Cellular and molecular mechanisms underlying the antinuclear autoimmune response in ANA+ juvenile idiopathic arthritis

• Applicant: Privatdozent Dr. Henner Morbach
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446925698

Juvenile idiopathic arthritis (JIA) is the most common autoimmune disease of childhood. A majority of patients is clinically characterized by chronic inflammation affecting joints and partly also eyes as wells as serologically by the appearance of antinuclear antibodies (ANAs). 20-30% of patients still suffer from permanent functional restriction of joints and/or eyes and up to half of patients require medical treatment beyond childhood and adolescence. Therefore, the treatment options currently available are still to some extent unsatisfying which may also be due to an inadequate understanding of disease aetiopathogenesis.Whereas the specific autoantigen targets have been characterized in many autoimmune diseases yielding detailed insights into disease pathogenesis these fundamental aspects have not yet been addressed in JIA. Therefore, the aim of this project is to identify the autoantigens targeted by the autoimmune response in JIA and to unravel the underlying cellular and molecular mechanism. Preliminary results revealed 1. a correlative association between CD4+ PD-1++CXCR5- peripheral T helper (TPH) cells and so called CD21lo/- B cells in the joints of ANA+ JIA patients and 2. a functional relation between both cell populations in vitro. Therefore we hypothesize, that both cell subsets represent the cellular basis of the autoimmune reaction in ANA+ JIA patients.By using state-of-the-art molecular technologies (RNA-sequencing, T cell receptor high-throughput sequencing, CRISPR-Cas9 mediated genome editing) we aim at elucidating the molecular mechanism underlying the development and function of synovial TPH cells in JIA. Additionally, we will a) assess the autoreactivity of the immunoglobulin-repertoire of CD21lo/- B cells by expression cloning of recombinant antibodies from single cells and b) identify the target antigens of these ex vivo derived monoclonal autoantibodies by mass spectrometry. The elucidation of TPH cell development and function as well as the identification of the autoantigens targeted by the TPH cell mediated autoimmune response will provide detailed insights into disease pathogenesis of “ANA+ JIA” and help to define potential targets of future therapies. Additionally, the intended project will define general concepts of TPH cell mediated B-cell dysregulation in the context of chronic inflammation that can be transferred to other diseases as well.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Stephan Hackenberg; Dr. Andreas Schlosser