Juvenile dermatomyositis: the association of the TNF alpha-308A allele and disease chronicity

Little is known concerning factors associated with the outcome of juvenile dermatomyositis (JDM), which can be variable and lethal. Previous work has documented that the association of DQA1*0501 with JDM is higher than in control groups and that the first symptoms (rash and weakness) of JDM appear to follow evidence of an infectious process--most frequently upper respiratory in nature. Preliminary data show that a long period of symptoms being left untreated before starting therapy and the TNF alpha-308A allele are associated with prolonged JDM symptoms requiring > or = 36 months of immunosuppressive therapy. A short duration of untreated disease is associated with a relative increase in CD8(+) T cells and CD56(+) natural killer (NK) cells in the untreated JDM muscle biopsy compared with a longer duration of untreated disease. The TNF alpha-308A allele is overrepresented in white children with JDM. In addition, it is associated with pathologic calcifications, increased production of TNF alpha by peripheral blood mononuclear cells in vitro and JDM muscle fibers in vivo, and occlusion of capillaries, which may be mediated in part by elevated circulating levels of thrombospondin-1, a potent anti-angiogenic factor. We speculate that DQA1*0501 is associated with JDM susceptibility to an infectious process, eliciting and activating NK cells early in the disease course. We conclude that the TNF alpha-308A allele indicates directly (or is a surrogate marker of) children with JDM who produce higher concentrations of TNF alpha in response to this undefined inflammatory stimulus, as well as increased concentrations of TSP-1 with resultant small vessel occlusion, contributing to subsequent disease chronicity.     

Juvenile dermatomyositis: immunogenetics,pathophysiology, and disease expression

Data are rapidly accumulating documenting disease susceptibility may be linked to genetic markers (DQA1*0501 or related alleles) which are associated with upregulation of IFN-alpha/beta inducible genes elicited in response to an antigen which may be viral. Continued immune-mediated inflammation, resulting in partial lipodystrophy and pathological calcifications, may be fanned by the increased production of TNF alpha usually associated with the TNF alpha-308A allele.     

HLA-DQ haplotypes in Spanish and German families with Graves' disease: contribution to DQA1*0501-DQB1*0301 mediated genetic susceptibility from fathers.

Genetic and environmental factors are involved in the pathogenesis of Graves' disease. The human leukocyte antigen (HLA) locus is considered to be one risk factor for Graves' disease but parent of origin effects have not been studied. Therefore, we investigated the transmission of HLA risk haplotypes DQA1*0501, DQA1*0501-DQB1*0201 (DQ2), and DQA1*0501-DQB1*0301 (DQ7) in two Graves' disease family-cohorts from Spain and Germany. Altogether 208 trio-families (109 from Spain and 99 from Germany; n = 624 individuals) with Graves' disease were genotyped for HLA-DQ alleles DQA1*0501 and the haplotypes DQA1*0501-DQB1*0201 (DQ2) and DQA1*0501-DQB1*0301 (DQ7). Since both family groups-German and Spanish-showed the same pattern of HLA transmission and nontransmission, they were analyzed together. HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) were significantly overtransmitted from the parents to the affected offspring (204 vs. 131, p = 0.0057, pc = 0.0228 and 109 vs. 55, p = 0.0036, pc = 0.0144, respectively). These haplotypes were preferentially transmitted from fathers and DQA1*0501-DQB1*0301 (DQ7) was also more prevalent in fathers (24.0% vs. 17.1%, p = 0.0162, pc = 0.0648). We conclude, that HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) are strongly associated with Graves' disease in both populations. A parent of origin effect of risk haplotypes can not be excluded at present, warranting further family studies.     

The association between the genetic polymorphism of HLA-DQA1, DQB1, and DRB1 and serum alanine aminotransferase levels in chronic hepatitis C in the Chinese population

Background and Aim:  To investigate a possible association between HLA genes with serum alanine aminotransferase (ALT) levels and evaluate whether the HLA-DQA1, DQB1, and DRB1 genes could influence the development of liver damage in chronic hepatitis C.
Methods:  A total of 145 patients with chronic hepatitis C virus (HCV) infection (36 patients with persistently normal ALT values; 109 patients with elevated ALT levels) and 160 uninfected healthy controls were examined for HLA-DQA1, DQB1, and DRB1 molecules by using polymerase chain reaction–sequencing based typing (PCR-SBT).
Results:  Among the patients chronically infected with HCV, the frequencies of DQA1*0501, DQB1*0301, and DRB1*0401 alleles were significantly increased in the normal ALT group compared with those with abnormal ALT levels, whereas that of DQB1*0201 was significantly lower. As compared to uninfected healthy controls, DQA1*0501, DQB1*0301, and DRB1*0401 allele frequencies were also statistically higher in the normal ALT group, whereas that of DQB1*0201 was the inverse. The haplotype frequencies of DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 were found to be significantly higher in the normal ALT group. Multivariate logistic regression indicated that female sex, and the DQB1*0301 allele and DRB1*0401 allele were independently associated with normal ALT values, whereas DQB1*0201 allele was the inverse.
Conclusions:  These results suggest that particular HLA alleles may have an influence on the serum ALT level of chronic HCV infection as a host genetic factor in the Chinese population. The DQA1*0501, DQB1*0301, and DRB1*0401 alleles, and the DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 haplotypes seem to be associated with low hepatitis activity; whereas DQB1*0201 allele is closely correlated with the progression of liver injury in chronic HCV infection.     

