Title:Ectopic Lymphoid Neogenesis and Lymphoid Chemokines in Sjogren’s Syndrome: At the Interplay between Chronic Inflammation, Autoimmunity and Lymphomagenesis
Volume: 13
Issue: 10
Author(s): Michele Bombardieri and Costantino Pitzalis
Affiliation:
Keywords:
Sjogren’s syndrome, lymphoid chemokines, ectopic lymphoid structures, activation-induced cytidine deaminase,
lymphomagenesis, autoantibodies, salivary glands (SG), lymphotoxins (LT), immune cells, chronic inflammation, autoreactive B cells, lymphoid organs, systemic manifestations and lymphoma, histopathological hallmark.
Abstract: It has long been demonstrated that a subset of patients with Sjogren’s syndrome (SS) develop ectopic lymphoid
structures (ELS) in the salivary glands (SG). These structures are characterised by periductal clusters of T and B lymphocytes,
development of high endothelial venules and differentiation of follicular dendritic cells (FDC) networks. Evidence
in patients with and animal models of SS demonstrated that the formation and maintenance of ELS in the SG is critically
dependent on the ectopic expression of lymphotoxins (LT) and lymphoid chemokines CXCL13, CCL19, CCL21 and
CXCL12. Several cell types, including resident epithelial, stromal and endothelial cells as well as different subsets of infiltrating
immune cells, have been shown to be capable of producing some of these factors during chronic inflammation in
SS. In this review we focus on the cellular and molecular mechanisms regulating the formation of ELS in SS SG, with
particular emphasis on the role of lymphoid chemokines. In addition, we summarise accumulating data in support of the
notion that ELS in SS represent functional niches whereby autoreactive B cells undergo affinity maturation, clonal selection
and differentiation into autoantibody producing cells, thus contributing to autoimmunity over and above secondary
lymphoid organs. Furthermore, we review the emerging role of ELS and lymphoid chemokines in driving extranodal B
cell lymphomagenesis in SS and we focus on recent evidence suggesting that ELS identify subsets of SS patients at increased
risk of developing systemic manifestations and lymphoma.