria can be found in the lesion, 784 J. L. TURK indicating that the degree of cell-mediated immunity mined characteristic that is present in a fixed is less, so that not all organisms are immediately proportion of all people everywhere. eliminated. The lepromin test is also not so inten- Evidence that leprosy in its various forms occurred sely positive as in the polar form (TT). Throughout more frequently in certain families in endemic areas the BB and BL forms, cell-mediated immunity has been cited by a number of workers since it was appears to be increasingly less as indicated by the first demonstrated by Daniellson and Bocck in 1848. negative lepromin test, decreasing lymphocytic infil- Jamison & Vollum (1968) have recently cited evi- tration in the lesions and increasing numbers of dence which suggests that leprosy occurs in families mycobacteria that can be found. in which there is a naturally occurring weakness in This loss of cell-mediated immunity increases so their ability to develop a cell-mediated immune that in the LI or polar LL forms of leprosy there response. When tuberculin-negative children with a may be no lymphocytic infiltration and the myco- family history of leprosy were vaccinated with an bacteria proliferate throughout the body as though avirulent strain of mycobacterium containing anti- the body possessed no defence mechanisms towards gens which cross-reacted with Myco. tuberculosis the organisms at all. Mycobacteria are found grow- (vole tuberculosis vaccine) only 18 % were converted ing in colonies and forming globi within the macro- to tuberculin positivity, whereas 90% of children phages in an apparently undisturbed manner. who came from families where there was no history Thus the spectrum of clinical leprosy from TT to of leprosy were converted to tuberculin positivity LL appears to reflect a massive cell-mediated immune by the vaccine. This would indicate that children response at the one extreme to a complete absence from families in which leprosy occurs are less able of cell-mediated immunity at the other. The main to develop a strong cell-mediated immune response, problems to be discussed in understanding the vari- than children frcm families in which leprosy does ous manifestations of leprosy are why in some not occur. patients there is this high degree of cell-mediated A similar relation between weakness of an ability immunity and in others cell-mediated immunity is to show a cell-mediated immune response and the absent, why some patients starting with lesions indi- development of leprosy can be shown in experi- cating a high degree of immunity can develop lesions mental animals. Under normal conditions it is only indicating a progressive loss of immunity, and why possible for Myco. leprae to proliferate locally and some patients with little or no immunity can, on for a limited number of generations when inoculated chemotherapeutic treatment, develop lesions of a into mice and other rodents, and after a period of different type, indicating that they are regaining a 8 months, the organisms are rejected by the body. certain degree of immunity against the organisms. However, if adolescent mice are thymectomized and This latter state may be particularly distressing irradiated with 900 R, a process known to suppress since, at the same time as they begin to eliminate the ability of the body to develop a cell-mediated organisms from them body, they will start to develop immune response, the mycobacteria are able to spread allergic reactions, affecting not only the skin but throughout the body and produce a disease resembl- also the nerves, of a cell-nmediated immune type ing leprosy in man (Rees et al., 1967). The signs directed against residual antigen. The resulting dis- include nodular swellings of the skin similar to those ease may not only be temporarily more severe than seen in patients with lepromatous leprosy. If the their original lepromatous state, but also may result mice received lymphoid tissue from animals with in permanent scarring or nerve damage. a normal state of cell-mediated immunity, the infec- tion was far less severe than in those animals which A CONSTITUTIONAL PREDISPOSITION had been thymectomized and irradiated but had not TO LEPROMATOUS LEPROSY received lymphoid cell replacement. If animals were allowed to develop an infection like lepromatous Lepromatous leprosy seems not to occur in a leprosy and were then given an inoculation of lym- fixed proporticn of leprosy infections. In a popula- phccytes the nodular swellings became inflamed and tion in which the rate of leprosy infection is decreas- subsided, after which the lesions developed a condi- ing there is not a parallel fall in the incidence of tion resembling that seen in borderline leprosy with lepromatous leprosy. It has therefore been suggested nerve damage (Rees & Weddell, 1968). This would by Newell (1966) that the development of leproma- indicate that in experimental animals, a condition tous leprosy in an infected person is a host-deter- resembling lepromatous leprosy can be produced in CELL-MEDIATED IMMUNOLOGICAL PROCESSES IN LEPROSY 785 experimental animals by eliminating cell-mediated matous