MHC-derived peptides and the CD4+ T-cell repertoire: implications for autoimmune disease.

The receptor repertoire of peripheral CD4+ cells is primarily determined by selection processes in the thymus. These result in the positive selection of T cells whose receptors weakly recognize self-peptides restricted by class II self-MHC heterodimers. A majority of such self-peptide partial agonists are likely to be derived from self-MHC molecules. It is suggested that these thymically selected, weakly autoreactive T cells may subsequently be stimulated by peripheral exposure to microbially derived agonists that 'mimic' corresponding self-MHC peptides. In turn, 'molecular mimicry' between microbial agonists and tissue-specific self-peptides may lead to T-cell-mediated autoimmune disease. Hence such disease may reflect 'three-way mimicry' between peptides of respectively target tissue, pathogen and self-MHC (or other self-peptide dominantly presented in the thymus). This hypothesis accounts for the role of MHC haplotype in determining susceptibility to (or protection from) autoimmune disease. Direct evidence is presented in favour of the model as applied to diseases such as rheumatoid arthritis, autoimmune uveitus and autoimmune diabetes. Strong circumstantial evidence, based primarily on sequence similarities, is also presented for other autoimmune diseases. However, it is noted that the statistics of database searches, and the lack of predictable correlation between sequence similarity and T-cell cross-reactivity, require that such evidence be substantiated by further direct experiment.

Association of leprosy with HLA-DR2 in a Southern Brazilian population

The association between HLA specificities and lweprosy was investigated in a Southern Brazilian population. One hundred and twenty-one patients and 147 controls were typed for HLA-A, B, Cw, DR and DQ. Patients were subdivided into the following subgroups, according to clinical, histological and immunological criteria: lepromatous (N=55), tuberculoid (N=32), dimorphous (N=20), and indeterminate (N=14). The frequencies of HLA specificities were compared between the total group of patients and controls, and between the same controls and each subgroup of patients. After correction of the probabilities, deviations were not significant, except for the DR2 specificity, which presented a frequency of 44.2% in the total group of patients and 56.3% in the subgroup of invididuals with the tuberculoid from of the disease, compared to 23.3% in the controls. Stratified analysis showed that the increased DR2 frequency in the total group of patients was due to the subgroups with the tuberculoid and dimorphus forms. The relative risk of tuberculoid leprosy for DR2-positive individuals was 4.2 and etiologic fraction of DR2 was 0,429. In conclusion, a positive association of the DR2 specificity with the tuberculoid form of leprosy, but not with the lepromatous, dimorphous, or indeterminate forms, was demonstrated in this Southern Brazilian population

Experimental mycobacterial infections of CBA/N mice.

In an effort to assess the contribution of B-lymphocyte-mediated mechanisms to the immune responses to several mycobacteria, responses to these intracellular pathogens were compared in immunologically normal CBA/CaHN mice and in histocompatible CBA/N (Xid) mice, which exhibit abnormalities of B-lymphocyte function. Swelling in response to local inoculation with Mycobacterium marinum was significantly greater in the hind feet of CBA/CaHN mice than in those of CBA/N mice, but the difference was very small. Survival of mice of both strains after i.v. challenge with M. marinum or i.p. challenge with M. leprae-murium did not differ significantly. Finally, multiplication of M. leprae in the footpads of mice of both strains did not differ significantly. Thus, B-lymphocyte-mediated mechanisms do not appear to be important in the immune responses of mice in experimental infections with these mycobacterial species.

HLA segregation of tuberculoid leprosy: confirmation of the DR2 marker.

Families with multiple cases of leprosy were tested for HLA (histocompatibility leukocyte antigen)-linked control of susceptibility to tuberculoid leprosy and association with HLA-DR2. Thirty-one non-HLA genetic markers were also examined for indications of non-HLA-linked genetic factors that might control susceptibility to tuberculoid leprosy. A significant (P = 0.002) preferential inheritance of HLA-DR2 by siblings affected with tuberculoid leprosy, but not by healthy siblings nor by siblings affected with lepromatous leprosy, was observed. In addition, combined family data showed a significant (P less than 0.0025) excess of identical HLA haplotypes inherited from healthy parents by siblings affected with tuberculoid leprosy. Segregation on non-HLA polymorphisms did not deviate significantly from what would have occured randomly. These data are compatible with a recessive inheritance of HLA-linked susceptibility to tuberculoid leprosy. The preferential segregation of DR2 observed in children with tuberculoid leprosy (P less than 0.001 for the combined data from India) indicates that the HLA-linked susceptibility gene is either DR2 or in linkage disequilibrium with it.

A study of cell-mediated immunity and histocompatibility antigens in leprosy patients in Iran.

