Genetic factors regulating experimental arthritis in mice and rats.
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Animals↗
Biomedical subjects
M M Griffiths
Publications and source records attributed to M M Griffiths.
HLA-DQ6/8 double transgenic mice develop auricular chondritis following type II collagen immunization: a model for human relapsing polychondritis.
We have generated transgenic (tg) mice expressing HLA-DQ8alphabeta (DQA1*0301/DQB*0302) or HLA-DQ6alphabeta (DQA1*0103/DQB1*0601) molecules lacking endogenous murine class II expression (A beta0) to investigate the ability of these HLA class II to present type II collagen (CII) and induce collagen-induced arthritis. The DQ8alphabeta tg mice responded strongly to CII, developing severe arthritis, while DQ6alphabeta tg mice were nonresponsive to CII. The addition of the mixed haplotype DQ8alpha6beta molecule did not significantly influence CII reactivity. To examine the interaction of DQ6alphabeta and DQ8alphabeta molecules in vivo, we generated double tg DQ6alphabeta/8alphabeta (A beta0) mice expressing both the alpha- and beta-chains of DQ6 and DQ8 molecules by mating DQ6alphabeta (A beta0) and DQ8alphabeta (A beta0) tg mice. CII-immunized DQ6alphabeta/8alphabeta tg mice developed severe experimental polychondritis, exhibiting both polyarthritis and auricular chondritis. The clinical, serologic, and histologic manifestations of experimental polychondritis are similar to those symptoms in human relapsing polychondritis. The susceptibility of DQ6alphabeta/8alphabeta tg mice compared with resistance in the parental strains suggests that expression of both the DQ6alphabeta and DQ8alphabeta tgs, unique to the DQ6alphabeta8alphabeta tg strain, is important in susceptibility to experimental polychondritis. The DQ6alphabeta/8alphabeta tg mice provide a model to investigate putative autoantigens and the mechanisms of pathogenesis involved in relapsing polychondritis as well as the influence of the expression of multiple HLA class II molecules on the disease process.
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Localization of quantitative trait loci regulating adjuvant-induced arthritis in rats: evidence for genetic factors common to multiple autoimmune diseases.
Adjuvant-induced arthritis (AIA) in rats is a widely used autoimmune experimental model with many features similar to rheumatoid arthritis (RA). To identify potential genetic regulatory mechanisms in RA, we conducted genome-wide linkage analysis in F2 progeny of arthritis-susceptible Dark Agouti (DA) and relatively resistant Fischer 344 (F344) inbred rats. We compared the data with our previously reported investigation of collagen-induced arthritis (CIA), which was expanded in the follow-up study reported in this work. We found two quantitative trait loci (QTLs) in common, i.e., Aia1/Cia1 on chromosome 20, which includes the MHC, and Aia3/Cia3 on chromosome 4. We also identified a second unique QTL in AIA, Aia2, on chromosome 4. Interestingly, the QTL region on chromosome 4 (Aia3/Cia3), like the MHC, appears to be involved in several other autoimmune diseases in rats, including insulin-dependent diabetes, thyroiditis, and experimental autoimmune uveitis. Moreover, an analysis of conserved synteny among rats, mice, and humans suggested that Aia2 and Aia3/Cia3, like Aia1/Cia1, contain candidate genes for several autoimmune/inflammatory diseases in mice and humans, including diabetes, systemic lupus erythematosus, inflammatory bowel disease, asthma/atopy, multiple sclerosis, and RA. The rat models appear to provide a powerful complementary approach to identify and characterize candidate genes that may contribute to autoimmune diseases in several species.
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Identification of a new non-major histocompatibility complex genetic locus on chromosome 2 that controls disease severity in collagen-induced arthritis in rats.
OBJECTIVE: To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type II collagen-induced arthritis (CIA). METHODS: We conducted a genome-wide scan to identify CIA regulatory quantitative trait loci (QTL) in an F2 cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II collagen (RII). These strains share the MHC/RT1av1 haplotype required for susceptibility to RII-induced CIA. RESULTS: F2 females had higher median arthritis scores than did males. Relative resistance in the males was determined by inheriting either a DA or an ACI Y chromosome and was independent of the source of the X chromosome. In addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of odds score 4.6). Cia7 is in a region that shows linkage conservation with chromosomal regions that regulate autoimmune diabetes and experimental autoimmune encephalomyelitis in mice and multiple sclerosis in humans. CONCLUSION: Sex chromosomes and Cia7 play an important role in regulating CIA in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role in several forms of autoimmune disease, including rheumatoid arthritis.
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A genetic linkage map of rat chromosome 20 derived from five F2 crosses.
