The clinical and immunological significance of ectopic lymphoneogenesis in the rehumatoid synovial membrane

Abstract

Despite the development of new biomarkers predicting prognosis in rheumatoid arthritis (RA) remains challenging and targeting of powerful biologics difficult. The presence of ectopic germinal centres (GC) within synovium has long been recognised (ectopic lymphoneogenesis [ELN]) and data have suggested that they manufacture antibody (Ab). High affinity class switched Ab production occurs through class switch recombination (CSR) and somatic hypermutation (SHM) both critically dependent on activation induced cytidine deaminase (AID). However, whether ectopic GCs express AID has not been known. Nonetheless data associating ELN with disease severity suggest a role for ELN in RA pathogenesis and as a potential biomarker. A classification system for RA synovium, based on the concept of ELN has been proposed as: (i) aggregate, (ii) aggregate GC+ and, (iii) an unorganised infiltrate. However whether these distinct pathotypes and/or degree of aggregation equate to disease severity is unclear. Thus my first aim was to develop and validate a pathological scoring system for rheumatoid synovium capable of quantifying the degree of ELN. My second aim was to investigate whether the presence and/or degree of ELN within the synovial membrane correlated with both clinical phenotype and predicted erosive damage. I demonstrate that the aggregational score developed is highly reliable and that ELN within synovial tissue associates with a higher level of synovial inflammation but is not predictive of damage. My third aim was to investigate whether GCs within RA synovium were functional. I provide evidence of functionality by demonstrating that ectopic GCs invariably express AID, are surrounded by anti-CCP+ plasma cells, support ongoing CSR and the manufacture of anti-CCP Abs. My final aim was to characterise a cohort of synovial B cells consistently found surrounding ectopic GCs. I identify a novel B cell subset within RA synovium, interfollicular large B cells, (5)(5)(5) and demonstrate that interfollicular large B cells in lymph node express a somatically mutated IgH.