Role Of HLA-DRB1 Research Articles

Investigating Acute Hepatitis after SARS-CoV-2 Vaccination or Infection: A Genetic Case Series.

(1) Background: Despite the advantages of COVID-19 vaccination, rare cases of acute hepatitis developing after the administration of the COVID-19 vaccine or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. The aim of the study is to describe a case series of patients who experienced the onset of acute hepatitis, with or without autoimmune features, following SARS-CoV-2 vaccination or infection and to hypothesize a genetic susceptibility in the pathogenesis. (2) Methods: A group of patients with acute onset hepatitis following SARS-CoV-2 vaccination or infection were evaluated in our hepatology outpatient clinic, where they underwent biochemical and autoimmune tests. Hepatitis A (HAV), B (HBV), and C virus (HCV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV) infections were excluded. Patients with a diagnosis of autoimmune hepatitis (AIH) or drug-induced liver injury (DILI) underwent HLA typing and histological testing. (3) Results: Five patients experienced new-onset AIH after COVID-19 vaccination, one of which developed mild symptoms after vaccination that strongly worsened during subsequent SARS-CoV-2 infection. One patient had AIH relapse after COVID-19 vaccination while on maintenance immunosuppressive treatment. All of them had HLA DRB1 alleles known to confer susceptibility to AIH (HLA DRB1*03,*07,*13,*14), and in three of them, HLA DRB1*11 was also detected. Two patients developed acute hepatitis without autoimmune hallmarks which resolved spontaneously, both positive for HLA DRB1*11. (4) Conclusions: An association between AIH and COVID-19 vaccine or infection can be hypothesized in individuals with a genetic predisposition. In patients without autoimmune features and spontaneous improvement of hypertransaminasemia, the diagnosis of drug-induced liver injury (DILI) is probable. Further studies are needed to determine the presence of an actual association and identify a possible role of HLA DRB1*11 in the pathogenesis of acute liver injury after SARS-CoV2 vaccination or infection.

Transcript levels of cytokine coding genes in peripheral blood and tissues of patients with periodontitis.

Periodontal diseases are common conditions in almost all age groups and a public health problem. Numerous risk factors have been demonstrated for this condition. The main mechanism of tissue destruction in the periodontitis is the functional interactions between microbial pathogens and host immune responses, thus cytokines have crucial roles in the pathogenesis periodontitis. Our previous study has demonstrated the susceptibility role of HLA-DRB1*04 allele in development of this disease. So, the individuals who were positive for HLA-DRB1*04 allele were excluded. We aimed to appraise the function of cytokines in the pathogenesis of periodontitis via assessment of tissue and blood levels of a number of cytokine coding genes, namely IL-1B, CXCL8, IL-17, IFNG, TGFB and TNFA1. Expressions of IFNG, IL-17, TGFB and TNFA1 were significantly higher in the peripheral blood of individuals with periodontitis compared with unaffected persons (Posterior beta = 1.91, P value = 0.043; Posterior beta = 1.84, P value = 0.033; Posterior beta = 0.713, P value = 0.009 and Posterior beta = 2.85, P value = 0.001, respectively). Moreover, expression of IL-17 was higher in females compared with males (Posterior beta = 1.47, P value = 0.036). As the interaction effect between gender and group was remarkable for IL-17 expression, we further conducted subgroup analysis within gender group. Expression of IL-17 was higher in male patients compared with unaffected males (Posterior beta = 1.9, P value = 0.048). We did not detect any significant difference in the expression of these cytokines in tissues obtained from affected individuals and unaffected controls. Therefore, our results imply dysregulation of cytokine coding genes in patients with periodontitis and warrant further mechanistical studies.

