Biomedical subjects

C S David

Publications and source records attributed to C S David.

At least 37 records · Page 2Linked to original sources

PubMed2000

Association of MHC and rheumatoid arthritis. Regulatory role of HLA class II molecules in animal models of RA: studies on transgenic/knockout mice.

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.

Animals↗

PubMed2000

Immune response of HLA-DQ transgenic mice to house dust mite allergen p2: identification of HLA-DQ restricted minimal epitopes and critical residues.

HLA-DQ8 (HLA-DQA1*0301; HLA-DQB1*0302) and HLA-DQ6 (HLA-DQA1*0103; HLA-DQB1*0602) genes were introduced into mouse class II (H-2A(o)(beta)) knockout mice. Transgenic HLA-DQ8 and HLA-DQ6 mice were individually immunized and challenged using synthetic peptides representing HDM (Dermatophagoides pteronyssinus) allergen p2. HLA-DQ8 mice responded to p2 peptides 1-20, 41-60, 51-70, 61-80, 91-110, and 101-120. HLA-DQ6 mice responded to peptides 1-20, 11-30, 21-40, 41-60, and 51-70. Using single amino acid truncated 30-mer peptides, residues necessary for HLA-DQ8 recognition were identified spanning regions 3-12, 50-70, and 91-120. A synthetic peptide comprising residues 3-12 was synthesized and a series of single alanine substitutions was introduced into the minimal peptide. Introduction of alanine residues at positions 3, 11, and 12 resulted in a significant loss of immune recognition. It was concluded that residues 4, 5, 7, 11, and 12 are critical for immune recognition by HLA-DQ8 mice.

Animals↗

PubMed2000

HLA-DQ polymorphism influences progression of demyelination and neurologic deficits in a viral model of multiple sclerosis.

The importance of genetic susceptibility in determining the progression of demyelination and neurologic deficits is a major focus in neuroscience. We studied the influence of human leukocyte antigen (HLA)-DQ polymorphisms on disease course and neurologic impairment in virus-induced demyelination. HLA-DQ6 or DQ8 was inserted as a transgene into mice lacking endogenous expression of MHC class I (beta(2)m) and class II (H2-A(beta)) molecules. Following Theiler's murine encephalomyelitis virus (TMEV) infection, we assessed survival, virus persistence, demyelination, and clinical disease. Mice lacking expression of endogenous class I and class II molecules (beta(2)m(o) Abeta(o) mice) died 3 to 4 weeks postinfection (p.i.) due to overwhelming virus replication in neurons. beta(2)m(o) Abeta(o) DQ6 and beta(2)m(o) Abeta(o) DQ8 mice had increased survival and decreased gray matter disease and virus replication compared to nontransgenic littermate controls. Both beta(2)m(o) Abeta(o) DQ6 and beta(2)m(o) Abeta(o) DQ8 mice developed chronic virus persistence in glial cells of the white matter of the spinal cord, with greater numbers of virus antigen-positive cells in beta(2)m(o) Abeta(o) DQ8 than in beta(2)m(o) Abeta(o) DQ6 mice. At day 45 p.i., the demyelinating lesions in the spinal cord of beta(2)m(o) Abeta(o) DQ8 were larger than those in the beta(2)m(o) Abeta(o) DQ6 mice. Earlier and more profound neurologic deficits were observed in beta(2)m(o) Abeta (o) DQ8 mice compared to beta(2)m(o) Abeta(o) DQ6 mice, although by 120 days p.i. both strains of mice showed similar extent of demyelination and neurologic deficits. Delayed-type hypersensitivity and antibody responses to TMEV demonstrated that the mice mounted class II-mediated cellular and humoral immune responses. The results are consistent with the hypothesis that rates of progression of demyelination and neurologic deficits are related to the differential ability of DQ6 and DQ8 transgenes to modulate the immune response and control virus.

Acute Disease↗

PubMed2000

Autoimmunity versus tolerance: analysis using transgenic mice.

