Aging, limitation in physical strength and effects of exercise

HLA typing was performed on 384 individuals of an isolated population of 1,500 people with a familial aggregate of lymphoma and immunodeficiency cases. Eighty-five % of the total population were descendants of the founding couple. First cousin marriages were common. There was a three-fold or higher increase of the following haplotypes as compared to the frequencies in Sheffield: HLA-A28,Bw35, HLA-A28, B18, HLA-A10, B18, HLA-A2, B18,HLA-A11, Bw40 and HLA-A11, B7. The frequency of HLA-A1, B8 was low (5.4%). The most common genotype was HLA-A2, B12/A2, B12 followed by HLA-A2, B12/A28, Bw35. We found 20 HLA homozygous individuals, of these 15 were HLA-A2, b12/a2, b12. There were two possible HLA cross-overs which may be confirmed and three postulated cross-overs which can never be confirmed as one or both parents of the individuals in question are deceased. Some of the haplotypes could be traced back to the first, second and third generations, i.e. to the first half of the nineteenth century. No single haplotype or antigen was shared by the patients.     

HLA antigens in psoriasis. A family study

HLA antigens were determined in 14 Finnish families with psoriatic members. The pedigrees of all families are presented. The results showed a clear association between HLA B13 and inheritable psoriasis, for all the 14 HLA analysed psoriatic patients in four families had B13. In one family all five psoriatic patients had the haplotype HLA-A10, Bw17; in two other families the association between Bw17 and psoriasis was less obvious. In three families six of the eight children with the haplotype A1, Bw37 had psoriasis. In all these families one parent had psoriasis or psoriatic relatives and the other parent contributed A1, Bw37. It is suggested that Bw37, in association with other genetic factors, indicates a high risk of developing psoriasis. In one family both the father with psoriatic arthritis and the son with post-urethritic Reiter's disease had A2, B27. This haplotype was also possibly associated with psoriatic arthritis in two families.     

Influence of HLA-DR phenotype on tumor necrosis factor-alpha production in renal-transplant recipients

In healthy subjects, previous studies have demonstrated a great interindividual variability in the ability for tumor necrosis factor-alpha (TNF-alpha) production. The gene for TNF-alpha is closely linked to and located in the major histocompatibility complex (MHC) and it has been suggested that these interindividual differences may be HLA related. Since TNF-alpha is likely to be an important mediator in renal allograft rejection, we investigated the role of HLA antigens on TNF-alpha production rates by peripheral blood mononuclear cells (PBMC) from renal transplant recipients during stable graft function. HLA-DR2-positive recipients showed significantly lower spontaneous TNF-alpha production than DR2-negative patients (p < 0.001). Upon stimulation with OKT3, HLA-DR2-positive patients also showed significantly lower TNF-alpha production than DR2-negative subjects (p < 0.001). HLA-DR3-positive recipients, however, showed significantly higher spontaneous TNF-alpha production than DR3-negative individuals (p < 0.05). These results suggest that differences in TNF-alpha production, both spontaneous and induced, may be due to the expression of certain DR allotypes.     

The impact of health policy on chiropractic

BACKGROUND: The presence of a genetic factor in the determination of leprosy has long been debated. This study tests whether the HLA-linked control of susceptibility to leprosy and/or for the types of leprosy could be confirmed. MATERIALS AND METHODS: In 15 multicase families, the method of DeVries et al., 1976, was used to detect nonrandom segregation of parental HLA haplotypes in their affected and healthy siblings. Linkage analyses, for two and three alleles were performed by the computer program LIPED: RESULTS: For the affected siblings, the segregations of the parental HLA haplotype were significantly nonrandom from the healthy parents and random from the affected parents, indicating that affected siblings were sharing their HLA haplotypes (segregated from the healthy parents) more than expected. The segregations to the healthy siblings from both the healthy and affected parents were random. Healthy siblings inherited the haplotypes shared among the leprosy siblings randomly as expected. There were excess DR2/DR2 homozygote individuals among tuberculoid siblings. The highest lod score was achieved when we considered our suggested three-alleles model for the susceptibility to the different types of leprosy. CONCLUSIONS: A closely HLA-linked gene on chromosome number 6 with multiple alleles (3 or more) in recombination fraction between 0.05 and 0.1 with 70 to 100% penetrance may be responsible for the susceptibility to the different types of leprosy, whereas the susceptibility to leprosy per se maybe the responsibility of non-HLA linked gene/s. DR2/DR2 homozygote individuals may be relatively at high risk of developing leprosy or tuberculoid leprosy.     

