Abstract
Background: In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA. Method: Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation (n = 15). Results: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients. Conclusion: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.
Highlights
Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease hallmarked by disease-specific autoantibody production against citrullinated proteins, but the underlying etiopathogenesis remains largely unknown [1,2]
First we investigated by immunohistochemistry the presence of peptidylarginine deiminase (PADI) enzymes required for citrullination in Lymph node (LN) tissue and cultured lymph node stromal cells (LNSCs) of a small cohort of individuals
Using unique monoclonal anti-citrullinated protein antibody (ACPA) isolated from rheumatoid arthritis (RA) patients’ synovial fluid, which are cross-reactive to one or more citrullinated antigens [34,35], we analyzed the presence of RA-associated citrullinated proteins in LN tissues and cultured LNSCs
Summary
Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease hallmarked by disease-specific autoantibody production against citrullinated proteins, but the underlying etiopathogenesis remains largely unknown [1,2]. Citrullination is a post-translational modification changing arginine side chain residues to citrulline, thereby altering structure and charge of the protein. This process occurs regularly under homeostatic conditions like apoptosis of cells where high levels of calcium activate the peptidylarginine deiminase (PADI) enzymes catalyzing citrullination. In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). Results: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Conclusion: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance
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