The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with From the Rheumatoid Arthritis Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.

A model of arthritis was established by the injection of type II collagen into mice. Only mice bearing the H-2q haplotype were susceptible to the disease. Susceptibility was further mapped by the use of recombinant strains on the Iq locus. Type II collagen arthritis was observed in the (resistant X susceptible) F1 cross. Mice strains were designated high, intermediate, or low responders with respect to the anti-type II antibody levels measured by radioimmunoassay. Arthritis-susceptible strains were all classified as high antibody responders. The clinical and histological appearance of type II collagen arthritis in the mouse indicates that it may be a good animal model for the investigation of various immunogenetic traits in rheumatoid arthritis.

Relapsing polychondritis is a unique, rare autoimmune disorder in which the cartilaginous tissues are the primary targets of destruction but the immune damage can spread to involve noncartilaginous tissues like the kidney, blood vessels, and so forth. The manifestations of the disease can take many different forms and the pathogenesis is still unclear. It may occur in a primary form or it may be associated with other disease states. This article summarizes important aspects of the disease with a focus on recent information regarding clinical manifestations, disease associations, pathogenesis, and advances in therapeutics.

Objective The gut microbiome regulates host immune homeostasis. Rheumatoid arthritis (RA) is associated with intestinal dysbiosis. In this study we used a human gut-derived commensal to modulate immune response and treat arthritis in a humanized mouse model. Methods We have isolated a commensal bacterium, Prevotella histicola, native to the human gut that has systemic immune effects when administered enterally. Arthritis-susceptible HLA-DQ8 mice were immunized with type II collagen and treated with P. histicola; disease incidence, onset and severity were monitored. Changes in the gut epithelial proteins and immune response as well as systemic cellular and humoral immune responses were studied in treated mice. Results DQ8 mice when treated with P. histicola in prophylactic or therapeutic protocols exhibited significantly decreased incidence and severity of arthritis as compared to controls. The microbial mucosal modulation of arthritis was dependent on the regulation by CD103+ dendritic cells and myeloid suppressors, CD11b+Gr-1, and by generation of T regulatory cells, CD4+CD25+FoxP3+, in the gut, resulting in suppression of antigen-specific Th17 response and increased transcription of IL-10. Treatment with P. histicola led to reduced intestinal permeability by increasing expression of enzymes that produce antimicrobial peptides as well as tight junction proteins, Zo-1 and Occludin. However, the innate immune response via TLR4 and TLR9 were not affected in treated mice. Discussion Our results demonstrate that enteral exposure to P. histicola suppresses arthritis via mucosal regulation. P. histicola is a unique commensal that can be explored as a novel therapy for RA and may have low/no side effects.

SummaryGenetic studies have indicated that susceptibility to rheumatoid arthritis (R.A) maps to the HLA-DP, locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DP,. 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 DQA 1"0301 and DQB 1"0302 genes from an RA predisposing haplotype (DQ8/DR.4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab ~ mice, and their susceptibility to experimental collagen-induced arthritis was evaluated. The HLA-DQ8+,H-2Ab ~ 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~ T cell receptors. Immunization of HLA-DQ8+,H-2Ab ~ mice with bovine type II collagen (CII) induced a strong antibody response that was crossreactive 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-2Ab ~ mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2Aq) controls. In contrast, HLA-DQ8-,H-2Ab ~ 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 estabhsh a novel animal model for the study of human arthritis.I t is widely accepted that a strong genetic component contributes to the susceptibility or resistance to certain human autoimmune diseases (1). Attempts to identify the particular genes involved in these disorders has been an area of major focus for many laboratories, and inroads have been clearly made. Among the numerous genes studied, one group that has garnered much attention are the genes encoding the class I and class II molecules of the HLA complex. Located on the short arm of chromosome 6, the primary function of HLA class I and II molecules is to bind and present processed antigenic peptides to T cells bearing receptors specific for the peptide-HLA complex. This presentation event plays a pivotal role in shaping the cellular immune repertoire and dictating the nature and scope of the immune response against a given antigen (2).A role for HLA molecules in the etiology of autoimmune disease derives from genetic studies showing a clear association between the presence or absence of certain HLA class I or II alleles, as well as increased or decreased susceptibility to a particular autoimmune disorder. A disease with a strong autoimmune foundation and HLA class II association is rheumatoid arthritis (RA) 1. In Caucasians, genetic studies initially showed a high prevalence of the HLA-DR4Dw4...

Human class I major histocompatibility complex allele HLA-B27 is associated with a group of human diseases called "spondyloarthropathies." Studies on transgenic rats expressing HLA-B27 and human beta 2-microglobulin have confirmed the role of HLA-B27 in disease pathogenesis. Here we report spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin (B27+ beta 2m-/-). In the absence of beta 2-microglobulin, B27+ beta 2m-/- animals do not express the HLA-B27 transgene on the cell surface and have a very low level of CD8+ T cells. Most of the B27+ beta 2m-/- male mice showed nail changes, hair loss, and swelling in paws, which leads to ankylosis. The symptoms occur only after the B27+ beta 2m-/- mice are transferred from the specific pathogen-free mouse colony. These results suggest that aberrant assembly, transport, and expression of the HLA-B27 molecule may predispose an individual for development of the disease when exposed to an appropriate environmental trigger.

Objective. To generate a mouse model that can mimic human rheumatoid arthritis (RA). A major difference between RA in humans and collagen-induced arthritis (CIA) in mice is the lack of sex bias and autoantibodies in the animal model. We used DRB1*0401-transgenic mice to understand the role of DR4 in susceptibility and sex bias in RA.Methods. A transgenic mouse was generated that lacked all endogenous mouse class II genes (AE o ) and expressed the RA susceptibility allele HLA-DRB1*0401. These transgenic mice were tested for incidence, severity, and sex distribution of CIA.Results. DRB1*0401.AE o mice developed CIA predominantly in females and produced rheumatoid factors, similar to the features of human RA. Another feature similar to human RA is the expression of class II molecules on antigen-presenting cells as well as T cells. Activated and sorted CD4؉ T cells can present DR4-restricted type II collagen (CII)-derived peptide in vitro, but cannot process the antigen. This suggests a role for these cells in epitope presentation locally in joints, which affects disease severity. After challenge with CII, female mice had higher cellularity and increased T cell proliferation and produced higher levels of proinflammatory cytokines than did the male mice.Conclusion. DR4.AE o mice expressed HLA similar to humans and displayed increased arthritis susceptibility in females, thus mimicking RA in humans. This model may be valuable for studying sex differences observed in humans and for understanding why autoimmunity is increased in women. These mice may also be useful for developing future therapeutic strategies.

In this cohort, outcomes such as end-stage renal disease or death from renal failure were not observed. Relapses may occur, and patients with IRF warrant long-term follow-up.