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A study of pemphigus in New Delhi, India, and Oxford, UK, was undertaken including 20 patients in Oxford and 50 in New Delhi. Data included clinical and histological subtypes and socio-economic data; patients were HLA typed. In New Delhi pemphigus vulgaris predominated, but in Oxford pemphigus vulgaris and pemphigus foliaceus have equal prevalence. Disease distribution with sex was the same, but age at onset was significantly lower in New Delhi (p = 0.0019). HLA typing in pemphigus vulgaris patients revealed a significant reduction in HLA-DR2 in New Delhi (p = 0.0008) and Oxford (p = 0.09). A small increase in HLA-DR1 and -DR4 was found in both groups and, in males only, a subtle increase in HLA-DR6 and reduction in HLA-DR3. No differences were found in the class I antigens. Thus there are striking differences in the types of pemphigus between the two populations, yet the genetic predisposition is the same.

Old Fort Lake, a small (1.6 ha), shallow, and recreational water body in Delhi (India) was studied through monthly surveys in two consecutive years (January, 2000–December, 2001). Precipitation is the major source of water for this closed basin lake. In addition, ground water is used for replenishing the lake regularly. This alkaline, hyposaline hard water lake contains very high ionic concentration, especially of nitrates. Based on overall ionic composition, this lake can be categorized as chloride–sulfate alkaline waters with the anion sequence dominated by SO42− > Cl− > HCO3−, and the cations by Mg++ > Ca++. The overall seasonal variability in physicochemical profile was largely regulated by the annual cycle of evaporation and precipitation, whereas the ground water largely influences its water quality. The lake exhibited phytoplankton-dominated turbid state due to dominance of the blue green alga, Microcystis aeruginosa. The persistent cyanobacterial blooms and the elevated nutrient levels are indicative of the cultural eutrophication of the lake. This study focuses on the relative importance of eutrophic vis-a-vis hyposaline conditions in determining the structure and seasonal dynamics of zooplankton species assemblages. A total of 52 zooplankton species were recorded and rotifers dominated the community structure qualitatively as well as quantitatively. The genus Brachionus comprised a significant component of zooplankton community with B. plicatilis as the most dominant species. The other common taxa were B. quadridentatus, B. angularis, Lecane grandis, L. thalera, L. punctata, Mesocyclops sp., and Alona rectangula. Multivariate data analysis techniques, Canonical Correspondence Analysis (CCA) along with Monte Carlo Permutation Tests were used to determine the minimum number of environmental factors that could explain statistically significant (P < 0.05) proportions of variation in the species data. The significant variables selected by CCA were NH3–N followed by percent saturation of DO, COD, SS, BOD, NO2–N, rainfall, silicates, and PO4–P. The results indicate that the seasonal succession patterns of the zooplankton species were largely controlled by physicochemical factors related directly or indirectly to the process of eutrophication, whereas hyposaline conditions in the lake determined the characteristic species composition.

Major Histocompatibility Complex and Future Vaccination Strategies

(1998). Laboratory studies on the colonization and succession patterns of periphytic microbiota on artificial and natural substrates. SIL Proceedings, 1922-2010: Vol. 26, No. 4, pp. 1614-1620.

The impact of fly ash on the biology of the Yamuna River, Delhi, was studied. Effluents come from a 200 MW capacity I.P. thermal power station. Seasonal variations in the biological features in the non-impacted (Y-1) and the impacted (Y-2) segments of the river receiving fly ash effluents were studied. 60 genera of phytoplankton including 29 Chlorophyceae, 19 Bacillariophyceae, 8 Cyanobacteria, and 4 Euglenophyceae were recorded. Phytoplankton diversity was reduced at the impacted site in comparison to the non-impacted site of the river and substantial changes in the composition of various groups inhabiting these areas were observed. Zooplankton were also reduced at Y-2 compared to Y-1, especially rotifers and protozoans, while copepods and nauplii larvae were not affected to the same degree. Species diversity was not significantly different at Y-2 and Y-1 but similarity index varied from low to high between the two stations. Thus, not only was the density, number of genera and diversity reduced, even the generic composition of the plankton was markedly affected in the impacted waters. The observed perturbations could be due to sedimentation of ash particles, pH or elevated metal or salt concentration. A change in the concentration of one or more constituents disturbs the relationship between biota and could be the possible cause of reduced densities in the impacted waters.

