Animal models of autoimmune diseases have been instrumental in advancing our understanding of autoimmunity in humans. Collagen-induced arthritis in mice is an autoimmune disease model of rheumatoid arthritis, which is MHC class II restricted and CD4 T cell dependent. To better understand the fundamental role of T cells in arthritis, we have generated a transgenic mouse carrying the rearranged Valpha11.1 and Vbeta8.2 TCR chain genes isolated from a type II collagen (CII)-specific T cell hybridoma. Cell surface analysis indicated that Vbeta8.2 chain was expressed on the surface of nearly all peripheral T cells. Analysis of T cell subsets in transgenic mice revealed a profound skewing in peripheral T cells towards the CD4 population. Although peripheral T cells were not tolerant to CII and responded to CII stimulation in vitro, transgenic mice did not develop spontaneous arthritis. However, a rapid onset of arthritis with severe clinical signs was detected in transgenic mice after immunization with CII in complete Freund's adjuvant. Histological analysis of inflamed joints showed a great resemblance to arthritic joints in man. This unique transgenic mouse model provides valuable insights into the mechanism of arthritis and into potential specific immune interventions.

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Collagen type II-induced arthritis (CIA) develops in susceptible mouse strains after intradermal injections of type II collagen (CII) in complete Freund's adjuvant (CFA). Susceptibility to CIA in mice is linked to genes of the major histocompatibility complex (MHC). Although the SWR mouse has a susceptible MHC haplotype (H2q), it is resistant to CIA. SWR exhibits at least two known immunological defects: (1) it contains a germline deletion of about 50% of T-cell receptor (TCR) Vbeta-chain gene segments, and (2) SWR is deficient in complement component C5. It has been shown that T cells that express TCRValpha11.1 and TCRVbeta8.2 play a substantial role in the pathogenesis of arthritis in the DBA/1 mouse (H2q). We generated SWR transgenic (tg) mice to determine whether the expression of pathogenic Valpha11.1 and/or Vbeta8.2 transgenes would confer arthritis susceptibility. Arthritis was induced in the SWR TCRalphabeta tg mice, but not in SWR TCRbeta tg mice. To address the role of Valpha11.1 in arthritis susceptibility, we examined the allelic polymorphisms of the Tcra-V11-gene subfamily members between the arthritis susceptible DBA/1 mouse and the arthritis-resistant SWR mouse strain. The amino acid sequences of the Valpha11.1 alleles differ at two positions (codons 18 and 68). Accordingly, these two amino acid changes are sufficient to allow the production of pathogenic T cells in SWR mice. This is the first demonstration of the association of a particular Tcra-V allele and arthritis susceptibility in mice.

PRSS16 is a serine protease expressed exclusively in cortical thymic epithelial cells (cTEC) of the thymus, suggesting that it plays a role in the processing of peptide antigens during the positive selection of T cells. Moreover, the human PRSS16 gene is encoded in a region near the class I major histocompatibility complex (MHC) that has been linked to type 1 diabetes mellitus susceptibility. The mouse orthologue Prss16 is conserved in genetic structure, sequence, and pattern of expression. To study the role of Prss16 in thymic development, we generated a deletion mutant of Prss16 and characterized T-lymphocyte populations and MHC class II expression on cortical thymic epithelial cells. Prss16-deficient mice develop normally, are fertile, and show normal thymic morphology, cellularity, and anatomy. The total numbers and frequencies of thymocytes and splenic T-cell populations did not differ from those of wild-type controls. Surface expression of MHC class II on cTEC was also similar in homozygous mutant and wild-type animals, and invariant chain degradation was not impaired by deletion of Prss16. These findings suggest that Prss16 is not required for quantitatively normal T-cell development.Peptide fragments, which are processed from self-proteins within the thymus and presented to developing thymocytes, shape the selection of T-cell receptors (TCR). Positive selection, mediated by cortical thymic epithelial cells (cTEC), selects TCR clones that are capable of engaging peptides bound to self-major histocompatibility complex (MHC) (1,11,16). Evidence that a diverse array of self-peptides is required for normal positive selection of the CD4 ϩ -TCR repertoire comes from mice in which a single peptide is bound to nearly all MHC class II molecules. In the H2-M-deficient mouse, the class II-associated invariant chain peptide fragment (CLIP) fails to be removed; in the A b EpIi Ϫ transgenic mouse, MHC class II molecules are covalently linked to the MHC class II peptide E␣ 52-68 (5, 13, 31). Although both of these strains select a surprisingly large number of T cells, the T-cell repertoire is altered. Further evidence of the role of self-peptide diversity in positive selection comes from mice expressing transgenic TCR ␤ chains. Nearly all T cells in these mice express the transgenic ␤ chain, but the ␣ chain locus undergoes normal rearrangement and selection (4,6,28). Sequence analysis of the parenteral ␣ chains has demonstrated a bias that is severely restricted when selected against a limited diversity of selfpeptides (4, 12).The cellular machinery generating self-peptides in cTEC is unique and likely plays an important role in the selection of the TCR repertoire (25). Unlike professional antigen-presenting cells (APC) and medullary thymic epithelial cells, cTEC efficiently process endogenous antigens but poorly process exogenous antigens (22,24). In addition, the MHC class II compartment in which peptides are generated and loaded occurs in early stages of endosome formation in cTEC as opposed to late stages of endosom...

The thymus-specific serine protease Prss16 is highly expressed by the epithelial cells in the thymic cortex. It has been suggested to play an important role in the positive selection of T cells through the antigen presention pathway of the cortical antigen presenting cells. Recently, the gene ecoding Prss16 has been linked to insulin dependent diabetes mellitus (IDDM) susceptibility independent of HLA-DR3 suggesting the Prss16 may be involved in the development of autoimmune disease. Due to the similarities of the gene structure and expression pattern between the human and mouse genes, we compared Prss16 between non-obese diabetic (NOD) and non-obese non-diabetic (NON) mice. Analysis of the Prss16 coding region failed to identify any differences in sequence. Northern analysis and semi-quantitative reverse transcriptase polymerase chain reaction showed that the mRNA was equal in size and abundance in the two strains. In situ hybridization showed similar patterns of staining. Therefore, our data suggests that there is no significant different in the gene structure, transcription level, and expression pattern of Prss16 gene between NOD and NON mice.