CMV-specific immune responses and HLA phenotypes of AIDS patients who develop CMV retinitis. HNRC Group. HIV Neurobehavioral Research Center

HLA phenotype and immune responses to CMV were studied to determine whether the subset of AIDS patients who developed CMV retinitis were immunogenetically or immunologically predisposed. CMV retinitis develops in approximately 28-35% of AIDS patients and CMV encephalitis develops in 40% of those with retinitis, often leading to death. T-cell proliferation responses to CMV and HIV were assayed prospectively in individuals enrolled in a longitudinal study at the HIV Neurobehavioral Research Center (HNRC) in San Diego. Seventy-three participants, at various stages of disease, have been HLA typed and followed, clinically and immunologically, for up to 5 years. Six HIV infected individuals who eventually developed CMV retinitis, and were assayed prospectively, had a history of low T-cell proliferation to CMV antigens before they were profoundly immunosuppressed. All 10 individuals with CMV retinitis had at least one of three HLA alleles (or combinations): A2B44 (p = 0.02), B51(p = 0.02), or DR7 (p = 0.01) (collective p value = 0.007). Three of the 10 had two or more of these alleles. Of AIDS patients with CD4 counts below 100 and actively at risk for retinitis, 7/15 with A2B44,51, or DR7 have developed retinitis compared to 0/13 without these HLA alleles (relative risk = 23.8). All 4 patients with these alleles who have died, had retinitis. These results suggest that HIV infected individuals with HLA phenotypes A2B44, B51, and DR7 have low T-cell immune responses to CMV and are predisposed to CMV retinitis and encephalitis as immunodeficiency progresses.     

Identification of HLA class II-restricted determinants of Mycobacterium tuberculosis-derived proteins by using HLA-transgenic, class II-deficient mice

T helper 1 cells play a major role in protective immunity against mycobacterial pathogens. Since the antigen (Ag) specificity of CD4(+) human T cells is strongly controlled by HLA class II polymorphism, the immunogenic potential of candidate Ags needs to be defined in the context of HLA polymorphism. We have taken advantage of class II-deficient (Ab0) mice, transgenic for either HLA-DRA/B1*0301 (DR3) or HLA-DQB1*0302/DQA*0301 (DQ8) alleles. In these animals, all CD4(+) T cells are restricted by the HLA molecule. We reported previously that human DR3-restricted T cells frequently recognize heat shock protein (hsp)65 of Mycobacterium tuberculosis, and only a single hsp65 epitope, p1-20. DR3.Ab0 mice, immunized with bacillus Calmette-Guérin or hsp65, developed T cell responses to M. tuberculosis, and recognized the same hsp65 epitope, p1-20. Hsp65-immunized DQ8.Ab0 mice mounted a strong response to bacillus Calmette-Guérin but not to p1-20. Instead, we identified three new DQ8-restricted T cell epitopes in the regions 171-200, 311-340, and 411-440. DR3.Ab0 mice immunized with a second major M. tuberculosis protein, Ag85 (composed of 85A, 85B, and 85C), also developed T cell responses against only one determinant, 85B p51-70, that was identified in this study. Importantly, subsequent analysis of human T cell responses revealed that HLA-DR3+, Ag85-reactive individuals recognize exactly the same peptide epitope as DR3.Ab0 mice. Strikingly, both DR3-restricted T cell epitopes represent the best DR3-binding sequences in hsp65 and 85B, revealing a strong association between peptide-immunodominance and HLA binding affinity. Immunization of DR3.Ab0 with the immunodominant peptides p1-20 and p51-70 induced T cell reactivity to M. tuberculosis. Thus, for two different Ags, T cells from DR3.Ab0 mice and HLA-DR3+ humans recognize the same immunodominant determinants. Our data support the use of HLA-transgenic mice in identifying human T cell determinants for the design of new vaccines.     