Role of HLA-DRB1*04 in the susceptibility and HLA-DRB1*08 in the protection for development of rheumatoid arthritis in a population of Southern Mexico: brief report.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with an increased prevalence in Mexico. Although its etiology is unknown, its development can be influenced by environmental factors such as smoking and viral infections. But among the factors influencing susceptibility, it is the genetic factors that predominate, mainly the HLA-DRB1 genes, and specifically the alleles that have the shared epitope (SE). A transversal study was performed, in which 31 patients (28 women and 3 men) with RA, treated at the autoimmunity clinic of the High Specialty Hospital Ciudad Salud in Tapachula, Chiapas, southern México, were enrolled. Clinical, biochemical, and demographic data were analyzed; ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), RF (rheumatoid factor), and ACPA (anticitrullinated peptide antibody) were recorded. All patients had at least one positive RA biological marker. For HLA alleles frequencies comparison, we enrolled ethnically matched healthy controls in a ratio of 3:1 for 25 cases and 4:1 for 6 cases in order to guarantee the balance between groups regarding the mean of age and proportion of gender (males vs females). HLA-DRB1*04 was found to be significantly increased in patients compared with ethnically matched healthy controls (p 0.0007, OR: 2.8, 95% CI 1.5-5.1); contrarily, DRB1*08 showed a protective effect (p 0.005, OR 0.1). This paper confirmed the involvement of HLA genes on risk determination for RA in a population of Mexican Mestizos from Tapachula, Chiapas. Key Points • HLA-DRB1*04 confirms the increased risk of rheumatoid arthritis. • HLA-DRB1*08 showed a more definite protective effect in southern Mexicans mestizos, a population with more Amerindian ancestry.

Role of HLA-DRB1*04 in Malay patients with Vogt-Koyanagi-Harada syndrome

Role of HLA-DRB1*04 in Malay patients with Vogt-Koyanagi-Harada syndrome

The Association Between Human Leukocyte Antigens and ITP, TTP, and HIT.

Autoimmune thrombocytopenia in immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and heparin-induced thrombocytopenia (HIT) is associated with immunologic degradation of platelets and reduced platelet counts in patients, leading to bleeding risk in patients. Considering the role of human leukocyte antigens (HLA) in the development of immune response, in this review, we examine the relationship between HLA and pathogenesis of the above-mentioned diseases. Relevant English-language literature was searched and retrieved from Google Scholar search engine and PubMed database (1979 to 2018). The following keywords were used: "Immune Thrombocytopenic purpura," "Thrombotic Thrombocytopenic Purpura," Human Leukocyte Antigen," and "Heparin-induced thrombocytopenia." In autoimmune thrombocytopenia, HLA molecule presents self-antigens or foreign antigens similar to self-antigens, provoking an immune response against platelets that results in the degradation of platelets in peripheral blood and possible bleeding in the patient. For example, HLA-DRB1 *11 presents the self-antigen and induces an immune response against ADAMTS13, which is associated with thrombocytopenia in TTP patients. HLA alleles can be used as prognostic biomarkers for immunologic disorders of platelet such as ITP, TTP, and HIT. Different DRB1 alleles enable the assessment of resistance to common ITP treatments as well as disease prognosis. Due to the genetic association between HLA-DR1 and HLA-DQ1 alleles and the role of HLA-DRB1 *11 in TTP, the HLA-DQB1 *02: 02 allele may also play a role in TTP pathogenesis.

Role of HLA DRB1*15 and HLA DRB1*16alleles in the genetic susceptibility to develop systemic lupus erythematosus (SLE) after Chikungunya and Zika viruses infection in México

Role of HLA DRB1*15 and HLA DRB1*16alleles in the genetic susceptibility to develop systemic lupus erythematosus (SLE) after Chikungunya and Zika viruses infection in México

A possible role for HLA-DRB1*04:06 in statin-related myopathy in Japanese patients

Statin-related myopathy (SRM) is a clinically important adverse reaction. Recent pharmacogenetic research, mainly in non-Asian populations, have indicated clinical relevance of some of genetic biomarkers to SRM, but predictive markers for SRM in Asian populations including Japanese has not yet been established. This study was aimed to identify clinically important genetic markers associated with SRM in Japanese patients. Allele frequencies of the three reported candidate markers — SLCO1B1 rs4149056, RYR2 rs2819742, and GATM rs9806699 — and carrier frequencies of HLA types were compared between patients with SRM patients (n = 52) and healthy Japanese subjects (n = 2878 or 86 (for rs9806699) as controls). No significant association of RYR2, SLCO1B1, and GATM variants with SRM were observed in our Japanese patients, but a significant association was detected for HLA-DRB1*04:06 with SRM (odds ratio: 3.19; 95% confidence interval: 1.53–6.66). This study suggested that HLA-DRB1*04:06 might be associated with SRM onset in a Japanese population. Further studies are required to validate these results.

