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PubMed1975

An evaluation of the mixed lymphocyte culture reaction in marmosets.

Marmosets are unique in that all members may be considered to be natural blood chimeras because of the high frequency of fraternal twinning and placental vascular anastomoses between the fetuses. The mixed lymphocyte culture (MLC) reaction utilizing blood lymphocytes was evaluated to determine whether this in vitro test could detect histocompatibility differences among related and unrelated marmosets. It was found that the responses could be correlated with the probable immunogenetic relationships of these animals. Thus, an allogeneic MLC reaction in which the responding (R) and stimulating (S) cells were obtained from unrelated animals within one subspecies of marmosets (Saquinus fuscicollis illigeri) yielded a lower response than a semi-xenogeneic reaction involving R and S cells from two different subspecies of marmosets (S.f. illigeri (R) versus S.f. lagonotus (S). In contrast, MLC reactions between cells from chimeric marmoset co-twins were essentially negative, indicating specific immune tolerance. Under certain experimental conditions, however, it was suggested that the dual lymphocyte cell population from a chimeric marmoset could undergo "autostimulation" as measured by label incorporation studies. The necessity of further experiments was recognized before the data could be truly accepted as reflecting an in vitro manifestation of incompatibility between the two different genetic populations of blood lymphocytes from a chimera.

Animals↗
PubMed1993

Anti-Ro(SS-A) HLA-DR3-positive women: the interrelationship between some ANA negative, SS, SCLE, and NLE mothers and SS/LE overlap female patients.

During the past 15 years, the clinical spectrum associated with the anti-Ro(SS-A) antibody response has been defined. Various clinical presentations, including subacute cutaneous lupus erythematosus, the neonatal lupus syndrome, the Sjögren's syndrome/lupus erythematous overlap syndrome, and primary Sjögren's syndrome, have been detected in association with the anti-Ro(SS-A) response. The anti-Ro(SS-A) antibody response is associated with the HLA-DR2 and HLA-DR3 phenotypes. There is now a good deal of evidence to suggest that many anti-Ro(SS-A)-positive HLA-DR3 women are genetically closely related, sharing in common an enriched frequency of the HLA-DR3-linked B8, DQw2, and DRW52 phenotypes. DNA sequence studies have confirmed this genetic relationship. These studies have led us to the following conclusions. 1) The HLA-DR2 and HLA-DR3 associations with systemic lupus erythematosus and the HLA-DR3 association with Sjögren's syndrome are related to the anti-Ro(SS-A) antibody response and not to the clinical disease expression. 2) HLA-DR3 anti Ro-positive female patients with first-degree Sjögren's syndrome, subacute cutaneous lupus erythematosus, or Sjögren's syndrome, or who are asymptomatic, are immunogenetically closely related even though the clinical presentations are strikingly different. All these HLA-DR3 anti-Ro(SS-A) antibody-positive women are at risk to give birth to a child with the neonatal lupus syndrome.

Adult↗
PubMed1981

Mysteries of the Amerindians.

Several South, Central and North American Indian populations have been characterized over the past 9 years. A summary is given here. Very few major antigens have been found, namely A2, A9, A28 and Aw31 and B5, B15, Bw16, Bw35 and B40. However, several known splits of these antigens have been identified, and new variants are also likely. Immunogenetic analyses of the Amerindians should be able to provide clues both to the origins of the Amerindian cultures and migrations of early man, and also provide new insights into the antigens and the loci of the MHC.

Blood Grouping and Crossmatching↗
PubMed1975

Phosphoglucomutase 3: formal and population genetics and observations on abnormal phenotypes.

514 healthy blood donors and 47 families with 122 offspring were studied for phosphoglucomutase 3 (PGM3) from leukocytes. There was a good agreement of allelic frequencies obtained compared to those reported previously in Caucasians. In addition, three individuals with abnormal phenotypes were observed: one was a patient with Hodgkin's disease, the other two were apparently healthy blood donors. In two cases, family members could be studied; none carried the abnormal type of the father. The possible background of these observations with respect to the attachment of the PGM3 locus to the immunogenetic linkage group--the major histocompatibility complex--on chromosome No. 6 in man is discussed.

Chromosome Mapping↗
PubMed1977

Genetic control of immune responsiveness in man.