Defective HLA class II expression in monocytes of type 1 diabetic patients. The Childhood Diabetes in Finland Study Group

Activation of T-helper cells is modulated by the intensity of HLA class II expression on antigen-presenting cells. We evaluated whether any abnormalities could be found in the expression of HLA-DR and -DQ molecules on monocytes in type 1 diabetic subjects. DR and DQ molecules were induced by human recombinant interferon-gamma on cultured peripheral blood monocytes obtained from children with type 1 diabetes (N = 28), their siblings (N = 18) and unrelated healthy controls (N = 21). The response in DQ induction varied considerably between different individuals, but the average responsiveness was significantly lower in patients compared to siblings and unrelated controls. In addition to the diabetic subjects deficient DQ induction was also observed in three siblings. One of them had high levels of islet cell antibodies and presented with diabetes 6 months later, and another had active rheumatoid arthritis. The response in DR induction was also slightly lower in patients than in siblings, but did not differ from that in unrelated controls. The results suggest abnormalities in the regulation of HLA class II expression in type 1 diabetic subjects possibly reflecting the ongoing autoimmune process.     

Evidence of a strong, positive association between atopy and the HLA class II alleles DR4 and DR7

BACKGROUND: Atopy, with or without associated asthma, provides a useful model for evaluating the genetic factors that control human immune responsiveness. HLA class II gene products are involved in the control of immune responses. OBJECTIVES: We investigated whether susceptibility or resistance to the disease was associated with HLA class II genes. METHODS: Blood samples were obtained from two groups of unrelated European-born white adults: 56 atopic patients (52 of them with asthma) and 39 healthy controls with no personal or familial history of asthma or atopy. Genomic DNA was extracted from peripheral blood lymphocytes. The exons of DQA1, DQB1, DRB and DPB1 genes were selectively amplified by the polymerase chain reaction (PCR) method. Genotyping was carried out by digestion of the amplified DNA products with allele-specific endonucleases (PCR-RFLP), which can recognize allelic variations in the polymorphic exon. RESULTS: We found no significant differences in the frequency of DPB1 alleles between patients and controls. HLA class II DR4 and DR7 alleles were present in 39.2% of the patients and in 2.5% of the healthy subjects (Pc*2 < or = 3.9 10(-3)). Conversely, DQA1*0103 and DQB1*0502 alleles were more frequent in the control subjects. These results confirm a previous study of an extended pedigree, which showed that DR4 and DR7 alleles were absent in all healthy members of the family and were frequently observed in atopic and/or in asthmatic subjects. CONCLUSION: We observed that HLA-DR 4 and DR7 alleles are significantly implicated in their susceptibility to the disease and suggest that this susceptibility is more related to atopy than to specific responses to allergens. According to previous studies, we could also submit that in atopic patients with asthma, DR4 alleles at the least, could be more closely associated with atopy than with asthma per se. Conversely, we suggest that some allelic DQA1 and DQB1 sequences might confer protection against the disease.     

HLA antigens and primary open-angle glaucoma in black Americans

Black patients with primary open-angle glaucoma, when compared to nonglaucomatous individuals, demonstrate significantly increased prevalences of the HLA antigens B7 and B12 and significantly decreased frequencies of A1 and A11. White patients with primary open-angle glaucoma have in common with blacks the increases in B7 and B12 and the decrease in A11, but present no deficit of A1. In addition, white patients with primary open-angle glaucoma demonstrate a significant increase of A3 and a decrease of Bw35, both of which are not found in blacks.     

HLA DR and DQ RFLP analysis in Crohn's disease

A study of 109 Swedish patients and 85 healthy Swedish controls with Crohn's disease (CD) by HLA class II RFLP genotyping was carried out. There was no significant association for any single DR or DQ specificity or phenotypic combination of DR and/or DQ specificities among our study group of Caucasian extraction.     