Gene dose effect of the DQB1*0201 allele contributes to severity of coeliac disease

OBJECTIVE: Coeliac disease (CD) susceptibility has been shown to be associated with the HLA alleles DQA1*0501 and DQB1*0201. This HLA-associated risk has been estimated to account for 29-40% of the genetic component of CD. Conflicting data have been published on the gene dose effect of these HLA alleles on the risk and severity of CD. In this study the aim was to investigate the association between the number of HLA risk alleles and the severity of CD. MATERIAL AND METHODS: Fifty-four Finnish CD families, including 144 CD patients mainly diagnosed in adulthood (94.4%), were enrolled in the study. The association between the number of DQA1*0501 and DQB1*0201 alleles and villous atrophy, symptoms and laboratory parameters at the time of diagnosis, and the association with villous atrophy after one year of treatment on a gluten-free diet were studied. RESULTS: The homozygosity for the DQB1*0201 allele was associated with a more severe form of CD assessed by more severe villous atrophy (p=0.011), younger age (p=0.036), more severe diarrhoea (p=0.048) and a lower level of blood haemoglobin at the time of diagnosis (p=0.010). Furthermore, the homozygosity for the DQB1*0201 allele was associated with a slower recovery of villous atrophy after a gluten-free diet (p=0.041). In contrast, the DQA1*0501 allele did not have a significant association with the severity of CD. CONCLUSIONS: Our results demonstrate a gene dose effect of the DQB1*0201 allele on the clinical heterogeneity of CD and on the rate of recovery from villous atrophy in patients on a gluten-free diet.     

HLA—DQA1位点寡核苷酸探针检测上海地区汉族IDDM易感性

应用聚合酶链反应(PCR)和寡核苷酸探针点杂交技术分析了中国上海地区汉族42例胰岛素依赖型糖尿病(IDDM)患者和40例正常对照的DQA_1基因。结果发现IDDM组DQA_1*0301和DQA_1*0501等位基因频率显著高于正常对照组,而IDDM组DQA_1*0103和DQA_1*0201等位基因频率显著低于正常对照组。这些表明在中国上海地区汉族人群中,DQA_1*0301和DQA_1*0501与ID-DM易感性相关联,而DQA_1*0103和DQA_1*0201则增强对IDDM的抵抗性。对DQA_1链52位氨基酸多态性分析,提示:DQA_1链52位编码精氨酸可能与IDDM易感性有关,52位非精氨酸与IDDM无     

Cytokines in juvenile dermatomyositis pathophysiology: potential and challenge

PURPOSE OF REVIEW: Cytokines are criticalmediators of the immune response. This review focuses on cytokine-specific information from children with juvenile dermatomyositis, and includes pertinent data from adults with polymyositis and dermatomyositis. RECENT FINDINGS: Much of the new data concern the role of possible antigens and the definition of genetic control of the immune response in juvenile dermatomyositis. Gene expression profile data of DQA1*0501 (present in 85% of patients) compared with age-matched control subjects show that the initial immune response is an interferon-alpha/beta-induced cascade with secondary stimulation of interferon-gamma. Specific epitopes of group A beta-hemolytic streptococcal M protein, with sequence homology for myosin, elicit both cell-mediated cytotoxicity and tumor necrosis factor-alpha production when incubated with mononuclear cells from children with active juvenile dermatomyositis. Tumor necrosis factor-alpha synthesis is increased in juvenile dermatomyositis patients with the tumor necrosis factor-alpha-308A allele, and is associated with increased thrombospondin-1 (an antiangiogenic agent) production and small vessel occlusion in untreated juvenile dermatomyositis. Studies in adults with polymyositis and dermatomyositis implicate interleukin-1alpha, transforming growth factor-beta, and endothelial cell perturbation early in the disease course. Cultured myoblasts were found to produce interleukin-15, which impacts local T-cell activation and proliferation. SUMMARY: The limited data suggest that a possible viral/microbial antigen may elicit an interferon-alpha/beta-induced response, and that antigenic epitopes may be shared. Increased synthesis of tumor necrosis factor-alpha, more common in juvenile dermatomyositis with the tumor necrosis factor-alpha-308A polymorphism, may augment this response and is associated with a wide range of pathologic consequences, as well as disease chronicity and calcifications. The muscle fibers themselves can regulate local inflammation by production of tumor necrosis factor-alpha, interleukin-15 and interleukin-1alpha, and transforming growth factor-beta.     