Interest in immunogenetics originated from two streams: (a) histocompatibility in mouse and man, and (b) inheritance of specific immune responses in the guinea pig and mouse. In the mouse, there are genes associated with the major histocompatibility complex (MHC) which (i) code for antigens determining allograft responses and mixed lymphocyte reactions, (ii) control responses to certain antigens (Ir genes), and (iii) code for cell-surface antigens which elicit specific antisera (anti-Ia). In man, there is genetic control, in part X-linked, over levels of immunoglobulins and immunoglobulin classes. Evidence for MHC-linked genetic control is derived from immune responses to (i) micro-organisms, (ii) pollen antigens, (iii) food antigens, (iv) vaccines, (v) inocuous test antigens, and (vi) autoantigens. Some evidence exists for allotype-linked genetic control. Practical aspects concern influences of the MHC on susceptibility to disease, within individuals and populations.

Antibody Formation↗
PubMed2006

Antituberculosis drugs and hepatotoxicity.

Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity.

Antitubercular Agents↗
PubMed2005

Hepatitis C virus-associated oral lichen planus: is the geographical heterogeneity related to HLA-DR6?

BACKGROUND: The association between hepatitis C virus (HCV) and oral lichen planus (OLP) is more common in the Mediterranean area and Japan, possibly because of immunogenetic factors. METHODS: Intermediate-resolution HLA-DRB typing by hybridization with oligonucleotide probes was performed in 31 Italian OLP patients with HCV infection, in 45 Italian OLP and in 48 British OLP patients without HCV infection. As healthy controls we included data from 145 unrelated Italian and 101 unrelated British bone marrow donors. RESULTS: Italian HCV+ve OLP patients possessed the HLA-DR6 allele more frequently than Italian and British OLP patients without HCV infection (51.6% vs. 17.7% vs. 16.7%; P corrected = 0.028 and 0.017, respectively). There was no difference in the frequency of the HLA-DR6 allele between Italian and British control subjects. CONCLUSIONS: The present data suggest that HLA-DR6 may be responsible for the peculiar geographic heterogeneity of the association between HCV and OLP.

Adult↗
PubMed2025

Differential Alloreactivity: Lessons Learned From a Singular HLA Locus.

Alloreactivity entails the recognition of cells and tissues from one individual as foreign by T cells and other immune effectors from another individual. Alloreactive immune responses play an important role in various clinical contexts, in particular in transplantation. Major drivers of these responses are the highly immunogenic, non-self HLA molecules. However, the immunogenicity of these allogeneic HLA molecules has been observed to vary according to certain immunobiological and immunogenetic parameters, leading to the concept of differential alloreactivity. Recent progress in unveiling the underpinnings of this phenomenon has been made for the frequently mismatched HLA-DP allotypes, whose singular genomic, structural and population genetics characteristics offer an ideal scenario for these investigations. Studies in the HLA-DP context have highlighted the immunopeptidome overlap between self and non-self HLA allotypes, as well as its editing by non-classical class II chaperones HLA-DM and HLA-DO, as a main determinant of their immunogenicity likely via indirect effects of thymic education. Recent evidence suggests that these observations could also be extended to alloresponses directed against HLA molecules encoded by other loci. How these functional characteristics of HLA molecules shape allorecognition by T-cell subsets, and how they translate into different clinical consequences in the context of transplantation will be the subject of the present review.

Humans↗
PubMed1989

The rat as an experimental animal.

The development and characterization of many inbred, congenic, and recombinant strains of rats in recent years has led to the detailed genetic description of this species, especially in regard to its major histocompatibility complex. This information has contributed substantially to the study of comparative genetics and has greatly enhanced the utility of the rat in a variety of areas of biomedical research. This article focuses on the use of the rat in immunogenetics, transplantation, cancer-risk assessment, cardiovascular diseases, and behavior.

Animals↗
PubMed1992

Evidence for the association of unexplained pulmonary hypertension in children with the major histocompatibility complex.

