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PubMed1998

HLA and clinical associations in systemic sclerosis patients with anti-Th/To antibodies.

OBJECTIVE: To determine the clinical and immunogenetic features of systemic sclerosis (SSc) patients with anti-Th/To autoantibodies. METHODS: HLA class II alleles were determined by DNA oligotyping in a large group of SSc patients with anticentromere antibodies (ACA), anti-topoisomerase I (anti-topo I), and anti-Th/To autoantibodies. RESULTS: Clinical features of the 28 anti-Th/To-positive SSc patients were similar to those observed in the 56 ACA-positive SSc patients, except for a decreased frequency of gastrointestinal involvement in anti-Th/To-positive patients. Immunogenetic analysis revealed a significant increase in the frequency of HLA-DR11 in the anti-Th/To-positive and the anti-topo I-positive patients. The anti-Th/To-positive patients also had a significant reduction in the frequency of HLA-DR7, similar to that seen in ACA-positive SSc patients. CONCLUSION: Despite clinical and immunogenetic similarities with both the ACA- and anti-topo I-positive patients, anti-Th/To-positive SSc patients present a characteristic pattern of clinical and immunogenetic features that may have implications regarding etiology, pathogenesis, and treatment.

Alleles↗
PubMed2000

Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.

BACKGROUND & AIMS: The detection of phenotype-determining genes as opposed to disease susceptibility genes requires precise phenotypic characterization of patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well recognized and are classified with the HLA-B*27-related spondyloarthropathies by the European Spondyloarthropathy Study Group. However, previous HLA studies in IBD have only shown this association with axial disease rather than peripheral arthropathy. We recently reported a clinical classification that describes 2 types of peripheral arthropathy, distinguished by their natural history and articular distribution. We now report the results of immunogenetic studies in these patients and compare them with other spondyloarthropathies. METHODS: IBD patients with type 1 (n = 57) and type 2 (n = 45) peripheral arthropathy were identified by case note review and questionnaire. Patients and 603 controls from Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence-specific primer polymerase chain reaction. Patient results were compared with controls (corrected for multiple comparisons), then with each other in light of existing hypotheses. The results were compared with those of a cohort of 30 patients with postenteric reactive arthritis (ReA) and 16 patients with IBD-associated ankylosing spondylitis (IBD-AS). RESULTS: Type 1 arthropathy was associated with HLA-DRB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001; relative risk [RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P = 0. 001; RR, 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P = 0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found in ReA, except that the HLA-B*27 association was significantly stronger and an association was found with DRB1*0101 (DR1) in 43% (P = 0.001; RR, 2.2). IBD-AS was associated only with HLA-B*27 and DRB1*0101. CONCLUSIONS: These data suggest that the clinical classification into type 1 and type 2 arthropathies describes immunogenetically distinct entities and establish that in polygenic disorders, genes may determine clinical phenotype without conferring overall disease susceptibility (in this case, HLA genes). Type 1 arthropathy is clinically and immunogenetically similar to the spondyloarthropathies, but different HLA associations may define phenotypically distinct groups. Type 2 arthropathy has different HLA associations and may have a different etiology. Further studies are now required to confirm these associations and to elucidate the different pathogenetic mechanisms.

Colitis, Ulcerative↗
PubMed1999

Association of HLA-DR and -DQ alleles with idiopathic achalasia.

