HLA-DRB1 shared epitope allele polymorphisms and rheumatoid arthritis: a systemic review and meta-analysis

Liu, Wenxin; Jiang, Yao; Hu, Qingxiang; You, Xie-Bo

doi:10.25011/cim.v39i6.27487

Cited by 16 publications

(10 citation statements)

References 23 publications

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“…Firmicutes were significantly higher in GDV dogs ( Table 2 ) and one risk allele for DLA Class II. In humans, mutations in Class II genes have been associated with autoimmune diseases such as celiac disease and rheumatoid arthritis [ 69 – 75 ]. Similar patterns have been observed in a humanized mouse model of rheumatoid arthritis [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

The canine gut microbiome is associated with higher risk of gastric dilatation-volvulus and high risk genetic variants of the immune system

Hullar¹,

Lampe²,

Torok‐Storb³

et al. 2018

PLoS ONE

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BackgroundLarge and giant dog breeds have a high risk for gastric dilatation-volvulus (GDV) which is an acute, life-threatening condition. Previous work by our group identified a strong risk of GDV linked to specific alleles in innate and adaptive immune genes. We hypothesize that variation in the genes of the immune system act through modulation of the gut microbiome, or through autoimmune mechanisms, or both, to predispose dogs to this condition. Here, we investigate whether differences in the canine fecal microbiome are associated with GDV and are linked to previously identified risk alleles.Methodology/Principle findingsFecal samples from healthy Great Danes (n = 38), and dogs with at least one occurrence of GDV (n = 37) were collected and analyzed by paired-end sequencing of the 16S rRNA gene. Dietary intake and temperament were estimated from a study-specific dietary and temperament questionnaire. Dogs with GDV had significantly more diverse fecal microbiomes than healthy control dogs. Alpha diversity was significantly increased in dogs with GDV, as well as dogs with at least one risk allele for DRB1 and TRL5. We found no significant association of dietary intake and GDV. Dogs with GDV showed a significant expansion of the rare lineage Actinobacteria (p = 0.004), as well as a significantly greater abundance of Firmicutes (p = 0.004) and a significantly lower abundance of Bacteroidetes (p<0.004). There was a significant difference in the abundance of 10 genera but after correction for multiple comparisons, none were significant. Bacterial phyla were significantly different between controls and dogs with GDV and at least one risk allele for DRB1 and TRL5. Actinobacteria were significantly higher in dogs with GDV and with one risk allele for DRB1 and TLR5 but not DLA88 genes. Furthermore, Collinsella was significantly increased in dogs with at least one risk allele for DRB1 and TLR5. Logistic regression showed that a model which included Actinobacteria, at least one risk allele,and temperament, explained 29% of the variation in risk of GDV in Great Danes.ConclusionsThe microbiome in GDV was altered by an expansion of a minor lineage and was associated with specific alleles of both innate and adaptive immunity genes. These associations are consistent with our hypothesis that immune genes may play a role in predisposition to GDV by altering the gut microbiome. Further research will be required to directly test the causal relationships of immune genes, the gut microbiome and GDV.

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Section: Discussionmentioning

confidence: 99%

The canine gut microbiome is associated with higher risk of gastric dilatation-volvulus and high risk genetic variants of the immune system

Hullar¹,

Lampe²,

Torok‐Storb³

et al. 2018

PLoS ONE

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“…HLA are an important part of the immune system triggering T cells of the immune system to produce antibodies. Associations of RA with HLA-DRB1 alleles have been observed in all racial and ethnic populations [ 7 , 8 ]. The shared epitope (SE), a 5-amino acid sequence motif in positions 70–74 of the HLA–DR β chain, is the most significant genetic risk factor for rheumatoid arthritis [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Intestinal Dysbiosis and Rheumatoid Arthritis: A Link between Gut Microbiota and the Pathogenesis of Rheumatoid Arthritis

Horta-Baas

Figueroa

Montiel-Jarquín

et al. 2017

Journal of Immunology Research

240

184

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Characterization and understanding of gut microbiota has recently increased representing a wide research field, especially in autoimmune diseases. Gut microbiota is the major source of microbes which might exert beneficial as well as pathogenic effects on human health. Intestinal microbiome's role as mediator of inflammation has only recently emerged. Microbiota has been observed to differ in subjects with early rheumatoid arthritis compared to controls, and this finding has commanded this study as a possible autoimmune process. Studies with intestinal microbiota have shown that rheumatoid arthritis is characterized by an expansion and/or decrease of bacterial groups as compared to controls. In this review, we present evidence linking intestinal dysbiosis with the autoimmune mechanisms involved in the development of rheumatoid arthritis.