BACKGROUND: A link between primary pulmonary hypertension (PPH) and autoimmune disorders has been postulated. To investigate this relation, we performed immunofluorescent antinuclear antibody tests (ANA) and serological human leukocyte antigen (HLA)-A, B, C, DR, and DQ typing on two groups of Caucasian children with unexplained pulmonary hypertension (PHT) and their parents. METHODS AND RESULTS: Group 1 consisted of 17 children with PPH including two patients with familial PPH and three patients with trivial congenital pulmonary to systemic communications. Group 2 consisted of 13 children with advanced PHT and anatomically large congenital pulmonary to systemic communications (PHT + shunt). Both groups had comparably severe pulmonary vascular disease documented by cardiac catheterization. The following statistically significant data (p less than 0.05) were obtained when the study groups were compared with those published for normal controls. Although positive ANAs and varying titers of autoantibodies were found in both groups of children and mothers (not fathers), +ANAs were only significant for the maternal groups. The PPH (group 1) children had increased frequencies of HLA-DR3, DRw52, and DQw2 and decreased DR5, whereas the group 2 (PHT + shunt) children (also their parents) had no statistically significant alterations in any of the DR or DQ alleles. The PPH mothers had decreased DQw3, an allele in linkage disequilibrium with DR5. CONCLUSIONS: These immunogenetic data suggest that childhood PPH appears to be associated with the major histocompatibility complex alleles HLA-DR3, DRw52, and DQw2. This newly found correlation of juvenile PPH with these alleles adds this disease to the DR3+ group of autoimmune diseases. Further studies are needed to determine whether there is also an immunological or autoimmune component in some children with PHT + shunt lesions because this group lacked an HLA association.

Adult↗
PubMed2006

Genetic associations between delusional disorder and paranoid schizophrenia: A novel etiologic approach.

OBJECTIVES: Genetic associations between delusional disorder and paranoid schizophrenia are not well understood, although involvement of biological factors has been suspected. We investigated the incidence of human leukocyte antigen (HLA) class I alleles in patients with delusional disorder and paranoid schizophrenia, first, to explore a possible immunogenetic etiology of these paranoid disorders and, second, to determine whether they share similar etiologic mechanisms. METHOD: We employed a nested case-control study design. Psychiatric reference data were available for 38,500 patients attending a hospital-based psychiatric outpatient department between 1998 and 2005. We enrolled 100 patients with delusional disorder and 50 patients with paranoid schizophrenia as the subject cases, using DSM-IV criteria. We considered equivalent numbers of healthy volunteers matched for age and ethnic background as control subjects. All subjects came from an India-born Bengali population. We applied the polymerase chain reaction-based molecular typing method to all patients and healthy subjects. RESULTS: The HLA-A*03 gene is significantly associated with delusional disorder as well as with paranoid schizophrenia. This HLA gene alone or in linkage disequilibrium with other HLA genes or other closely linked non-HLA genes may influence susceptibility to delusional disorder and paranoid schizophrenia. CONCLUSIONS: The study reveals important associations between HLA genes and paranoid disorders. Delusional disorder and paranoid schizophrenia may share similar etiologic mechanisms. This preliminary observation may help our understanding of the genetic basis of these paranoid disorders.

Adult↗
PubMed1992

The clinical genetics of lupus.

Genetic aspects of lupus are reviewed, including recognition of genetic and clinical heterogeneity, genetic factors in the aetiology and heritability of disease, reproductive implications and genetic counselling of patients. Despite a large literature on the genetic epidemiology and immunogenetics of lupus, it remains difficult to apply the results of laboratory findings to the circumstances of individual patients. Generally, lupus is not transmitted as a simple Mendelian trait, and genetic counselling is based on the multifactorial model of disease aetiology with interaction of multiple genetic and environmental factors. Further studies are needed to clarify the heritability of lupus and improve the data for recurrence risk prediction in lupus families.

Female↗
PubMed2006

The role of immunomodulation in the management of factor VIII inhibitors.

Approximately 25% of persons with hemophilia A will have their treatment complicated by the development of anti-FVIII inhibitory antibodies. This adverse event requires the use of alternative hemostatic agents to treat bleeding and the consideration of a protocol to generate immunological tolerance to FVIII. The pathogenetic factors contributing to FVIII inhibitor generation include both patient- and concentrate-related characteristics. The FVIII genotype contributes to this risk as do other, less well defined, immunogenetic factors. The role of the type of FVIII concentrate as a precipitant for inhibitor generation appears to be less influential. Immunomodulatory management of FVIII inhibitors requires sustained and repeated exposure to FVIII through a variety of intravenous immune tolerance induction (ITI) protocols. Certain pre-ITI characteristics predict for the likelihood of success, most especially the pre-ITI anti-FVIII inhibitor titer. Currently, two major areas of debate remain unresolved with relation to the optimal form of ITI schedule. The best FVIII dose to generate FVIII tolerance is under investigation in an international prospective trial, while the issue of whether von Willebrand factor-containing concentrates may provide more powerful tolerizing effects remains open for further discussion. With a variety of ITI protocols, success rates of approximately 80% have been achieved with good-risk patients. In those that fail initial attempts at ITI, additional treatments using agents such rituximab are now being explored with further evidence of success in 60-80% of these salvage patients. Finally, several pre-clinical studies of innovative approaches to achieving FVIII tolerance suggest that combinations of immunomodulatory therapy may be of benefit in the future.

