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Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis.

ABSTRACT: Both type I and II interferons (IFNs) have been implicated in the pathogenesis of Sjogren's syndrome (SS). We aimed to explore the contribution of type I and II IFN signatures in the generation of distinct SS clinical phenotypes including lymphoma development. Peripheral blood (PB) from SS patients (n = 31), SS patients complicated by lymphoma (n = 13) and healthy controls (HC, n = 30) were subjected to real-time PCR for 3 interferon inducible genes (IFIGs) preferentially induced by type I IFN, 2 IFIGs preferentially induced by IFN? as well as for IFN? and IFN? genes. The same analysis was performed in minor salivary gland tissues (MSG) derived from 31 SS patients, 10 SS-lymphoma patients and 17 sicca controls (SC). In PB and MSG tissues, overexpression of both type I and type II IFIGs was observed in SS patients versus HC and SC, respectively, with a predominance of type I IFN signature in PB and a type II IFN signature in MSG tissues. In SS-lymphoma MSG tissues, lower IFN?, but higher IFN? and type II IFIG transcripts compared to both SS and SC were observed. In receiver operating characteristic curve analysis, IFN?/IFN? mRNA ratio in MSG tissues showed the best discrimination for lymphoma development. Discrete expression patterns of type I and II IFN signatures might be related to distinct SS clinical phenotypes. Additionally, IFN?/IFN? mRNA ratio in diagnostic salivary gland biopsies is proposed as a novel histopathological biomarker for the prediction of in situ lymphoma development in the setting of SS.

SUBMITTER: Nezos A

PROVIDER: S-EPMC4564326 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis.

Nezos Adrianos A Gravani Fotini F Tassidou Anna A Kapsogeorgou Efstathia K EK Voulgarelis Michael M Koutsilieris Michael M Crow Mary K MK Mavragani Clio P CP

Journal of autoimmunity 20150714

Both type I and II interferons (IFNs) have been implicated in the pathogenesis of Sjogren's syndrome (SS). We aimed to explore the contribution of type I and II IFN signatures in the generation of distinct SS clinical phenotypes including lymphoma development. Peripheral blood (PB) from SS patients (n = 31), SS patients complicated by lymphoma (n = 13) and healthy controls (HC, n = 30) were subjected to real-time PCR for 3 interferon inducible genes (IFIGs) preferentially induced by type I IFN, ...[more]

PMID: 26183766

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Project description: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.

Project description:ObjectiveSjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features.MethodsClinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed.ResultsA total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high-titer antinuclear antibody, anti-SSA, and high focus score on labial salivary gland [LSG] biopsy). Three distinct patterns of IFN were evident: type I-predominant, type II-predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II-predominant IFN.ConclusionThe SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN-targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient.

Dataset Information

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis.

Publications

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis.

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