had the polar LL form of the disease or a immunity, and that the lepromatous state can swing form between LL and BB. towards the borderline state if cell-mediated immu- In another report by Bullock (1968), the Ridley- nity is restored partially by a transfusion of viable Jopling scale (TT-LL) was used to place the patients lymphocytes capable of mounting an immune reac- more accurately according to the clinical and histo- tion against Myco. leprae. logical state of their disease. As well as pre-existing This suggests also that the constitutional defect sensitivity to lepromin, tuberculin, Candida and predisposing to the development of lepromatous trichophytin, the ability ofpatients to become actively leprosy might be a weakness in thymus function in sensitized was assessed by their response to picryl the young person, or an equivalent defect in the adult. chloride. Picryl chloride is a much weaker sensitizer than DNCB in experimental animals. It is known THE ABILITY TO SHOW OTHER ASPECTS that DNCB will sensitize some 90% of normal OF CELL-MEDIATED IMMUNITY individuals, and Bullock (1968) was able to sensitize IN LEPROMATOUS LEPROSY 28 out of 30 normal people with this agent. Although patients in this series were originally classified accord- A generalized depression of the ability to mount ing to the Ridley-Jopling scale, patients with TT a cell-mediated immune response has been demon- and BT leprosy are referred to as tuberculoid and strated recently, by a number of authors, in patients patients with BL and LL as lepromatous. In the with lepromatous leprosy (Waldorf et al., 1966; patients with lepromatous leprosy who had been Bullock, 1968). The general disability to show delayed under treatment for less than 18 months, 70% could hypersensitivity reactions was demonstrated by an not be sensitized with picryl chloride; however a inability of patients with lepromatous leprosy to discrepancy again exists because only 50 % of these become sensitized with DNCB (Waldorf et al., 1966). patients were tuberculin-negative. Moreover, 15 % Altogether, 75 % ofpatients with lepromatous leprosy of the patients were lepromin-positive, suggesting without erythema nodosum leprosum failed to be that they were closer to the borderline or tuberculoid sensitized to DNCB whereas only 1 out of 5 patients end of the spectrum than the other patients in this with dimorphous (borderline) leprosy failed to be group. sensitized in this way; the technique used to assess In a second group of lepromatous patients who whether sensitivity had developed was to skin-test had been treated for longer than 18 months, only the patients with 100 pg and 50 pg of DNCB in 47% could not be sensitized with picryl chloride. acetone. The result is curious since it has been found In this group, 40 % were lepromin-positive. A further that the applications of 100 ,ug of DNCE in acetone problem in interpreting this result is that as many can produce a non-specific inflammatory reaction in as 55% of the patients with tuberculoid leprosy unsensitized individuals (Turk & Waters, 1969). failed to be sensitized with the picryl chloride. There Moreover, 6 out of the 17 patients who could appears to be no logical explknation why patients not be sensitized with DNCB were shown at the with tuberculoid leprosy fail to be sensitized to same time to be able to mount a cell-mediated picryl chloride when 90 % of controls can be sen- immune reaction to tuberculin. As no record is sitized easily. One possible thought is that the given of what proportion of patients reacted 2 populations are not identical and that the controls to the 100-pug dose only and what proportion to both come from a population which is more readily the 100-pug and 50-,ug doses, this report shows some sensitized to picryl chloride than the group from unsatisfactory features. The authors also found it which the patients with tuberculoid leprosy are difficult to explain why a similar state of anergy or derived. One explanation that Bullock (1968) him- inability to be sensitized with DNCB did not occur self has suggested is that in tuberculoid leprosy cell- in patients in the same part of the lepromatous mediated immunity is deviated so strongly to pro- spectrum but who were having attacks of erythema duce the reaction against Myco. leprae that no nodosum leprosum. Also, it is difficult to interpret reserves are available to react with other antigens. these results because the patients were only classified The report of increased immunological activity fol- broadly into lepromatous or dimorphous leprosy lowing therapy in patient swith lepromatous leprosy without any assessment as to whether they were is interesting and has been observed in other groups moving in the clinical spectrum of leprosy. We do ofpatients (Waters, personal communication). How- not know whether the patients classified as lepro- ever, difficulty is obtained in interpreting these 786 J. L. TURK results as BL and LL patients are grouped together dicate that these patients show prolonged survival and it would be important to know whether increased of allogeneic skin grafts. In normal cultures of ability to be sensitized to picryl