Evaluation of human histocompatibility leukocyte antigen (HLA) class II genes in 54 cases of tuberculoid leprosy (TL) and 44 controls has shown a positive association with HLA-DRB1 alleles that contain Arg13 or Arg70-Arg71. Among TL patients, 87% carry specific alleles of DRB1 Arg13 or Arg70-Arg71 as compared to 43% among controls (p = 5 x 10(-6)) conferring a relative risk of 8.8. Thus, susceptibility to TL involves three critical amino acid positions of the beta chain, the side chains of which, when modeled on the DR1 crystal structure, line a pocket (pocket 4) accommodating the side chain of a bound peptide. This study suggests that disease susceptibility may be determined by the independent contribution of polymorphic residues participating in the formation of a functional arrangement (i.e., pocket) within the binding cleft of an HLA molecule.

Unclassifiable seronegative spondyloarthropathy (SSA) syndrome is primarily considered to be an affliction of males. In this report from northern India, 25 HLA-B27 antigen positive females with this condition are described and compared with 39 HLA-B27-positive males with the same disease. All these patients presented with typical features of spondyloarthropathy such as predominantly lower limb synovitis, enthesopathy and inflammatory spinal pain. The onset was insidious in 56% of the females and in 64% of the males. The mean age of onset as also the mean duration of symptoms prior to diagnosis were significantly higher in females (26.2 vs 19.4 yr and 8 vs 2 yr, respectively). A mono- or oligo-arthritis was seen in 52% of the females and in 53% of the males, but the average number of joints involved was less in females (4.8 vs 7.7). Lower limb joints alone were involved in 56% of the females and 49% of the males, with the knees, ankles and hips being most commonly involved, often asymmetrically. The mean degree of symmetry was significantly lower in females (62 vs 76). Ninety-two per cent of females and 74% of males had inflammatory spinal pain. Radiographic sacroiliitis was demonstrable in 56% females and 74% males. It is concluded that 'unclassifiable' SSA syndrome is not infrequent in females but is diagnosed late. Fewer joints tend to be involved and there is greater tendency towards asymmetry in females.

We report our experience and long-term outcome of pediatric renal transplantation at a referral center in New Delhi. During 1995-2008, 45 transplants were performed in 43 patients at a mean age of 13.3 ± 4.0 (range 3.8-18) yr. The chief causes for ESRD were reflux nephropathy, obstructive uropathy, vasculitis, renal dysplasia, and focal segmental glomerulosclerosis. Most (91.1%) donors were living related. Post-transplant immunosuppression comprised prednisolone, a calcineurin inhibitor and azathioprine or MMF. AR and CR were seen in 14 (31.1%) and 12 (26.7%) allografts, respectively. Predictors of CR were unsatisfactory compliance and multiple episodes of AR (p = 0.002 each). Urinary infections (n = 13), septicemia (4), tuberculosis (4), CMV disease (7), viral hepatitis (7), and pneumonia (3) were important causes of morbidity. Two patients each had lymphoproliferative disease and new-onset diabetes. There were eight (17.8%) graft losses and six (14%) deaths. The one-, five- and 10-yr graft survivals were 91.1%, 80.4% and 75.1%, respectively; the mean graft survival was 119.4 ± 8.38 months. The respective patient survivals were 95.3%, 87.9%, and 76.9% at one-, five- and 10 yr. Our results affirm that despite scarcity of resources and frequent infections, long-term outcomes of pediatric renal transplantation are highly satisfactory.

The objective of this study was to evaluate the donor-specific antibody repertoire against T and B cells and monocytes, as well as the non-donor anti-HLA, and MICA (MHC class I-related chain A) antibodies in recipients of the live related donor renal transplantation. Sera collected before and after transplantation were tested by ELISA for the presence of HLA class I- and class II-specific antibodies and by Luminex MICA single-antigen bead assay for the detection of MICA antibodies. Patients having a combination of both anti-HLA and MICA antibodies had worse graft survival and more rejection episodes as compared to the group without antibodies. Further, presence of IgG antibodies against the donor cells (T, Bmonocytes) led to a compromised graft survival along with higher incidence of acute rejection as compared to the negative groups. These results suggest that a comprehensive assessment of anti-donor antibody repertoire and monitoring of anti-HLA, MICA antibodies following transplantation is a useful exercise to detect the sensitization status of the recipient and this can prove to be of immense prognostic value in renal transplantation.

