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.
Objective. To define the immunohistologic features of the synovial membrane (SM) of patients with psoriatic arthritis (PA) and to compare them with those of an age‐ and disease‐duration–matched population of patients with rheumatoid arthritis (RA).
Methods. Synovial membrane needle biopsy was performed on 15 PA patients with knee involvement (8 had asymmetric oligoarthritis and 7 had symmetric polyarthritis) and on 15 RA controls. Specimens were stained with monoclonal antibodies against T cells (CD3, CD8, CD4, CD45RO), B cells (CD20), macrophages (Mac387, CD14), and cells bearing class II antigens (DAKO‐DR). Vascular endothelium was examined using a polyclonal antibody to Factor VIII–related antigen, and adhesion molecule expression was examined using antibodies 1.3B6, 6.5B5, and 1.4C3, which identify endothelial leukocyte adhesion molecule 1 (ELAM‐1), intercellular adhesion molecule 1 (ICAM‐1), and vascular cell adhesion molecule 1 (VCAM‐1), respectively.
Results. There was significantly less lining layer hyperplasia, fewer macrophages, and a greater number of blood vessels in PA SM than in RA SM. ELAM‐1 expression was less intense in PA than in RA SM, while there was no difference in expression of ICAM‐1 and VCAM‐1. Numbers of B cells, T cells, and T cell subsets (predominantly CD4, CD45RO T cells) were similar in both groups of patients.
Conclusion. Our findings demonstrate important differences in the immunohistologic features of PA and RA SM. The PA SM is more vascular, ELAM‐1 expression is less intense, and fewer macrophages invade the stroma and migrate to the lining layer than in RA SM. However, the lymphocytic infiltrate in the SM of both groups is similar.
Objective. To study the effect of chimeric anti-CD4 monoclonal antibody (MAb) therapy on synovial inflammation, in order to interpret the clinical experience with anti-CD4 treatment.Methods. The immunohistologic features of synovial biopsy specimens before and 4 weeks after anti-CD4 MAb (cM-T412) therapy were studied in patients with rheumatoid arthritis. The patients received intravenous doses of either placebo (n = 1) or 10 mg (n = 4), 25 mg (n = 2), or 50 mg (n = 1) of cM-T412 daily for 5 consecutive days.Results. Although the patients did not experience clinical improvement, significant decreases in the number of circulating CD4+ cells, the degree of synovial inflammatory infiltration, and the mean scores for expression of adhesion molecules were found in the 7 patients 4 weeks after receiving cM-T412. The scores for infiltration with CD4+ and other inflammatory cells were particularly reduced following treatment with either 25 mg or 50 mg cM-T412. Cytokines, such as interleukin-lp and tumor necrosis factor a, could still be detected in the synovial tissue after treatment.Conclusion. The decline in the numbers of inflammatory cells and adhesion molecules in synovial tissue after CD4+ cell depletion supports the view that
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