Anatomic Localization of Immature and Mature Dendritic Cells in an Ectopic Lymphoid Organ: Correlation with Selective Chemokine Expression in Rheumatoid Synovium

Abstract

It remains to be clarified whether dendritic cells (DC) reach the rheumatoid arthritis (RA) synovium, considered an ectopic lymphoid organ, as mature cells or undergo local maturation. We characterized by immunohistochemistry the DC subsets and used tonsils as a control. Immature and mature DC were defined by CD1a and DC-lysosome-associated membrane protein/CD83 expression, respectively. Immature DC were mainly detected in the lining layer in RA synovium. Mature DC were exclusively detected in the lymphocytic infiltrates. The DC-lysosome-associated membrane protein/CD1a ratio was 1.1 in RA synovium and 5.3 in tonsils, suggesting the relative accumulation of immature DC in RA synovium. We then focused on the expression of CCL20/CCR6 and CCL19/CCR7, CCL21/CCR7 chemokine/receptor complex, which control immature and mature DC migration respectively. A close association was observed between CCL20-producing cells and CD1a+ cells, suggesting the contribution of CCL20 to CCR6+ cell homing. Conversely, CCL21 and CCL19 expression was only detected in perivascular infiltrates. The association among CCL19/21-producing cells, CCR7 expression, and mature DC accumulation is in line with the roles of these chemokines in mature CCR7+ DC homing to lymphocytic infiltrates. The role of DC in disease initiation and perpetuation makes chemokines involved in DC migration a potential therapeutic target.

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

“…We observed, in keeping with previous reports [20,21], that CCL21 expression was associated with scattered or clustered cells (Fig. 6A, B) as well as with vascular structures (Fig.…”

“…Some of these scattered nonvascular CCL21 + cells, whose phenotype is currently under investigation, appeared irregular in shape, with prolonged cytoplasmic processes (not shown). Although it has been suggested that CCL21 may play a role in ectopic lymphoid neogenesis in RA synovium [20,21], no comparative analysis between the vascular and nonvascular pattern was carried out in those studies. Our systematic in situ analysis demonstrated that nonvascular CCL21-producing cells were specifically associated with lymphoid aggregates; they were only rarely or were not detected in the sublining stroma devoid of a consistent mononuclear infiltrate.…”

“…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.…”

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

“…In fact, several observations indicate the potential role of DCs in RA disease pathogenesis. First, DCs are abundantly present at strategic locations in RA synovium (17)(18)(19). Second, models of experimental arthritis have shown that presentation of collagen-derived peptides by mature DCs is sufficient for the induction of arthritis (20), and finally, genetically modulated DCs were able to abrogate experimental arthritis (21).…”

Detection of major histocompatibility complex/human cartilage gp‐39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker

“…HC gp-39 is also abundantly present in inflamed RA synovial membrane and correlates with the degree of joint destruction (9). Furthermore, several studies have highlighted the presence and the role of fully differentiated dendritic cells and ectopic lymphoid follicles in the synovial membrane in RA (7,10,11).…”