Insulin-dependent diabetes mellitus is associated with renal failure, diabetic retinopathy, neuropathy and vasculopathy. We report the first successful simultaneous pancreas-kidney transplant in India in a young diabetic with renal failure. The dual transplant has cured his diabetes and renal failure and has had a beneficial effect on his neuropathy, retinopathy and quality of life. Obstacles to dual transplant in India include a lack of suitable recipients and a cadaver donor programme that is still in its infancy.

Mutations in the HFE gene have been shown to be strongly associated with hereditary haemochromatosis, an autosomal recessive disease of iron overloading. The majority of patients with hereditary haemochromatosis possess a homozygous mutation C282Y that disrupts the binding of the HFE gene with beta2 microglobulin and prevents its surface expression. Another HFE mutation H63D is known to increase the relative risk of developing hereditary haemochromatosis. This disease is rare in India although secondary haemochromatosis is commonly seen among children suffering from thalassaemia major. The status of HFE mutations has not been explored among Indians, particularly in patients with thalassaemia major. It is also possible that in India clinical haemochromatosis could be masked by iron deficiency.We examined a cohort of 59 unrelated, healthy individuals from north India, 57 from south India and 75 thalassaemia major patients from north India for HFE mutations (C282Y and H63D) in cis/trans by the polymerase chain reaction sequence-specific primer method.The C282Y and H63D mutations in the HFE gene were rare among Indians. Although the HFE mutations were increased among patients of thalassaemia their effect on iron burden or disease pathogenesis remains unclear.Hereditary haemochromatosis is rarely observed among Indians and so are the C282Y and H63D mutations in the HFE gene. Long-term follow up studies would be required to determine whether the relatively higher frequency of these mutations among patients of thalassaemia has any influence on iron accumulation.

There are seventeen drains, which discharge their untreated urban and industrial wastewaters into the Delhi segment of river Yamuna. The Najafgarh drain is the first and the largest drain, and it alone contributes 1667.84 mld i.e. 60% of the total wastewater discharge into the river Yamuna and as such add 81.36 tons of BOD load per day. As per the available data approximately 95% of the wastewater of this drain is biodegradable. In the present study, an attempt has been made to reduce the BOD load and COD levels of wastewater of Najafgarh drain using autochthonous microbial consortium. During this study the raw wastewater samples were treated for 6 h time interval with different concentration of consortium. It was observed that by increasing the existing microbial population in the wastewater sample by 150-200% there is a significant decrease in BOD and COD levels. Finally, BOD/COD ratios before and after biotreatment have been analyzed to assess the efficacy of the natural consortium.

The aim of this study was to determine whether a common diabetic haplotype, including human leukocyte antigen (HLA)-B8 and HLA-DR3, in Northern India is the same haplotype as the European HLA-B8-DR3 haplotype. DNA samples from Northern Indian subjects selected on the basis of HLA-B8 and HLA-DR3 were tested for microsatellite and single nucleotide polymorphism alleles throughout the major histocompatibility complex (MHC). It was found that the Indian samples represent a conserved haplotype in which all alleles were shared by Indian subjects with HLA-B8 and HLA-DR3, but were different to those that are characteristic of the European 8.1 ancestral haplotype. The Indian and European haplotypes share HLA-B*0801, HLA-DRB1*0301 and HLA-DQB1*02 but differ for subtypes of HLA-Cw*07 and HLA-DRB3 and all central MHC alleles tested. In contrast, Indian subjects selected on the basis of HLA-B58 ( 1-17) and HLA-DR3 shared the same alleles at other MHC loci as have been described in the common Chinese haplotype with HLA-B58/17 and HLA-DR3. A third haplotype, HLA-B50/21 and HLA-DR3, was also found to be highly conserved but shares little in common with the other two HLA-DR3-containing Indian haplotypes.