chloride was asso- lymphocytes, approximately 80% of the cells can be ciated with clinical evidence of an increase in the transformed into lympho-blastoid type cells by the immune state, such as a movement across the addition ofPHA. Dierks & Shepard (1968) found that immunological spectrum of the disease from LL the cells from 8 active lepromatous patients had & low to BL. response to PHA (only 10% of the cells being trans- The finding of patients who were tuberculin- formed by this mitogen). Of these patients, 4 had sensitive but unable to be sensitized to DNCB, erythema nodosum leprosum and this did not affect poses an interesting problem. These patients could the response of the patients. In another series, 3 pa- have a degree of cell-mediated immunity high tients with active lepromatous leprosy were found to enough to respond to antigens to which they were have a markedly diminished response. One surprising exposed before they developed leprosy, but insuffi- result in this series was that 3 patients with tuberculoid cient to respond while they had their leprosy. leprosy also had a diminished response to PHA. The Another possibility is that contact-sensitizing agents reason why patients with lepromatous leprosy fail to provide a weaker antigenic stimulus than bacterial be stimulated with PHA and that these patients show antigens. In recent experiments (Turk & Waters, a diminished ability to manifest delayed hyper- 1969) it has been found that patients with leprosy who sensitivity reactions, could be explained as being due could not be sensitized to DNCB could, however, be to a general failure of these patients to manifest cell- sensitized to develop delayed hypersensitivity to mediated immune reactions. This might be genetic as keyhole-limpet haemocyanin (KLH). KLH pro- suggested by Jamison & Vollum (1968). However, vides a more powerful antigenic stimulus than other causes should be considered, such as the changes DNCB which acts by modifying the body's own which are seen in the lymphoid organs of such proteins. The inability to respond to DNCB does patients which will be discussed in another section. not therefore indicate a complete anergy in respect Whether these changes themselves are also hereditary to cell-mediated immunity, but suggests that this and due to thymus dysfunction will also be discussed. property is only somewhat weakened. More difficult to understand is the diminished responsiveness of the lymphocytes of patients with IN VITRO REACTIVITY OF LYMPHOCYTES tuberculoid leprosy to respond to PHA. This may be FROM LEPROMATOUS PATIENTS associated with the diminished ability of these patients to develop delayed hypersensitivity to picryl The failure of lymphocytes from patients with chloride. One suggestion that has been put forward impaired cell-mediated immunity, by non-specific (Bullock, personal communication) is that the mitogens such as PHA has been described in a lymphoid tissue of such patients is responding so number of diseases. These include primary thymic strongly to antigens from Myco. leprae that there is dysplasia, Hodgkin's disease, sarcoidosis, Sjogren's no residual activity to respond to other antigens. This disease and primary biliary cirrhosis. It is possible would explain an inability to respond to an antigen, that in these conditions the lymphocytes which are but it is difficult to see how this effect could cause an capable of being stimulated are those that are under inability of the lymphocytes to respond to non- the control of the thymus in neonatal life and are specific mitogenic stimulation with PHA. thus the same class oflymphocytes that can be stimul- Extremely interesting experiments have been ated to proliferate into " sensitized lymphocytes " in a described by Bullock & Fasal (1968). In these experi- cell-mediated immune response. As has been dis- ments, a depression of DNA synthesis, indicative of cussed above, considerable evidence is accumulating the transformation of lymphocytes into blast cells that there is an impaired ability of patients with was found in lymphocytes from patients with lepromatous leprosy to manifest a wide range of cell- lepromatous leprosy when exposed to PHA and mediated immune reactions. These include contact streptolysin 0 (SLO) which also acts as a non- sensitivity to simple chemical sensitizers and delayed specific mitogen probably through its antigenic pro- hypersensitivity to antigens from Candida and perties. A similar depression in the transformation of trichophytin. Moreover, experiments by Job & Karat lymphocytes of patients with tuberculoid leprosy was (personal communication, cited by Hart & Rees, found, as was described by Dierks & Shepherd (1968). 