BACKGROUND & AIMS: Idiopathic achalasia is a motility disorder of the esophagus characterized by incomplete relaxation of the lower esophageal sphincter and a loss of normal peristaltic activity in the body of the esophagus. The loss of inhibitory neurons in the distal esophagus, as well as abnormalities in the vagus nerve, dorsal motor nucleus of the vagus nerve, and autonomic nervous system, have been described in achalasia. Although the underlying cause of idiopathic achalasia is unknown, the diffuse neuronal effects found suggest a possible viral or neurodegenerative mechanism. By use of serological methods, a significant association between the HLA-DQ1 phenotype and idiopathic achalasia has been found, suggesting a possible immunogenetic mechanism. To further define immunogenetics in the pathogenesis of idiopathic achalasia, we performed tissue typing in patients with achalasia to determine their specific HLA phenotypes. METHODS: We prospectively studied 32 patients (23 white and 9 black) with idiopathic achalasia. Peripheral blood was collected, and HLA-DR and -DQ typing by polymerase chain reaction with sequence-specific primers was performed. Results were compared with those from 268 racially matched local controls. RESULTS: Idiopathic achalasia and the broad HLA-DQ1 allele were not significantly associated in either population, although a trend was found in white subjects (odds ratio [OR], 2.16; chi2 = 5.36, P corrected [Pc] = 0.0824). Further subtyping in white subjects revealed a significant association between idiopathic achalasia and the DQB1*0602 allele (OR, 3.10; chi2 = 7.32, Pc = 0.0408). A strong trend was also found with the DRB1*15 allele (OR, 2.83; chi2 = 8.11, Pc = 0.0572). In the black population, there was no association between idiopathic achalasia and DQB1*0602 or DRB1*15, but a trend was found with DRB1*12 (OR, 6. 19; chi2 = 5.19, P = 0.0227 uncorrected, Pc = 0.295). CONCLUSIONS: Idiopathic achalasia is associated with HLA alleles in a race-specific manner. These results support an immunogenetic mechanism in the pathogenesis of idiopathic achalasia.

Adult↗
PubMed2000

Immunological importance of chimerism in transplantation: new conditioning protocol in BMT and the development of chimeric state.

Chimerism is an exceptional immunogenetic state, characterized by the survival and collaboration of cell populations originated from two different individuals. The prerequisits to induce chimerism are immuno-suppression, myeloablation, or severe immunodeficiency of the recipients on the one side and donor originated immuno-hematopoietic cells in the graft on the other. The pathologic or special immunogenetic conditions to establish chimerism are combined with bone marrow transplantation, transfusion, and various kinds of solid organ grafting. Different types of chimerism are known including complete, mixed and mosaic, or split chimerism. There are various methods used to detect the type of chimera state, depending on the immunogenetic differences between the donor and recipient. The induction of complete or mixed chimerism is first determinated by the effect of myeloablative therapy. The chimera state seems to be one of the leading factors to influence the course of the post-transplant period, the frequency and severity of GVHD, and the rate of relapse. However, the most important contribution of the chimeric state is in development of graft versus leukemia effect. A new conditioning protocol (DBM/Ara-C/Cy) for allogeneic BMT in CML patients and its consequence on chimera state and GVL effect is demonstrated.

Antineoplastic Agents, Alkylating↗
PubMed2002

HLA class II markers and clinical heterogeneity in Swedish patients with primary biliary cirrhosis.

Genetic susceptibility to PBC can, at least in part, be ascribed to the major histocompatibility complex. The relevance of immunogenetic markers for the clinical presentation and course, however, is unclear. Thus, the aim of this study was to investigate the contribution of HLA class II genes to susceptibility, clinical presentation and course of disease in PBC patients. HLA genotyping for HLA-DRB1, -DQB1 and -DPB1 was carried out in a total of 99 Swedish PBC patients and 158 controls. Clinical parameters including epidemiologic variables, signs and symptoms of PBC-related liver disease and histologic data were collected and analyzed in 92 patients at study entry and at follow-up five years later. Significant clinical heterogeneity was seen among PBC patients upon study entry. Although a significant disease association was seen for HLA DRB1*08 and DQB1*0402, immunogenetic markers identified neither a particular subset of patients nor an association with the clinical course of the disease. HLA-DRB1*08 and DQB1*0402 provide the strongest immunogenetic influence in PBC. However, this association is not restricted to any particular, clinically defined subgroup of patients and it is not predictive for the course of the disease.

Adult↗
PubMed2002

Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes.

