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

Abstract

CXCL13 and CCL21 have been functionally implicated in lymphoid tissue organization both in the upstream phases of lymphoid tissue embryogenesis and in ectopic lymphoid neogenesis in transgenic mice. Here, we analyzed the relationship between CXCL13 and CCL21 production and lymphoid tissue organization in rheumatoid synovitis as a model of a naturally occurring ectopic lymphoneogenesis. Through systematic analysis of mRNA and protein expression, we defined the microanatomical relationship between CXCL13 and CCL21 in progressive aggregational and structural phases of synovial inflammatory infiltrate. We provide the first direct in situ evidence that production of CXCL13 and CCL21 (rather than simply protein binding) is associated with inflammatory lymphoid tissue formation and development with the demonstration, in organized aggregates, of a secondary lymphoid organ-like compartmentalization and vascular association. Notably, the presence of CXCL13 and CCL21 (protein and mRNA) was also demonstrated in non-organized clusters and minor aggregational stages, providing evidence that their induction can take place independently and possibly upstream of T-B compartmentalization, CD21 + follicular dendritic cell network differentiation and germinal center formation. Our data support the concept that, under inflammatory conditions, CXCL13 and CCL21 participate in lymphoid tissue microanatomical organization, attempting to recapitulate, in an aberrant lymphoid neogenetic process, their homeostatic and morphogenetic physiologic functions.

Lymphangiogenesis Is Upregulated in Kidneys of Patients With Multiple Myeloma

“…Angeli et al (2006) depicted a close interaction between antigen-presenting dendritic cells, B cells, and lymph vessels. Together with T cells, these three components are the main characteristics of the so-called tertiary lymphoid organs, whose occurrence has been described in chronic inflammatory processes such as rheumatoid arthritis (Manzo et al, 2005) or in infectious diseases caused by Helicobacter pylori or hepatitis C virus (Freni et al, 1995). Renal lymphoid neogenesis has been observed in kidney allografts underlying chronic rejection (Thaunat et al, 2005).…”

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.…”

B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

“…Synovial lymphoid neogenesis, defined as microstructural organization of lymphoid infiltrates, has been assessed by different criteria, including the presence of lymphoid aggregates (10), the size of these aggregates (22,23), and the presence of additional features of SLO, such as FDC and GC (15). These different criteria reflect the fact that tertiary lymphoid organs are under constant development and change (24) and do not always display the prototype characteristics of activated follicles in SLO such as a dark and light zone, T/B cell segregation, and FDC (15,25).…”

“…These different criteria reflect the fact that tertiary lymphoid organs are under constant development and change (24) and do not always display the prototype characteristics of activated follicles in SLO such as a dark and light zone, T/B cell segregation, and FDC (15,25). In this study, we defined synovial lymphoid neogenesis as the presence of organized aggregates of lymphoid cells with a diameter of Ն12 cells as smaller synovial lymphoid aggregates do not display features of lymphoid organogenesis and aggregates of this size are always composed of B and T cells (23,26). This definition includes both the aggregate and GC-like infiltrates (defined by the presence of FDC) described by others (15) as one of the aims of the study was to assess the degree of differentiation toward GC-reactions rather than to assume that the distinction between aggregates and GC-like infiltrates has a biological or clinical relevance.…”