On the basis of our extensive studies on collagen induced arthritis in HLA class II transgenic mice, we proposed a hypothesis to explain role of shared epitope in rheumatoid arthritis (RA) association. According to our hypothesis, complementation between both DQ and DR molecules is required for susceptibility or protection from disease. While certain DQ alleles predispose individuals to RA, DRB1 molecule can modulate disease by shaping T-cell repertoire in the thymus by providing self-peptides and presented by DQ molecules. Using A beta o.DQ8 transgenic mice, we tested ability of peptides derived from HV3 of DR molecules, implicated in RA positively or negatively, to activate T cells. While the peptides derived from RA susceptible DR molecule were poor binders and poor in activating T cells, the peptides derived from RA resistant DR molecules were high affinity binders and efficient T-cell activators. Our experiments suggest that high affinity DR peptides could induce tolerance to autoimmunity while the low affinity peptides could be permissive to autoimmunity. Using peptide from DRB1*0402 molecule, known to be associated with resistance to RA, prior to induction of collagen induced arthritis prevents the onset of disease. Thus, self-peptides derived from HLA molecules could potentially generate tolerance or autoimmunity depending on their binding affinity with HLA molecules.

Animals↗

PubMed2000

Complementation between specific HLA-DR and HLA-DQ genes in transgenic mice determines susceptibility to experimental autoimmune encephalomyelitis.

To investigate the contribution of human leukocyte antigen (HLA) class II molecules in susceptibility to inflammatory demyelination, we induced experimental autoimmune encephalomyelitis (EAE) in transgenic (tg) mice expressing the HLA-DR3, HLA-DQ8 and HLA-DQ6 molecules in the absence of endogenous class II (Ab(o)). Following immunization with mouse myelin, HLA-DR3 tg mice mounted strong T-cell proliferative responses, and developed inflammatory lesions and demyelination in the central nervous system with mild to moderate clinical symptoms of EAE. HLA-DQ8 and HLA-DQ6 tg mice elicited weak T-cell proliferative responses and did not develop clinical symptoms of EAE. HLA-DR3/DQ6 double tg mice immunized with mouse myelin experienced clinical disease similar to the single tg HLA-DR3 tg mice, indicating that expression of DQ6 in this line had no effect on disease. In contrast, HLA-DR3/DQ8 double tg mice developed severe inflammatory lesions and clinical disease in response to immunization with mouse myelin. Our data suggest that in the presence of two susceptible class II alleles, namely HLA-DR3 and DQ8, there is additional selection and expansion of potential autoreactive T cells, resulting in enhanced severity of disease.

Animals↗

PubMed2000

HLA-B27 transgenic mice are susceptible to collagen-induced arthritis: type II collagen as a potential target in human disease.

HLA-B27 is highly linked with a group of human diseases called spondyloarthropathies (SpA). Many of these disorders begin after an infection with an enterobacteria. The symptoms seen in patients with spondyloarthropathies are inflammatory pain in the spine and asymmetrical arthritis of lower limbs. Additional symptoms related to SpA include inflammation in the eyes, bowel, and skin. The autoantigen(s) in SpA are not known. Proteins such as collagen and proteoglycans have been thought to be potent autoantigens in arthritidis including B27-associated human diseases. Type II collagen is a common denominator among eyes and joints, affected tissues in B27-linked diseases. Moreover, a few reports indicated CII specific T cells and antibodies in patients with spondyloarthropathies. We and others have previously described development of spontaneous arthritis and nail disease in HLA-B27 transgenic animals. To determine whether CII may be a target antigen in the B27-linked diseases, B27 + m beta 2 m% (HLA-B27) transgenic mice lacking mouse beta 2m with and without human beta 2m) mice were immunized with type II collagen inside the barrier facility. Male HLA-B27 transgenic mice developed collagen-induced arthritis compared to transgene negative littermates or female counterparts. There was no difference in the incidence of arthritis in HLA-B27 transgenic mice with and without human beta 2m. Our data suggest that beta 2m free heavy chain of HLA-B27 may present soluble antigens such as type II collagen to trigger specific T cells contributing in the development of arthritis. Our data also suggest that CII may be a potential target antigen in the cartilage during the disease process.

Animals↗

PubMed2000

Identification of HLA-class-II-restricted epitopes of autoantigens in transgenic mice.

