Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjögren's syndrome.
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.


CONCLUSIONS
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.
Amft
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Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston, UK.
Curnow
S J
SJ
Scheel-Toellner
D
D
Devadas
A
A
Oates
J
J
Crocker
J
J
Hamburger
J
J
Ainsworth
J
J
Mathews
J
J
Salmon
M
M
Bowman
S J
SJ
Buckley
C D
CD
D001402:B-Lymphocytes / Q000378:metabolism*; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000032:analysis / Q000096:biosynthesis*; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D014066:Palatine Tonsil / Q000378:metabolism / Q000473:pathology; D010306:Parotid Gland / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000096:biosynthesis; D012470:Salivary Glands, Minor / Q000378:metabolism* / Q000473:pathology; D012859:Sjogren's Syndrome / Q000378:metabolism* / Q000473:pathology; D014069:Tonsillitis / Q000378:metabolism / Q000473:pathology
C515255:CXCL12 protein, human; C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D019743:Chemokines, CXC; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine