THU0228 EXPRESSION OF APOBEC FAMILY MEMBERS AS REGULATORS OF ENDOGENOUS RETROELEMENTS AND MALIGNANCY IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJÖGREN’S SYNDROME

Abstract

Background: Activation of type I and II interferon (IFN) pathways contributes to the pathogenesis of systemic autoimmune diseases. We have previously shown increased expression of the LINE-1 (L1) endogenous retrotransposon in systemic lupus erythematosus (SLE) kidneys and in minor salivary glands (MSG) from primary Sjogren’s syndrome patients (SS) that strongly correlates with IFNα expression in the same tissues. Moreover, an imbalance between type I and II IFNs in SS salivary gland tissues has been related to non-Hodgkin’s lymphoma (NHL) development. Members of a family of retroviral resistance factors (APOBECs) have been implicated in L1 control and are regulated by both type I and II IFNs. Objectives: We investigated whether these mechanisms are involved in the response to inappropriate expression of L1 retroelements in primary SS and SLE, as well as in SS related lymphomagenesis. Methods: MSG and kidney biopsy specimens were obtained from 41 patients with primary SS and 23 patients with SLE, respectively. Peripheral blood mononuclear cells (PBMC) and sera were also collected from 73 SLE patients. Relative mRNA expression was quantified by real-time polymerase chain reaction for full-length L1 transcripts, along with members of the APOBEC family [APOBEC3A, APOBEC3B, APOBEC3G, AID (activation-induced cytidine deaminase)] and IFNα and γ transcripts. Type I IFN activity was assessed in lupus plasma by a reporter cell assay. The induction of APOBEC3A and B by IFNα in healthy control PBMCs was also assessed. Results: APOBEC3A, previously implicated in control of endogenous retroelements, was increased in SS MSG and lupus nephritis kidney tissues and in SLE PBMC and strongly correlated with L1 retroelement expression in both SS and SLE tissues. APOBEC3A was also associated with IFNα mRNA expression in SS MSG tissues and lupus kidneys and with type I IFN activity in lupus plasma. While APOBEC3A expression was induced by IFNα, such a relationship was not observed with APOBEC3B. Moreover, a strong correlation was detected between AID and APOBEC3G with IFNγ expression in SS MSG tissue, a relationship particularly relevant to development of NHL. Conclusion: Increased expression of APOBEC3A reflects a host-intrinsic and IFNα-dependent mechanism regulating potentially harmful L1 retroelements in patients with SS and SLE. Moreover, IFNγ-related induction of APOBEC3G, together with AID, might contribute to SS-related lymphomagenesis by increasing mutational load or epigenetic alterations. These data reveal a previously unappreciated role of APOBEC family proteins in the pathogenesis of autoimmune disorders. Disclosure of Interests: None declared