Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice (original) (raw)
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Journal of Clinical Investigation, 1997
Certain HLA-DR alleles have been associated with predisposition to human rheumatoid arthritis (RA). There is also evidence that certain HLA-DQ alleles may also be important in determining susceptibility to RA. We have previously demonstrated that mice transgenic for HLA-DQ8, a DQ allele associated with susceptibility to RA, develop severe arthritis after type II collagen immunization. To investigate the influence of polymorphic difference at the DQ loci on susceptibility to arthritis, we generated mice transgenic for HLA-DQ6, an allele associated with a nonsusceptible haplotype. The DQ6 mice were found to be resistant to collagen-induced arthritis. We also assessed the combined effect of an RA-susceptible and an RA nonassociated DQ allele by producing double-transgenic mice expressing DQ6 and DQ8 molecules, representing the more prevalent condition found in humans where heterozygosity at the DQ allele is common. The double-transgenic mice developed moderate CIA when immunized with CII when compared with the severe arthritis observed in DQ8 transgenic mice, much like RA patients bearing both susceptible and nonsusceptible HLA haplotypes. These studies support a role for HLA-DQ polymorphism in human RA. (
Modulation of HLA-DQ-restricted collagen-induced arthritis by HLA-DRB1 polymorphism
International Immunology, 1998
Mouse class II-deficient HLA-DQB1*0302, DQA1*0301 (DQ8) transgenic mice are susceptible to severe collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. To examine whether polymorphism at the DRB1 locus can modulate DQ-restricted arthritis, we generated double-transgenic (DR/DQ) mice. HLA-DRB1*1502 (DR2) and DRB1*0301 (DR3) were introduced separately into CIA susceptible DQ8.A β o transgenic mice to generate DQ8/DR2.A β o and DQ8/ DR3.A β o mice.
Do the HLA-DQ and DP genes play a role in rheumatoid arthritis?
Joint Bone Spine, 2001
Whereas the DRB1 alleles have well-established associations with rheumatoid arthritis (RA), the DQ and DP alleles are of more controversial relevance to RA. Early studies of the DQB1 genes in RA determined the frequencies of the two DQB1*03 subtypes that are in linkage disequilibrium with DR4, DQB1*0301 (DQw7) and *0302 (DQw8). Their results are conflicting and difficult to interpret because molecular biology techniques for determining DR4 specificity polymorphism were not available at the time. None of the more recent studies found compelling evidence that the DQB1 alleles influenced the susceptibility to RA. A few studies suggest that the DQ alleles may influence the clinical or biological expression of the disease, perhaps through a complementary effect of the DRB1 and DQB1 alleles. DR-DQ complementarity has been demonstrated in the DQ8 transgenic mouse model, although this is not necessarily relevant to the human disease. The role of DPB1 remains hypothetical but may involve an influence of some alleles in relatively mild forms of RA. The DQB1 and DPB1 alleles are in strong linkage disequilibrium with the DRB1 alleles, making the elucidation of their independent effects a challenging task. Studies are needed to determine whether these linkage disequilibriums can influence the development of autoimmune diseases.
No support for HLA-DQ encoded susceptibility in rheumatoid arthritis
Arthritis & Rheumatism, 1999
Objective. To test predictions based on data from immunogenetic and peptide-binding studies of collageninduced arthritis in mice, in which it has been suggested that susceptibility to rheumatoid arthritis (RA) might be determined by the interaction between susceptibility alleles at the HLA-DQ locus and protective alleles at the HLA-DRB1 locus (including susceptibility effects for HLA-DQ7 and DQ8).
CD74/DQA1 dimers predispose to the development of arthritis in humanized mice
Immunology, 2015
Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying non-RA 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 alpha 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 modeling suggests that DQA1*0103/CD74 form a pocket with similarity to antigen binding pocket. DQA1*0103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant D...
