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HLA-DRB1 alleles associated with SLE, Ps + PsA, RA, SSc, MS, and MG.
Source publication
Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with...
Context in source publication
Context 1
... different hypothesis proposes that different alleles can modulate the immunologic profile of an individual, through antigen-independent mechanisms, resulting in either pro- moting a higher autoimmune predisposition or, in oppo- sition, a more efficient immune regulation. Given the consistent association of HLA-DRB1 alleles with different autoimmune diseases (Table 1), we explored the idea that the same HLA-DRB1 alleles could be influencing several different autoimmune diseases. To this end we compared the immunogenetic profile in different AIDs. ...
Citations
... In IBM, the HLA DRB1*13:01 was associated with the highest age of onset and the lower strength [88]. Nevertheless, intriguingly, HLA DRB1*13 was protective against autoimmune diseases such as systemic lupus erythematosus, psoriasis, systemic sclerosis, and others [93]. However, HLA DRB1*13 is also associated with a slow progression of HIV [94]. ...
The ubiquitous RNA-processing molecule TDP-43 is involved in neuromuscular diseases such as inclusion body myositis, a late-onset acquired inflammatory myopathy. TDP-43 solubility and function are disrupted in certain viral infections. Certain viruses, high viremia, co-infections, reactivation of latent viruses, and post-acute expansion of cytotoxic T cells may all contribute to inclusion body myositis, mainly in an age-shaped immune landscape. The virally induced senescent, interferon gamma-producing cytotoxic CD8+ T cells with increased inflammatory, and cytotoxic features are involved in the occurrence of inclusion body myositis in most such cases, in a genetically predisposed host. We discuss the putative mechanisms linking inclusion body myositis, TDP-43, and viral infections untangling the links between viruses, interferon, and neuromuscular degeneration could shed a light on the pathogenesis of the inclusion body myositis and other TDP-43-related neuromuscular diseases, with possible therapeutic implications.
... The topics of protective HLA polymorphism related to autoimmune diseases in general [24,25] and, more specifically, to SARS-CoV-2 infectivity have been extensively reported [8,[26][27][28][29][30][31][32][33][34][35][36], despite some controversary on the latter topic [37]. Interestingly, some HLA variants were described to confer resistance to CD development. ...
The SARS-CoV-2 pandemic continues to pose a global threat. While its virulence has subsided, it has persisted due to the continual emergence of new mutations. Although many high-risk conditions related to COVID-19 have been identified, the understanding of protective factors remains limited. Intriguingly, epidemiological evidence suggests a low incidence of the COVID-19-infected CD patients. The present study explores whether their genetic background, namely the associated HLA-DQs, offers protection against severe COVID-19 outcomes. We hypothesize that the HLA-DQ 2/8 alleles may shield CD patients from SARS-CoV-2 and its subsequent effects, possibly due to memory CD4 T cells primed by previous exposure to human-associated common cold coronaviruses (CCC) and higher affinity to those allele's groove. In this context, we examined potential cross-reactivity between SARS-CoV-2 epitopes and human-associated CCC and assessed the binding affinity (BA) of these epitopes to HLA-DQ 2/8. Using computational methods, we analyzed sequence similarity between SARS-CoV-2 and four distinct CCC. Of 924 unique immunodominant 15-mer epitopes with at least 67% identity, 37 exhibited significant BA to HLA-DQ 2/8, suggesting a protective effect. We present various mechanisms that might explain the protective role of HLA-DQ2/8 in COVID-19-afflicted CD patients. If substantiated, these insights could enhance our understanding of gene-environment enigma and viral-host relationship, guiding potential therapeutic innovations against the ongoing SARS-CoV-2 pandemic.
... Regarding HLA-DRB1*13:03, which was also associated with AHA in our study, different publications have consistently reported its association with the risk of autoimmune diseases in spite of the low frequency that this allele generally presents in European populations, being close to 1% and rarely observed at frequencies greater than 3% worldwide [38]. In particular, HLA-DRB1*13:03 has been demonstrated to play a role in susceptibility to multiple sclerosis. ...
