Biomedical subjects
Publications and source records attributed to N K Mehra.
Nine multiplex RA families of North Indian origin were tissue typed to determine the segregation of parental haplotypes among sibs. The assortment of haplotypes in 18 affected sibs was not random, with seven sib pairs being HLA identical and two haploidentical with the proband (P = 0.0007). HLA-DR4 occurred in eight out of nine probands (88.8%) and in 11 out of 13 familial RA subjects (84.6%).
The quantitation of cells bearing CD3, CD4, CD8, and B cell phenotypic markers, as well as an estimation of serum immunoglobulin (Ig)G, IgA, and IgM, was carried out in a group of 39 glioma patients with different grades of malignancy. The findings were compared with those obtained from 21 normal healthy control subjects. The analysis revealed a significant decrease both in the absolute numbers and in the percentages of circulating CD3+ (p less than 0.001) and CD4+ (p less than 0.001) cells, while the CD8+ and Pan B+ cells remained within the normal range irrespective of the type and grade of tumor. The CD4+:CD8+ ratio was significantly decreased in all categories of patients. The CD4 lymphopenia was also evident in 10 patients who had no history of previous immunosuppressive drug therapy (steroids and anticonvulsants) until the commencement of the study. The Ig levels were within the normal range in patients with malignant astrocytoma and glioblastoma multiforme, whereas a three- and fourfold increase in the IgM level was observed in patients with astrocytoma. It is suggested that T cell lymphopenia in glioma patients could mainly be due to a selective depletion of CD4+ cells and that it occurs principally as a reaction to the tumor.
Up-to-date available data on HLA and sarcoidosis suggest that: 1. HLA-B8 and -DR3 occur in association with acute form of sarcoidosis. 2. There is no "linkage" of HLA associated alleles with the disease susceptibility gene(s) in sarcoidosis.
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Studies to find engraftment following fetal liver infusion (FLI) in aplastic anaemia (AA) and acute myeloid leukaemia (AML) were carried out in 24 patients (17 AA and 7 AML patients) out of the 56 who received FLI. HLA studies done in 13 patients (3 AA and 5 AML), repeatedly after FLI, showed no significant change in HLA antigen pattern before and after FLI. Red cell antigen studies were done in five (1 AA and 4 AML) patients, 3 weeks to 7 months after FLI. One patient with AML who was Rh negative prior to reinduction chemotherapy became Rh positive two months after FLI; six months later he was Rh negative again. In the remaining patients there was no change in red cell antigen pattern after FLI. Radio-immuno-assay to detect alpha-fetoprotein levels, carried out in 10 (8 AA and 2 AML) patients repeatedly after FLI, demonstrated no increase. In 13 patients (8 AA and 5 AML) in whom there was a sex difference between donor and recipient, bone marrow cultures for sex chromosomes revealed mixture of XX and XY cells in 3 male patients with aplastic anaemia. One male patient with AML demonstrated complete engraftment after induction chemotherapy and FLI: all the mitoses studied were of XX pattern. Engraftment was however temporary as repeated studies revealed reversion to XY pattern. The present work suggests that infusion of fetal liver cells may sometimes induce temporary chimerism or engraftment in an adult host; in the majority of cases, however, engraftment could not be established.
Fetal liver infusion (FLI) was tried as an alternate mode of therapy in 40 patients with aplastic anaemia and in 16 patients with acute myeloid leukaemia. The fetal HLA typing carried out on spleen and thymus cells revealed that, while it was more difficult to HLA type the thymus than the spleen cells, 'full house' antigens could be determined only in fetuses of 18 weeks or older. No special effort was made to transfuse HLA- matched or partially matched donor cells into the recipient. The recipients were HLA typed at varying time intervals following FLI in an attempt to document a possible chimerism. None of the patients revealed a 'shift' in their HLA antigen profile and there was no evidence of any donor cell engraftment. No relationship between the HLA match of donor and recipient, and the general condition, the prognosis or the total survival of the patient was evidenced. These data indicate that, even though fetal liver cells express HLA antigens, these cells are functionally incompetent to cause an apparent graft-versus-host disease in the host.
Forty-eight unrelated North Indian patients with non-cirrhotic portal fibrosis were studied for the distribution of HLA-A, B and DR antigens. No significant differences were observed in the distribution of HLA-A and B locus antigens. In the DR locus, the frequency of DR3 was significantly increased in the patients as compared to the controls (71.7% vs 26.1%, X2 = 25.3), while HLA-DR2 was significantly reduced (X2 = 11.3). Another striking observation was the presence of DR7 in all males negative for HLA-DR3. The results suggest an autoimmune pathogenesis of the disease and that susceptibility to non-cirrhotic portal fibrosis may be HLA class II mediated, with HLA-DR3 influencing susceptibility and DR2 conferring protection. Other genetic factors are also involved.