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Animals↗
Immunity to type IX collagen in rodents: a study of type IX collagen for autoimmune and arthritogenic activities.
Type IX collagen (CIX), a cartilage-specific glycoprotein, constitutes < or = 10% of cartilage collagen. To ascertain whether CIX can induce arthritis as shown for type II and XI collagen (CII and CXI), outbred rats were sensitized with bovine, chick and human CIX; inbred rats, mice, and guinea pigs were sensitized with bovine CIX. Mice and guinea pigs proved resistant to arthritis, as did rats sensitized with CIX/Freund's incomplete adjuvant (FIA). Arthritis was seen in rats when 100 microg of Mycobacterium tuberculosis (Mtb) were added to FIA, but seldom with smaller doses of Mtb, suggesting the arthritis was adjuvant-induced. High levels of antibodies to rat CIX, containing complement-fixing subclasses, were detected in rat sera in addition to DTH and lymphocyte proliferation responses to rat CIX. Given the potential for CIX-induced disease, CIX-sensitized rats were injected intraperitoneally with lipopolysaccharide (LPS) to stimulate proinflammatory cytokine release, and intra-articularly with rat CIX to stimulate arthritis. LPS stimulation was ineffective; however, intra-articularly injected CIX produced transient synovitis. When rats with stable adjuvant arthritis were sensitized with CIX/FIA, significant increases in paw volume were measured compared with controls given CI/FIA. Immunohistochemical studies of actively and passively sensitized rats revealed deposits of CIX antibody, but not C3, at the joint margins where proteoglycan staining was weak. Together, these findings suggest that autoimmunity to CIX, in contrast to CII and CXI, is not directly pathogenic but may contribute to joint injury provided arthritis is initiated by an independent disease process.
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Modulation of HLA-DQ-restricted collagen-induced arthritis by HLA-DRB1 polymorphism.
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.Abeta transgenic mice to generate DQ8/DR2.Abeta and DQ8/ DR3.AbetaO mice. The HLA-DR molecules in these mice were found to be functional on the basis of their positive/negative selection of the Vbeta T cell repertoire. Introduction of the DR2 gene led to a significant decrease in disease incidence in DQ8.Abeta mice, while the DR3 transgene had no effect. In vitro T cell proliferative responses against bovine Cll collagen in primed mice were higher in DQ8/DR3 mice compared with DQ8/DR2 mice. Cytokine analysis showed a Th2 profile in DQ8/DR2 mice, while DQ8/DR3 mice showed a Th1 profile. These results suggest that DRB1 polymorphism can modulate the disease.
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HLA-DQB1 polymorphism determines incidence, onset, and severity of collagen-induced arthritis in transgenic mice. Implications in human rheumatoid arthritis.
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.
Age Factors↗
Human leukocyte antigen-DRB1*1502 (DR2Dw12) transgene reduces incidence and severity of arthritis in mice.
A strong correlation exists between susceptibility to RA in humans and some DRB1 alleles of the MHC region, such as DRB1*0401 and DRB1*0101. Meanwhile, incidences of other DR specificities, such as DR2, DR5, or DR7 have often been found reduced among RA patients. Like RA, susceptibility to mouse CIA is influenced by the MHC class II loci. To analyze the effect of a DRB1 molecule associated with low incidence of RA on mouse CIA, a human DRB1*1502 (DR2Dw12) transgene was introduced into CIA-susceptible B10.RQB3 (H2Aq) mice. Transgene-positive DRB1*1502 mice showed a significant reduction in the incidence and severity of arthritis. Moreover, the clinical reduction of arthritis correlated with the T-cell proliferative response of B10.RQB3-DRB1*1502 mice against a self-derived DRB1 peptide from the third hypervariable region. Our results suggest that the DRB1*1502-mediated protection against CIA can be explained by the DRB1 molecule acting as a source of self-antigenic peptide which interferes with the T-cell response against immunodominant regions(s) of the arthritogenic type II collagen molecule. By analogy, a similar mechanism might play a critical role in influencing the class II-associated predisposition to RA.
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Genetic maps of polymorphic DNA loci on rat chromosome 1.
