OBJECTIVE: To test the hypothesis that the formation of ectopic germinal center (GC)-like structures in Sjögren's syndrome (SS) is associated with the ectopic expression of the constitutive lymphoid tissue-homing chemokines B cell-attracting chemokine 1 (BCA-1; or, CXCL13) and stromal cell-derived factor 1 (SDF-1; or, CXCL12). METHODS: Immunohistochemical and immunofluorescence analysis was used to determine the expression of the constitutive chemokines BCA-1 (CXCL13) and SDF-1 (CXCL12) in salivary glands from 5 SS patients and 3 non-SS patients. In addition, the expression of their respective receptors (CXCR5 and CXCR4) was examined on infiltrating lymphocytes. Human tonsil was used as a positive control for secondary lymphoid tissue. RESULTS: BCA-1 (CXCL13) was expressed within lymphoid aggregates in SS, which shared many structural features with GCs in tonsil. BCA-1 (CXCL13) was completely absent in control biopsy samples from patients who did not have SS. High levels of BCA-1 (CXCL13) were also found on endothelial cells in salivary glands from SS patients. Diseased SS tissue was infiltrated by CXCR5-expressing B cells which organized into GC-like clusters. In complete contrast, SDF-1 (CXCL12), a constitutive chemokine involved in leukocyte retention within lymphoid tissue, was expressed by epithelial cells in both diseased and control samples. The chemokine receptor for SDF-1, CXCR4, was expressed on T cells that accumulated in a periductal distribution in diseased tissue. CONCLUSION: The ectopic expression of BCA-1 (CXCL13) on endothelial cells and within GC-like structures, together with the strong expression of SDF-1 (CXCL12) on ductal epithelial cells, is a unique feature of inflamed glands in SS. By creating a local microenvironment supportive of focal B cell aggregation and differentiation, with structural features that are remarkably similar to GCs, BCA-1 (CXCL13) and SDF-1 (CXCL12) may contribute to the excessive production of high-affinity, class-switched autoantibodies and to the high incidence of B cell lymphomas classically associated with SS.
OBJECTIVE: To test the hypothesis that the formation of ectopic germinal center (GC)-like structures in Sjögren's syndrome (SS) is associated with the ectopic expression of the constitutive lymphoid tissue-homing chemokines B cell-attracting chemokine 1 (BCA-1; or, CXCL13) and stromal cell-derived factor 1 (SDF-1; or, CXCL12). METHODS: Immunohistochemical and immunofluorescence analysis was used to determine the expression of the constitutive chemokines BCA-1 (CXCL13) and SDF-1 (CXCL12) in salivary glands from 5 SS patients and 3 non-SS patients. In addition, the expression of their respective receptors (CXCR5 and CXCR4) was examined on infiltrating lymphocytes. Human tonsil was used as a positive control for secondary lymphoid tissue. RESULTS:BCA-1 (CXCL13) was expressed within lymphoid aggregates in SS, which shared many structural features with GCs in tonsil. BCA-1 (CXCL13) was completely absent in control biopsy samples from patients who did not have SS. High levels of BCA-1 (CXCL13) were also found on endothelial cells in salivary glands from SS patients. Diseased SS tissue was infiltrated by CXCR5-expressing B cells which organized into GC-like clusters. In complete contrast, SDF-1 (CXCL12), a constitutive chemokine involved in leukocyte retention within lymphoid tissue, was expressed by epithelial cells in both diseased and control samples. The chemokine receptor for SDF-1, CXCR4, was expressed on T cells that accumulated in a periductal distribution in diseased tissue. CONCLUSION: The ectopic expression of BCA-1 (CXCL13) on endothelial cells and within GC-like structures, together with the strong expression of SDF-1 (CXCL12) on ductal epithelial cells, is a unique feature of inflamed glands in SS. By creating a local microenvironment supportive of focal B cell aggregation and differentiation, with structural features that are remarkably similar to GCs, BCA-1 (CXCL13) and SDF-1 (CXCL12) may contribute to the excessive production of high-affinity, class-switched autoantibodies and to the high incidence of B cell lymphomas classically associated with SS.
Authors: Shehnaz K Hussain; Weiming Zhu; Shen-Chih Chang; Elizabeth Crabb Breen; Elena Vendrame; Larry Magpantay; Dan Widney; Daniel Conn; Mary Sehl; Lisa P Jacobson; Jay H Bream; Steven Wolinsky; Charles R Rinaldo; Richard F Ambinder; Roger Detels; Zuo-Feng Zhang; Otoniel Martínez-Maza Journal: Cancer Epidemiol Biomarkers Prev Date: 2012-12-18 Impact factor: 4.254