Cellular immunity in lepromatous and tuberculoid leprosy

The depression of cellular immunity in lepromatous patients is not understood. While the blood monocytes of leprosy patients appear to be activated normally by lymphokines, T cell proliferation and production of lymphokines in response to Mycobacterium leprae are impaired in lepromatous patients. Attempts to restore responsiveness in cells from these patients have been unsuccessful in our hands. The addition of exogenous IL-2 to leukocyte cultures does not appear to restore responsiveness to M. leprae in cells from nonresponder patients. Rather, some enhancement, often not antigen specific, is observed in cells from patients with a preexisting response. Similarly, depletion of monocytes does not restore responsiveness to M. leprae in non-responder patients, but a nonspecific enhancement of proliferation is observed in monocyte-free cultures from patients that do respond to M. leprae. Thus, the defect in lepromatous non-responder patients does not result from a simple lack of IL-2 production or suppression by monocytes and/or their products. Possibly, there is a low level or lack of M. leprae responsive T cells in the circulation of these patients.     

Cell-mediated immunity in leprosy and transfer of delayed hypersensitivity reactions

Eighty-nine patients with leprosy, 65 classified as lepromatous and 24 as tuberculoid, were examined in this study. Skin test responses to protein antigens and dinitrochlorobenzene (DNCB) were depressed in lepromatous patients compared to controls. Tuberculoid patients did not exhibit a significant depression to microbial antigens, but they showed a definite depression in the ability to be sensitized with DNCB. The transfer of delayed hypersensitivity reactions to tuberculin, trichophytin, and lepromin (Fernandez and Mitsuda reactions) was accomplished in lepromatous and indeterminate leprosy patients using viable lymphocytes from donors presenting positive reactions to these antigens. The lepromin reaction was also transferred to patients with South American blastomycosis and cutaneous leishmaniasis. The positive reactions of adoptive immunity were confirmed by histologic examination of skin biopsies.     

Antibodies to Mycobacterium tuberculosis-specific epitopes in lepromatous leprosy.

Sera from patients with leprosy or tuberculosis and healthy subjects have been analysed for the presence of antibodies to four species-specific mycobacterial epitopes, four different viruses and five autoantigens. Antibodies to the Mycobacterium leprae-specific 35-kD protein and phenolic glycolipid I epitopes were not present in patients with active pulmonary tuberculosis. In contrast, antibody levels to species-specific epitopes of the 38-kD and 14-kD antigens M. tuberculosis were significantly elevated in patients with lepromatous leprosy. Neither of the two antigens is cross-reactive with M. leprae at the B cell level. However, it was considered that cross-reactive helper T cells could recall the response of M. tuberculosis-specific memory B cells, which had been primed through prior self-healing tuberculous infection. As an alternative explanation, the possible role of polyclonal B cell stimulation was considered. This seemed unlikely, however, since: (i) antibody levels to autoantigens, except anti-smooth muscle, were not elevated, and (ii) antibody levels to four distinct viruses, unlike those to all mycobacterial epitopes, showed no correlation with titres, to M. tuberculosis-specific epitopes.     

Autoantibodies in lepromatous leprosy

Lepromatous leprosy patients often develop erythema nodusum leprosum (ENL) reactions mainly during treatment of the disease. Hence, this study sought to investigate correlation between the prevalence of certain autoantibodies and ENL reactions in these patients. The patients included in the study were fifty patients with lepromatous leprosy and a similar number of normal controls. Sera were collected from the patients and normal controls and the prevalence of circulating rheumatoid factor antinuclear and antismooth muscle antibodies was determined. The prevalence of autoantibodies was increased in lepromatous leprosy as compared with normal controls. The prevalence of these autoantibodies were affected differently by the ENL reactions. ENL lepromatous leprosy showed a slight decrease in prevalence of antinuclear and antismooth muscle antibodies, whereas there was a slight increase in the prevalence of rheumatoid factor in ENL lepromatous leprosy. The levels of serum immunoglobulins tended to show a decline towards ENL lepromatous patients compared with the uncomplicated lepromatous patients. The significance of these finding is discussed in relation to their possible role in the pathogenesis of ENL reaction. It is concluded that some of these autoantibodies and immunoglobulins may be utilized during ENL reactions in the formation of immune complexes.     