HLA-DQβ 3.1 allele is a determinant of susceptibility to DR4-associated rheumatoid arthritis
Human Immunology, 1989
Rheumatoid arthritis is associated with HLA-DR4 in several ethnic groups. Since DR4 haplotypes encode a diverse array of class II molecules, it is of interest to characterize the nature of the primary association. We have examined molecular polymorphisms of HLA class II gene products expressed by normals and rheumatoid arthritis patients using monoclonal antibodies and two-dimensional electrophoresis. Most homozygous DR4 rheumatoid arthritis patients express DR~I molecules associated with Dw4 or DwI4 mixed lymphocyte culture determinants. In Caucasoids, two DR4-1inked DQw3-associated [3-chain alleles are defined by two-dimensional electrophoresis. These variants, designated DQ[3 3.1 and 3.2, are associated with the serologic determinants DQw7 and DQw8, respectively. A panel of 40 DR4-posith,e normals was also examined for nucleotide sequence polymorphisms associated with DQB3.1 and 3.2 genes using the polymerase chain reaction and specific oligonucleotide probes. At the DQ[3 level the rheumatoid arthritis panel was distinguished by enrichment for the DQ[3 3.1 allele with 100% of patients positive for DQw7. Results presented here suggest that specific DQfl alleles may modify the effect of HLA-DR4[31 alleles in conferring susceptibility to rheumatoid arthritis in a phenotype-specific fashion.
Journal of Experimental Medicine, 1996
Genetic studies have indicated that susceptibility to rheumatoid arthritis (RA) maps to the HLA-DR locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DR genes associated with RA, however, suggests that HLA-DQ molecules may also play a role in RA susceptibility. To examine the role of HLA-DQ molecules in arthritis, we generated transgenic mice expressing the DQA1*0301 and DQB1*0302 genes from an RA predisposing haplotype (DQ8/DR4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab0 mice, and their susceptibility to experimental collagen-induced arthritis was evaluated. The HLA-DQ8+,H-2Ab0 mice displayed good expression of the DQ8 molecule, while no surface expression of endogenous murine class II molecules could be detected. The DQ8 molecule also induced the selection of CD4+ T cells expressing a normal repertoire of V beta T cell receptors. Immunization of HLA-DQ8+,H-2Ab0 mice with bovine type II coll...
Arthritis research, 2000
Human leucocyte antigen (HLA) class II molecules have been shown to be associated with predisposition to rheumatoid arthritis (RA). We generated HLA-DR and DQ transgenic mice that lacked endogenous class II molecules to study the interaction between the DR and DQ molecules and define the immunologic mechanisms in rheumatoid arthritis. Using collagen-induced arthritis (CIA) as an experimental model for inflammatory polyarthritis, we show that both DQ and DR are involved in predisposition or resistance to arthritis. Our studies suggest that polymorphism in DQB1 genes may determine predisposition to RA while the DRB1 polymorphism may dictate severity/protection of the disease. These mice provide powerful tools to develop immunotherapeutic protocols.
HLA-DR antigens and HLA-DQ beta chain polymorphism in susceptibility to rheumatoid arthritis
Annals of the Rheumatic Diseases, 1990
Forty four patients with rheumatoid arthritis (RA) were studied for HLA-DR antigens and for HLA-DQ 13 chain gene restriction fragment length polymorphism using DNA hybridisation. A significant increase in the prevalence of the DR4 antigen and a tendency towards an increase of DRI was found in patients with RA. No allelic form of HLA-DQ restriction fragment length polymorphism patterns was increased, but the prevalence of an allele characterised by a combination of 7-5 and 3 kb fragments was decreased among patients with RA. The DQw8 subtype represented by a 12 kb fragment was the most common DR4 associated allele, and a 3.7 kb fragment related to DQw7 was found in only 5/25 (20%) DR4 positive patients and 2/12 (17%) controls. The results support the hypothesis that RA susceptibility factors are primarily located within HLA-DR genes but HLA-DQ genes may have a role in protection from the disease.