Antibodies↗
PubMed2006

In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype.

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1-0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.

Adult↗
PubMed2003

Genetic studies of pulmonary arterial hypertension.

These genetic studies of primary pulmonary hypertension (PPH) initially tried to define immunogenetic subsets. Because only small subsets could be classified when defined by HLA/autoantibody associations and the familial form of PPH failed to segregate with the HLA class II locus, the focus shifted to a genome scan of families with PPH (FPPH). This approach identified a gene on chromosome 2q33,34 called PPH1. Mutations in this gene, now known to be bone morphogenetic protein receptor 2 (BMPR2), can cause PPH. Mutations in a second gene, ALK-1, present in families with hereditary hemorrhagic telangiectasia type 2, also causes PPH. Both genes, involved in TGF-B signaling, provide exciting clues for defining the pathogenesis of PPH.

Bone Morphogenetic Protein Receptors, Type II↗
PubMed1990

Susceptibility to thyroid autoimmune disease: molecular analysis of HLA-D region genes identifies new markers for goitrous Hashimoto's thyroiditis.

Hashimoto's thyroiditis has been shown to be associated with the HLA-specificities DR4 and DR5. Since former association studies yielded variable results, we used novel molecular typing methods to assess predisposing immunogenetic factors. Gene analysis of the HLA-DR-DQ and tumor necrosis factor region was performed in a group of Hashimoto's thyroiditis patients and randomly chosen controls using standards and nomenclature of the 10th International Histocompatibility Workshop. Genomic DNA of patients and controls was analyzed using a cDNA probe of the DQB1 gene. The resulting restriction fragment patterns allowed the determination of newly defined DQw-types 1-9. We find the strongest relative risk conferred by DQw7 (RR = 4.7), that is observed in 36 of 64 patients (56%) and only 21 of 98 controls (21%) (P corr less than 0.002). Comparison of DNA sequence variation in the DQB1 gene, that is found predominantly in Hashimoto's thyroiditis patients, indicates that codons 45 and 57 are critical features in DQw7 which distinguish it from other DQw specificities. The adjacent DQA1 genes also display a significant association with Hashimoto's thyroiditis (DQA1*0201/*0301 heterozygotes were found in 37% of patients and 15% controls, P less than 0.03). No significant association could be found with polymorphisms of the tumor necrosis factor gene. These results provide a new basis for the concept of genetic susceptibility in Hashimoto's thyroiditis and will help to elucidate the underlying autoimmune mechanisms that lead to disease at the functional level.

Amino Acid Sequence↗
PubMed2000

The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome.

OBJECTIVE: To evaluate the clinical spectrum of anti-GAD-positive patients with stiff-person syndrome (SPS) and provide reproducible means of assessing stiffness. BACKGROUND: SPS can be difficult to diagnose. Delineation of the clinical spectrum in a well defined population will increase diagnostic sensitivity. METHODS: In 20 anti-GAD-positive patients with SPS (six men, 14 women), screened among 38 referred patients, the authors assessed symptoms and signs, degree of disability, associated conditions, and immunogenetic markers. Degree of bending, distribution of stiff areas, timed activities, and magnitude of heightened sensitivity were examined monthly for 4 months in five patients. RESULTS: Average age at symptom onset was 41.2 years. Time to diagnosis was delayed from 1 to 18 years (mean 6.2). Stiffness with superimposed episodic spasms and co-contractures of the abdominal and thoracic paraspinal muscles were characteristic. All had stiff gait and palpable stiffness in the paraspinal muscles. Stiffness was asymmetric or prominent in one leg in 15 patients (stiff-leg syndrome) and involved facial muscles in 13. In one patient spasms lasted for days (status spasticus). Twelve patients needed a cane and seven a walker due to truncal stiffness and frequent falls (average three to four per month). Distribution of stiffness and degree of heightened sensitivity were two reproducible indices of stiffness and spasms. Autoimmune diseases or autoantibodies were noted in 80% and an association of with DRss(1) 0301 allele in 70%. CONCLUSIONS: SPS is 1) frequently misdiagnosed due to multifaceted presentations and asymmetric signs, 2) disabling if untreated, and 3) associated with other autoimmune conditions.

Adult↗
PubMed2005

Immunopathogenesis of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology;however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease--especially ulcerative colitis--and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.

Animals↗