Pediatric Rheumatology Online Journal → August 2003 →  Basic Immunology  → Abstract #169   

DIVERSION OF ORGAN SPECIFIC ARTHRITIS TO SYSTEMIC AUTOIMMUNITY VIA THE INTRODUCTION OF A TCR AGONIST UNDER THE MHC II PROMOTER

F. F. Shih,¹ P. M. Allen.²

¹Pediatrics, St Louis Children's Hospital, St Louis, MO, United States; ²Pathology, Washington University School of Medicine, St Louis, MO, United States

K/BxN is a spontaneous murine model of rheumatoid arthritis exhibiting many of the clinical and histologic features of the human disease with synovitis predominantly in the distal small joints and immune hyper-reactivity with hypergammaglobulinemia and splenomegaly. K/BxN mice were generated by crossing KRN TCR transgenic (Tg) mice to non-obese diabetic (NOD) mice. In this setting, KRN TCR is an autoreactive specificity, recognizing peptide 282-294 of the glycolytic enzyme, glucose-6-phosphate-isomerase(GPI) bound to I-Ag7. Provision of cognate T cell help to anti-GPI B cells spurred the production of anti-GPI antibodies which are necessary and sufficient for arthritis. As GPI is a ubiquitously expressed self antigen, present in the cytoplasm of all cells, it is unclear why KRN T cells evade negative selection and are activated in the periphery by endogenously presented GPI. To study thymic selection of KRN T cells, we have engineered a Tg mouse, designated G7mTg, that expressed a peptide mimic of GPI 282-294 termed G7m under the MHC II promoter. Through this transgene approach, G7mTg splenocytes stimulated KRN T cells with 1000-fold increased potency compared to the NOD splenocytes. KRN/G7mTg double Tg mice exhibited a much attenuated arthritiis course with a concomitant loss of anti-GPI antibody response, indicating tolerance of GPI-specific T cells. Surprisingly, KRN/G7mTg mice succumbed to wasting manifesting with multi-organ inflammation, auto-antibody production and hematologic derangements. Over-expression of the KRN TCR ligand in the thymus resulted in deletion of 95% of thymocytes, leaving behind a population of CD4+ T cells expressing low level of TCR, memory phenotype but lacking CD25. Moreover, we extended our findings to another TCR system [anti-hen egg lysozyme (HEL) TCR/HEL mice> where similarly extensive thymic deletion also resulted in disease. As such, our data suggest overzealous thymic deletion as a novel mechanism of systemic autoreactivity