BACKGROUND & AIMS: There are few systematic studies on the natural history or immunogenetic associations of erythema nodosum (EN) or ocular inflammation in inflammatory bowel disease (IBD), but they are reportedly more common in patients with other extraintestinal manifestations (EIMs), particularly arthritis. Immunogenetic associations have previously been described in IBD arthritis and in EN associated with sarcoidosis. This study examined the clinical features and HLA-B, DR, and tumor necrosis factor alpha (TNF-alpha) associations of ocular inflammation and EN and their clinical and immunogenetic relationship to arthritis in IBD. METHODS: Details of EN and ocular inflammation were gathered by case-note review and questionnaire in 976 ulcerative colitis patients and 483 Crohn's patients. Sequence-specific PCR typing for polymorphisms in HLA-B, DR, and TNF-alpha was performed in 39 EN and 40 ocular patients. Results were compared with 490 IBD controls without EIMs, 38 patients with type 1 and 31 with type 2 peripheral arthritis, and 16 AS patients. RESULTS: EN and ocular inflammation were more common in women, were associated with IBD relapse, and recurred in approximately 30% of patients. They occurred more commonly with arthritis and AS than expected by chance. Ocular inflammation was strongly associated with HLA-B*27, B*58, and HLA-DRB1*0103. There is a weak association between EN and HLA-B*15 but a strong association with the -1031 TNF-alpha. CONCLUSIONS: EN, uveitis, and arthritis associated with IBD occur together commonly. They are associated with genes in the HLA region, and linkage disequilibrium between these genes may account for the clinical picture of overlapping but independent clinical manifestations.

Erythema Nodosum↗
PubMed1994

Relationship between ultraviolet radiation-induced immunosuppression and carcinogenesis.

The capacity of ultraviolet B (UVB) radiation to damage the cutaneous immune system has been extensively documented, and there is good reason to believe that UVB-induced damage is a critical, albeit permissive, factor in the development of sunlight-induced skin cancers. A summary of the evidence shows that acute, low-dose UVB protocols, which resemble quantitatively and qualitatively the manner in which human beings typically experience sun exposure, alter the cutaneous immune system in at least two important ways: they impair the induction of contact hypersensitivity to cutaneous antigens, and induce antigen-specific tolerance. In mice there is compelling evidence that immunogenetic factors dictate whether UVB radiation will impair contact hypersensitivity induction or not. The genetic loci that contain the relevant polymorphic alleles include tumor necrosis factor-alpha and lipopolysaccharide. Because the effects of UVB radiation on contact hypersensitivity induction are mimicked by intracutaneous injections of subinflammatory doses of tumor necrosis factor-alpha or cis-urocanic acid, the favored hypothesis to explain the mechanism of action of UVB radiation in UVB-susceptible individuals is that UVB-dependent transformation of trans- to cis-urocanic acid in the epidermis triggers the intracutaneous release of excess amounts of tumor necrosis factor-alpha. By transiently immobilizing Langerhans cells and other local antigen-presenting cells within the skin, the requirement that hapten be brought to the draining lymph node to sensitive naive hapten-specific T cells is not met, and contact hypersensitivity fails to develop. Because the UVB-susceptibility and UVB-resistance traits have also been demonstrated in human beings, the hypothesis is advanced that these traits are similarly under control of immunogenetic factors, and that a constellation of immune susceptibility genes contributes to the risk of developing sunlight-induced skin cancer. The cellular and molecular basis of UVB-induced tolerance is not as well described, but current evidence suggests that different mechanisms, and presumably different polymorphic genes, dictate whether tolerance will emerge after UVB exposure in mice. Because acute, low-dose UVB also induces tolerance in human beings, the immunogenetic factors that dictate tolerance of this type may also contribute to the risk of developing sunlight-induced skin cancer.

Animals↗
PubMed1997

Immunologic consequences of blood transfusion and their clinical manifestations.