Fifty-six male and 14 female leprosy patients, aged 11-62, were studied for cell-mediated immunity (CMI) and histocompatibility antigens. Healthy blood donors were used as normal controls. All patients were receiving antileprosy drugs. T and B cells were detected by E and EAC rosette formation technics, and the leukocyte migration test (LMT) was done in the presence of PHA. HLA antigens were defined by a modified N.I.H. lymphocytotoxicity test in order to type 48 patients and 100 controls. There was a significant difference (p less than 0.01) in the number of T cells between tuberculoid and lepromatous forms of the disease as compared to normal controls. We did not observe any differences in EAC rosette cells. It should be noted that the migration index is significantly higher in controls than in leprosy patients for PHA. There are no significant differences in the distribution of the A locus antigens between leprosy patients and controls, although a higher percentage of A-11 was obtained in leprosy patients. A slight elevation of B5 antigen was observed but these results are preliminary and our information regarding the B locus is incomplete. Thus, it is difficult to establish any precise relationship between HLA antigen and leprosy at this stage.

An examination of HLA frequencies in three age groups.

The question as to whether the distribution of HLA antigens differs between old and young persons has been studied only in a few population groups. There are observations showing an increase of heterozygosity of the HLA system (Bender et al. 1973, Gerkins et al. 1974) which indicate an advantage of heterozygosity for survival, but other studies fail to confirm this finding )Albert et al. 1974, Mucurová et al. 1975, Bender et al. 1976). Since the present authors, in a study of HLA gene frequencies on five small Danish islands (Hansen et al. 1974) had found a tendency to a changed frequency of certain HLA types among the oldest persons, it was decided to examine this question by typing larger numbers of persons of different age groups.

Histocompatibility antigens in patients with leprosy.

The frequencies of distribution of 25 histocompatibility antigens were determined in 92 Mexican patients with leprosy and compared with those in 315 Mexicans who did not have the disease. No statistically significant differences were found between the patients and the controls in regard to histocompatibility antigens, and subgroups with a significant difference could not be identified by division of the patients according to the density of Mycobacterium leprae or the presence or absence of cell-mediated immunity directed against antigens of M. leprae.

HLA-linked genetic control of host response to Mycobacterium leprae.

Non-random parental HLA-haplotype segregation is demonstrated in siblings with leprosy. A new method is described for the statistical analysis of non-random segregation among sibships of different sizes. Sibs with the same type of leprosy show a significant excess of identical HLA haplotypes. This is also true for families in which only tuberculoid leprosy is found, which is by far the commonest type in the population studied. However, sibs affected with different types of leprosy share a haplotype less often than expected. This indicates that both susceptibility to and type of leprosy are controlled by at least two HLA-linked genes. Our findings suggest that the equivocal results of previous population studies are due to differences of linkage disequilibrium between HLA-linked genes controlling the host response to Mycobacterium leprae and alleles of HLA A and B loci in various populations.

Histocompatibility antigens (HL-A) in leprosy.

HL-A antigens of 70 leprosy patients and 40 normal healthy individuals were determined by the standard microlymphocytotoxicity test. Both lepromatous and non-lepromatous leprosy patients were tested for the presence of 11 HL-A antigens, and the frequency of each specificity was compared with that in a normal population of the same ethnic group. Although the statistical significance of HL-A8 specificity was found to be marginal in lepromatous leprosy patients, when using ordinary 2 times 2 statistics, there did seem to be a decreased frequency of HL-A9 among the non-lepromatous type. Other antigens tested did not reveal any significant differences between the two groups of subjects.

Histocompatibility antigens in leprosy.

Results of HL-A typing are presented in 82 patients with leprosy and 50 normal Filipinos from Cebu, and 144 normal Filipino immigrants from the Luzon area. Comparisons of HL-A antigen frequencies among the total patients and normals of Cebu showed no statistically significant differences; however, HL-A10 was increased in frequency among the patients with lepromatous disease compared to the normals, and HL-A5 was increased among the tuberculoid patients compared to the lepromatous patients. None of these comparisons was statistically significant when corrected for the number of antigens tested. Comparisons of HL-A antigen frequencies between normal Filipinos of the Cebu and Luzon regions showed increased W-5 in the Luzon population (corrected p smaller than 0.025).

T Cells in immunodeficiencies as evaluated by an antihuman T-cell serum.

An antihuman T-cell has been prepared in rabbits by infecting lymphocytes from a patient with Bruton-type agammaglobulinemia and absorption with cultured B-lymphoblast cells. Cytotoxicity of the antiserum was assayed with peripheral blood lymphocytes in the presence of rabbit complement and its specificity for T vs B cells was verified. This anti-T-cell serum killed 66% (range 49-78) of normal blood lymphocytes. In patients with Bruton-type agammaglobulinemia the percentage of cells sensitive to the antiserum was above normal (77-89%), whereas it was decreased in some patients with lepromatous leprosy or under antilymphocyte globulin therapy.