Neonatal pemphigus vulgaris associated with mild oral pemphigus vulgaris in the mother during pregnancy

PURPOSE: Autoimmunity has been proposed to play a role in the pathogenesis of the abdominal aortic aneurysm (AAA). Several autoimmune diseases are associated with specific HLA DR alleles. These experiments were carried out to determine whether the same HLA DR types that have been reported to be associated with AAA in a mixed North American population are similarly associated with AAA in a more homogeneous group of patients in Japan. METHOD: HLA DR typing was performed by a serologic method on samples of peripheral blood of patients with nonspecific infrarenal AAA in Nagasaki University Hospital in Japan. The frequencies of HLA DR antigens were compared with those of volunteers approximately matched for age and sex from the same referral area. RESULTS: HLA DR haplotypes were determined in 46 Japanese patients with AAA and in 50 patients in a control group. The HLA-DR2(15) antigen was observed in 27 (58.7%) patients (29 alleles 31.5%) with AAA and in 14 (28%) subjects (16 alleles 26.0%) in the control group (p < 0.005). CONCLUSIONS: The data suggest that HLA-DR2(15) has an important role as a genetic risk factor for AAA in Japanese patients, as previously reported in a mixed North American population.     

Analysis of restriction fragment length polymorphism for the HLA-DR gene in Japanese patients with sarcoidosis

BACKGROUND: It is commonly assumed that some immunological disorder may play a part in the pathogenesis of sarcoidosis. Previous studies by several groups have shown a significant association with HLA-DR antigens in patients with sarcoidosis. In this study, restriction fragment length polymorphism (RFLP) analysis of the HLA-DR gene was designed to confirm the association at the gene level and to look for a gene rearrangement which may influence susceptibility to sarcoidosis. METHODS: Thirty two unrelated Japanese patients with sarcoidosis were tested for HLA antigens and subjected to RFLP analysis after digestion with Eco RI, Pst I, Bam HI, Pvu II, and Hind III by using an HLA-DR beta cDNA probe. A group of 47 unrelated healthy Japanese subjects served as controls. Frequencies of each restriction fragment were compared between the patients and the control subjects. Correlation between fragment frequencies and clinical features were also analysed. RESULTS: No restriction fragments of HLA-DR beta gene were found specific to the patients with sarcoidosis. The RFLP analysis could detect polymorphism of HLA-DR beta genes that was not distinguishable by conventional serological methods. Several restriction fragments of the DR beta gene were seen only in DRw52 positive individuals, and showed higher frequencies in the patients than in control subjects. The patients with these DNA fragments were likely to have limited stage disease with no ophthalmic involvement. CONCLUSIONS: An association between HLA and sarcoidosis was noted at the DNA level, although no restriction fragments were specific for this disease. RFLP analysis of the HLA gene is a more useful method than the usual HLA typing, and should be the first step in identifying the gene sequence which is connected with susceptibility to sarcoidosis.     

"The sarcoidosis map": a joint survey of clinical and immunogenetic findings in two European countries

We pooled immunogenetic data obtained in independent studies in two European populations (Italian and Czech) of patients affected by sarcoidosis. Correspondence analysis was used to investigate the associations between clinical and immunogenetic data. Two hundred and thirty-three patients were enrolled in the study, of which 126 were from the Czech Republic and 107 from Italy. Using a common protocol, we examined each patient for sex, age of disease onset, roentgenologic stage, extrapulmonary spread, and clinical course. One thousand and ten healthy individuals, HLA typed for class I and II serologic polymorphisms, served as controls. Findings that were essentially in agreement in both populations were: (1) a positive association of sarcoidosis with HLA-A1, B8, and DR3 markers, and a negative association with HLA-B12 and DR4; (2) a prevalence of HLA-DR3 and DR4 among females and of DR5 among males; (3) a relationship of B13 and B35 with early onset and of A30, B8, DR3, and DR4 with late onset of disease; (4) an association of B27 with sarcoidosis restricted to the lungs; (5) a relationship of A1, B8, B27, and DR3 to roentgenologic stage I and of B12 and DR4 to stage III; and (6) an association of HLA-DR3 with a good outcome. Population-restricted findings essentially concerned the alleles HLA-B13 and B22, the former being associated with the disease, male sex, early onset, extrapulmonary localization and relapse only in Czechs, and the latter to disease spread only in Italians. Our results seem to support the concept that immunogenetic background may at least partly account for the clinical heterogeneity of sarcoidosis.     