Reduced suppressor cell response to Mycobacterium leprae in lepromatous leprosy.

We have previously shown that concanavalin A (ConA) induction of suppressor cell activity is impaired in patients with lepromatous leprosy (LL). In this study, we demonstrated that the proportion of cells bearing the Leu8 antigen (associated with suppressor-inducer cells) is low in LL patients and tends to normalize during the erythema nodosum leprosum (ENL) episode. Antigen-induced suppressor cell function was evaluated by a two-stage assay. In the first stage, peripheral blood mononuclear cells (PBMC) were cultured for 5 days either in the presence of gamma-irradiated Mycobacterium leprae or in tissue culture medium as a control. In the second stage, mitomycin C-treated suppressor or control cells were added to phytohemagglutinin (PHA)- or ConA-stimulated autologous PBMC. The results indicate that the ability of M. leprae to induce suppressor activity was lower in LL patients than in patients with tuberculoid (TT) and intermediate clinical (BB, BL, BT) forms and Mycobacterium bovis BCG-immunized normal controls. In ENL patients, the percent suppression was between that of TT and normal individuals. M. leprae-induced suppression was more effective on ConA- than on PHA-triggered T-cell proliferation in all groups. In contrast, normal PBMC cultured for 5 days in RPMI 1640 medium (N-C) and cells from patients with leprosy (TT-C and LL-C) had effects of their own on PHA- or ConA-induced proliferation. LL-C depressed the response to ConA and enhanced PHA-induced proliferation of autologous cells. Conversely, TT-C reduced PHA-induced proliferation and increased the ConA response. Suppression of proliferation could not be overcome with exogenous interleukin-2 and was not related to the induction of the Tac antigen. The abilities of LL, TT, ENL, and normal cells to proliferate upon PHA or ConA stimulus were similar, indicating that the defect in the generation of in vitro suppression by M. leprae in LL patients occurred during the induction period (step 1 of assay).     

Cell-mediated immunity in anorexia nervosa.

Twelve patients with anorexia nervosa were studied for cell-mediated immunity in terms of delayed hypersensitivity reactions to recall antigens, lymphocyte transformation responses to T-cell mitogens, and numbers of circulating leucocytes and T-cell subpopulations. Compared to controls, all patients had reduced cutaneous reactions and four were anergic. There was a mild leucopenia in patients and both T4+ and T3+ numbers were slightly reduced. Mean peak transformation responses for patients were slightly lower than controls for phytohaemagglutinin, but not for concanavalin A; however, patients required greater doses of mitogens to elicit peak transformation responses. Plasmas from patients did not contain inhibitors of transformation responses. We conclude that there are functional cellular abnormalities associated with the under-nutrition of anorexia nervosa.     

Cell-mediated immunity to Sendai virus infection in mice.

The development of a cell-mediated immune response to Sendai virus infection in mice was examined by the use of a 51Cr release assay of cytotoxicity. A low level of "background cytotoxicity" to Sendai virus-infected L cells was found in the spleens of uninfected CBA mice. Spleen cells from Sendai-infected mice showed an elevated level of cytotoxicity against these target cells for a period of 5 weeks, commencing 4 days after infection of the mice. A more transient response was observed in the spleens of mice infected with a serologically distinct virus, the Kunz strain of influenza. This cross-reacting, cell-mediated immune response was intermediate between that observed in unsensitized and Sendai-sensitized spleen cells. The relevance of these cell-mediated immune responses to respiratory tract virus infections is discussed.     