1967) in 4 patients with lepromatous leprosy in- However, one of the most fascinating aspects of this CELL-MEDIATED IMMUNOLOGICAL PROCESSES IN LEPROSY 787 investigation was that the depression of response to lymphocytes, without affecting the lymphocytes in SLO was found only when the lymphocytes from the lymph follicles, thought to be of direct bone- lepromatous patients were suspended in autologous marrow origin, the germinal centres and the plasma plasma. When the cells were suspended in homolo- cells in the medulla, involved in humoral antibodies gous plasma from normal subjects no depression of production. Thus the presence of an antilymphocytic activity was found. When the cells of normal subjects antibody in the circulation selectively inhibits cell- were suspended in the plasma of some lepromatous mediated immune processes without affecting the subjects depression in the ability of these cells to be production of most types of circulating antibody. If transformed by SLO was observed. However, plasma an antilymphocytic antibody was present in the from lepromatous patients did not suppress the circulation, this could account for the anergy in response of lymphocytes from normal subjects to respect to cell-mediated immunity in certain patients PHA. Thus the plasma from some patients with with lepromatous leprosy. How could such an anti- lepromatous leprosy contains a factor which can body develop? Such an antibody would be an inhibit the response of normal lymphocytes to SLO. " autoantibody ". Autoantibodies of a wide variety Much might be learned about the depression of have been found in patients with lepromatous cell-mediated immunity in leprosy if the nature of this leprosy; they include the rheumatoid factor, thyro- factor could be discovered. globulin autoantibodies, antinuclear factor and the A similar phenomenon has been described by Wasserman antibody which is an autoantibody Melli et al. (1968) in patients treated with hetero- directed against heart muscle (Bonomo & Dammacco, logous antilymphocyte serum. After 14-21 days of 1968). The presence of these different autoantibodies treatment, there was a severe depression of the re- may be due to the exposure of hidden antigenic sponse of the patients' lymphocytes to PHA. How- groups as a result of tissue damage caused by the ever, this only occurred if the cells were cultured in presence of such large amounts of micro-organisms autologous plasma. In the presence of homologous throughout the body. A similar wide spectrum of plasma the response of the cells was normal. Corre- autoantibodies is found in a number of other chronic spondingly, the plasma of patients treated in this way infective diseases such as tuberculosis and syphilis. would inhibit the ability of PHA to transform lym- In experimental animals the production of autoanti- phocytes from normal people. Melli et al. (1968) con- bodies can be stimulated by the injection of an emul- sidered, reasonably, that the factor present in the sion of homologous tissues in oil containing myco- plasma of patients treated with antilymphocytic bacteria, thus reproducing the antigenic stimulus serum, which inhibited the transformation of lym- which the body receives from its own tissues in phocytes by PHA, was in fact an antilymphocyte certain chronic infective diseases. antibody. It would thus appear that a factor is Thus an important step forward in understanding present in the plasma of both patients with lepro- the mechanism of the loss of cell-mediated immunity matous leprosy and those treated with antilympho- in patients with lepromatous leprosy will be the cytic serum which could inhibit the response of characterization of the factor which inhibits the normal lymphocytes by non-specific mitogens. In transformation of lymphocytes by SLO in the plasma both these cases it should be easy to find out whether of some of these patients. the factor involved is an immunoglobulin, and thus an antibody. If an antilymphocytic antibody is IN VITRO EXAMINATION OF MACROPHAGE present in the circulation of patients with leproma- ACTIVITY IN LEPROSY tous leprosy, this could have considerable implica- tions. It is now well known that antilymphocytic Although much work has been done on the antibodies act specifically by suppressing the circul- behaviour of macrophages in experimental animals ating pool of long-lived small lymphocytes, influ- with tuberculosis, little study has been made of enced by the thymus in neonatal life, which are macrophage activity in patients with leprosy. Bei- necessary for the normal manifestation of a cell- guelman (1967) has developed a technique for testing mediated immunological reaction. Treatment of the lysogenic ability of macrophages for Myco. animals with antilymphocytic antibody has an effect leprae. He observed the behaviour of macrophages very similar to thymectomy in neonatal life, in from leprosy patients maintained in a tissue-culture depleting the paracortical area of lymph nodes and medium after the addition of dead leprosy bacilli. the corresponding area of the spleen of these small The macrophages from both lepromatous and 788 J. L. TURK

