TY - JOUR
T1 - Distinct profiles of Sjögren's syndrome patients with ectopic salivary gland germinal centers revealed by serum cytokines and BAFF
AU - Szodoray, Peter
AU - Alex, Philip
AU - Jonsson, Malin V.
AU - Knowlton, Nicholas
AU - Dozmorov, Igor
AU - Nakken, Britt
AU - Delaleu, Nicolas
AU - Jonsson, Roland
AU - Centola, Michael
N1 - Funding Information:
We thank the Department of Oral Pathology and Forensic Odontology, Institute of Odontology, University of Bergen and Marianne Eidsheim at the Broegelmann research laboratory for technical assistance, and also Dr. Johan G. Brun at the Department of Rheumatology, Haukeland University Hospital, University of Bergen for providing the clinical data of the patients. This work was funded by the National Institutes of Health National Center for Research Resources (grant numbers 1 P20 RR020143-01, P20 RR 017703, R21-AR-48378, NIH 1 P20 RR15577, and NIH 1 P20 RR16478-04 from the National Institutes of Health), and the Faculty of Medicine, University of Bergen, Bergen, Norway.
PY - 2005/11
Y1 - 2005/11
N2 - The formation of ectopic germinal centers (GC) has been described in Sjögren's syndrome (SS), although little is known about the molecular basis of this phenomenon. These structures are a focus of in situ autoantibody production and have been hypothesized to be involved in lymphomagenesis in SS patients. Serum cytokines also play an important role in SS pathogenesis in part via immune dysregulation and may therefore contribute to ectopic GC formation. Herein, highly multiplex cytokine screening of SS patients with (SSGC+) and without (SSGC-) GC formation was done to identify cytokine profiles that correlate with this phenomenon. Serum levels of B-cell activating factor (BAFF) were also screened as a potential biomarker of immune dysregulation in SS and SSGC formation. Univariate analysis demonstrated that serum levels of a broad spectrum of immune and inflammatory modulating cytokines are upregulated in SSGC+ and SSGC- patients relative to unaffected controls IL-1β, IL-2, IL-6, IL-15, IFN-γ and CCL4 (MIP-1β). SSGC+ patients were distinguished from healthy individuals by higher levels of IL-4, IL-10, GM-CSF, IFN-α, CCL3 (MIP-1α), CCL11 (Eotaxin) and BAFF, while SSGC+ and SSGC- patients differed in CCL2 (MCP-1) expression. Discriminant function analysis (DFA), a multivariate discrimination method that uses observed differences to characterize groups when casual relationships are not well understood, was employed to identify a subset of these biomarkers that maximally discriminate among SSGC+, SSGC- and unaffected individuals. The biomarker having the strongest discriminatory power identified by DFA besides CCL11 (Eotaxin) and IFN-γ was BAFF. The variables identified by DFA are interdependent and are often of mechanistic significance to the pathologic states they distinguish, suggesting that these factors modulate SS pathology and SSGC formation in a synergistic manner.
AB - The formation of ectopic germinal centers (GC) has been described in Sjögren's syndrome (SS), although little is known about the molecular basis of this phenomenon. These structures are a focus of in situ autoantibody production and have been hypothesized to be involved in lymphomagenesis in SS patients. Serum cytokines also play an important role in SS pathogenesis in part via immune dysregulation and may therefore contribute to ectopic GC formation. Herein, highly multiplex cytokine screening of SS patients with (SSGC+) and without (SSGC-) GC formation was done to identify cytokine profiles that correlate with this phenomenon. Serum levels of B-cell activating factor (BAFF) were also screened as a potential biomarker of immune dysregulation in SS and SSGC formation. Univariate analysis demonstrated that serum levels of a broad spectrum of immune and inflammatory modulating cytokines are upregulated in SSGC+ and SSGC- patients relative to unaffected controls IL-1β, IL-2, IL-6, IL-15, IFN-γ and CCL4 (MIP-1β). SSGC+ patients were distinguished from healthy individuals by higher levels of IL-4, IL-10, GM-CSF, IFN-α, CCL3 (MIP-1α), CCL11 (Eotaxin) and BAFF, while SSGC+ and SSGC- patients differed in CCL2 (MCP-1) expression. Discriminant function analysis (DFA), a multivariate discrimination method that uses observed differences to characterize groups when casual relationships are not well understood, was employed to identify a subset of these biomarkers that maximally discriminate among SSGC+, SSGC- and unaffected individuals. The biomarker having the strongest discriminatory power identified by DFA besides CCL11 (Eotaxin) and IFN-γ was BAFF. The variables identified by DFA are interdependent and are often of mechanistic significance to the pathologic states they distinguish, suggesting that these factors modulate SS pathology and SSGC formation in a synergistic manner.
KW - B-cell activating factor
KW - Circulating cytokines
KW - Ectopic germinal center
KW - Sjögren's syndrome
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U2 - 10.1016/j.clim.2005.06.016
DO - 10.1016/j.clim.2005.06.016
M3 - Article
C2 - 16126006
AN - SCOPUS:26044481687
SN - 1521-6616
VL - 117
SP - 168
EP - 176
JO - Clinical Immunology
JF - Clinical Immunology
IS - 2
ER -