Cell-mediated immunity to intestinal infection

Specified pathogen-free B6D2F1 mice were orally infected with various doses of Listeria monocytogenes. Oral inocula containing more than 2.5 X 10(8) live organisms consistently initiated infection in the Peyer's patches (PP) of the small intestine. At lower doses the infection was sporadic, with many mice showing no apparent infection in the PP. The PP appeared to be the only site of tissue invasion and L. monocytogenes survival in the intestinal tissues, as no organisms were recovered from mucosa dissected free of all visible PP. Within the PP, the bacteria multiplied and the infection then disseminated to the mesenteric lymph node (MLN), liver, and spleen. However, bacteria were almost completely eliminated from all tissues, both systemic and gut-associated by 6 days postinfection. Mice given a primary L. monocytogenes infection by the oral route were highly resistant to subsequent intravenous or oral challenge. Likewise, sublethal intravenous infection rendered mice highly resistant to subsequent oral infection. In addition, lymphocytes from the PP, MLN, and spleens of mice recovering from a primary oral infection were able to adoptively transfer immunity to normal recipients. Finally, after oral infection, mice did not display peripheral delayed hypersensitivity to L. monocytogenes antigens until the organisms had penetrated to the spleen.     

CD2 expression and function in lepromatous leprosy.

Leprosy is a spectral disease in which clinical presentation is thought to be related to the host immune response. Previous investigations have suggested that selective unresponsiveness to Mycobacterium leprae in patients with lepromatous leprosy is due to the presence of M. leprae-specific T-suppressor cells. However, it has recently been suggested that CD2 modulation was the mechanism for the observed impaired immune response in lepromatous patients. Therefore, we studied the expression of CD2 and CD3 on lymphocytes in lepromatous skin lesions and peripheral blood mononuclear cells (PBMC). Using immunohistochemical techniques, we found that virtually all of the CD3+ cells in leprosy skin lesions expressed CD2. In addition, indirect immunofluorescence flow cytometry demonstrated that most CD3+ cells in the peripheral blood possessed the CD2 marker, suggesting that CD2 expression of T-lymphocytes is normal. T-cell activation using paired anti-T11(2) and anti-T11(3) or anti-CD3 monoclonal antibodies demonstrated similar 3H-thymidine incorporation and gamma interferon production in the PBMC of lepromatous patients in comparison with the PBMC of their contacts and tuberculoid patients. However, lepromatous PBMC did not proliferate or produce gamma interferon in response to M. leprae. Our data suggest not only that CD2 expression is normal on T lymphocytes in lepromatous leprosy skin lesions but also that CD2 expression in peripheral blood lymphocytes is functional in T-cell activation. Defective CD2 modulation does not appear to be the mechanism for specific unresponsiveness in lepromatous leprosy.     

Antibodies against testicular germinal cells in lepromatous leprosy.

Testicular germinal cell antibodies were found in 44 of 59 patients with lepromatous leprosy and in 4 of 10 patients with tuberculoid disease. A similar pattern was found in 12 of 262 controls and normal subjects. The antibody was found to be of the IgG class and 40 of 49 of these antibodies were shown to be complement fixing. Spermatozoal antibodies were detected in 12 patients, but no ovarian antibodies were found in any specimen. There was no close correlation between erythema nodosum leprosum and testicular antibodies. It was found that the characteristic of the testicular antibody in leprosy was its ability to be absorbed by Mycobacterium BCG suspension suggesting that this is another antibody induced by infection. A similar fluorescent pattern was seen in some patients who did not have leprosy, but in these cases, it could not be abolished with BCG. It is concluded that autoimmunity may be 1 of the factors involved in the pathogenesis of orchitis in leprosy.     

Cell-mediated immunity to hepatitis B surface antigen in man.

An aqueous preparation of hepatitis B virus (HBV) vaccine was used as an intradermal skin test antigen to assess delayed hypersensitivity to hepatitis B surface antigen (HBsAg). Thirty-five persons were tested including 10 individuals seronegative for all HBV markers, 10 positive for HBsAg (chronic carriers) and 15 positive for antibody to HBsAg (anti-HBs), five of whom had received the HBV vaccine. All patients were also studied for lymphocyte blastogenic responses to phytohaemagglutinin, concanavalin A, pokeweed mitogen and purified HBsAg. Only one individual had a positive delayed skin test reaction to HBsAg. This person had received the HBV vaccine and had high titres of anti-HBs in serum. However, neither this individual nor any other subject exhibited a positive lymphocyte blastogenic response to HBsAg in vitro. Thus, delayed hypersensitivity skin test reactivity to HBsAg was not detected after natural infection with HBV and was rarely present in hyperimmunized individuals. In vitro assays of immune responsiveness failed to demonstrate cellular immunity to HBsAg even in hyperimmunized persons. These studies provide no evidence that cell-mediated immunity to HBsAg plays a role in the immunopathogenesis of acute or chronic type B hepatitis.     

