CD40L-Dependent Pathway Is Active at Various Stages of Rheumatoid Arthritis Disease Progression.
Yanxia Guo, Alice M Walsh, Ursula Fearon, Malcolm D Smith, Mihir D Wechalekar, Xuefeng Yin, Suzanne Cole, Carl Orr, Trudy McGarry, Mary Canavan, Stephan Kelly, Tai-An Lin, Xuejun Liu, Susanna M Proudman, Douglas J Veale, Costantino Pitzalis, Sunil Nagpal
Author Information
Yanxia Guo: Immunology, Janssen Research, Spring House, PA 19477; yguo49@its.jnj.com snagpal2@its.jnj.com.
Alice M Walsh: Immunology, Janssen Research, Spring House, PA 19477.
Ursula Fearon: St. Vincent's University Hospital, Dublin 4, Ireland.
Malcolm D Smith: Rheumatology Unit, Repatriation General Hospital, Adelaide, South Australia 5041, Australia.
Mihir D Wechalekar: Rheumatology Unit, Repatriation General Hospital, Adelaide, South Australia 5041, Australia. ORCID
Xuefeng Yin: Immunology, Janssen Research, Spring House, PA 19477.
Suzanne Cole: Immunology, Janssen Research, Spring House, PA 19477.
Carl Orr: St. Vincent's University Hospital, Dublin 4, Ireland.
Trudy McGarry: St. Vincent's University Hospital, Dublin 4, Ireland.
Mary Canavan: St. Vincent's University Hospital, Dublin 4, Ireland. ORCID
Stephan Kelly: Queen Mary University of London, London EC1M 6BQ, United Kingdom.
Tai-An Lin: Immunology, Janssen Research, Spring House, PA 19477.
Xuejun Liu: Immunology, Janssen Research, Spring House, PA 19477. ORCID
Susanna M Proudman: Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia; and. ORCID
Douglas J Veale: St. Vincent's University Hospital, Dublin 4, Ireland.
Costantino Pitzalis: Queen Mary University of London, London EC1M 6BQ, United Kingdom. ORCID
Sunil Nagpal: Immunology, Janssen Research, Spring House, PA 19477; yguo49@its.jnj.com snagpal2@its.jnj.com. ORCID
The inflammatory CD40-CD40L pathway is implicated in various autoimmune diseases, but the activity status of this pathway in various stages of rheumatoid arthritis (RA) progression is unknown. In this study, we used gene signatures of CD40L stimulation derived from human immature dendritic cells and naive B cells to assess the expression of CD40-downstream genes in synovial tissues from anti-citrullinated protein Ab-positive arthralgia, undifferentiated arthritis (UA), early RA, and established RA cohorts in comparison with healthy donors. Interestingly, the expression of and active full-length was increased in the disease tissues, whereas that of a dominant-negative isoform was decreased. Gene set variation analysis revealed that CD40L-responsive genes in immature dendritic cells and naive B cells were significantly enriched in synovial tissues from UA, early RA, and established RA patients. Additionally, CD40L-induced naive B cell genes were also significantly enriched in synovial tissues from arthralgia patients. In our efforts to characterize downstream mediators of CD40L signaling, we have identified and as novel components of the pathway. In conclusion, our data suggest that therapeutic CD40-CD40L blocking agents may prove efficacious not only in early and established RA, but also in inhibiting the progression of the disease from arthralgia or UA to RA.