The present study aims to determine the genetic diversity of the HLA-A19 allelic family in the North Indian and Japanese populations. The HLA-A*19 group of alleles occurred at similar frequencies in North Indians and Japanese as in Caucasians. All the known serological splits of HLA-A19 were observed among the North Indians, i.e. A*33 (15.6%), A*32 (8.6%), A*31 (3.5%), A*30 (3%), A*29 (1.2%) and A*74 (0.77%), while only A*30 (0.7%), A*31 (17.6%) and A*33 (11.7%) were observed in the Japanese. High resolution analysis indicated that the A*29, A*30, A*31 and A*32 alleles were represented by only single subtypes among the North Indians while the HLA-A*33 group comprised two alleles, A*3301 (4.3%) and A*3303 (43.7%). All 15 of the HLA-A*33 positive samples from the Tamil population of South India were found to be A*3303. One novel subtype of A*33, A*3306 was also observed in the North Indian sample. Conversely, only one subtype each of A*30, A*31 and A*33 was encountered in the Japanese population, of which A*3101 and A*3303 were the most frequent (58.5% and 39%, respectively, among the HLA-A*19 group of alleles). All other subtypes of A19 were not found in the Japanese in the present study. The study suggests a significant amount of genetic admixture in the North Indian gene pool from other racial groups, with profound oriental influence.

Living unrelated donor (LURD) renal transplantation has shown a rising trend over the last 5 yr at our center following the passing of The Transplantation of Human Organs Act by the Government of India in 1994. In this paper, the results of LURD and cadaver (CAD) donor renal transplantation are compared. We have also looked into factors that have a bearing on graft survival such as the extent of HLA mismatch (MM), infections, acute rejections (AR), donor age and sex.A total of 42 LURD and 25 CAD renal transplants performed between March 1994 and February 1999 has been included in the study. HLA typing, panel reactive antibody (PRA) screening and T and B cell cross match assay were performed by the complement dependent cytotoxicity (CDC) method for all patients.The graft survival rates were generally higher in the LURD category as compared to the CAD group and were significant at 6 month period (90 vs 56%, P = 0.002). A follow up of the patients up to 60 months revealed a matching effect since the 3, 4 allele MM group had better survival rates as compared to the 5, 6 MM group. Twenty six of the 67 recipients (39%) experienced episodes of acute rejection (AR). Patients with 3, 4 MM had fewer such episodes than those with 5, 6 allele MM (P0.05). Of the 32 deaths, 20 were those with a functional kidney, of which 15 were caused by severe infections.Better HLA matching ensures fewer episodes of rejection and better long term graft survival in comparison to the poorly matched grafts. The graft survival for LURD recipients was appreciably higher than that of CAD recipients.

The North Indians are considered predominantly Caucasoid with an admixture of genes from the Mongoloid and Aryan races. The present study was undertaken to investigate the genetic diversity of HLA-A*02 in the North Indian population and determine the frequency distribution of its molecular subtypes at the population level. The study revealed a high occurrence of A*0211 (33.8%) in this population along with increased frequencies of the common Oriental alleles, A*0206 (7.5%) and A*0207 (32.5%) and also of HLA-A*0205 (15%) commonly observed in negroid populations. HLA-A*0211 has only been reported with very low frequencies among the Ticuna Jews, Thai population, and Colombian Blacks in the malaria endemic areas of Africa. Significantly, we observed an unexpectedly low frequency of A*0201 (3.8%) in contrast to its distribution in Western Caucasians in whom it constitutes 95% of the HLA-A2 repertoire. Prevalence of HLA-A*0211 at very high frequencies among North Indians may be a consequence of the founder effect, racial admixture or selection pressure due to environmental factors in this population.

Takayasu's arteritis (TA) and thrombangiitis obliterans (Buerger's disease) are idiopathic, inflammatory arteriopathies with strong indications for the involvement of autoimmunity and host genetic factors in their immunopathogenesis. The exact etiology of these arteriopathies still remains unknown even after almost nine decades of their description. A series of immunogenetic studies conducted worldwide seeking to define genetic factors in governing immune response in these diseases have yielded conflicting results on the involvement of HLA molecules. While an association of HLA-B5 or its molecular subtypes with Takayasu's arteriitis has been emphasized in patients from Japan, Korea and India, no such association has been reported in Mexican and North American patients. On the other hand, a limited data is available on the association of HLA antigens with Buerger's disease. In this article, we provide an overview of the immunogenetics of Buerger's disease and Takayasu's arteriitis in the context of studies in North Indian patients and those in other ethnic groups. Our studies indicate a positive association of Takayasu's arteriitis with the HLA-B5 molecule with no preferential association with its two major subtypes. In Buerger's disease, we have observed a strong positive association with HLA-DRB1*1501 consistent with the findings in Japanese patients. These results suggest an important role of HLA linked factors in governing susceptibility to both arteriopathies.

