Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis.
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.
Manzo
Antonio
A
Rheumatology Unit, Guy's, King's and St Thomas' School of Medicine, Guy's Campus, London, UK.
Paoletti
Samantha
S
Carulli
Maresa
M
Blades
Mark C
MC
Barone
Francesca
F
Yanni
Ghada
G
Fitzgerald
Oliver
O
Bresnihan
Barry
B
Caporali
Roberto
R
Montecucco
Carlomaurizio
C
Uguccioni
Mariagrazia
M
Pitzalis
Costantino
C
D001172:Arthritis, Rheumatoid / Q000150:complications / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000276:immunology; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000276:immunology; D047108:Embryonic Development / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008221:Lymphoid Tissue / Q000196:embryology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D013585:Synovitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
C515478:CCL21 protein, human; C110663:CXCL13 protein, human; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D019742:Chemokines, CC; D019743:Chemokines, CXC