tuberculoid patients actively phagocytosed the dead The technique of S0berg & Bendixen (1967) lends leprosy bacilli; the macrophages from the tuberculoid itself as an in vitro approach which could be used to patients completely lysed the ingested bacilli, so that investigate cellular immunity against Myco. leprae they became free of lipids. However, the macrophages in human. The antigen could be killed Myco. leprae, from the lepromatous patients were unable to lyse the similar to that used by Beiguelman (1967) to inves- organisms and became transformed into typical lepra tigate macrophage activity. The technique of Thor cells. Their cytoplasm was found to contain numerous (1967) is more difficult in that it uses lymph-node bacilli and droplets of lipid material which stained cells which are more difficult to obtain than peripheral readily with Sudan Black. A similar study was report- blood leucocytes and also entails a 72-hour culture ed by Hanks (1947, pp. 21, 31, 48) who cultured of the cells as a free-cell suspension, with the asso- phagocytic cells morphologically resembling fibro- ciated risks of any long-term tissue culture. blasts from patients with leprosy. Those from patients In further experiments, Thor et al. (1968) incubated with tuberculoid leprosy were able to lyse the orga- peripheral blood lymphocytes with soluble antigen nisms, whereas the cells from patients with lepro- for 24-48 hours, then added the supernatant to a matous leprosy degenerated and released the orga- suspension of guinea-pig peritoneal macrophages in nisms free into the medium. Although unable to lyse capillary tubes. The incubation of specifically Myco. leprae, cultured macrophages from patients sensitized human lymphocytes with the specific with lepromatous leprosy have been reported to be antigen causes the release of a migration inhibition able to lyse Myco. lepraemurium and Myco. tuber- factor similar to that described by Bennett & Bloom culosis (Beiguelman, 1967). (1968) which inhibits the migration of the guinea-pig The inhibition of migration of macrophages in macrophages. This technique, although also using vitro in the presence of sensitized lymphocytes and peripheral blood cells, is difficult and involves cultiv- antigen is now a technique regularly used in the study ation of the lymphocytes prior to the release of the of cell-mediated immunity. This technique, developed factor; being a 2-stage cultivation procedure, it is originally in experimental animals by Rich & Lewis not an easy technique but could be adapted to leprosy in 1932 using tissue explants, has been adapted to research under carefully controlled experimental free-cell suspensions by George & Vaughan (1962). conditions. More recently, methods have been described where Extensive research on cell-mediated immunity this technique can be adapted for use with human in vitro is thus recommended along 2 lines. The first, tissues. In one of these methods (Thor, 1967; Thor & using the leucocyte-inhibition technique of S0berg & Dray 1967) human lymph node cells are cultured as a Bendixen (1967) or Thor et al. (1968), should give free suspension for 72 hours prior to being placed in information on the presence ofsensitized lymphocytes the capillary tubes. The lymph-node cells then grow capable of secreting a migration inhibition factor out in a fan-like manner, similar to that seen in after reaction with Myco. leprae or soluble antigens cultures of guinea-pig macrophages. In the presence derived from the organisms. This substance can be of specific antigen they are inhibited from migrating. presumed to act on leucocyte cell surfaces causing Another modification is that described by S0berg increased stickiness of these cells. The second ap- & Bendixen (1967). In this modification, peripheral proach should be *an extension of the work of blood leucocytes are used in the capillary tubes and Beiguelman (1967) to investigate what it is that causes inhibition of their migration by specific antigen. Both the macrophages of tuberculoid leprosy patients to adaptations of the leucocyte migration technique lyse Myco. leprae after phagocytosis, whereas the appear to correlate well with the presence of delayed macrophages from lepromatous patients cannot lyse hypersensitivity. The first technique has the disad- the organisms. It could perhaps be shown that there vantage that it uses lymph-node cells and needs was inhibition of leucocyte migration by Myco. biopsy, whereas the second technique uses peripheral leprae using the blood from tuberculoid leprosy leucocytes. Moreover, the second technique has been patients and that Myco. leprae fails to inhibit the performed with particulate organisms, especially migration of leucocytes from lepromatous leprosy Brucella abortus. The development ofthe cells' ability patients. Moreover, a soluble substance could be to be inhibited from migrating in the presence of obtained from the culture supernatants of leucocytes specific antigen correlates well with the known course from tuberculoid leprosy patients with Myco. leprae, in time of the development of cellular, rather than which mightbeabletostimulatethemacrophagesfrom humoral, immunity (S0berg, 1968). patients withlepromatous leprosy to lyseMyco. leprae. CELL-MEDIATED IMMUNOLOGICAL PROCESSES IN LEPROSY 789