Cold reactive lymphocytotoxic antibodies (LCA) are more reactive in cold than at 37 degrees C and occur following infection, immunization or vaccination and in various autoimmune diseases. In the present study, LCA activity against T and B-lymphocytes has been investigated in patients with pulmonary tuberculosis (PTB), their various clinical sub-groups and consanguineous relatives. Further, the relevance of HLA factors in LCA activity was analyzed. The sera from 144 PTB patients, 52 family contacts and 52 healthy individuals were tested for presence of LCAs by a modified two-stage NIH microlymphocytotoxicity assay. A significant increase in LCA activity against both T (32.6% vs 5.7%, P0.0001) and B (59.7% vs 13.4%, P0.0000001) cells was observed in PTB patients as compared to healthy controls. There was no correlation between serum LCA activity and sputum acid-fast bacilli status. However, only B cell LCAs revealed significant increase in parallel to disease advancement as assessed by X-ray chest examination. Further, LCA activity was more pronounced in drug responders than drug failure group of patients. No significant difference in the distribution of HLA class I and class II antigens was observed between LCA positive and LCA negative patients. However, panel cells carrying HLA-A1, -A11 and -DR3 were often found reactive in LCA positive patient sera. In household family contacts, LCAs were significantly increased only against B cells as compared to healthy controls (38.4% vs 13.4%, P0.01). This study suggests that Mycobacterium tuberculosis infection/exposure could account for the occurrence of LCAs in pulmonary tuberculosis and the strength of these antibodies is related to disease severity and the extent of lung involvement.

Heat shock proteins (HSP) act as immunological target structures either by themselves because of an unusual expression pattern, or they are carrier proteins for immunogenic peptides. A three-allele polymorphism of HSP70-1 promoter region was analysed in random patients with pulmonary tuberculosis (PTB), or with tuberculoid (TT) leprosy and healthy controls from North India. HSP70-1A and HSP70-1C occurred more frequently (60%) while HSP70-1B occurred infrequently in this population. Only HSP70-1A allele was significantly increased in TT leprosy as compared to healthy controls (91.8% Vs 71.1%, Pc0.03, RR = 4.58). Although a strong association of HLA-DR15 was observed with both of these patient groups in earlier studies, no correlation was found between HSP70-1 promoter alleles with any of the HLA allotypes. Amongst six possible genotype combinations of HSP70-1 promoter allele, only four (A/A, A/B, A/C, C/C) were encountered in Asian Indians. A significant increase of HSP70-1 A/C genotype was observed among DR15 negative PTB patients as compared to DR15 negative controls (87.5% Vs 35.7%, X2 = 8.6, Pc0.02) giving highest relative risk of 12.6. These findings suggest that HSP70-1 genes may play a secondary role to HLA-DR in governing susceptibility to mycobacterial infectious diseases.

HLA class I antigen profile was studied in 153 unrelated patients with pulmonary tuberculosis (PTB), 40 family contacts and 289 healthy individuals by the NIH microlymphocytotoxicity test to find out the role of HLA-A, -B, -C alleles in influencing susceptibility to PTB and its various clinical groups. HLA-A2 was found to be significantly increased in the total patient group as compared to controls (38.6% vs 26.3%, p0.01, RR = 1.76). The increase of HLA-A2 was more pronounced in the sputum negative patients (59.4%, pc0.001, RR = 4.1) suggesting its possible role in the mediation of CD8+ suppressor T cell activity against Mycobacterium tuberculosis, resulting in the development of limited disease in these patients. Further, HLA-B18 was found to be decreased in patients as compared to controls (2.6% vs 7.3%, p0.05, RR = 0.34). None of the class I antigens was associated with the dynamics of chemotherapy or disease severity as assessed by the extent of lung involvement on chest X-ray examination.