The past year has seen a spate of research in the use of HLA transgenic mice in the identification of self antigens associated with autoimmunity. Dominant T cell determinants - and, in a few cases, B cell determinants - have been characterized in the context of disease-predisposing HLA DR and DQ genes for at least three prominent and devastating autoimmune diseases: rheumatoid arthritis, multiple sclerosis and insulin-dependent diabetes mellitus.

Animals↗

PubMed2000

HLA-DQ/human CD4-restricted immune response to cockroach allergens in transgenic mice.

We investigated the immune response to the German cockroach (Blattella germanica), and one of its major antigens, Blattella germanica group 5 (Bla g 5), in a double-transgenic, double-knockout mouse expressing human HLA-DQ8, HLA-DQ6 and CD4 molecules in the absence of mouse class II and mouse CD4. Transgenic mice were primed and challenged with CR extract or individual synthetic peptides representing Bla g 5. Strong T-cell responses to CR extract were detected in both HLA-DQ/hCD4+ transgenic mice. The responses were two times lower in mice expressing HLA-DQ molecule in the context of mouse CD4. Under similar treatment, no responses were found in the double-knockout Abetadegrees/mCD4degrees mice and in mice expressing human CD4 molecule alone. HLA-DQ/hCD4+ mice produced primarily interleukin (IL)-5, IL-10, and IL-13. Minimal amounts of IL-4 were detected only in HLA-DQ6/ hCD4+ mice. Interferon (IFN)-gamma production was low in both transgenic mouse, suggesting a predominantly T-helper 2 (Th2)-type response. Cockroach allergen extract immunized HLA-DQ8/hCD4+ mice recognized only one of the 20 peptides of Bla g 5 while HLA-DQ6/hCD4+ mice responded primarily to three peptides. Primed with individual peptides, both HLA-DQ/hCD4+ mice responded maximally to peptides 10 (residues 91-110) and 17 (residues 161-180). In addition, HLA-DQ6/hCD4+ mice responded to peptide 16 (residues 151-170). Thus, peptides 10 and 17 contained the major HLA-DQ-restricted hCD4+ T-cell epitopes and could be recognized by both HLA-DQ8 and HLA-DQ6 transgenic mice. Transgenic mice represent a new tool for investigating the immune responses to cockroach allergen. Our results suggest that therapeutic strategies aimed at developing antagonist peptides might be a useful treatment (immunotherapy) for allergic asthma.

Allergens↗

PubMed2000

V(beta)8(+) T cells protect from demyelinating disease in a viral model of multiple sclerosis.

Previous studies illustrated the influence of T cell subsets on susceptibility or resistance to demyelination in the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. Genetic segregation analysis showed a correlation with disease phenotype in this model with particular V(beta) genes. In this study we investigated the contribution of specific V(beta) TCR to the pathogenesis of virus-induced demyelinating disease. Spectratype analysis of cells infiltrating the CNS early in infection demonstrated an over-representation of V(beta)8(+) T cells in mice expressing a susceptible H-2 haplotype. We infected transgenic mice expressing the V(beta)8.2 TCR directed against a non-TMEV antigen and found an increase in demyelinating disease in mice of either susceptible or resistant background compared with littermate controls. In addition, depletion studies with an anti-V(beta)8-specific antibody in both susceptible (B10.Q) and resistant (C57BL/6) mice resulted in increased demyelination. TCR analysis of VP2-specific cytotoxic T cell clones from mice with a resistant genotype identified only the V(beta)8.1 TCR, suggesting that limited T cell diversity is critical to TMEV clearance. Together, these results support a protective role for V(beta)8(+) T cells in virus-induced demyelinating disease.

Animals↗

PubMed2000

Assessing the binding of four Plasmodium falciparum T helper cell epitopes to HLA-DQ and induction of T-cell responses in HLA-DQ transgenic mice.

