TY - JOUR
T1 - Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis
AU - Manzo, Antonio
AU - Paoletti, Samantha
AU - Carulli, Maresa
AU - Blades, Mark C
AU - Barone, Francesca
AU - Yanni, Ghada
AU - Fitzgerald, Oliver
AU - Bresnihan, Barry
AU - Caporali, Roberto
AU - Montecucco, Carlomaurizio
AU - Uguccioni, Mariagrazia
AU - Pitzalis, Costantino
PY - 2005/5
Y1 - 2005/5
N2 - 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.
AB - 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.
KW - Arthritis, Rheumatoid
KW - B-Lymphocytes
KW - Chemokine CCL21
KW - Chemokine CXCL13
KW - Chemokines, CC
KW - Chemokines, CXC
KW - Embryonic Development
KW - Female
KW - Humans
KW - Immunohistochemistry
KW - In Situ Hybridization
KW - Lymphoid Tissue
KW - Male
KW - Middle Aged
KW - Synovitis
KW - T-Lymphocytes
U2 - 10.1002/eji.200425830
DO - 10.1002/eji.200425830
M3 - Article
C2 - 15832291
SN - 0014-2980
VL - 35
SP - 1347
EP - 1359
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 5
ER -