Genetic linkage maps of loci defined by polymorphic DNA markers on rat chromosome 1 were constructed by genotyping F2 progeny of F344/N x LEW/N, BN/SsN x LEW/N, and DA/Bkl x F344/Hsd inbred rat strains. In total, 43 markers were mapped, of which 3 were restriction fragment length polymorphisms and the others were simple sequence length polymorphisms. Nineteen of these markers were associated with genes. Six markers for five genes, gamma-aminobutyric acid receptor beta3 (Gabrb3), syntaxin 2 (Stx2), adrenergic receptor beta1 (Adrb1), carcinoembryonic antigen gene family member 1 (Cgm1), and lipogenic protein S14 (Lpgp), and 20 anonymous loci were not previously reported. Thirteen gene loci (Myl2, Aldoa, Tnt, Igf2, Prkcg, Cgm4, Calm3, Cgm3, Psbp1, Sa, Hbb, Ins1, and Tcp1) were previously mapped. Comparative mapping analysis indicated that a large portion of rat chromosome 1 is homologous to mouse chromosome 7, although the homologs of two rat genes are located on mouse chromosomes 17 and 19. Homologs of the rat chromosome 1 genes that we mapped are located on human chromosomes 6, 10, 11, 12, 15, 16, and 19.
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HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: a novel model for human polyarthritis.
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 collagen (CII) induced a strong antibody response that was cross-reactive to homologous mouse CII. Also, in vitro proliferative responses against bovine CII, which were blocked in the presence of an antibody specific for HLA-DQ and mouse CD4, were detected. Finally, a severe polyarthritis developed in a majority of HLA-DQ8+,H-2Ab0 mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2Aq) controls. In contrast, HLA-DQ8-,H-2Ab0 fullsibs did not generate CII antibody and were completely resistant to arthritis. Therefore, these results strongly suggest that HLA-DQ8 molecules contribute to genetic susceptibility to arthritis and also establish a novel animal model for the study of human arthritis.
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Nitric oxide production during adjuvant-induced and collagen-induced arthritis.
OBJECTIVE: To investigate the role of nitric oxide (NO) production and NO synthase (NOS) induction during adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in Dark Agouti rats. METHODS: Urinary nitrate excretion and immune NOS (INOS) messenger RNA (mRNA) expression were measured in the joint, lymph node, spleen, and liver tissues following the induction of either AIA or CIA. RESULTS: Urinary nitrate excretion and iNOS mRNA expression increased substantially during joint inflammation in both models of arthritis. However, the increases in urinary nitrate excretion and iNOS mRNA expression observed in the joint, liver, and spleen tissues during AIA were greater than those observed during CIA, although iNOS induction in the lymph nodes was similar for both models. A prior injection with Mycobacterium bovis heat-shock protein resulted in suppression of arthritis and NO production in AIA, but not in CIA. CONCLUSION: Differences in NO production during AIA versus CIA are a reflection of the fundamental pathophysiologic differences between these 2 models of arthritis. Thus, NO production in these 2 models could not be merely a nonspecific reaction to the adjuvant injection, nor simply a byproduct of local inflammation in the joint.
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The mechanism of autoantibody formation to cartilage in rheumatoid arthritis: possible cross-reaction of antibodies to dietary collagens with autologous type II collagen.
In order to study the mechanism of autoantibody formation to type II collagen in rheumatoid arthritis (RA), IgG and IgA antibodies in sera from 259 RA patients and 285 non-RA controls were evaluated for their specificity as to collagen type (I and II) and species (chick, bovine, and porcine) using an improved enzyme-linked immunosorbent assay. IgG and IgA anti-type II collagen antibodies were commonly found in both RA (IgG, 41%; and IgA, 45%) and non-RA (IgG, 36%; and IgA, 31%) sera. Both IgG and IgA collagen antibodies were highly reactive with one or more heterologous type II or type I collagen; however, approximately 35% of IgG and 50% of IgA antibody-positive sera from both RA patients and non-RA controls cross-reacted with human type II collagen (HII) to some degree. However, no antibodies specific to HII were observed in either RA or control sera. In individual patient sera, IgG and IgA antibodies had identical collagen-type and species specificities. Importantly, IgG anti-HII antibodies purified from RA sera by affinity chromatography reacted equally with human, chick and bovine type II collagens, suggesting reactivity with conserved epitopes shared by all three species. In contrast, purified IgG anti-HII antibodies from non-RA control sera commonly lacked reactivity with one or the other of the heterologous type II collagens, suggesting reactivity limited to epitopes shared by HII and only one of the heterologous type II collagens. These data suggest that dietary collagens could elicit circulating IgG and IgA anti-collagen antibodies that cross-react with autologous type II collagen. Also the epitope specificity of IgG autoantibodies may be relevant to the pathogenesis of RA.
Adult↗
A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats.