Aspects of clinical immunology, in the context of transfusion medicine, became highlighted in the last decade as a consequence of the accelerating expansion of basic immunology, immunogenetics and molecular biology. In addition sophisticated new technologies, which were capable of producing pure and safe blood products, attracted more attention to research and monitor the consequences of transfusion. These technologies also had obvious effects on supportive hematological therapy. The transfusion of blood components follows the rules of organ transplantation: when there is a mismatch between the donor and the recipient, the transfusion has the potential to induce various kinds of immune response against alloantigens. Antigen-compatible transfusions that involve major and rare blood groups are in almost all cases mismatched with respect to various polymorphic systems expressed on the cellular blood components. These include histocompatibility leukocyte antigens (HLA), tissue-specific and differentiation alloantigens, and, in the case of plasma, immunoglobulins, complement components, heat shock proteins, and shedded soluble membrane alloantigens. Clinical manifestations of alloimmune responses are typically deleterious. For example, immediate antigen-antibody binding and its consequences as secondary activations are paralleled by the nonhaemolytic febrile reaction, HLA sensitization can lead to a state of platelet refractoriness and inconvenient clinical symptoms. In certain immunogenetic situations and in immunodeficient patients graft-versus-host disease can be induced by blood products that contain live lymphocytes. Leukocyte filtration techniques are widely used to avoid most but not all of these harmful side effects of blood component therapy. In contrast to these harmful side effects in certain immunogenetic conditions, alloantigens that are expressed on various blood products can elicit an advantageous suppression of the immune response in the recipient. In the context of kidney transplantation this is termed the 'beneficial transfusion effect', and typically results in the prolongation of the graft's survival. In cases of recurrent habitual abortion and IgG therapy associated with certain autoimmune diseases, immunization with leukocytes specifically takes advantage of this phenomenon. To date the beneficial transfusion effect is not fully understood. In certain cases of malignancies or gastrointestinal surgeries this suppression of immune regulation that is induced by transfusion can worsen the clinical state either by permitting the spread of the tumor or by allowing severe infections to proceed unchecked. In conclusion it is imperative to monitor the immunological consequences of transfusion in order to deter the disadvantageous side effects. Taking advantage of the 'beneficial transfusion effect' may also provide a new means for immune therapy using the various blood products.

Blood Cells↗
PubMed1994

High frequency of HLA-DQB1*0301 allele in patients with pure ocular cicatricial pemphigoid.

Two factors, is classification and its immunogenetics, may have contributed to an incomplete understanding of the pathogenic mechanism in the disease group commonly termed 'cicatricial pemphigoid'. We have previously demonstrated that pure ocular cicatricial pemphigoid (OCP) is a unique clinical and immunopathological entity. In an effort to better define the immunogenetic characteristics for patients with pure OCP, we performed HLA typing for the class II MHC gene HLA-DQB1*0301 allele, by amplifying genomic DNA extracted from patients with polymerase chain reaction, followed by hybridization with a sequence-specific oligonucleotide probe on dot-blotted and Southern-blotted amplified DNA samples. Ninety percent (9/10) of patients with pure OCP had the DQB1*0301 allele, in contrast to 52% (17/33) of normal individuals who had the DQB1*0301 allele. The high frequency of the HLA-DQB1*0301 allele in patients with pure OCP may point to a distinct immunogenetic pattern and possibly a distinct pathomechanism for the disease.

Alleles↗
PubMed1996

Primary pulmonary hypertension in HIV infection: an outcome determined by particular HLA class II alleles.

Primary pulmonary hypertension (PPH) may have an autoimmune basis that is influenced by host immunogenetics. The pathogenesis of primary pulmonary hypertension in human immunodeficiency virus (HIV) infection is unclear. The objective of this study was to determine whether patients with PPH and HIV infection have distinctive immunogenetic profiles. Ten racially mixed HIV-infected patients with PPH were typed for human leukocyte antigen (HLA) class II (DRB1, 3, 4, 5 and DQB1) by DNA-PCR sequence-specific oligonucleotide probes. Results were compared with two control groups: 128 HIV-negative Caucasians and a previously reported group of 97 HIV-positive, racially mixed control subjects. In those with PPH, there was a significantly increased frequency of HLA-DR6 (-DRB1*1301/2 subtypes) and of HLA-DR52 (DRB3*0301 subtype). These findings suggest that HIV-associated PPH reflects a host response to HIV-1 determined by one or more HLA-DR alleles located within the major histocompatibility complex. The same HLA-DR6 subtype found at increased frequency in our patients has previously been associated with the development of a CD8 lymphocytic host response to HIV-1, termed diffuse infiltrative lymphocytosis syndrome (DILS), which resembles autoimmune Sjogren's disease and is associated with prolonged survival. Together, these findings suggest that HIV-positive PPH may represent a clinical outcome that has similarities with that resulting from the immunogenetically determined host response present in DILS.

Adult↗
PubMed2003

HLA-related subpopulations of MS in Japanese with and without oligoclonal IgG bands. Human leukocyte antigen.