Role of HLA-DRB1, PTPN22, CTLA4 Gene Polymorphisms in Susceptibility to Rheumatoid Arthritis

Background and AIM: The genetic and environmental factors are believed to play an important role in the pathogenesis of rheumatoid arthritis (RA), the precise etiology is still uncertain. Regarding its genetic components, the strongest genetic association with RA is that found for certain alleles of HLA-DRB1. Recent studies have revealed that the single‐nucleotide polymorphism (SNP) of non-HLA PTPN22 and CTLA4 gene were associated with RA. The associations of HLA, PTPN22 and CTLA4 polymorphisms with RA risk have been less well replicated. Thus, the current study was undertaken to investigate the effects of HLA-DRB1, PTPN22, CTLA4 gene polymorphisms and autoantibodies in susceptibility to RA. Methods: A total of 200 patients fulfilled the criteria for RA and 200 healthy individuals were included in the study. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured by enzyme-linked immunosorbent assay (ELISA). HLA-DRB1 alleles were determined by polymerase chain reaction-sequence specific primer (PCR-SSP) method. Samples were genotyped for PTPN22 1858C/T (rs2476601) and CTLA4 CT60 (rs3087243) variants using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: In RA patients 88% and 82% were positive for anti-CCP and RF autoantibodies, respectively. A significant increase in the frequency of HLA-DRB1*01, HLA-DRB1*04, HLA-DRB1*10, HLA-DRB1*14 shared epitope (SE) alleles were identified in RA patients, whereas in healthy subjects, they were HLADRB1*03, HLA-DRB1*07, HLA-DRB1*11, HLA-DRB1*13. There was no association of the PTPN22 1858T variant with RA and it seems to be independent of MHC associations. The frequency of CTLA4 CT60 A allele carriers was significantly higher in RA patients and also it is preferentially in SE-positive RA patients. Conclusion: Our results confirmed the previously reported HLA-DRB1 SE alleles associations with RA. The CTLA4 polymorphism appears to interfere with HLA-DRB1 susceptibility to RA. On the other hand, we failed to provide evidence for the association of the PTPN22 SNP with RA.

The possible role of the tumour necrosis factor polymorphisms and human leucocyte antigens in the development of prostate cancer.

The cause of prostate cancer (PC), one of the most common cancers found among ageing men, remains unclear, but genetic predisposition is believed to play a major role in its aetiology. The aim of the study was to examine HLA genes polymorphism and TNF polymorphisms in PC development. Patients diagnosed with PC (N=113) and 150 healthy individuals were tested for HLA-A, HLA-B and HLA-DRB1 genes and for TNFa, TNFb and TNFd microsatellites. The comparison of patients and controls revealed a positive association of HLA-DRB1*12, TNFa2 and TNFb5, and a negative association of HLA-DRB1*13 and TNFb4 with PC. A division of patients into groups according to age, pre-operative PSA level, Gleason score (GS) and involvement of prostatic capsule, seminal vesicles or bladder neck and perineural invasion of PC demonstrated the following: a positive correlation of HLA-DRB1*12 and a negative correlation of HLA-DRB1*13 with younger patients (<65years), GS>7 and the positive association of prostatic capsule, seminal vesicles, bladder neck and perineural invasion of PC; TNFb4 allele's negative association with older patients displaying higher PSA levels, higher GS and positive surrounding tissue involvement; positive association of TNFb5 allele for both older and younger patients. Investigation of HLA genes and TNF microsatellites demonstrated a possible role of HLA-DRB1 and TNF regions in PC aetiology.

Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology

Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical outcome. Spinal cord pathology is common and contributes significantly to disability in the disease. The influence of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown. A post-mortem cohort of pathologically confirmed cases with multiple sclerosis (n = 108, 34 males) with fresh frozen material available for genetic analyses and fixed material for pathology was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15-positive (n = 21) and negative (n = 26) cases for detailed pathological analyses. For each case, transverse sections from three spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons and inflammation. The influence of HLA-DRB1*15 on pathological outcome measures was evaluated. Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure 15+: 23.7% versus 15-: 12.16%, P = 0.004), parenchymal (cervical, P < 0.01; thoracic, P < 0.05; lumbar, P < 0.01) and lesional inflammation (border, P = 0.001; periplaque white matter, P < 0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination through controlling the extent of parenchymal inflammation. Meningeal inflammation correlated significantly with small fibre axonal loss in the lumbar spinal cord (r = -0.832, P = 0.003) only in HLA-DRB1*15-positive cases. HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord. This study casts light on the role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked.

HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

Studies in many populations consistently have showed that the human leukocyte antigens (HLA) and especially the DRB1*15 allele has by far the strongest genetic association with multiple sclerosis (MS). The aim of this study was to investigate the role of HLA-DRB1* alleles in MS risk/resistance and onset. A sample of 165 Hellenic MS patients (18 with pediatric-, 24 with adolescent- and 123 with adult-onset MS) and 107 healthy volunteers were examined with molecular techniques. Comparisons were made according to the Benjamini-Yekutieli method for p value correction. Both adult-onset MS patients and early-onset MS patients (age at onset below 20 years-old) had a significantly higher frequency of the DRB1*15 allele and a significantly lower frequency of the DRB1*11 allele compared to controls. For the early-onset vs. healthy group comparison, subgroup analyses revealed that both the pediatric- and the adolescent-onset MS groups contributed to the aforementioned DRB1*15 significant difference, while the DRB1*11 difference was ascribed solely to the adolescent-MS onset vs. healthy group comparison. Within MS patients comparisons revealed that early-onset MS patients had a tendency for higher DRB1*03 allele and a lower DRB1*16 allele frequency frequencies compared to adult-onset MS patients, although both non-significant. Notably, pediatric-onset MS patients showed complete absence of the DRB1*16 allele, along with a non-significant tendency for higher DRB1*15 allele frequency relative to the adult-onset group. Finally, the adolescent-onset MS group was presented with a lower DRB1*11 allele frequencies compared both to the pediatric- and the adult-onset MS group. Our findings confirm previous studies on the role of HLA-DRB1* in MS. New findings that need to be confirmed by further studies are the pathogenetic role of DRB1*03 for early-onset MS and the putative protective role of the DRB1*16 allele in the pediatric-onset MS.

Genetics of ANCA-associated vasculitis in Japan: a role for HLA-DRB1*09:01 haplotype

The epidemiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is considerably different between European and Asian populations. Whereas granulomatosis with polyangiitis is the most common form of AAV in northern European populations, microscopic polyangiitis (MPA) accounts for the majority of AAV in Japan. This difference may at least in part derive from the difference in genetic background. In this review, I focus on our observation on HLA, an obvious candidate gene for immune disorders, and discuss its potential implication. In Japanese AAV, significant association was detected with HLA-DRB1*09:01, the carrier frequency of which was increased in MPA [P=0.0087, odds ratio (OR) 1.90, 95% confidence interval (CI) 1.17-3.08] and in myeloperoxidase (MPO)-ANCA-positive AAV (P=0.0016, OR 2.05, 95% CI 1.31-3.23) when compared with healthy Japanese controls. HLA-DRB1*09:01 is one of the most common HLA-DRB1 alleles in Asians but is rare in Caucasian populations. Interestingly, HLA-DRB1*09:01 has been shown to be associated with multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus, suggesting that either HLA-DRB1*09:01 itself or other genes in tight linkage disequilibrium may play a role in a molecular pathway shared by various autoimmune diseases in Japanese and possibly in other Asian populations.

HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance

BackgroundMany epidemiological studies have shown that the genetic factors of the host play a role in the variability of clinical response to infection caused by M. leprae. With the purpose of identifying genes of susceptibility, the present study investigated the possible role of HLA-DRB1 and DQA1/DQB1 alleles in susceptibility to leprosy, and whether they account for the heterogeneity in immune responses observed following infection in a Southern Brazilian population.MethodsOne hundred and sixty-nine leprosy patients and 217 healthy controls were analyzed by polymerase chain reaction amplification and reverse hybridization with sequence-specific oligonucleotide probes and sequence-specific primers(One Lambda®, CA, USA).ResultsThere was a positive association of HLA-DRB1*16 (*1601 and *1602) with leprosy per se (7.3% vs. 3.2%, P = 0.01, OR = 2.52, CI = 1.26–5.01), in accord with previous serological studies, which showed DR2 as a marker of leprosy. Although, HLA-DQA1*05 frequency (29.8% vs. 20.9%, P = 0.0424, OR = 1.61, CI = 1.09–2.39) was higher in patients, and HLA-DQA1*02 (3.0% vs. 7.5%, P = 0.0392, OR = 0.39, CI = 0.16 – 0.95) and HLA-DQA1*04 (4.0% vs. 9.1%, P = 0.0314, OR = 0.42, CI = 0.19 – 0.93) frequencies lower, P-values were not significant after the Bonferroni's correction. Furthermore, HLA-DRB1*1601 (9.0% vs. 1.8%; P = 0.0016; OR = 5.81; CI = 2.05–16.46) was associated with susceptibility to borderline leprosy compared to control group, and while HLA-DRB1*08 (11.2% vs. 1.2%; P = 0.0037; OR = 12.00; CI = 1.51 – 95.12) was associated with susceptibility to lepromatous leprosy, when compared to tuberculoid leprosy, DRB1*04 was associated to protection.ConclusionThese data confirm the positive association of HLA-DR2 (DRB1*16) with leprosy per se, and the protector effect of DRB1*04 against lepromatous leprosy in Brazilian patients.

Association of aplastic anaemia and Fanconi's disease with HLA‐DRB1 alleles

One of the most fascinating areas of research within the field of histocompatibility at present time concerns an observation that a major human histocompatibility system, human leucocyte antigen (HLA), is deeply involved in the development of a great number of diseases. Major histocompatibility complex is the most polymorphic system in the genome of different species. Recognition of HLA alleles could be useful in transplantation and disease studies. Genetic construct of HLA DRB1 was studied in Iranian normal populations and patients with aplastic anaemia and Fanconi's disease. DNA was extracted from the whole blood of 466 normal, 35 aplastic anaemia and 10 Fanconi's individuals. Then DRB1 gene polymorphism was studied by polymerase chain reaction-sequence-specific primer method. The HLA DRB1 gene analysis showed increase of DRB1*07 in aplastic anaemia patients compared to normal population (P = 0.02). According to this study, the frequency of DRB1*07 in normal individuals was 8.3, and in aplastic anaemia patients, 15.7%. Additionally, the frequency of DRB1*04 in normal, aplastic anaemia and Fanconi's individuals was 10, 5.7 and 20%, respectively. Our results of investigation showed correlation between some HLA alleles with the studied diseases. We reported the frequency of various DR types in aplastic and Fanconi's patients. This study could imply the possible role of HLA-DRB1*07 in the incidence of aplastic anaemia. Moreover, the frequency of DRB1*04, DRB1*03 and DRB1*15 alleles showed intermediate correlation with Fanconi's anaemia.

The role of HLA-DRB1*04 alleles and their association with HLA-DQB genes in genetic susceptibility to rheumatoid arthritis in Hungarian patients.

We investigated the HLA-DRB, and DQB polymorphism and haplotypes in RA subjects of Hungarian origin by PCR typing using sequence-specific primers. Molecular subtyping of HLA-DRB1*04 alleles in RA patients showed strongest association with highest relative risk with DRB1*0404. A significantly decreased frequency of DRB1*0403 was observed in patients compared to controls. A significant number of patients carried DR4 haplotypes on DQB1*0302 (54%) relative to DQB1*0301 which was present on 36% of the haplotypes. When compared to controls, the frequency was higher in the latter allele only. Few unique DRB-DQB haplotypes were observed in Hungarian RA patients. In spite of the fact, that the Hungarian population has been isolated linguistically over centuries, a considerable racial admixture has occurred following immigration and invasions, thus the present study confirms in Hungarian patients with RA, previous findings for RA and HLA in European countries.