B cell subpopulations in the pathogenesis of rheumatoid arthritis

Abstract

B cell depleting therapy has proven to be an effective treatment in rheumatoid arthritis (RA), a disease characterized by the presence of autoantibodies against citrullinated proteins (ACPA) and the Fc portion of IgG (rheumatoid factor, RF). This demonstrates the vital role B cells play in the disease. The aim of this thesis was to explore the role of B cell subpopulations in the pathogenesis of RA. Our interest in a specific B cell population arose with the discovery of murine autoreactive B cells, CD21-/low cells, which expressed low surface levels or lacked the complement receptor 2 (CD21). CD21 helps activate B cells, as it is a part of the B cell co-receptor complex. In Studies I-III we analyzed B cell populations in human peripheral blood with the help of flow cytometry utilizing multiple cell markers. In Studies II-III, clinical as well as radiographic data was collected from RA patients. In Study I we established that CD21-/low B cells are found in human peripheral blood and discovered that in healthy donors (HDs) this B cell population is mainly composed of memory B cells (MBCs) based on their phenotype and response to combined stimuli. In Study II we compared the B cell populations in peripheral blood of patients with established RA and HDs. We saw a higher proportion of a CD21-/low subpopulation, i.e. CD21-/low CD27-IgD- (double negative, DN) in patients with autoantibodies (ACPA/RF) compared to HDs. Additionally, the frequency of CD21- /low DN cells was higher in ACPA/RF positive patients with more joint destruction compared to those with less, and the CD21-/low DN population correlated positively with the level of destruction. The CD21-/low DN population was highly enriched in the inflamed joints of RA patients and a third of the cells expressed RANKL, which stimulates osteoclastogenesis. In Study III, we compared the B cell populations in peripheral blood in newly diagnosed untreated RA patients and HDs. We observed that the proportion of CD21+CD27+ MBCs correlated positively with RF and ACPA titers. In addition, the frequency of CD21+ DN cells and CD21-/low DN MBCs correlated positively with tender joint count and joint narrowing score respectively. In conclusion, it seems that different MBCs have different roles in RA where CD21+ CD27+ MBCs appear to drive the autoantibody response, the CD21+DN MBCs the joint inflammation and the CD21-/low DN MBCs the joint damage.