Noncirrhotic portal fibrosis is a common cause of portal hypertension in India. We report four families with more than one member afflicted with this disorder. Six of the seven (85.5%) patients in whom HLA studies were carried out were HLA-DR 3 positive. The possibility of an immunogenetic basis of noncirrhotic portal fibrosis should be investigated further.
The HLA haplotype segregation and autoantibody spectrum in 7 type I (insulin-dependent) diabetic multiplex families of North Indian origin were determined. Of the total of 17 diabetic sibs, 7 shared both haplotypes and 3 shared one haplotype with the proband. No HLA-non-identical sibs were observed. This distribution of haplotypes was non-random (P approximately equal to 0.005). The mode of inheritance was compatible with an autosomal recessive model, while a dominant model was unlikely. Pancreatic islet-cell antibodies were found in 23.5% of affected sibs, but in no healthy family member. A high incidence of other autoantibodies (parietal-cell and thyroglobulin/thyroid microsomal antibodies) was detected in both the diabetic patients (26.3%), and in healthy first-degree relatives (22.2%). These findings emphasize the role of HLA-linked genes and autoimmunity in the pathogenesis of type I diabetes in North India.
The Indian population can be divided broadly into Dravidians and the Aryans. In this report, we have attempted to analyze the HLA genetic profile of 400 native North Indian Hindus of Aryan descent. The gene frequencies of a majority of class I and II antigens show similarity to the Caucasoid population. An interesting finding was a complete lack of antigen B14 while B16 and B41 occurred with the least frequency. Haplotype A10, B8 with significant positive linkage disequilibrium as well as showing the highest incidence is characteristic of North Indians.
The distribution of HLA-A, -B and -DR antigens as well as blood groups and secretor status was studied in sporadic, North Indian patients of rheumatic fever and rheumatic heart disease. While HLA-Aw33 occurred with an increased frequency in the patient group (X2 = 4.01), no statistically significant differences were observed in the frequency of B-locus antigens. In the DR locus, HLA-DR3 was found to be significantly increased (50% vs 26.1%, X2 = 13.8) and DR2 significantly reduced (21.8% vs 47.0%, X2 = 15.6). Also, there was a preponderance of non-'O' blood group individuals in the patient group as compared to controls. The DR3 association was significant only in those patients of RHD who did not have any previous history of rheumatic fever. These results indicate that susceptibility to rheumatic heart disease is HLA-class II mediated, with HLA-DR3 influencing susceptibility and DR2 conferring protection.
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In order to clarify the discrepancy between population studies showing association of rheumatoid arthritis (RA) with HLA-DR4/Dw4 and family studies failing to show linkage with HLA, we analysed 16 multicase families in which RA and DR4 status of both parents was known. 120 HLA-haplotypes of affected and unaffected children could be analysed for co-segregation with RA. In a combined analysis of both affected and unaffected children co-segregation of RA with the DR4 carrying haplotype was observed when both parents were unaffected (p = 0.001). Co-Segregation of RA with one of the two haplotypes of affected parents was observed (p = 0.01), but in this case there was no preference for the DR4 carrying haplotype. In both cases preferential inheritance of the other (not associated with RA) haplotype was observed in unaffected siblings. These data indicate that susceptibility to RA is controlled by an HLA-linked gene. This gene is often but not always identical to the gene coding for a product carrying the DR4 epitope or in strong linkage disequilibrium with it. Combined with previous population data, the present data provide evidence for genetic heterogeneity of RA. Finally, they contain a paradox, based on which a new hypothesis for HLA-linked susceptibility to RA is formulated.
Eighty-eight North Indian patients with type I, insulin-dependent diabetes mellitus (IDDM) and 113 unaffected individuals were typed for HLA-DR antigens from DR1 to DR7. The frequency of HLA-DR3 was significantly increased in the patients as compared with the controls (78.4% versus 25.7%, corrected P = 1.68 X 10(-12], the relative risk (RR) of 10.52 being much higher than that reported in the Western IDDM population. HLA-DR2 showed a significant negative association (RR = 0.18, corrected P = 1.03 X 10(-5], but DR4 had no relationship with IDDM in the present study (RR = 1.12, P = 0.12). These results emphasize the differences in HLA-IDDM associations among different ethnic groups.
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The HLA antigen profile of 129 North Indian patients with ankylosing spondylitis, 66 patients with Reiter's syndrome and 57 patients with 'unclassifiable' arthritis was compared with 380 normal, healthy controls. Besides B27 which appeared with a significantly increased frequency in the three patient groups, other HLA antigens, viz. A2 and B35, showed deviated frequencies. The HLA supratype A2, B27 was found to be at an elevated frequency in patients with ankylosing spondylitis and unclassifiable arthritis whereas the B35, B27 combination showed a decreased frequency in our Reiter's syndrome sample. These data suggest that besides B27, other HLA-linked factors influence susceptibility to spondylitic disorders and might act as 'modifier' genes for the type and severity of spondylo-arthropathy in a B27-positive individual.