Date Published: January 13, 2009
Publisher: Public Library of Science
Author(s): Rene E. M Toes, Tom W. J Huizinga
Abstract: Rene Toes and Tom Huizinga discuss a new study indicating that lymphoneogenesis in the inflamed synovial tissue of patients with rheumatoid arthritis is fostering potentially pathogenic immune responses.
Partial Text: Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting joints, often with severe and disabling consequences. Although cells and intracellular signals characterizing inflamed tissue in RA are not qualitatively different from those found in other conditions, in about one third of patients with RA ectopic lymphoid structures can be found in affected tissue . These structures, which form in response to sustained local inflammation, reflect the anatomical organization through which lymph nodes regulate the initiation and maturation of productive adaptive immune responses. Ectopic lymphoid structures therefore appear potentially capable of similarly mediating the encounter and interaction of immune cells with antigens.
It has long been speculated that ectopic lymphoid structures are not only generated in response to inflammation, but might also contribute to inflammation itself by supporting the formation and perpetuation of pathogenic immune responses .
The authors analyzed the presence of follicular dendritic cells (FDCs) as a measure of the presence and extent of ectopic lymphoid structures. In lymph nodes, FDCs make intimate contact with B cells and play a key role in selecting antigen-binding B cells during the development of antibody responses. The authors observed that the presence of FDCs was strictly correlated with the expression of activation-induced cytidine deaminase (AID), an enzyme involved in antibody-isotype switching and affinity maturation, two processes crucial to the development of B cell antibody responses. Likewise, AID expression was correlated with markers implicated in the formation of lymphoid structures. Interestingly, cellular aggregates containing FDCs and expressing AID were found to be surrounded with cells recognizing citrullinated proteins but not control proteins, indicating the presence of ACPA-producing B cells. Together, these results indicate that the cellular aggregates associated with FDCs are functional and suggest that they contribute to the production of ACPAs.
The data presented by Pitzalis and co-workers show that B cells that are associated with ectopic lymphoid structures express the molecular machinery required for antibody-isotype switching and affinity maturation. Likewise, they indicate that these ectopic lymphoid structures could act as a functional tertiary lymphoid organ capable of producing isotype-switched autoantibodies. These observations are in line with the evidence suggesting that new B cells are continuously recruited into the ACPA response and indicate that the inflamed synovium is facilitating and contributing to a perpetual reactivation of the RA-specific ACPA response during the course of ACPA-positive arthritis .
The new data presented by Pitzalis and colleagues indicate that lymphoneogenesis in the inflamed synovial tissue of patients with RA is fostering potentially pathogenic immune responses by assisting the local production of ACPAs. This could promote local inflammation, leading to a vicious circle in which more lymphogenic factors are produced, allowing a further perpetuation of the autoimmune responses that drive the ongoing disease process . Overall, the data presented increase our understanding of the relevance and functional consequences of the microanatomical immunological units present in a substantial number of patients with RA and provide a rationale to target these units as a new treatment modality for RA.