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“…Shared epitope motifs are especially frequent in native Americans (19). MHCII molecules play a crucial role in the presentation of antigens, and their association with RA is a consistent finding in many populations of different ancestry (20)(21)(22)(23)(24). MHCII molecules are central in directing adaptive immune responses.…”

Section: Inborn Factors In Ramentioning

confidence: 99%

“…This led them to conclude that an appropriate level of host response and maintenance of a stable balance despite the persistence of a dysbiotic biofilm could be achieved in chronic PD (104,107). Variants in the MHC II complex definitely have an important impact on the strength of adaptive immune responses, and an overwhelming amount of data from around the globe shows their importance for the development of RA (20)(21)(22)(23)(24). In comparison, the strongest known genetic associations for PD are observed with genes outside the MHC II complex (23,24,108), and they are much weaker.…”

Section: Pathology Of Pdmentioning

confidence: 99%

Infectious Triggers in Periodontitis and the Gut in Rheumatoid Arthritis (RA): A Complex Story About Association and Causality

et al. 2020

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Rheumatoid arthritis (RA) is a systemic immune mediated inflammatory disease of unknown origin, which is predominantly affecting the joints. Antibodies against citrullinated peptides are a rather specific immunological hallmark of this heterogeneous entity. Furthermore, certain sequences of the third hypervariable region of human leukocyte antigen (HLA)-DR class II major histocompatibility (MHC) molecules, the so called "shared epitope" sequences, appear to promote autoantibody positive types of RA. However, MHC-II molecule and other genetic associations with RA could not be linked to immune responses against specific citrullinated peptides, nor do genetic factors fully explain the origin of RA. Consequently, non-genetic factors must play an important role in the complex interaction of endogenous and exogenous disease factors. Tobacco smoking was the first environmental factor that was associated with onset and severity of RA. Notably, smoking is also an established risk factor for oral diseases. Furthermore, smoking is associated with extra-articular RA manifestations such as interstitial lung disease in anatomical proximity to the airway mucosa, but also with subcutaneous rheumatoid nodules. In the mouth, Porphyromonas gingivalis is a periodontal pathogen with unique citrullinating capacity of foreign microbial antigens as well as candidate RA autoantigens. Although the original hypothesis that this single pathogen is causative for RA remained unproven, epidemiological as well as experimental evidence linking periodontitis (PD) with RA is rapidly accumulating. Other periopathogens such as Aggregatibacter actinomycetemcomitans and Prevotella intermedia were also proposed to play a specific immunodominant role in context of RA. However, demonstration of T cell reactivity against citrullinated, MHC-II presented autoantigens from RA synovium coinciding with immunity against Prevotella copri (Pc.), a gut microbe attracted attention to another mucosal site, the intestine. Pc. was accumulated in the feces of clinically healthy subjects with citrulline directed immune responses and was correlated with RA onset. In conclusion, we retrieved more than one line of evidence for mucosal sites and different microbial taxa to be potentially involved in the development of RA. This review gives an overview of infectious agents and mucosal pathologies, and discusses the current evidence for causality between different exogenous or mucosal factors and systemic inflammation in RA.

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HLA-DRB1 shared epitope allele polymorphisms and rheumatoid arthritis: a systemic review and meta-analysis

Abstract: HLA-DRB1 shared epitope allele polymorphisms and rheumatoid arthritis: a systemic review and meta-analysis Abstract Purpose: A meta-analysis was preformed to determine which HLA-DRB1 alleles are associated with increased risk of rheumatoid arthritis (RA) in Asian patients.

Cited by 16 publications

References 23 publications

The canine gut microbiome is associated with higher risk of gastric dilatation-volvulus and high risk genetic variants of the immune system

The canine gut microbiome is associated with higher risk of gastric dilatation-volvulus and high risk genetic variants of the immune system

Intestinal Dysbiosis and Rheumatoid Arthritis: A Link between Gut Microbiota and the Pathogenesis of Rheumatoid Arthritis

Infectious Triggers in Periodontitis and the Gut in Rheumatoid Arthritis (RA): A Complex Story About Association and Causality

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