Abstract
Sjögren’s Syndrome (SS) is a chronic autoimmune disorder characterized by focal mononuclear cell infiltrates that surround the ducts of the exocrine glands, impairing the function of their secretory units. Compared to other autoimmune disorders, SS is associated with a notably high incidence of non-Hodgkin lymphoma (NHL) and more frequently mucosa associated lymphoid tissue (MALT) lymphoma, leading to increased morbidity and mortality rates. High risk features of lymphoma development include systemic extraepithelial manifestations, low serum levels of complement component C4 and mixed type II cryoglobulinemia. The discrimination between reactive and neoplastic lymphoepithelial lesion (LEL) is challenging, probably reflecting a continuum in the evolution from purely inflammatory lymphoid infiltration to the clonal neoplastic evolution. Early lesions display a predominance of activated T cells, while B cells prevail in severe histologic lesions. This strong B cell infiltration is not only a morphologic phenomenon, but it is also progressively associated with the presence of ectopic germinal centers (GCs). Ectopic formation of GCs in SS represents a complex process regulated by an array of cytokines, adhesion molecules and chemokines. Chronic antigenic stimulation is the major driver of specific B cell proliferation and increases the frequency of their transformation in the ectopic GCs and marginal zone (MZ) equivalents. B cells expressing cell surface rheumatoid factor (RF) are frequently detected in the salivary glands, suggesting that clonal expansion might arise from antigen selection of RF-expressing B cells. Abnormal stimulation and incomplete control mechanisms within ectopic lymphoid structures predispose RF MZ like cells to lymphoma development. Immunoglobulin recombination, somatic mutation and isotype switching during B cell development are events that may increase the translocation of oncogenes to immunoglobulin loci or tumor suppressor gene inactivation, leading to monoclonal B cell proliferation and lymphoma development. Concerning chronic antigenic stimulation, conclusive data is so far lacking. However immune complexes containing DNA or RNA are the most likely candidates. Whether additional molecular oncogenic events contribute to the malignant overgrowth remains to be proved.
Highlights
Sjögren’s Syndrome (SS) is benign autoimmune disease characterized by organ specific as well as systemic manifestations
These findings indicate that these B cell clones represent a highly selected B cell population with enhanced ability to bind to the same or identical antigen
FcRL4 is an immunoregulatory receptor, selectively expressed by B cells with a marginal zone phenotype localized in the subepithelial regions and within the epithelium of tonsils and Peyer patches [75,76] Neoplastic B-cells-associated Mucosa associated lymphoid tissue (MALT) lymphomas, especially those involved in lymphoepithelial lesion (LEL), have been shown to express FcRL4 [76]
Summary
Sjögren’s Syndrome (SS) is benign autoimmune disease characterized by organ specific as well as systemic manifestations. Of interest this benign autoimmune disease can potentially lead to lymphomagenesis. Lymphoepithelial sialadenitis (LESA), a notable histological feature of SS, is characterized by the presence of lymphoid populations surrounding and infiltrating the salivary ducts, along with disorganization and proliferation of the ductal epithelial cells [25]. The spectrum of histopathologic features of LESA ranges from a fully benign lymphoid infiltrate, sometimes associated with lymphoid follicular structures, that does not display immunoglobulin (Ig) light chain restriction in B-cells, to lymphoproliferative lesions with presence of centrocyte-like cells with or without areas of Ig light chain restriction in B cells [26]. The evolution from persistent polyclonal B cell activation to monoclonal B cell expansion and thereafter lymphoma development is a multistep process
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