THE HISTOLOGICAL APPEARANCE OF LYMPHOID immunity) there was evidence of the beginning of TISSUE FROM PATIENTS WITH LEPROSY repopulation of the paracortical areas with small lymphocytes. Some of the capillaries in the para- As has been mentioned above, the lymph nodes cortical area were dilated and were surrounded by a from experimental animals treated in various ways cuff of small lymphocytes. At the tuberculoid end of to suppress cell-mediated immunity show a particular the spectrum a completely different picture is seen. histological appearance. Neonatal thymectomy or The paracortical areas are well developed and packed treatment with antilymphocyte serum causes a full of small lymphocytes; an occasional immuno- marked depletion of lymphocytes from the paracort- blast can also be found. Germinal centres are not ical areas of the lymph nodes and these cells are seen in the epitrochlear nodes and only an occasional replaced by pale-staining reticulo-histiocytes. The plasma cell is seen. This is consistent with the observ- germinal centres and their marginal cuff of small ation of Hanks (1961) that no significant levels of lymphocytes are unaffected by this process, as also antibody are found in those forms of the disease are the plasma cells at the cortico-medullary junction (tuberculoid) that are characterized by very small and in the medullary cords. A similar picture is found numbers of bacilli, strong lepromin reactions and a in the lymphoid tissue of children with congenital frank tendency to self-healing. On the other hand, thymic aplasia or with the Wiskott-Aldrich syndrome patients with leprcmatous leprosy, who have no which is also associated with a failure on the part of immunity to infection, possess large amounts of the patient to show cell-mediated immune responses. circulating antibody to mycobacterial antigens. A However, lymph follicles, germinal centre formation similar finding was made by Rees et al. (1965) who and plasma cell proliferation in the medulla, which found precipitating antibody in the sera of all patients are associated with humoral antibody formation are with lepromatous leprosy directed against a number unaffected by this process. of different mycobacterial antigens and crude homo- In a recent study, a similar histological pattern has genates of leprosy tissue. In contrast, antibodies been found in the lymph nodes of patients with directed against mycobacterial antigens were only lepromatous leprosy (Turk & Waters, 1968). The rarely found in the sera of patients at the tuberculoid lymphocytes in the paracortical area of the lymph end of the leprosy spectrum. nodes were almost completely replaced by reticulo- histiocytes. These cells were morphologically similar ERYTHEMA NODOSUM LEPROSUM to the cells seen replacing the lymphocytes in the paracortical area of lymph nodes from the guinea- Although the antibodies against mycobacterial pigs treated with antilymphocyte serum (Turk & antibodies do not contribute to the elimination of the Willoughby, 1967). These cells also had striking mycobacteria, they are in a position to react with phagocytic activity and in advanced cases they were mycobacterial antigens in vivo. It is probable that the seen to have ingested large numbers of Myco. leprae. interactions between these antibodies and myco- However, this appears to be a secondary phenomenon bacterial antigens exposed as a result ofchemotherapy as in cases that were nearer the borderline part of the underlie the condition known as erythema nodosum spectrum, often there were no bacilli within these leprosum. This condition takes the form of an acute cells. The infiltration was confined exclusively to the vasculitis in the skin associated with polymorpho- paracortical areas of the lymph nodes. The germinal nuclear leucocytic infiltration. It may be associated centres were normal and their marginal zone of with iridocyclitis, arthritis and even glomerulo- small lymphocytes was not decreased. The medullary nephritis. This symptom complex is reminiscent of cords of the lymph nodes were unaffected and con- that found in serum sickness and is then associated tained large numbers of plasma cells. In borderline with the circulation of antigen-antibody complexes leprosy there was some infiltration of the paracortical formed ln slight antigen excess which circulate and areas with these histiocytic cells but there were con- become deposited in small blood vessels, producing siderable numbers of small lymphocytes still present. in the skin lesions which resemble the Arthus In one case, where the biopsy specimen had been phenomenon. There is no doubt that the skin lesions taken after treatment for 7 months (during which the of erythema nodosum leprosum have many features patient had moved clinically from the lepromatous in common with the Arthus reaction as seen in end of the spectrum to borderline leprosy, indicating experimental animals and may even have a haemor- that he had regained a certain degree of cell-mediated rhagic centre. 790 J. L. TURK