The purpose of the present study was to determine the profile of HLA class I antigens, antinuclear antibodies (ANA), and antineutrophil cytoplasmic antibodies (ANCA) in ulcerative colitis (UC) patients from Northern India.The study consisted of 100 UC patients with or without extraintestinal manifestations. Data on HLA, ANA, and ANCA were analyzed with respect to age at onset, sex, duration of disease, and occurrence of extraintestinal manifestations, and data were correlated with those of healthy controls from the same population.The most common extraintestinal manifestations in order of occurrence were arthralgia (53.8%), ocular lesions (18%), sacroiliitis (12.7%), hepatobiliary (7.7%), cutaneous (5%), and vascular (2.6%). ANA and ANCA were positive in only 3% of cases. Of the HLA class I antigens, HLA-A19 was significantly increased in UC patients compared with controls (63.4% vs. 33.5%, p0.001, RR = 3.4), particularly its subtype HLA-A33 (20.7% vs. 4%, p0.001, RR = 6.3). There was no deviation in the frequency of HLA-B locus antigens, whereas HLA-Cw6 was increased significantly in patients compared with controls (14.6% vs. 3.5%, p0.001, RR = 4.4).The occurrence of extraintestinal manifestations in Indian patients with UC is similar to that reported elsewhere, although ANA and ANCA positivity is lower. HLA studies revealed that A19(33) and Cw6 are associated with UC.

We investigated the DRB, DQA1, and DQB 1 polymorphism and haplotypes in sporadic and familial RA subjects of Asian Indian origin by PCR oligotyping using biotinylated SSOPs. Molecular subtyping of DRB 1*04 in RA patients showed strongest association with highest relative risk with DRB 1*0405, followed by DRBI*0401. A significant decreased frequency of DRBI*1502 was observed in patients compared to controls (chi 2 = 4.5). Among other alleles, DRBI*1001 was found to be significantly increased. A total of 73.3% of patients carried the shared sequence of the third HVR (67-74) of DRB1 domain compared to its presence in only 37.6% of controls. A significant number of patients carried DR4 haplotypes on DQBI*0302 (58%) as against DQBI*0301 which was present only on 10.5% of the haplotypes. When compared to controls, the difference was significant for the latter allele only. Few unique DRDQ haplotypes were observed in Asian Indians. Among DR-DQ haplotypes, DRB1*0401-DQB1*0302 gave the highest risk whereas DRB1*0403-DQB1*O301 was negatively associated. Alleles with negative charge at position 70 confer protection or are negatively associated with RA whereas among the associated alleles, glycine at position 86 resulted in higher risk than those with valine at this position. A heterogenous association of DQB1 alleles with DR4 subtypes, influencing susceptibility to RA, suggests the DQB locus is not primarily associated with RA and susceptibility lies in the sequence 67-74 of the DRB1 loci.

The distribution of HSP70-1 promoter alleles was studied in 90 adult Caucasian RA patients (65 European and 25 Asian Indian) and 113 normal control (60 European and 53 Asian Indian). The HSP70-1 promoter alleles were defined by oligonucleotide typing of polymerase chain (PCR)-amplified genomic DNA. The prevalence of HSP70-1 promoter allele "B" was significantly (p0.0004, pc0.0012; RR = 5.1) higher in RA patients (22.2%) compared to normal controls (5.3%). It is likely therefore that HSP70-1 promoter allele B is associated with susceptibility to RA.

In this study, 60 HLA-B27+ve SSA patients and 17 healthy controls belonging to North India were analyzed to ascertain heterogeneity of the B27 molecule in this population. ID-IEF and PCR-SSOP technologies were used to analyze polymorphism in exon 2 and 3 of the HLA-B27 gene. Four different subtypes were encountered: B*2702,04,05 and 07. Other subtypes of B27 viz B*2701,03,06 and 08 were not encountered. B*2704 (common oriental subtype) and B*2705 (common Caucasian subtype) were the most common subtypes in the control and patient groups. B*2707 was less frequently encountered in both groups and B*2702 was found in only one AAU patient. B*2704 was the predominant subtype in the AS group (70.8%) compared to its frequency of 47% in healthy controls (RR = 2.73) while in the undiff SpA group, B*2705 occurred most frequently (73.1%, RR = 3.05). B27 subtypes segregated differently in males and females. 12 of the 17 male AS patients carried B*2704 as compared to 1 of 8 healthy males (X2 = 3.9, P < 0.05). On the other hand, in the undiff SpA, B*2705 was significantly raised in female patients (100%) as compared to healthy females (22.2%, X2 = 4.9, P < 0.05). Subtype distribution is indicative of racial admixture in the Asian Indian population.