A subunit vaccine for Plasmodium falciparum malaria will need to contain well-defined T helper cell epitopes that induce protective immune responses to the parasite. One major barrier to the use of subunit vaccines is the requirement for T helper cell epitopes to be presented by the HLA class II molecules that are present in the population being vaccinated. Since the majority of malaria studies have focused on HLA-DR, little information on the role of HLA-DQ in the binding and immune response to malarial epitopes is available. This study used an in vitro peptide-binding assay to predict the extent of HLA-DQ binding of four conserved T helper cell epitopes identified from asexual-stage malaria vaccine candidate antigens. Epstein-Barr virus (EBV)-transformed human B-cell lines expressing 14 different DQ molecules (DQ2.1, -2.2, -4.1, -4.2, -5.1 to -5.3, -6.1, -6.2, -6.4, -7.1, -7.3, -8, and -9) representing all broad serological specificities, including common DQ molecules present in populations in areas where malaria is endemic, were used in the binding assay. Moreover, an HLA-DQ transgenic mouse model was employed to evaluate the correlation between the in vitro DQ binding of the peptides and the generation of in vivo immune responses following peptide immunization. This study identified two broad DQ-binding peptides, ABRA#14 and SERA#9. ABRA#14 also induced T-cell proliferation and Th1-associated cytokine production in DQ8(+) transgenic mice. The combination of peptide binding to EBV-transformed cell lines and DQ transgenic mice provides a method for identifying additional T-cell epitopes for inclusion in a vaccine.

Animals↗

PubMed2000

Hla-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice.

In multiple sclerosis (MS) patients who carry the Class II major histocompatibility (MHC) type HLA-DR2, T cells specific for amino acids 95-116 in the proteolipid protein (PLP) are activated and clonally expanded. However, it remains unclear whether these autoreactive T cells play a pathogenic role or, rather, protect against the central nervous system (CNS) damage. We have addressed this issue, using mice transgenic for the human MHC class II region carrying the HLA-DR2 (DRB1* 1502) haplotype. After stimulating cultured lymph node cells repeatedly with PLP95-116, we generated 2 HLA-DR2-restricted, PLP95-116-specific T-cell lines (TCLs) from the transgenic mice immunized with this portion of PLP. The TCLs were CD4+ and produced T-helper 1 (Th1) cytokines in response to the peptide. These TCLs were adoptively transferred into RAG-2/2 mice expressing HLA-DR2 (DRG1* 1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested ataxic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory foci primarily restricted to the cerebrum and cerebellum, in association with scattered demyelinating lesions in the deep cerebral cortex. These results support a pathogenic role for PLP95-116-specific T cells in HLA-DR2+ MS patients, and shed light on the possible correlation between autoimmune target epitope and disease phenotype in human CNS autoimmune diseases.

Amino Acid Sequence↗

PubMed2000

Co-expression of HLA DR3 and DQ8 results in the development of spontaneous insulitis and loss of tolerance to GAD65 in transgenic mice.

Specific HLA DQ and DR alleles have been associated with susceptibility to type 1 diabetes. HLA DQ8 and DQ2 have been shown to strongly predispose to disease and to be in linkage disequilibrium with at-risk DR4 and DR3 alleles, respectively. Inheritance of a mixed DR3/DR4 haplotype confers the greatest risk. A double transgenic mouse expressing both DR3 and DQ8 was generated to investigate potential major histocompatibility complex class II interactions. The DR3/DQ8 transgenic mice developed a spontaneous loss of tolerance to GAD65, in which the T-cell response to GAD65 was restricted by HLA DR. Although the mice also showed spontaneous insulitis, they did not progress to overt diabetes. Mice expressing either transgene (DQ8 or DR3) alone showed mild infiltration of their islets, which disappeared when DQ8 or DR3 was co-expressed with a resistant DR2 allele or the neutral DQ6 allele. Therefore, in a fashion analogous to human diabetes, the murine model demonstrated a requirement for a combination of at-risk DR and DQ allotypes for the initiation of spontaneous autoimmunity.

Animals↗

PubMed2000

New revelations in susceptibility to autoimmune thyroiditis by the use of H2 and HLA class II transgenic models.