Identification of specific genetic loci that contribute to susceptibility to rheumatoid arthritis (RA) in humans has been hampered by several factors, including: i) multiple interacting genetic loci contributing to susceptibility; ii) complex interactions of environmental and genetic factors; iii) genetic heterogeneity; and iv) low penetrance. We have, therefore, mapped quantitative trait loci (QTLs) that control inflammatory arthritis susceptibility and/or severity in progeny of two inbred rat strains with significantly different susceptibilities to collagen-induced arthritis (CIA), an animal model for RA. Not surprisingly, we identified a major susceptibility factor, Cia1, on chromosome 20 in the vicinity of the rat major histocompatibility complex (MHC). However, by limiting the analysis to animals with arthritis-susceptible MHC genotypes and using genome-wide QTL analytic techniques, we also found four non-MHC QTLs-Cia2, 3, 4 and 5-on chromosomes 1, 4, 7 and 10, that contributed to disease severity. In addition, a QTL on chromosome 8 was suggestive for linkage. Characterization of the genes underlying these QTLs will facilitate the identification of key biochemical pathways regulating experimental autoimmune arthritis in rats and may provide insights into RA and other human autoimmune diseases. These genes may also represent novel targets for therapy.
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Induction by chronic autoimmune arthritis in DBA/1 mice by oral administration of type II collagen and Escherichia coli lipopolysaccharide.
We have developed a new model of autoimmune arthritis in DBA/1 mice by feeding chick type II collagen (CII) for 2-3 week intervals over a 15 week period. Clinically evident arthritis occurred in 8/10 mice receiving native CII (nCII; 100 micrograms/mouse) alone at 9-13 weeks. Arthritis was aggravated by the further ingestion of CII, while remission occurred after withdrawal of the CII. Heat-denatured CII (dCII; 200 micrograms/mouse) was also arthritogenic if co-administered with ovoinhibitor (OVI; 2 mg/mouse), a proteinase inhibitor. Co-oral administration of lipopolysaccharide (LPS; 10 micrograms/mouse) with CII enhanced the antibody production and T-cell responses to CII, and induced a more chronic arthritis that progressed spontaneously without further administration of CII or LPS. Long-term oral administration of LPS alone also induced a mild arthritis characterized by destruction of bone rather than cartilage. These observations suggest that abnormal gastrointestinal absorption of dietary mimic antigens and intestinal bacterial toxins can potentially disrupt self-tolerance mechanisms, thereby precipitating or exacerbating autoimmune disease in genetically susceptible individuals.
Administration, Oral↗
H2-A polymorphism contributes to H2-Ebeta-mediated protection in collagen-induced arthritis.
Collagen-induced arthritis (CIA) is an animal model of auto-immune inflammatory polyarthritis which has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC) and is restricted to the H2 haplotypes q and r. In previous experiments, we have found that the introduction of an H2-Ebd transgene in H2-Aq CIA-susceptible mice was able to protect these mice against disease development. More recently, we have proposed that the polymorphism of the first domain of the Ebeta molecule modulates this protection, and that the presentation of a peptide from the third hypervariable region of the Ebeta chain by the H2-Aq molecule plays an important role in this mechanism. In the present report, we investigated whether the H2-E-mediated protection is H2-Aq-specific and whether the source of collagen has any influence. While the source of collagen had no effect on the protection, our results showed that the H2-E molecule failed to protect B10.RIII (H2(r)) mice against CIA. Further, the H2 haplotype r exerted a negative effect on the Ebetad-mediated protection in H2-Aq-restricted disease. Our results provide additional proof that self-MHC-derived peptides, such as Ebeta peptides, may play an important role in the T-cell repertoire education and/or modulation of the T-cell response in the periphery.
Amino Acid Sequence↗
Oral administration of an immunodominant human collagen peptide modulates collagen-induced arthritis.
Human type II collagen (HuCII) may be one of the autoantigens involved in human rheumatoid arthritis (RA). By using over-lapping peptides, we have previously described an immunodominant region (HuCII.250-270) on HuCII. In the present study, this 21-mer HuCII.250-270 peptide was used as tolerogen, and its effect on both early and effector phase of collagen-induced arthritis (CIA) was examined. Upon immunization with HuCII-derived peptide 250-270, HuCII.250-270-tolerized mice showed diminished T cell proliferation that was mediated by Th1 cytokine, IL-2. More interestingly, oral tolerance with HuCII.250-270 peptide diminishes primarily a Th1 type of immune response. Arthritis severity was reduced markedly in mice orally tolerized with HuCII.250-270 peptide both at early and effector phases. Suppression of CIA at the effector phase by oral administration of HuCII peptide suggests a potential immunotherapeutic use of collagen II peptide in the treatment of human RA.
Administration, Oral↗
Effect of constrained T-cell receptor repertoires on collagen-induced arthritis in T-cell receptor V beta transgenic and congenic mice.
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Animals↗