Ectopic germinal center formation in rheumatoid synovitis
Weyand, CM; Goronzy, JJ; ,
| HERO ID | 7047906 |
|---|---|
| In Press | No |
| Year | 2003 |
| Title | Ectopic germinal center formation in rheumatoid synovitis |
| Authors | Weyand, CM; Goronzy, JJ; , |
| Journal | Annals of the New York Academy of Sciences |
| Page Numbers | 140-149 |
| Abstract | Synovial inflammation in rheumatoid arthritis is closely related to the formation of ectopic lymphoid microstructures. In synovial tissue from some patients, one rinds seemingly diffuse infiltrates; in others, T cells and B cells cluster in aggregates with interdigitating dendritic cells (DCs) but no follicular DCs (FDCs). In a third group, T cell/B; cell follicles with germinal center (GC) reactions are generated. Within a given patient, aggregates and GCs are mutually exclusive and stable over time. Because antigen storage capacity, lymphoid density, and three-dimensional topography of GCs optimize immune responses, synovial GCs should play a crucial role in the breakdown of self-tolerance. We have identified factors critical for ectopic GCs, thereby transforming the synovial inflammatory process. Tissues with GCs produced 10- to 20-fold higher amounts of the chemokines CXCL13 and CCL21. CXCL13 derived from three sources, endothelial cells, synovial fibroblasts, and FDC networks. The level of CXCL13 transcripts strongly predicted GCs; however, some tissues had high levels of CXCL13 but lacked GCs. Tissue expression of LT-P emerged as a second key factor. LT-P protein was detected on follicular center and mantle zone B cells. Multivariate regression analysis identified CXCL13 and LT-P as the only cytokines predicting GCs. Remarkably, LT-a did not contribute independently. The contribution of B cells to ectopic lymphoid organogenesis was not limited to LT-P production. Rather, synovial tissue B cells were critical in regulating T cell activation. In adoptive transfer experiments in human synovium-SCID mouse chimeras, activation of synovium-derived CD4 T cells was strictly dependent on T cell/B cell follicles. Depletion of synovial tissue B cells abrogated T cell function, and non-B cell antigenpresenting cells could not maintain T cell stimulation. Unexpectedly, GC function in the rheumatoid lesion was also dependent on CD8 T cells. The majority of T cell receptors derived from CD8 T cells were shared between distinct GCs. Depletion of CD8 T cells disrupted synovial GCs, FDC networks disappeared, and transcription of LT-beta, IgG, and Igkappa declined. Follicle-sustaining CD8 T cells were located at the edge of or within the mantle zone. Cell-cell communication in the mantle zone, including CD8 T cells, appears to be critical for ectopic GC formation in rheumatoid synovitis. |
| Doi | 10.1111/j.1749-6632.2003.tb06042.x |
| Pmid | 12727633 |
| Wosid | WOS:000183319000016 |
| Is Certified Translation | No |
| Dupe Override | No |
| Conference Location | ST GEORGES, W IND ASSOC ST |
| Conference Name | Conference on Immune Mechanisms and Disease |
| Is Public | Yes |
| Language Text | English |