Background/Purpose: The objective of our research is to understand the genetic architecture and molecular mechanisms that contribute to the development and progression of the autoimmune disease systemic lupus erythematosus (SLE). SLE occurs when the immune system loses self tolerance and triggers a self-directed immune response, often leading to inflammation and tissue damage. Recent evidence demonstrates that both the acquired and innate immune responses are implicated in SLE pathogenesis, however the role of innate immunity is largely understudied. Additionally, while a large number of genes have been linked to SLE, efforts into understanding the basis of the disease have been hindered by this genetic complexity. In order to understand the role of innate immune responses and to unravel the underlying genetics, we have developed a Drosophila model of SLE. Drosophila provides many advantages for this research, including a wealth of genetic tools, experimental tractability and a highly conserved innate immune response. To develop the SLE model, we have focused on a mutant strain of Drosophila which mounts a self-directed cellular inflammation response that results in the damage of self tissue.

Methods: We have characterized the Drosophila SLE model using a combination of cell biology approaches including immunofluorescence and cell stains, genetic mapping, and RNA interference mediated reverse genetics.

Results: We find that the Drosophila SLE-like phenotype arises from two distinct mutations. The first mutation is a gain of function mutation in the Drosophila homolog of Janus Kinase (JAK). Mutations in JAK are linked to a variety of autoimmune diseases including SLE. The second mutation is a loss of function mutation in an enzyme of the N-glycosylation pathway, and accordingly we find that the mutants have decreased N-glycosylation of extracellular matrix (ECM) proteins. Interestingly, altered N-glycosylation is seen in SLE patient samples, and mutations in ECM proteins have been linked to SLE pathogenesis. Additionally, reverse genetics suggests that the Drosophila homolog of the SLE-linked integrin gene ITGAM plays a central role in the self tolerance mechanism that is mediated by ECM protein N-glycosylation.

Conclusion: These results demonstrate a high degree of genetic conservation between SLE and our Drosophila model. Our data have uncovered a functional link between SLE risk factors, including increased JAK activity, altered N-glycosylation of ECM proteins and decreased integrin receptor signaling, that has not been previously identified in traditional SLE models. This establishes the benefit of our high-throughput and genetically tractable Drosophila model to better understand the genetic complexity underlying SLE pathogenesis. Our findings further suggest that additional research into the genetic basis of the Drosophila model will likely uncover new SLE genes and provide insight into the molecular interactions between SLE risk factors, and may therefore open new avenues for clinical research or point to new therapeutic strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/using-a-drosophila-model-to-unravel-the-genetic-complexity-of-systemic-lupus-erythematosus/