... In severe HA, HLA-DRB1*13:01 has been found to be associated with alloantibody development against exogenous FVIII in replacement therapy, which would suggest a common pathogenic mechanism involving specific HLA-DRB1*13 alleles for the development of either allo-or autoantibodies against FVIII [39]. Conversely, previous studies have proposed HLA-DRB1*13 as a universal protective factor against autoimmune diseases, possibly mediated by the presence of the DERAA sequence at positions 70-74 [38]. This apparent conflict with our results can be explained by the absence of the DERAA epitope in HLA-DRB1*13:03, which is contained, however, in HLA-DRB1*13:01, HLA-DRB1*13:02, and HLA-DRB1*13:04 [40]. ...
... This apparent conflict with our results can be explained by the absence of the DERAA epitope in HLA-DRB1*13:03, which is contained, however, in HLA-DRB1*13:01, HLA-DRB1*13:02, and HLA-DRB1*13:04 [40]. Accordingly, HLA-DRB1*13:01 and HLA-DRB1*13:02 have been described as the main mediators of the protective effect in autoimmune diseases [38]. Therefore, HLA-DRB1*13:03 could be considered a new risk factor for AHA and, potentially, for other autoimmune diseases. ...
Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the presence of autoantibodies against factor VIII (FVIII). As with other autoimmune diseases, its etiology is complex and its genetic basis is unknown. The aim of this study was to identify the immunogenetic background that predisposes individuals to AHA. HLA and KIR gene clusters, as well as KLRK1, were sequenced using next-generation sequencing in 49 AHA patients. Associations between candidate genes involved in innate and adaptive immune responses and AHA were addressed by comparing the alleles, genotypes, haplotypes, and gene frequencies in the AHA cohort with those in the donors’ samples or Spanish population cohort. Two genes of the HLA cluster, as well as rs1049174 in KLRK1, which tags the natural killer (NK) cytotoxic activity haplotype, were found to be linked to AHA. Specifically, A*03:01 (p = 0.024; odds ratio (OR) = 0.26[0.06–0.85]) and DRB1*13:03 (p = 6.8 × 103, OR = 7.56[1.64–51.40]), as well as rs1049174 (p = 0.012), were significantly associated with AHA. In addition, two AHA patients were found to carry one copy each of the low-frequency allele DQB1*03:09 (nallele = 2, 2.04%), which was completely absent in the donors. To the best of our knowledge, this is the first time that the involvement of these specific alleles in the predisposition to AHA has been proposed. Further molecular and functional studies will be needed to unravel their specific contributions. We believe our findings expand the current knowledge on the genetic factors involved in susceptibility to AHA, which will contribute to improving the diagnosis and prognosis of AHA patients.
... 27,30 It has been proposed that a defect in the In our study, we found that HLA-DR2 (ie, HLA-DR15 and HLA-DR16 taken together) is positively correlated with susceptibility to SLE. Conversely, we also noted that possession of HLA-DR6 appeared to trend toward negative correlation with SLE, and although this result was not statistically significant, it was consistent with findings from previous studies, such as the protective effects conferred by HLA-DR6 alleles including DRB1*13 and *14 as reported by Furukawa et al, 33 and HLA-DR6 allele HLA-DRB1*13 as reported by Bettencourt et al. 34 SLE affects the kidneys in about 50% of patients, with lupus nephritis being the most common cause of SLE-related kidney injury, of which 10% of patients will progress to end-stage renal disease. 35 HLA-DR2, specifically the variant HLA-DR15, has been associated with lupus nephritis in many discrete populations [36][37][38][39][40][41][42] ; additionally, the subvariant HLA-DRB1*1503 has been found by Bastian et al 43 to be associated with new or worsening proteinuria. ...
Background
Different HLA-DR genotypes have been known to be associated with the risk of development of systemic lupus erythematosus (SLE) in different populations, although Lu et al. has reported previously that no correlation exists between the HLA-DR genotype and disease manifestation in SLE patients in Taiwan. We investigated the effects different HLA-DR genotypes had on SLE incidence in Taiwanese patients as to whether risk alleles were associated with different clinical manifestations, and the effects risk alleles had on the age of disease onset.
Methods
234 SLE patients and 346 healthy controls were enrolled. HLA-DR genotyping was performed with the HLA FluoGene DRDQ kit for each subject. Chi-square tests and t -tests were performed for statistical analysis.
