Role of HLA class II genes in susceptibility/resistance to inflammatory arthritis: studies with humanized mice

Taneja, Veena; David, Chella S.

doi:10.1111/j.0105-2896.2009.00858.x

Cited by 60 publications

(58 citation statements)

References 76 publications

(79 reference statements)

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“…A role of trans-heterodimer between two non-associated DQ alleles suggested a significant but indirect role of the DQA1 gene in CIA in transgenic mice. 17,31 In this study, we show for the first time that the DQA1*0103 gene can cause transgenic mice to develop severe CIA. The possibilities by which DQA1*0103 predisposes to CIA include (i) formation of homodimers capable of presenting antigens, (ii) expression as a heterodimer with H2M that can present antigen, or (iii) DQA1*0103 chains bind CD74 in the cytoplasm but in the absence of the b-chain, CD74 is not cleaved off and is expressed as a dimer on the cell surface.…”

Section: Discussionmentioning

confidence: 61%

CD74/DQA1 dimers predispose to the development of arthritis in humanized mice

et al. 2015

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SummaryRheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non-associated alleles develop arthritis is still unexplained. The trans-heterodimer between two RA non-associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA1*0103/DQB1*0604, suggesting a role for DQ a chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA1*0103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA1*0103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA1*0103 mice generated an antigen-specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA1*0103/CD74 form a pocket with similarity to the antigen binding pocket. DQA1*0103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant DQA1*0103/DQB1*0601 allele, suggesting that the DQA1*0103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis.

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Section: Discussionmentioning

confidence: 61%

CD74/DQA1 dimers predispose to the development of arthritis in humanized mice

et al. 2015

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“…Class ii hlas-named hla-d and subclassified into hla-dr, hla-dq, hla-dp, and so on-are expressed mainly in immunocells. They function as labelled molecules to activate the immune response and regulate the interaction of immunocells [22][23][24] .…”

Section: Discussionmentioning

confidence: 99%

Relationship between HLA-DRB1 Allele Polymorphisms and Familial Aggregations of Hepatocellular Carcinoma

Wei

et al. 2016

Current Oncology

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Objective We explored the relationship between HLA-DRB1 allele polymorphisms and familial aggregation of hepatocellular carcinoma (fhcc).Methods Polymerase chain reaction sequence-specific primers were used to determine HLA-DRB1 genotypes for 130 members of families with 2 or more liver cancer patients and for 130 members of families without any diagnosed cancers. The genotype profiles were then compared to explore the relationship between HLA-DRB1 gene polymorphism and fhcc.Result Of 11 selected alleles, the frequencies of DRB1*11 and DRB1*12 were significantly lower in the fhcc group than in no-cancer group (p < 0.05; odds ratio: 0.286; 95% confidence interval: 0.091 to 0.901; and odds ratio: 0.493; 95% confidence interval: 0.292 to 0.893). Differences in the frequencies of the other 9 alleles were not statistically significant in the two groups (p > 0.05). ConclusionsOur research suggests that if genetic factors play a role in fhcc, the deficiency in the DRB1*11 and DRB1*12 alleles might be the risk factor at work in Guangxi Zhuang Autonomous Region, P.R.C.

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“…CD4 + T cell mediated diseases are generally restricted to a limited set of HLA alleles [6],, and analogous MHC molecules encoded by them may not be expressed by mice [7], preventing the simulation of the contexts in which the antigenic peptides are presented to autoantigen-specific T cells. Genetic components (e.g.…”

Section: The Limitations Of Mice When Modeling Human Autoimmunitymentioning

confidence: 99%

“…To mention but a few, mice are available that express not only human MHC alleles such as 0401, but also human CD4 molecules [7]. These transgenic animals are often better tools for testing hypotheses (generated from patient data) that particular MHC molecules present particular autoantigens in a non-tolerogenic context.…”

Section: Humanized Mice For Modeling Antigen Specific T-cellsmentioning

confidence: 99%

Building Rational Models of Humoral Autoimmunity: The Example of Lupus Tubulointerstitial Nephritis

Kinloch¹

2013

Rheumatol Curr Res

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Mice have proven to be extremely useful tools for simulating pathways involved in humoral autoimmune diseases observed in patients. A relevant animal model can act as a means with which existing drugs can be tested, and new ones rationally designed. With a view to rationally developing animal models, the common features of organ-specific autoantibody-mediated diseases are briefly recalled herein. Historically however, hurdles have often existed that have thwarted the description of these features,, and therefore the development, and testing of hypotheses that explain pathways that yield autoimmune pathologies. The difficulties in assembling these hypotheses from human data have included acquisition of sufficient information regarding antibodies, antigens, and genetics,, and the subsequent marrying of these data-sets with particular clinical manifestations. Moreover, once well-assembled hypotheses have been generated, appropriate platforms for their testing are frequently absent. In the mouse, the immunologists' 'go-to' simulation platform, components integral to mounting antigen specific immune responses are often poorly conserved, or even absent. In this review, following a description of some of the cross species inconsistencies, tools such as plasmids for expressing murine monoclonal antibodies with human variable regions,, and mice engineered to express human Fcγ receptors,, and HLA molecules, often capable of surmounting these issues, are highlighted. By avoiding historical pitfalls,, and considering how new technologies could be employed in the future, a rational approach will be devised for the detailed characterization of the recently discovered organ-specific autoimmune phenomenon of lupus tubulointerstitial nephritis (TIN),, and an animal model that simulates it. Humoral Autoimmunity: The Conventional ModelIrrespective of the order in which their distinguishing characteristics have been identified, most T cell dependent, antibody-mediated autoimmune diseases end up adhering to the same (admittedly oversimplified) conventional model; in individuals, genetically predisposed to being less immunologically tolerant, who are exposed to particular environmental factors (not discussed in this article),, and with the capacity to present autoantigens because of carriage of particular HLA alleles, autoimmunity to particular autoantigens ensues (Wegner et al. [1]). Providing sufficient accumulation of target autoantigens, the autoantibodies that develop (often measurable in the serum) perpetuate chronic inflammation in particular tissues. Characterization of autoimmune phenomena in patients often results in the development of clinically useful serological assays for diagnosing particular diseases,, and hypotheses regarding pathogenic pathways. However, it is the development of animal models that many researchers often strive most vehemently towards. This is because they not only serve to test our hypotheses regarding disease pathways, they may also be useful as in vivo systems, with which drugs can be tes...

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Role of HLA class II genes in susceptibility/resistance to inflammatory arthritis: studies with humanized mice

Cited by 60 publications

References 76 publications

CD74/DQA1 dimers predispose to the development of arthritis in humanized mice

CD74/DQA1 dimers predispose to the development of arthritis in humanized mice

Relationship between HLA-DRB1 Allele Polymorphisms and Familial Aggregations of Hepatocellular Carcinoma

Building Rational Models of Humoral Autoimmunity: The Example of Lupus Tubulointerstitial Nephritis

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