Differential peptide binding motif for three juvenile arthritis associated HLA-DQ molecules

OBJECTIVE: In the oligoarticular subgroup of juvenile idiopathic arthritis, a strong association has been found with the expression of human leukocyte antigen class II molecules HLA-DQA1 *0401-DQB1*0402 and DQA1*0501-DQB1*0301, whereas DQA1*0501-DQB1*0201 is neutral and DQA1 *0201-DQB1*0201 protective. A presentation of different peptides by these DQ alleles would support their role in the disease process. METHODS: Using a synthetic nonapeptide library, a peptide binding motif was determined for the associated DQA1*0501-DQB1*0301 molecule and compared to the neutral and the protective DQ molecules. RESULTS: A differential motif for the three molecules could be deduced, suggesting that peptides preferentially binding to the associated vs. the neutral/protective DQ-molecules are mutually exclusive. CONCLUSION: These results imply a role for differential peptide presentation in the pathogenesis of oligoarthritic JIA. The search for peptides initiating the disease process might be facilitated which could then lead to therapeutical interventions.     

HLA DQA1-DQB1-TAP2 haplotypes in IDDM families: no evidence for an additional contribution to disease risk by the TAP2 locus

Summary The TAP2 gene, located in the HLA class II region, encodes a subunit of a transporter involved in the endogenous antigen-processing pathway, and has been suggested to contribute to the genetic risk for insulin-dependent diabetes (IDDM). In order to determine whether the TAP2 locus modulates the risk conferred by HLA DQ loci, HLA DQA1-DQB1-TAP2 haplotypes were analysed in 48 IDDM probands, their first degree relatives, and in 62 normal control subjects. A decreased frequency of the TAP2B allele was confirmed in this IDDM cohort (12 vs 28% in control subjects, p _c <0.05). Analysis of 73 informative meiotic events in IDDM and control families demonstrated a recombination fraction between HLA DQB1 and TAP2 loci of 0.041 (Log of the odds score=16.5; p<10^–8) indicating strong linkage between these loci. Family haplotype analysis demonstrated linkage disequilibrium between TAP2 and HLA DQA1-DQB1, and showed that the reduced frequency of TAP2B was associated with its absence on the IDDM susceptible DQA1*0301-DQB1*0302 haplotype, its low frequency on DQA1*0501-DQB1*0201, and the association of TAP2B with DQA1*0101-DQB1*0501 haplotypes which were less frequent in IDDM patients. Comparison of transmitted with non-transmitted haplotypes in IDDM families showed a slight but not significant decrease in TAP2B allele frequency on transmitted (3 of 37) vs non-transmitted (2 of 9) HLA DQA1*0501-DQB1*0201 haplotypes. No other differences were observed. Twenty-four unrelated DQA1*0501-DQB1*0201 haplotypes from non-diabetic families had a TAP2B allele frequency (4%) similar to that in IDDM haplotypes. These findings suggest that the decreased TAP2B allele frequency in Italian IDDM patients is due to HLA DQ haplotype differences between IDDM patients and control subjects, and do not support a contribution to IDDM risk by the TAP2 locus.Abbreviations ARMS Amplificatory refractory mutation system - IDDM insulin-dependent diabetes mellitus - MHC major histocompatibility complex - PCR polymerase chain reaction - TAP transporter associated with antigen processing     

The human leukocyte antigen HLA DRB3*020/DQA1*0501 haplotype is associated with Graves' disease in African Americans

Information on genetic susceptibility to Graves' disease in African Americans is limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4 polymorphisms in 49 African American patients with adult onset Graves' disease and 47 racially-matched controls using PCR-based sequence-specific priming methods. There were no significant differences in DRB1 or DQB1 allelic frequencies or CTLA-4 polymorphisms between patients and controls. However, we found that the frequency of DRB3 was significantly increased in the patients (75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype (53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in concordance with our previous observations in Caucasian patients with adult-onset Graves' disease. In addition, whereas the frequency of DQA1*0501 was increased (P = 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 = 7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202, particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s) for Graves' disease in adult African Americans. Considering these data with those in Caucasian patients, our results would suggest that the primary Graves susceptible locus is likely DRB3 and not DRB1.