Results
HLA-DR2 was significantly more frequently found in SLE patients than in controls (OR= 2.05, 95% CI= 1.44-2.92, p < 0.001). Notably, HLA-DR6 appeared to trend towards negative correlation with SLE, while HLA-DR8 appeared to trend towards positive correlation. HLA-DR2 patients had an earlier onset of disease as well as a higher prevalence of oral ulcer, avascular necrosis of bone, and renal involvement (lupus nephritis).
Conclusion
HLA-DR2 was associated with SLE susceptibility in this Taiwanese population as well as lower age of disease onset and more severe clinical manifestations.
... Autoimmune diseases (AIDs) are a heterogeneous group [1][2][3][4][5][6][7][8][9][10][11][12][13] with different phenotypes (organ-specific vs. systemic or non-organ specific) [14] and an estimated world prevalence of 3-9.4% [14][15][16][17]. This represents a significant burden on social and medical resources, with direct and indirect costs and impact on quality of life [3][4][5]18]. ...
... The vast majority of AIDs occur as one single disease (monoautoimmunity). However, the existence of clinical subphenotypes common to several AIDs suggests shared physiopathological mechanismsautoimmune tautology [4,5,8,9,11,12,[19][20][21][22][23]. This is corroborated by three levels of evidence: 1) clinical observations indicating a possible shift from one disease to another over time or the coexistence of more than one AID in a single patient (polyautoimmunity) or family (familial autoimmunity); 2) known shared pathophysiological mechanisms between AIDs and 3) evidence implying common genetic factors [8,9,19,21]. ...
... Several studies and genetic mapping have reported an association between several HLA alleles on classes I and II and AIDs [14]. Two etiopathogenic models provide possible explanations for the increased AID risk associated with specific HLA alleles -the molecular mimicry hypothesis and the central selection failure hypothesis [12]. The latter proposes that specific peptide-HLA class II combinations affect T-cell development and/or tolerance, which may confer susceptibility to AIDs [29]. ...
Introduction:
The existence of subphenotypes common to several autoimmune diseases (AIDs) suggests a shared physiopathology - autoimmune tautology. Multiple Autoimmune Syndrome (MAS) - the coexistence of three or more AIDs in one person-, best illustrates that polyautoimmunity is more than a coincidence.
Objectives:
Characterize and compare the monoautoimmune and MAS patients. Understand if clustering of AIDs leads to differences in disease severity, autoantibodies expression or genetic polymorphisms that could be markers for polyautoimmunity.
Methods:
Currently adult patients were selected from unit cohort. MAS was assumed when ≥3 AIDs were present. 343 patients were included after exclusion criteria: having two AIDs or undetermined diagnosis. Clinical and immunological data were collected from medical files. HLA-DRB1 was genotyped by PCR-SSP methodology and PTPN22(rs2476601) polymorphisms by TaqMan Real Time PCR. Data were analysed using Chi-Square, Fisher's exact tests and logistic regression. Odds ratios (OR) and 95% confidence intervals were calculated.
Results:
In comparison with control population: ELEVATED FREQUENCIES: HLA-DRB1×03 in study cohort (OR=3.68,p<0.001) and in monoautoimmune SLE (OR=2.79,p<0.001) and SjS (OR=8.27,p<0.001); HLA-DRB1×15 in monoautoimmune SjS (OR=2.39,p = 0.011); HLA-DRB1×16 in MAS SLE (OR=2.67,p = 0.031); PTPN22_T in all groups except monoautoimmune SjS and triple positive systemic MAS.