H2 and HLA transgenes were utilized to clarify the role of class II genes in susceptibility to experimental autoimmune thyroiditis (EAT), a model for Hashimoto's thyroiditis (HT). Susceptibility was transferred by H2 class II transgenes to a resistant haplotype and by HLA-DRA/DRB1*0301 (DR3) transgene into class II-negative Ab0 mice. Mice with a HLA-DRB1*1502 (DR2) transgene remain resistant to mouse thyroglobulin (mTg)-induced EAT, illustrating the role of HLA-DRB1 polymorphism. A role for HLA-DQ polymorphism was shown with hTg-induced EAT in HLA-DQ*0301/DQB1*0302 (DQ8), but not HLA-DQ*0103/DQB1*0601 (DQ6), transgenic mice. Yet, both DQ8+ and DQ6+ mice were unresponsive to mTg. Single transgenes obviate the problems from DR/DQ linkage disequilibrium and may distinguish the degree of susceptibility and the response to shared or specific epitopes. The introduction of conserved Eak transgene into Ab0 mice reveals a new role for H2E molecules in EAT. Without H2A molecules, EalphaEbetab molecules and T cells respond to hTg or pTg with severe thyroiditis, but not to mTg, thus distinguishing self from nonself. However, IAb genes in resistant mice ameliorate Eak transgene-mediated thyroiditis, similar to the effect of Eak transgene on IAs-mediated EAT. Studies in HLA DQ/DR double transgenic mice simulating human haplotypes could reveal HLA class II gene interactions in HT.

Animals↗

PubMed2000

Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats.

Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model. First, a subchronic concentration-response study was conducted in wild-type male Long-Evans rats to determine increased cell proliferation without severe nephrotoxicity. Rats were dosed with sodium barbital in the feed at 0, 50, 250, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation within the cortex and nephrotoxicity were quantitated. Enhanced proliferation with minimal nephrotoxicity occurred at 500 p.p.m. A second study was conducted in male Tsc2 mutant rats given sodium barbital in the feed at 0, 100 or 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additional group of rats was treated with sodium barbital for 6 months and then provided control feed until 12 months of age. Rats necropsied at 6 months of age had a concentration-dependent increase in preneoplastic and total renal lesions. Sodium barbital-treated rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Total combined preneoplastic and neoplastic lesions in the 6 month, high dose group was the same as the 12 month control group. These data show that sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant rats but did not increase their overall number. These data suggest that enhanced cell proliferation without significant cytotoxicity exerted a promotional influence in this hereditary model.

Animals↗

PubMed1999

Identification of T cell determinants on human type II collagen recognized by HLA-DQ8 and HLA-DQ6 transgenic mice.

HLA-DQA1*0301 and HLA-DQB1*0302 genes encoding the HLA-DQ8 molecule and HLA-DQA1*0103 and HLA-DQB1*0601 genes encoding the HLA-DQ6 molecule were introduced into H-2Abetao knockout mice. Three lines of transgenic mice were established: HLA-DQ8, HLA-DQ6, and HLA-DQ8beta6alpha. HLA-DQ8 mice are susceptible to collagen-induced arthritis, while HLA-DQ6 mice are resistant. HLA-DQ8beta6alpha mice develop polychrondritis in addition to arthritis. Transgenic mice were primed and challenged with individual synthetic peptides representing human type II collagen. A total of 101 synthetic peptides were tested in each transgenic line of mice. HLA-DQ8 mice responded to 15 synthetic peptides representing all cyanogen bromide fragments. In contrast, HLA-DQ6 mice responded to a subset of the peptides recognized by HLA-DQ8 T cells. HLA-DQ8beta6alpha mice, although exhibiting diminished responses to the majority of HLA-DQ8-restricted determinants, elicited enhanced responses to two peptides. In addition, HLA-DQ8beta6alpha mice respond to two unique peptide determinants contained within cyanogen bromide fragments CB10 and CB11 showing the significance of mixed isotype dimers in the immune response. The determinants recognized by the HLA-DQ transgenic mice are distinct from those previously identified using conventional laboratory mice. These results suggest that human class II transgenic mice offer a means of identifying human class II-restricted epitopes associated with potential human autoantigens.

Amino Acid Sequence↗

PubMed1999

Analysis of MHC class II genes in the susceptibility to lupus in New Zealand mice.

Hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice spontaneously develop a disease similar to human systemic lupus erythematosus. MHC and non-MHC genes contribute to disease susceptibility in this murine model. Multiple studies have shown that the NZW H2z locus is strongly associated with the development of lupus-like disease in these mice. The susceptibility gene(s) within H2z is not known, but different lines of evidence have pointed to class II MHC genes, either H2-E or H2-A (Ez or Az in NZW). Recent studies from our laboratory showed that Ez does not supplant H2z in the contribution to lupus-like disease. In the present work we generated C57BL/10 (B10) mice transgenic for Aaz and Abz genes (designated B10.Az mice) and used a (B10.Az x NZB)F1 x NZB backcross to assess the contributions of Az genes to disease. A subset of backcross mice produced high levels of IgG autoantibodies and developed severe nephritis. However, no autoimmune phenotype was linked to the Az transgenes. Surprisingly, in the same backcross mice, inheritance of H2b from the nonautoimmune B10 strain was strongly linked with both autoantibody production and nephritis. Taken together with our previous Ez studies, the present work calls into question the importance of class II MHC genes for lupus susceptibility in this model and provides new insight into the role of MHC in lupus-like autoimmunity.

Animals↗

PubMed1999

H2-E transgenic class II-negative mice can distinguish self from nonself in susceptibility to heterologous thyroglobulins in autoimmune thyroiditis.

Susceptibility to experimental autoimmune thyroiditis (EAT) is linked to H2-A class II genes; k and s haplotypes are susceptible, while b and f are resistant. EAT is inducible with thyroglobulins (Tgs) from several mammalian species which share portions of identical sequences. But cross-activation and cross-tolerance studies with mouse (m), human (h), and porcine (p) Tg have indicated mTg-unique T-cell epitope(s), in addition to conserved, in EAT induction. The recent introduction of the HLA-DRB1*0301 (DR3) transgene rendered major histocompatibility complex (MHC) class II-negative (Ab(0)) mice susceptible to EAT induction by both hTg and mTg, suggesting usage of conserved epitopes. Here, we introduced the H2-Ea(k) transgene into resistant B10 (H2(b)) or Ab(0) mice with a defective Ea gene to provide functional surface H2E (b haplotype) expression. Surprisingly, both transgenic strains showed severe inflammation only after hTg, but not mTg, immunization, although the moderating influence of the A(b) gene in B10 was evident. In proliferative assays, hTg-primed cells did not respond to mTg, nor to conserved 12mer peptides from three primary hormonogenic sites, two of which can activate T cells for thyroiditis transfer and cytotoxicity. The vigorous response to hTg stimulation was reduced only by Ebeta(b)-specific monoclonal antibody. EAT induction with bovine and pTg showed responses similar to hTg, suggesting thyroiditogenic epitopes shared with hTg, but not mTg. This is the first demonstration of: (1) nonpermissiveness for EAT induction with mTg, normally the most thyroiditogenic Tg and the one with unique epitopes for susceptible mice, and (2) the separation of hTg from mTg in EAT induction in H2-E-transgenic mice.

Animals↗

PubMed1999

Peptide binding alpha1alpha2 domain of HLA-B27 contributes to the disease pathogenesis in transgenic mice.

Human spondyloarthropathies are strongly associated with a major histocompatibility complex (MHC) class I allele, HLA-B27. HLA-B27 transgenic mice and rats demonstrate many features of these diseases further confirming the role of HLA-B27 in disease. Yet the exact role of this molecule in disease pathogenesis is not clearly understood. We have previously reported spontaneous arthritis and nail disease in HLA-B27 transgenic mice lacking beta2-microglobulin (B27+beta2m(o)). These observations along with binding studies of B27 derived peptides to HLA-B27 molecule itself led to two hypotheses: (i) HLA-B27 derived peptide as a source of autoantigen; and (ii) HLA-B27 functions as an antigen presenting molecule. In this report, we confirm spontaneous disease in transgenic mice expressing a hybrid B27 molecule with alpha1alpha2 domain of B27 and alpha3 domain of mouse H-2Kd. These mice developed spontaneous arthritis and nail disease when transferred from specific pathogen free barrier facility to the conventional area. Other control mice with MHC class I transgene (e.g., HLA-B7, HLA-Cw3, and H2-Dd) did not develop such disease. In a MHC reassembly assay, binding of similar peptides to both wild type and hybrid B27 molecules was observed. In addition, the hybrid B27 molecule lacks at least one of the 3 proposed peptides from the third hypervariable (HV3) region of HLA-B27. These data strongly suggest that HLA-B27 molecule is an antigen presenting molecule rather than a peptide donor in the disease pathogenesis.

Animals↗