Background/Purpose: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with various immunological abnormalities and a diverse range of clinical symptoms. In contrast to the traditional belief that SLE is solely an adaptive immune disorder, multiple studies of patient samples and mouse models have revealed the involvement of innate immune mechanisms in the initiation of SLE. However, the exact role of innate immunity in SLE pathogenesis is unknown, thus we have developed a new model to understand the genetic complexity of disease development and susceptibility. Drosophila is well suited to this research as the innate immune pathways are well conserved between humans and mammals including the JAK-STAT pathway which has been specifically implicated in pathology of SLE in humans. To understand the regulation of the JAK-STAT pathway and its role in SLE, we are utilizing our newly developed Drosophila SLE model, which has a gain of function mutation in the Drosophila homolog of JAK. Our goal is to identify genes that contribute to the SLE-like phenotype with a particular focus on JAK-STAT signaling.

Methods: To identify genes that modify the Drosophila SLE model phenotype, we performed two genetic screens. Forward genetic screening was performed in which 20% of the Drosophila genome was screened to look for regions containing genes involved in the autoimmune response in the Drosophila SLE model. To understand the role of JAK-STAT signaling in regulating autoimmunity, we conducted a reverse genetic screen in which we tested the role of candidate transcriptional factors in the SLE model autoimmune phenotype. We selected these genes based on previous links to JAK-STAT and then used RNAi to knockdown these genes in immune cells in our Drosophila model.

Results: We performed genetic screening and identified novel genes associated with SLE that may regulate conserved transcriptional networks which underlie self-tolerance. Our genetic modifier screen revealed 12 regions that modified the SLE phenotype. We predict that these regions contain genes that function in SLE-associated autoimmune mechanisms. Since our SLE mutant has a gain of function mutation in JAK-STAT, we conducted a reverse genetic screen that focused on understanding of the role of this pathway in autoimmunity. We discovered that RNAi mediated knockdown of candidate transcription factors in mutant immune cells suppressed the phenotype, suggesting that these genes promote JAK-STAT activity.

Conclusion: This study uncovers novel genetic interactions that may play a role in the contribution of the JAK-STAT pathway to SLE pathogenesis. The human homologs of two of our identified JAK-STAT interacting genes, AFF1 and BACH2, have been previously linked to SLE, whereas the others represent putative novel SLE risk factors. Identification of these new genes and genetic interactions will expand our knowledge of the processes which lead to autoimmune disorders, and investigating their molecular role in the Drosophila SLE model may well open a new window for the understanding and clinical treatment of this complex disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-analysis-of-a-drosophila-systemic-lupus-erythematosus-model-reveals-lupus-susceptibility-genes/