Diminished frequencies:
HLA-DRB1×11 in study cohort (OR=0.57,p = 0.013), in MAS SLE (OR=0.39,p = 0.031) and monoautoimmune SjS (OR=0.10,p = 0.005); HLA-DRB1×13 in study cohort (OR=0.52,p = 0.001) and in monoautoimmune SLE (OR=0.53,p = 0.009) and SjS (OR=0.38,p = 0.031); HLA-DRB1×14 in study cohort (OR=0.32,p = 0.013) and monoautoimmune SLE (OR=0.21,p = 0.021); SLE group: HLA-DRB1×07 frequency was higher in monoautoimmune patients (OR=0.43,p = 0.023). MAS patients had significantly more NPSLE (OR=2.99,p<0.001), subacute cutaneous lesions (OR=2.30,p = 0.037), muscle&tendon (OR=2.00,p = 0.045), and haematological (OR=3.18,p = 0.006) involvement and Raynaud's (OR=2.94,p<0.001). SjS group: MAS patients had more frequently cryoglobulins (OR=2.96,p = 0.030), low complement (OR=2.43,p = 0.030) and Raynaud's (OR=4.38,p<0.001); monoautoimmune patients had more parotid enlargement (OR=0.12,p<0.001). APS group: MAS patients had more non-thrombotic manifestations (OR=4.69,p = 0.020) and Raynaud's (OR=9.12,p<0.001). Triple positive systemic MAS (SLE+SjS+APS) had more frequently severe kidney involvement (OR=11.67,p = 0.021) and CNS thrombosis (OR=4.44,p = 0.009). Anti-U1RNP increased frequency was transversally attributable to MAS.
Conclusions:
The coexistence of AIDs contributes to a more severe disease course. We confirmed previously established genetic risk and protection factors and suggest a new protective one - HLA-DRB1×14. HLA-DRB1×07 and anti-U1RNP could be markers for mono and polyautoimmunity, respectively; HLA-DRB1×13 could be a predictor for vascular risk in patients with multiple AIDs. PTPN22(rs2476601) polymorphism could be associated with less severe disease.
... 25,27,28 With regard to aging, previous research has documented agerelated deviations in SNI characterized by increased network variability that are remarkably absent in individuals carrying HLA-DRB1*13, 12 which confers protection against several immune-related conditions. 29,30 Here we extend those findings to evaluate the influence of a large number of HLA alleles on aging-related changes in SNI. ...
Recent evidence documented a protective effect of Class II human leukocyte antigen (HLA) DRB1*13 on brain health across the lifespan including evidence of reduced neural network variability relative to non-carriers. Here, in an extension of those findings, we evaluated the influence of a large number of Class I and Class II HLA alleles on aging-related changes in neural network variability. Cognitively healthy women (N = 178) ranging in age from 28 to 99 years old underwent a magnetoencephalography scan from which neural network variability was calculated and provided a blood sample from which HLA and apolipoprotein E (ApoE) genotype were determined. The primary analyses assessed the dependence of network variability on age in carriers of a specific HLA allele compared to non-carriers. Effects were considered protective if there was a significant increase of network variability with age in the absence of a given HLA allele but not in its presence, and were considered to confer susceptibility if the converse was documented; HLA alleles that did not influence the dependence of network variability on age in their presence or absence were considered neutral. Of 50 alleles investigated, 22 were found to be protective, 7 were found to confer susceptibility, and 21 were neutral. The frequencies of those 50 alleles were not associated significantly with ApoE genotype. The findings, which document the influence of HLA on age-related brain changes and highlight the role of HLA in healthy brain function, are discussed in terms of the role of HLA in the human immune response to foreign antigens.
... They are both associated with reduced risk of the autoimmune disorders rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis, OR: 0.4-0.6 (online suppl. Table S8) [24][25][26]. Mutations within the MHC region on chromosome 6p21.3 can give rise to complement C2 and C4 deficiencies, resulting in SLE and other autoimmune disorders [27]. ...
... The protective allele DRB1*13:02 is also associated with protection against psoriasis, OR 0.6 (online suppl. Table S8) [26]. Onychomycosis and psoriasis may be positively correlated, although the evidence is conflicting [33]. ...
Introduction:
Antigen presentation and antimicrobial immune responses involve the human leukocyte antigen (HLA) system. Onychomycosis is primarily caused by dermatophytes and affects around 5.5% of the population worldwide. Yet, only limited data exist on the associations between the HLA system and onychomycosis. Thus, the objective of the study was to investigate if there is an association between HLA alleles and onychomycosis.
Methods:
Participants in the Danish Blood Donor Study were defined as cases of onychomycosis and controls based on antifungal prescriptions in the national prescription registry. Associations were investigated using logistic regressions adjusted for confounders and were Bonferroni corrected for multiple tests.
Results:
A total of 3,665 participants were considered onychomycosis cases, and 24,144 participants were considered controls. We found two protective HLA alleles of onychomycosis: DQB1*06:04, odds ratios (OR) 0.80 (95% confidence interval (CI) 0.71-0.90), and DRB1*13:02, OR 0.79 (95% CI: 0.71-0.89).