Augmentation of natural killer cell activity in mice by oral administration of transforming growth factor-beta

OBJECTIVE: To analyze the effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis (AS). METHODS: Three hundred sixty-three white British AS patients were studied; 149 were carefully assessed for a range of clinical manifestations, and disease severity was assessed using a structured questionnaire. Limited HLA class I typing and complete HLA-DR typing were performed using DNA-based methods. HLA data from 13,634 healthy white British bone marrow donors were used for comparison. RESULTS: A significant association between DR1 and AS was found, independent of HLA-B27 (overall odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-1.8, P = 0.02; relative risk [RR] 2.7, 95% CI 1.5-4.8, P = 6 x 10(-4) among homozygotes; RR 2.1, 95% CI 1.5-2.8, P = 5 x 10(-6) among heterozygotes). A large but weakly significant association between DR8 and AS was noted, particularly among DR8 homozygotes (RR 6.8, 95% CI 1.6-29.2, P = 0.01 among homozygotes; RR 1.6, 95% CI 1.0-2.7, P = 0.07 among heterozygotes). A negative association with DR12 (OR 0.22, 95% CI 0.09-0.5, P = 0.001) was noted. HLA-DR7 was associated with younger age at onset of disease (mean age at onset 18 years for DR7-positive patients and 23 years for DR7-negative patients; Z score 3.21, P = 0.001). No other HLA class I or class II associations with disease severity or with different clinical manifestations of AS were found. CONCLUSION: The results of this study suggest that HLA-DR genes may have a weak effect on susceptibility to AS independent of HLA-B27, but do not support suggestions that they affect disease severity or different clinical manifestations.     

Immune phenotype of chronic liver disease

Immune disorders in chronic liver disease may reflect common host propensities or disease-specific factors. Our aim was to determine the principal bases for these expressions. Four hundred fifty-one patients with various chronic liver diseases were assessed prospectively for concurrent immune disorders. Individuals with immune diseases were more frequently women (73% vs 60%, P = 0.02) and they had HLA DR4 more often than counterparts with other HLA (46% vs 23%, P = 0.000008). The association between HLA DR4 and immune disease was apparent within individual liver diseases and within different categories of liver disease. Women with HLA DR4 had a higher frequency of immune disease than women without HLA DR4 (52% vs 22%, P < or = 0.000001), and they also had immune diseases more commonly than DR4-positive men (52% vs 31%, P = 0.03). DR4-positive men, however, had higher frequencies of immune disease than DR4-negative men, especially in the nonimmune types of liver disease (26% vs 4%, P = 0.002). We conclude that HLA DR4 and female gender constitute an immune phenotype that is an important basis for autoimmune expression in chronic liver disease.     

Increased reactivity to myelin oligodendrocyte glycoprotein peptides and epitope mapping in HLA DR2(15)+ multiple sclerosis

Multiple sclerosis (MS) is a central nervous system-specific inflammatory and demyelinating disease where a myelin-directed autoimmune response is thought to be pathogenetically relevant. Myelin oligodendrocyte glycoprotein (MOG) is a surface-exposed minor myelin component that is a prime candidate autoantigen. We have investigated peripheral blood lymphocyte responses to synthetic 15-26 amino acids long overlapping MOG peptides in 20 MS patients and 14 healthy controls with the MS-associated HLA haplotype DR2(15). There were significantly increased responses, in terms of numbers of cells secreting IFN-gamma detected by Elispot in response to several MOG-derived peptides in the MS patients, but not the healthy controls. MOG peptide 63-87 evoked the strongest response, and the stimulatory property of this peptide was confirmed in additional DR2(15)+ MS patients where a peptide concentration-dependent proliferative response, which was inhibited by the addition of anti-HLA class II antibodies, was observed. This is the first work detailing putative immunodominant T cell epitopes of MOG in DR2(15)+ MS patients.     

