Lymphoid Chemokine B Cell-Attracting Chemokine-1 (CXCL13) Is Expressed in Germinal Center of Ectopic Lymphoid Follicles Within the Synovium of Chronic Arthritis Patients

Abstract

A unique feature in inflammatory tissue of rheumatoid arthritis (RA) is the formation of ectopic lymphoid aggregates with germinal center (GC)-like structures that can be considered to contribute to the pathogenesis of RA, because local production of the autoantibody, rheumatoid factor, is thought to be a causative factor in tissue damage. However, the factors governing the formation of GC in RA are presently unknown. To begin to address this, the expression of B cell attracting chemokine (BCA-1) (CXCL13), a potent chemoattractant of B cells, was examined in the synovium of patients with RA or with osteoarthritis (OA). Expression of BCA-1 mRNA was detected in all RA samples, but in only one of five OA samples. Lymphoid follicles were observed in four of seven RA samples and in two of eight OA samples, and in most of them BCA-1 protein was detected in GC. BCA-1 was not detected in tissues lacking lymphoid follicles. Notably, BCA-1 was detected predominantly in follicular dendritic cells in GC. CD20-positive B cells were aggregated in regions of BCA-1 expression, but not T cells or macrophages. These data suggest that BCA-1 produced by follicular dendritic cells may attract B cells and contribute to the formation of GC-like structures in chronic arthritis.

Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis

“…In this context, extending previous immunohistochemical analysis indicating the colocalization between CXCL13 protein and FDC in ectopic GC [17,18], we found the CK produced both within CD21 + FDC network-rich area and in the external B cell distribution zone ( Fig. 3O-Q for structure and R, S for CXCL13).…”

“…The concept that CXCL13 and CCL21 may also be involved in human ectopic lymphoid tissue organization is supported by their detection in several chronic inflammatory conditions including rheumatoid arthritis (RA) [17][18][19][20][21][22]. An attempt to define the functional roles of CXCL13 and CCL21 in synovial lymphoid neogenesis in RA was made by Takemura et al [18], who examined the relationship between mRNA levels of CXCL13 and CCL21 on homogenized synovial tissues and the organizational pattern of the inflammatory infiltrate.…”

Identification of CXCL13 as a marker for rheumatoid arthritis outcome using an in silico model of the rheumatic joint

“…Serum CXCL13 levels were also reported to respond to therapeutic intervention with anti-TNF␣ therapy (12). Evidence of joint localization of CXCL13 has been demonstrated, both by the detection of messenger RNA in inflamed synovial tissue (26) and by the presence of ectopic lymphoid follicles expressing CXCL13 in the synovium of patients with chronic RA (27). CXCL13 has been reported to attract B lymphocytes and to interact with the receptor CXCR5, which is expressed by B cells as well as follicular B helper T cells (28)(29)(30)(31).…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Notably, ELFs are described at all stages of the disease and include patients with early active disease who have not received biological agents, patents with more progressive forms of rheumatoid arthritis, and those that have already received biological intervention 43, 112, 113. Although the mechanisms contributing the development of this form of pathology are largely unclear, ELFs in rheumatoid arthritis are associated with heightened synovial expression of CXCL13, CCL21, CCL19 and CXCL12, and cytokines LT α 1 β 2 and IL‐7 21, 44, 114, 115. Importantly, these structures correlate with disease severity and are associated with local T‐cell priming and autoantibody production 43, 116, 117, 118.…”