Conclusion:
The finding of two novel protective alleles of onychomycosis indicates that certain HLA alleles have certain antigen presentation properties affecting the risk of fungal infection. These findings may provide the basis for future research identifying immunologically relevant antigens of fungi causing onychomycosis, which could ultimately lead to targets of new drugs with antifungal effects.
... In terms of genetics, although considered a minor criterion for the diagnosis of ASIA (Table 1), it holds an important role in the interplay by providing fertile grounds for ASIA to propagate. When speaking of genetic factors for ASIA and other autoimmune diseases, genes such as HLA-DRB1 and HLA DQB1 [41], alongside PTPN22, take the spotlight of genetic susceptibility to ASIA [42]. Moreover, certain studies suggest epigenetic involvement, because despite the high rates of exposure to environmental factors, susceptibility to ASIA is still rather low [43]. ...
Since vaccines are in fact manufactured chemical compounds such as drugs, the appearance of side effects following their use is not surprising. Similarly, as the main goal of vaccines is to stimulate the immune system bringing out the production of protective antibodies, autoimmune-related side effects as a consequence of increased immune activity do not seem irrational. Fortunately, the rate of such side effects is low; however, the importance of reporting adverse events following vaccinations, understanding the mechanisms behind their appearance, making early diagnosis, and appropriate treatment cannot be overemphasized. In fact, autoimmune-related side effects of vaccines, particularly those based on adjuvants, were reported long before the introduction of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Nevertheless, ASIA gathered and united the side effects of vaccines under one title, a step which helped organize the research and call for better immune stimulators than adjuvants. New technologies and methods of making vaccines were clearly noticed during the pandemic of COVID-19 after the introduction of mRNA-based vaccines. In our current paper, we introduce the notion of side effects to vaccines, particularly those of autoimmune nature, the mechanisms of ASIA, and the main vaccines linked with the syndrome including the recent COVID-19 vaccines. The transition from side effects to ASIA is the main idea behind our work.
... Even in the Brazilian population, HLA-DRB1*03:01 has a secondary association with the disease (26). Similarly, DRB1*03 is also a susceptible allele for various other autoimmune disorders such as autoimmune thyroiditis (27), PR3-ANCA-associated vasculitis (28), systemic lupus erythematosus, multiple sclerosis, and myasthenia gravis (29). ...
Autoimmune hepatitis (AIH) is a chronic and progressive disease of the liver. This is a multifactorial autoimmune disease with both environmental factors and genetic factors playing a role in its pathogenesis. Certain environmental agents like viruses, drugs, etc., can trigger the disease in a genetically susceptible individual. The present study was aimed to explore the distribution of human leukocyte antigen (HLA)-DRB1, Protein tyrosine phosphatase non-receptor type 22 (PTPN22) and Cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) polymorphisms in North Indian adult AIH patients and their associations with clinical and pathological characteristics associated with the disease. A total of 147 subjects with 47 cases and 100 healthy controls were enrolled. Diagnosis of AIH was made by Revised International Autoimmune Hepatitis Group scoring system. HLA-DRB1 Typing was done by Luminex-based reverse Sequence-Specific Oligonucleotide Probing (SSOP). Single nucleotide variant (SNV) genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP arrays. Results indicated SLA positive AIH patients are poor responders to therapy. A significant predispositional association of HLA-DRB1*03 was observed in AIH patients from the North Indian population (p= 0.0001, OR=4.83 (2.30-10.15). The frequency of the GG genotype of CTLA-4 CT 60 was significantly increased in AIH patients compared to controls. Multinomial analysis showed that CTLA-4 CT 60 is an independent predictor for cases.
... However, HLA-DRB1*07 was negatively associated with membranous glomerulonephritis in Caucasians [27]. Various studies have explored the association of HLA-DRB1*07 in different diseases such as cervical cancer hypersensitivity and anti-asparaginase-sensitive patients, and psoriasis or psoriatic arthritis (Ps+PsA) patients [28]. The extensive polymorphism in HLA class II genes results in multiple alleles leading to significant variations in interaction with antigenic peptides, allorecognition, and enormous variability of immune response patterns among individuals. ...