Serological and immunogenetic markers of extraglandular primary Sj?gren's syndrome

The clinical course of 48 patients with primary Sj?gren's syndrome (primary SS) was reviewed. Forty-three north European patients were typed for HLA class I and class II alloantigens. In this population with primary SS HLA B8, DR3 and DRw52 all occurred more frequently than in the control population (P < 0.009, P < 0.0035, P < 0.02 respectively). The subgroup of primary SS patients with antibodies to Ro and/or La antigen had the greatest prevalence of DR3 (relative risk 33.4). The primary SS patients fall into two distinct groups: those with extraglandular disease in whom lymphopaenia, hypergammaglobulinaemia, antibodies to Ro and/or La and HLA DR3 were all more frequent and those patients with either glandular disease alone or only one extraglandular feature. There was no difference in disease duration between the two groups, although on average the latter group were 10 years older.     

Acetone in urine as biological index of occupational exposure to isopropyl alcohol

To analyze whether HLA may be a determinant of the risk of developing cervical cancer precursor lesions, the association between HLA and cervical neoplasia among HPV16-seropositive and -negative subjects was determined in a population-based cohort in the V?sterbotten county of Northern Sweden. HLA genotyping of DR and DQ was done by PCR in 74 patients and 164 healthy controls matched for age, sex and area of residence. The presence of DQA1*0102 was weakly associated with cervical neoplasia in HPV16-seropositive patients. DQB1*0602 was weakly associated with disease in all patients, but was strongly increased among HPV16-seropositive patients compared to HPV16-seropositive controls. DR15 had an association with disease that was particularly strong among HPV16-seropositive subjects. The haplotype DQA1*0102-DQB1*0602 (DQ6) was also weakly associated with disease in all patients and significantly increased among HPV16-positive patients when compared to HPV16-positive controls. A similar association was seen when analysis was restricted to CIN 2-3 patients. DQA1*0501-DQB1*0301 (DQ7) was more common among HPV16-negative patients than among HPV16-negative controls and was also more common among HPV16-negative patients than among HPV16-positive patients. In conclusion, DQA1*0102-DQB1*0602 (DQ6) is associated with an increased risk of cervical neoplasia among HPV16-seropositive subjects and DQA1*0501-DQB1*0301 (DQ7) with an increased risk among HPV16-seronegative subjects.     

Relationship between HLA antigens and infectious agents in contributing towards the development of Graves' disease

Graves' disease (GD) is an autoimmune thyroid disorder which is associated with the human leucocyte antigens HLA-DR3 and DQA1* O501 in Caucasians. We have explored the possibility that some patients with certain HLA specificities develop anti-HLA antibodies which are correlated with environmental factors that may contribute to the development of GD. We studied 40 GD patients and 157 healthy individuals (controls). Serology was used to type HLA-A, -B, -Cw, and -DR antigens. The frequencies of these antigens in relation to lymphocytotoxic anti-HLA-A-B-Cw-DR antibodies and two environmental factors (Yersinia enterocolitica and Coxsackie B virus) were determined. The frequencies of HLA-B15, -B21 and DR3 antigens were increased, whereas HLA-DR5 antigen was decreased in GD patients. A significant association between HLA-DR3 antigen and lymphocytotoxic antibodies was observed, i.e., IgGs from GD patients were cytotoxic to HLA-DR3+ normal B cells. Following absorption with Yersinia enterocolitica or Coxsackie-B-virus, only Coxsackie-B virus completely inhibited the lymphocytotoxic reactions against HLA-DR3+ B cells. Besides confirming the association of HLA-DR3 with GD, this study also suggests the role of Coxsackie-reactive HLA-DR3 antibodies as contributing factors to the pathogenesis of the disease.