BACKGROUND: Oligoclonal IgG bands (OCB) are present in most patients with MS in Western countries; however, in Japanese MS patients, the OCB-positive rate is not as high. A relationship between immunogenetic backgrounds, namely, human leukocyte antigen (HLA) DR2 and DR4 positivity, and OCB production in MS patients from Hokkaido, the northernmost island of Japan, has been previously suggested by the authors. OBJECTIVES: To investigate the role of OCB in Japanese MS and to verify the interaction between immunogenetic backgrounds and OCB positivity. METHODS: OCB, DR2(15), and DR4 positivity were studied in 45 patients with newly diagnosed MS. In addition to confirming the authors' previous findings, the clinical and demographic features, MRI findings, OCB positivity, and DRB1*15 and DRB1*04 polymorphisms of an expanded data set of 99 MS patients were investigated by using multivariate analysis. Patients with opticospinal MS (OS-MS) were excluded from this study. RESULTS: A relatively low OCB-positive rate (53.3%), HLA-DR15 association with OCB-positive MS (p = 0.0044), and DR4 association with OCB-negative MS (p = 0.0410) were confirmed. DR15 was not associated with OCB-negative MS. Demographic features, disease course, and disability were similar in the OCB-negative and OCB-positive group, whereas there was a preponderance of women in the OCB-positive group. An independent negative association of DRB1*0405 (p = 0.0021, adjusted odds ratio = 0.21) with OCB positivity was found. CONCLUSIONS: MS is heterogeneous in its association with HLA alleles, and based on the immunogenetic differences, the MS patients in this population include at least two HLA-related subpopulations with and without OCB.

Adolescent↗
PubMed1990

Genetic profile of alloxan-induced diabetes-susceptible mice (ALS) and-resistant mice (ALR).

Two inbred strains from a foundation stock derived from Crj: CD-1 (ICR) mice were established after more than 20 generations of full-sib mating, and by simultaneous selective breeding for developing and not developing diabetes after alloxan administration (45 mg/kg in males, 47 mg/kg in females). To elucidate the genetic background of the two inbred strains, i. e., alloxan-induced diabetes-susceptible (ALS) strain and alloxan-induced diabetes-resistant (ALR) strain, their biochemical genetic markers and immunogenetic markers were examined. 1) For both strains, investigation of biochemical genetic markers at 19 loci and immunogenetic markers at 11 loci revealed no variation in any gene within the same strain, showing to be homogeneous, thus indicating establishment of the inbred strains. 2) The two strains differed from each other at 2 loci of biochemical genetic markers and at 5 loci of immunogenetic markers. 3) The ALS and ALR strains can be regarded as new inbred strains derived from ICR mice. 4) The results show that the marker genes of the two strains are different at 7 loci, but it remains unclear whether or not these genes are involved in the difference between the two strains in susceptibility to alloxan.

Alloxan↗
PubMed2001

[Clinical and immunopathological significance of chimerism in bone marrow and organ transplantations]

Chimerism is an exceptional immunogenetic state, characterized by the survival and collaboration of cell populations originated from two different individuals. The prerequisites to induce chimerism are immunosuppression, myeloablation or severe immunodeficiency of the recipients on one side and donor originated immuno-hematopoietic cells in the graft on the other. Special immunogenetic conditions to establish chimerism are combined with bone marrow transplantation, transfusion and various kinds of solid organ grafting. There are various methods to detect the type of chimera state depending on the immunogenetic differences between the donor and recipient. The chimera state seems to be one of the leading factors to influence the course of the post-transplant period, the frequency and severity of graft-versus-host disease (GVHD), and the rate of relapse. However, the most important contribution of the chimeric state is the development of graft versus leukemia (GVL) effect. A new conditioning protocol (DBM/Ara-C/Cy) for allogeneic BMT in CML patients and its consequence on chimera state and GVL effect is demonstrated.

Journal Article↗
PubMed2002

HLA and cytokine gene polymorphisms in relation to occurrence of palindromic rheumatism and its progression to rheumatoid arthritis.