Mycobacterium leprae heat-shock proteins hsp65 and hsp18 have received immense attention as major T-cell target antigens in leprosy. Both of these hsps and their tryptic fragments were characterized for their ability to stimulate CD4+ T cells derived from polar leprosy cases and healthy contacts. The optimal digestion of hsps with trypsin yielded four fragments of hsp65--TDB65-1 (24 kDa), TDB65-2 (18 kDa), TDB65-3 (17 kDa), TDB65-4 (14 kDa)-- and three of hsp18--TDB18-1 (10 kDa), TDB18-2 (5 kDa), TDB18-3 (3 kDa). While all of these tryptic fragments and undigested hsps triggered CD4+ T cells from tuberculoid (TT) leprosy patients and healthy contacts (SI2), only two fragments--TDB65-2 and TDB18-3--were found to be stimulatory in anergic lepromatous (LL) leprosy patients (SI = 5.27 and 3.0, respectively). Blocking studies using allele-specific anti-DR monoclonal antibodies revealed multiple HLA-Dr restriction, with DR2 providing the strongest restriction in both TT as well as LL leprosy. These findings indicate that M. leprae hsps and their trypsin-digested fragments are promiscuous and recognizable in the context of diverse HLA alleles, of which DR2 is the most efficient restriction element. The 18-kDa fragment of hsp65 and the 3-kDa fragment of hsp18 are the most versatile fragments that could elicit in vitro proliferation in both polar forms of leprosy.

This study reports our observations on the correlation between HLA-DR2 subtypes and their DR-DQ haplotypes in patients with tuberculoid (TT) leprosy and pulmonary tuberculosis (PTB). DRB1*1501 was significantly increased in patients with PTB (90%) as compared to controls (p0.05); whereas the prevalence of DRB1*1502 was significantly increased in patients with TT leprosy (p0.05), suggesting allele-specific binding of the pathogen to form disease-causing motifs to the T-cell receptor. Among DR2-DQ haplotypes, the deviation was noted in the distribution of unique and common haplotypes in patients with TT leprosy and PTB. A significant decrease of haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0502 in TT leprosy and a significant increase of DRB1*1501-DRB5*0101-DQA1*0103-DQB1*0601 in PTB patients were observed. The occurrence of specific DR2 subtypes and their haplotypes in the two disease groups suggests their involvement in disease pathogenesis.

Serum samples from 95 recipients, transplanted with kidneys from live related donors, were tested for the presence of panel reactive antibodies (PRA) in pre- and post-transplant serum samples by the extended microdroplet lymphocytotoxicity test. The immunoglobulin class of antibodies was tested by treatment of serum with dithiothreitol. A significant correlation was found between the high PRA found in the 75 pretransplant sera tested and the subsequent rejection episodes. In addition, the level of pretransplant PRA activity was associated with graft survival in that patients with low PRA had significantly superior graft survival than those with high PRA. Furthermore, the present data show that patients with historical high PRA, but current low PRA, had graft survival similar to that in recipients who had moderate PRA in their current sera. High PRA patients had more often a positive crossmatch than patients with low PRA. The PRA level was also associated with prolonged waiting period. Immunoglobulin class of antibodies was related to graft acceptance in that the presence of IgM antibodies was not detrimental to transplantation. The results in the present study suggest that PRA of10% is negligible, while more attention should be paid to patients with PRA10%.

We studied the effects of D-penicillamine (DP) on the clinical response, immunoinflammatory parameters and the lymphocyte subsets in 46 patients with rheumatoid arthritis (RA). Patients were evaluated before the start of the drug and then at 3 and 9 months during the follow up. 38 of 46 (82.6%) patients could continue DP treatment for over 9 months, while in 8 the drug was withdrawn due to adverse effects. Improvement in the various disease activity indices of more than 50% (responders) was seen in 25 of 38 (65.8%) patients. Responders showed a significant decrease in the serum IgA and IgM at 9 months, and in IgM only at 3 months. The serum levels of C3 and C4 did not show any significant change. Serum levels of C-reactive protein and rheumatoid factor (RF) showed a significant decrease at 3 and 9 months. A significant decrease in CD3+ and CD4+ lymphocytes along with a fall in CD4+/CD8+ lymphocyte ratio was also seen in responders at 3 and 9 months, compared to the baseline. Our results suggest that DP may have immunomodulatory action in RA.