Erythema nodosum leprosum always occurs in enon as a result of extensive tissue damage during that part of the leprosy spectrum where cell-mediated infection with Myco. leprae. immune processes against the mycobacteria are Another non-specific factor that could be relevant absent or minimal and under conditions where there to the depression of cell-mediated immunity in lep- are large amounts of circulating antibodies against rosy is that the ability to develop delayed hypersensi- mycobacterial antigens, so high that they can be tivity is suppressed in guinea-pigs pretreated with detected by techniques as crude as precipitation in Freund's adjuvant (Jankovic, 1962). The infiltration agar (Rees et al., 1965). of tissues with Freund's adjuvant containing myco- bacteria, might produce conditions similar to those found in leprosy. Guinea-pigs treated in this way are POSSIBLE CAUSES OF DEFICIENCIES OF not only not able to produce cell-mediated immune CELL-MEDIATED IMMUNITY IN LEPROSY reactions when actively stimulated with antigen but also have a reduced ability to manifest passively Depression of cell-mediated immunity in lepro- transferred reactivity (Asherson & Allwood, 1969). matous leprosy is probably due to an interaction of a All these factors will contribute to a non-specific number of different factors and cannot be attributed depression of cell-mediated immunity. However, to a single mechanism. except in the polar form of lepromatous leprosy, the In the first place, there is no doubt that in patients inability to show cell-mediated immunity is specific with lepromatous leprosy a fundamental constitu- to Myco. leprae and a non-specific depression does tional defect contributes considerably to the eventual not occur in either parts of the spectrum where bacil- deficiency. This is indicated by the observation that lary growth may be little controlled. Thus a specific lepromatous disease is a host-determined character- immunological tolerance must play a certain role in istic that is possessed by a fixed proportion of all the ability to respond to the organism. Moreover, people everywhere (Newell, 1966). This observation this tolerance must be in respect of cell-mediated is supported by the finding that the children of immunity only, as humoral antibody production, parents with leprosy show a marked reduction in far from being depressed, is actually increased. their ability to become converted to tuberculin posi- Such " split tolerance " or immune deviation is found tivity when vaccinated with vole tuberculosis vaccine, in experimental animals following the injection of as compared with normal children (Jamison & alum-precipitated antigens (Asherson & Stone, 1965) Vollum, 1968). or by the intravenous injection of soluble antigen The appearance of lymph nodes from patients with (Dvorak et al., 1965) prior to immunization. A lepromatous leprosy is very similar to that seen in similar state of split tolerance involving chemical- children with congenital thymic aplasia (Turk & contact-sensitivity has been produced in already Waters, 1968) and suggests that the defect might be highly sensitive guinea-pigs (Polak & Turk, 1968). due to an inherent deficiency in thymus control of Thus, a cell-mediated immunity can be suppressed cell-mediated immunity. The suggestion is supported after it has developed. This may explain certain by the observation of Rees et al. (1967) that a disease aspects of loss of immunity during the exacerbation resembling lepromatous leprosy can be produced of leprosy, which may occur when a patient with by infection in mice following a combination of borderline leprosy swings towards lepromatous lep- adolescent thymectomy and deep X-irradiation. rosy, or a patient at the tuberculoid end of the spec- However, a similar appearance in the lymph nodes trum develops a disease with certain lepromatous is found in animals treated with anti-lymphocytic aspects (borderline leprosy). serum. There is a suggestion from the work of Therefore, it is probable that the loss of cell- Bullock & Fasal (1968) that an antilymphocytic mediated immunity in leprosy could originally be the antibody could be present in the plasma-of such result of the development of a state of specific immu- patients. Moreover Gaugas (1968) has found that a nological tolerance in an individual who already has a combination of thymectomy at 6 weeks of age and basic constitutional defect in cell-mediated immunity. treatment with antilymphocytic antibody will allow With progressive infiltration of the tissues with Myco. Myco. leprae to proliferate to the extentofreproducing leprae, the basic constitutional defect is aggravated so many of the features of lepromatous leprosy. As has that there occurs a generalized non-specific failure to been discussed above, such an antilymphocytic anti- show certain aspects of cell-mediated immunity such body could be developed as an autoimmune phenom- as contact sensitivity and homograft rejection. How- CELL-MEDIATED IMMUNOLOGICAL PROCESSES IN LEPROSY 791 ever, this in itself is never complete. Patients with over, there is no increased incidence in the develop- lepromatous leprosy do not die within 6 months from ment ofcancer by these patients, as might be expected virus and parasitic infections, as do babies with con- if there was no ability retained to show cell-mediated genital thymic aplasia. A certain degree of cell- immunity. If anything, leprologists have the im- mediated immunity is always retained and patients pression that cancer is somewhat less prevalent in who cannot be sensitized with DNCB can be sensi- patients with leprosy than it is in the general tized with a stronger antigen such as KLH. More- population.