OBJECTIVE: Palindromic rheumatism (PR) is an episodic arthropathy that may precede typical rheumatoid arthritis (RA), although pathogenetic relationships between these disorders remain unclear. The predictive value for those immunogenetic risk factors implicated in RA for disease progression in PR remains to be established. A previous retrospective analysis from our group has implicated rheumatoid factor in disease progression. Our objective was to determine the contribution of HLA and cytokine gene polymorphisms implicated in RA to predisposition to PR and to progression of PR to chronic joint inflammation. METHODS: We studied 147 patients with PR seen in a tertiary referral center; 87 were selected retrospectively from the period 1986-96 using a structured selection process and 60 were selected prospectively in the period 1997-2001. Comparison groups included 149 patients with RA and 149 ethnically matched controls. Typing for HLA-DRB1 alleles and HLA-DRB1-04 subtypes was performed following polymerase chain reaction (PCR) amplification using sequence-specific primers (SSP). Cytokine genotypes were ascertained following PCR-SSP with and without digestion with restriction enzymes. Time-adjusted survival analysis (Kaplan-Meier) and multivariate logistic regression were used to assess the independent contribution of immunogenetic markers in assessing progression of PR to chronic joint inflammation. RESULTS: Thirty-one percent of patients progressed to connective tissue disease after a mean of 10.6 (retrospective group) and 3.9 (prospective group) years. A significantly increased prevalence of the shared epitope (SE) allele was noted in patients with PR (65%) versus controls (39%) (OR 2.9, 95% CI 1.8-4.6, p < 0.001). This primarily reflected increased prevalence of the DRB1-0401 and 0404 and not DRB1-01 alleles. A weak contribution to disease susceptibility was also noted with carriage of the IL4 promoter -590T (OR 1.8, 95% CI 1.1-3.0, p = 0.02) and IL4 intron 3 RP1 (OR 1.7, 95% CI 1.1-2.9, p = 0.03) alleles. The TNFa +489A allele was associated with RA (OR = 2.7, 95% CI 1.5-5.1, p = 0.001) in both SE+ and SE- patients, but not with PR. Time-adjusted and multivariate Cox regression analysis revealed that only homozygosity for SE alleles was a significant independent risk factor for disease progression to chronicity in PR (hazard ratio 2.9, 95% CI 1.2-6.9, p = 0.02). However, none of 8 patients homozygous for SE- DRB1 XP4n alleles developed chronic disease after 10 years of followup (p = 0.07). CONCLUSION: The immunogenetic risk profile for PR resembles that for RA, indicating that PR is likely not an independent entity. A significant gene dose effect for SE alleles is operative in determining risk for progression from PR to RA.

Adult↗
PubMed1993

HLA-DR antigens, Gm allotypes and antiallotypes in early rheumatoid arthritis--their relation to disease progression.

OBJECTIVE: Evaluation of the prognostic value of immunogenetic markers in early rheumatoid arthritis (RA). METHODS: Ninety-nine patients with definite RA and disease duration 24 months or less were followed with standardized assessment. Disability was assessed by the HAQ index and radiographic changes in hands and feet by the Larsen method. The frequencies of HLA-DR genes were determined by serological typing, Gm allotype distribution by classical hemagglutination inhibition test, and occurrence of anti-Gm allotypes by use of anti-Rh coats. The immunogenetic findings were related to disease severity after 2 years' followup. RESULTS: Functional capacity was well preserved, disease activity was less, but radiographic changes in hands and feet had increased considerably at study finish. A group of 13 patients had developed rapidly progressive changes of hip and/or shoulder joints, all requiring arthroplasty. There was a significantly increased frequency of HLA-DR4. Twenty-seven of the 68 HLA-DR4 positive patients were putatively homozygous. HLA-DR4 was not related to disability or to severe small joint destruction. However, progressive large joint damage was significantly more prevalent in homozygous patients (p < 0.01). Gm allotype distribution was normal and not related to clinical findings. Anti-Gm antibodies were common and frequently specific for nonhost Gm allotype. Fifty-six patients carried anti-G1m(a), and occurrence of this antibody was significantly associated with radiographic progression of small joints (p = 0.01), presence of nodules (p < 0.01) and number of active joints (p = 0.001). CONCLUSION: Immunogenetic markers aided in identifying patients with early RA with more severe disease.

Adult↗
PubMedDate not supplied

Heterogeneity of type 1 diabetes at onset in children: results from the French Incidence Study.