Cell-mediated immunity in an ageing population.

Eight hundred and eighty patients hospitalized in a geriatric hospital were routinely tested with 2, 10, 30 and 100 i.u. tuberculin. Among these, fifty-four patients were selected on the basis of negative skin tests and absence of evident diseases interfering with the function of the immune apparatus. A battery of tests analysing cell-mediated immunity was applied to those fifty-four patients. It appears that elderly patients having a negative test to 100 i.u. tuberculin show very infrequent sensitization to three other thymus-dependent antigens. The capacity of this selected population to become sensitized to DNCB is poor (20%). Furthermore they exhibit a low per cent of peripheral blood T cells (36%) and a poor capacity to respond in vitro to mitogens such as PHA. Testing the in vitro response to a battery of antigens demonstrates a good correlation with the results of the skin tests. Finally the leucocytes of 25% of this selected population failed to produce LIF in vitro in the presence of PHA. These results suggest not only an absolute decrease in the population of circulating T lymphocytes in those elderly humans; but very likely, at least in some cases, a functional impairment of T cells.     

Cell-mediated immunity in human cytomegalovirus infection.

The direct leukocyte migration inhibition test, in response to cytomegalovirus stimulation, was used to study cell-mediated immunity in a group of children with cytomegalovirus infection. The test was impaired in children with chronic disease associated with cytomegaloviruria. In those cases with no viruria at the moment of the test, leukocyte migration inhibition was normal. Our data suggest that the acquired chronic cytomegalovirus infection may be sustained by a state of specific cellular desensitization, as already demonstrated for congenital infection.     

A case of lepromatous leprosy

The paper describes a case of lepromatous lepra diagnosed from the skin biopsy specimen taken in a 23-year-old male patient. It provides histologic signs that are beneficial for correct diagnosis. Emphasis is placed upon the necessity for staining by the Ziehl-Neelsen method to detect microorganisms in infiltrative and granulomatous skin lesions.     

Cell-mediated immunity in the uremic rat.

The popliteal node assay of the graft-versus-host reaction in the inbred rat provides a sensitive measure of cell-mediated immunity. Spleen cells from uremic Lewis rats as well as normal cells cultured in uremic serum demonstrated significant immunosuppression which was proportional to the severity of the uremia.     

Cell-mediated immunity to cytomegalovirus in patients receiving immunosuppressive therapy.

Employing the techniques of complement-fixation (CF), immunofluorescence (IF), and in vitro lymphocyte transformation (LTF), the humoral antibody response and cell-mediated immune (CMI) response to cytomegalovirus (CMV) were studied in the serum and peripheral blood lymphocytes in 19 normal children (controls) and 23 patients with renal disease who were receiving immunosuppressive therapy or undergoing hemodialysis. The LTF activity was determined by the whole blood microassay using two strains of CMV (AD-169 and Davis) and phytohemagglutinin (PHA). The antibody level responses to CMV in different groups of subjects were generally similar. The LTF response to PHA as evidenced by delta cpm activity was moderately depressed in immunosuppressed and hemodialyzed subjects compared to the response observed in the controls. The mean delta cpm activities in response to AD-169 and Davis strains of CMV in seropositive immunosuppressed patients were about one-fifth and one-third lower respectively than those of seropositive normal controls. These observations suggest that an impairment of CMV specific cellular immunity may be an important mechanism underlying the increased susceptibility to CMV infections in patients with chronic renal disease who receive immunosuppressive therapy.