RItSUME

RtPONSES IMMUNITAIRES A SUPPORT CELLULAIRE DANS LA LtPRE

L'organisme peut reagir a un stimulus antig6nique de lymphocytes et les mycobacteries se multiplient de fagon deux fagons differentes, soit par la production d'anticorps incontrolee. circulants, soit par le declenchement d'un processus I1 existe une predisposition constitutionnelle aux immunitaire a support cellulaire. L'intervention de ce formes lepromateuses de la lepre. En plus des deficiences dernier type d'immunite est indispensable pour l'elimina- specifiques de l'immunite cellulaire vis-a-vis de Myco. tion de virus, de protozoaires, d'helminthes, d'agents leprae dans la lepre lepromateuse, on constate chez fongiques, de certaines bacteries et, entre autres, des certains patients une perte non specifique de la capacite de mycobacteries. L'immunite cellulaire joue aussi un r6le presenter d'autres reactions immunitaires du meme type, dans les reactions allergiques cutanees (reactions d'hyper- comme la sensibilisation apres contact ou le rejet d'un sensibilite de type retarde) aux antigenes bact6riens, tols homogreffon. On decele en outre chez eux un affaiblisse- que la tuberculine, et est A la base des ph6nomenes de ment de I'aptitude des lymphocytes A reagir in vitro, qui sensibilisation apres contact avec des substances chimiques peut etre d6montre par l'epreuve de la phytohemaggluti- simples (comme le dinitro-2,4 chlorobenzene) et de rejet nine. Enfin, on note en cas de lepre lepromateuse une des homogreffons cutanes. disparition quasi complete des lymphocytes dans les La reactivite immunologique a support cellulaire est zones corticales profondes des ganglions lymphatiques, contr6lee par le thymus au cours de la periode neo-natale ces zones etant precisement celles qui sont inactives dans et est tres affaiblie chez les nouveau-nes atteints d'aplasie l'aplasie cong6nitale du thymus et qui sont le siege d'une congenitale du thymus. Son developpement s'accompagne proliferation lymphocytaire intense au cours du developpe- d'une proliferation des lymphocytes dans les zones ment de l'immunite cellulaire.. corticales profondes des ganglions lymphatiques ou dans des zones correspondantes, soumises A l'influence du L'affaiblissement de la reponse immunitaire A support thymus, de la rate. Des lymphocytes dotes d'une sensibi- cellulaire dans la lepre lepromateuse peut etre dQ a lite specifique peuvent etre deceles dans la circulation, ou l'action reciproque d'une serie de facteurs: anomalie le contact avec l'antigene a pour effet de liberer une constitutionnelle; tolerance immunologique specifique A substance soluble qui agit directement sur les macro- l'egard de Myco. leprae; envahissement des zones des phages. Le mecanisme de cette interaction qui rend les tissus lympholdes soumises a l'influence du thymus par'des macrophages aptes A eliminer les mycobacteries n'est pas histiocytes contenant des mycobacteries lepreuses et encore completement elucide. inhibition de la proliferation locale des lymphocytes. On peut demontrer que les divers aspects cliniques de la Cependant, en depit de cette carence de l'immunite lepre sont influences par l'intensite de la reponse immuni- cellulaire dans la lepre lepromateuse, les sujets qui en sont taire A support cellulaire que l'h6te oppose A Mycobacte- atteints sont parfois porteurs, A des titres eleves, d'anti- rium leprae. Dans la lepre tuberculoide, ofu l'immunite corps circulants dont la production n'est pas diminuee. cellulaire est tres developpee, les lesions sont infiltrees par Lors de la liberation par les mycobacteries d'un antigene un grand nombre de lymphocytes et on n'y trouve que soluble, par exemple apres un traitement par les sulfones, peu de mycobacteries. En revanche, dans la lepre l6pro- on pourra observer l'apparition de sympt6mes cutanes mateuse, A l'autre extremite de la gamme des aspects (erythema n9dosum leprosum) dus a la reaction antigene- cliniques, l'immunite cellulaire est virtuellement inexis- anticorps, parfois accompagnes d'irido-cyclite, d'arthrite tante: les lesions sont caracterisees par l'absence de ou de glomerulo-nephrite. 792 J. L. TURK

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