To analyze segregation of rheumatoid arthritis (RA) with HLA-DR4 and/or other alleles in multicase RA families and to compare the segregation patterns among affected and unaffected sibs.Forty-one multicase families (22 multiplex and 19 simplex) of northern Indian origin were studied for HLA haplotype segregation.HLA haplotype sharing among affected sibs was observed more often than expected in families in which both parents were healthy (P0.05). RA cosegregated with a DR4 haplotype among offspring only in multiplex families in which both parents were unaffected (P0.05), while in simplex families, the disease segregated with DR4 only when the allele was from the affected DR4-heterozygous parent. In DR4-negative affected sib pairs, DR1, DR6, and DR10 were inherited from healthy parents more often than expected.Dissimilar modes of inheritance are seen among multiplex and simplex RA families. The results of segregation analysis are compatible with the hypothesis that an epitope, rather than an individual DR antigen(s), is responsible for increased risk for development of RA.

Finger tip and palmar dermatoglyphics were studied in 31 patients (22 females and 9 males) with rheumatoid arthritis (RA) and 38 matched controls (20 females and 18 males) from North India. While not many differences were observed in palmar patterns, a low ending of line A was found on both hands of two patients. Finger tip patterns were significantly different in patients compared to controls. No association with any dermatoglyphic feature and HLA antigens was observed.

HLA haplotypes were studied in 41 unrelated families from North India with multiple cases of rheumatoid arthritis. Affected sibpairs shared parental HLA haplotypes more often than expected (chi 2 = 13.6) according to Mendelian segregation. Using the method of sibpair ratio, nonrandom segregation of parental haplotypes was observed among affected sibs. HLA-DR4 was observed in 70% of the probands while among DR4 negative probands, DR10 occurred more frequently. However no specific haplotypic association with the disease was observed in these families.

This study of 168 north Indian patients with rheumatoid arthritis (RA) confirms the significant association of susceptibility to RA with DR4 specificity (P less than 0.0001). This association was observed equally in familial as well as sporadic patients. The HLA-DR2 and DR5 alleles were identified to be conferring protection in RA, DR5 being reduced significantly in the non-familial patients only. None of the other DR antigens revealed any association with RA in this population, including the DR4 negative group of patients. An analysis of the DR phenotypes in patients and controls revealed that DR4 in combination with DR1 provided the highest relative risk (71.9) followed by DR4, DR4 (RR = 4.1). These results demonstrate that susceptibility to RA is not due to a single HLA specificity but the effect of a group of related epitopes occurring in common among subtypes of DR4 as well as in some DR1 alleles.

Twenty patients with systemic lupus erythematosus (SLE) and their 51 household contacts were screened for the presence of lymphocytotoxic antibodies. A high prevalence of lymphocytotoxic antibodies (LCTAB) was observed in the patients (80% against T cells and 100% against B cells). The antibodies carried specificity for HLA-B5/35 and HLA-DR2/DR3. A high prevalence of LCTAB was also observed in contacts (55% LCTAB-T cells, 88% LCTAB-B cells) with no difference being seen between consanguineous and non-consanguineous male or female relatives.

The HLA associations reported so far have implication in diagnosis prognosis and prophylaxis for a few of the diseases and in several cases, they have helped to clarify disease heterogenicity. However ′ the area where a full consensus is yet to be achieved is regarding the mechanism by which these disease associations with HLA antigens work. Numerous investigators have discussed various possible mechanisms in the light of individual diseases. In general diseases associated with HLA class I antigens may in some way involve cytotoxic T lymphocytes whereas those more strongly associated with HIA - class II antigens (-DR) may involve T helper or suppressor lymphocytes. With the availability of new genetic methodology, significant advances in our understanding of the inheritance pattern of some diseases have been made. Studies of the newly discovered HLA polymorphisms, such as the DQ and DP markers at the- cellular level (Class - 11 genes products) and restriction sites at the DNA level are likely to lead to new associations. Further, the discovery of the monoclonal antibodies recognizing distinct epitopes on HLA class - 11 molecules and DNA probes recognizing DNA flanking sequences would help greatly in providing much stronger genetic marker systems in these diseases.

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.

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.

An evaluation of the immune state in leprosy was done by the application of a system of graft-versus-host reaction. Peripheral blood lymphocytes obtained from patients with different forms of leprosy and from normal healthy individuals were injected intravenously into the irradiated mice. The rate of blast transformation of the donor cells was measured by the radio-active thymidine uptake. The number of cells labelled with tritiated-thymidine was much higher in the normal individuals and patients with tuberculoid leprosy than in the patients with lepromatous leprosy with the borderline group placed in between the two. However, following successful treatment with DDS, an increased responsiveness and active DNA synthesis could be observed in the previously less responsive lepromatous lymphocytes.

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.

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.