OBJECTIVE: The aim of this survey was to identify specific relationships between clinical and biological features and immunogenetic markers at presentation in a large cohort of newly diagnosed Type 1 diabetic children recruited from the French incidence registry, in which country the incidence rate of the disease is low. RESEARCH DESIGN AND METHODS: A prospective study of the incidence of Type 1 diabetes has been set up in four regions of France since 1988 (2.3 million inhabitants under 20 years of age) where the epidemiological characteristics of the children have been studied as well as presentation at diagnosis. RESULTS: Five hundred and twenty one cases of newly diagnosed Type 1 diabetes were identified over the 3 years of the study in subjects aged 0-19 yr. The mean incidence rate was 7.6/10(5) per year. Eighty-two percent of the children had a symptomatic period shorter than or equal to 2 months. The mean weight loss was -9.2 +/- 7% of body weight. Forty-eight percent of the children demonstrated plasma total CO2 values < or = 18 mmol/l. Islet cell antibodies and insulin auto-antibodies were found in 86% and 41% of the children, respectively. Insulin auto-antibody positivity was significantly more frequent in the younger age group (0-4 yr: 78%, p = 0.0001) but not so for islet cell antibodies. HLA-DR3/DR4 phenotype was found in 32% of the children, and 11% carried none of these antigens, irrespectively of age. DR3 phenotype was significantly associated with a lesser frequency of islet cell antibodies (p < 0.001), but no other immunogenetic marker was associated to any clinical feature studied at presentation. CONCLUSIONS: France is a country with a low incidence rate of Type 1 diabetes within Europe. The heterogeneity of the risk for Type 1 diabetes across this continent has recently been confirmed. The variability of the risk according to age has also been shown in many parts of the world. Young age is an important factor for severity at presentation, but immunogenetics do not seem to play a major role in the heterogeneity of the picture at diagnosis.

Adolescent↗
PubMed1995

Position 26 of the first domain of the HLA-DQB1 allele in post-silicone implant scleroderma.

OBJECTIVE: To determine whether women with scleroderma (systemic sclerosis, SSc) and silicone implants have the same or distinctive immunogenetic findings compared to those reported for idiopathic scleroderma. METHODS: In this case-control study, 9 Caucasian women with SSc and silicone implants (7 breast, 1 chin, 1 toe) and 128 healthy Caucasian controls were typed for HLA class II (DRB1,3,4,5, and DQB1) by DNA polymerase chain reaction (PCR) sequence specific oligonucleotide probes (SSOP). RESULTS: All women with SSc had HLA-DQ5 or DQ7 (DQB1*0301). These 2 alleles have glycine (Gly) or tyrosine (Tyr), and not hydrophobic leucine (Leu), at position 26 in the 2nd hypervariable region of the DQB1 first domain. The increased frequency of at least one Leu 26 negative allele (Gly + or Tyr +) in the women with SSc (100%) compared with controls (73%) was not statistically significant. In contrast, the low frequency of one Leu 26+ allele in the patients (28 vs 57%, p = 0.03, RR = -3.3) and 2 Leu 26+ alleles (0 vs 35%, p = 0.03, RR = -10.4) was significant. CONCLUSION: The presence of Gly 26 or Tyr 26 in the HLA-DQB1 first domain in our cases with SSc and silicone implants is consistent with immunogenetic findings reported in Caucasian with idiopathic SSc anticentromere autoantibodies. Whether all the immunogenetic features in SSc associated with silicone implants remain indistinguishable from those seen in idiopathic.

Alleles↗
PubMed1985

HLA-Bw54 and glaucomatocyclitic crisis.

Twenty-two Japanese patients with glaucomatocyclitic crisis were typed for HLA-A, HLA-B, and HLA-C antigens to detect the immunogenetic factors in this disease. It was shown that HLA-Bw54 was present in nine (41%) of 22 patients, a significant increase even after correcting the P value for the number of antigens studied. The haplotype frequency of HLA-Bw54-Cw1 showed a significant association, and it was not due to linkage disequilibrium in the Japanese. Our results suggest that immunogenetic factors closely associated with the major histocompatibility complex may play an important role in the pathogenesis of glaucomatocyclitic crisis.

Adolescent↗