In Vivo Identification of SLE1B: LY108 Mediates Autoantibody Production

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Title: In Vivo Identification of SLE1B: LY108 Mediates Autoantibody Production
Author: Chan, Alice
Abstract: In the NZM2410 model of murine lupus , Sle1b mediates anti -nuclear autoantibody (ANA ) production . Our goal is to determine the causative gene in the Sle1b locus . Seven members of the SLAM /CD2 family are located within the Sle1b interval , and previous work has shown that structural and expression polymorphisms in lymphocytes distinguish two major SLAM /CD2 haplotypes . To further narrow the interval , we utilized a BAC transgenic rescue approach whereby BACs carrying the lupus -resistant B6 alleles were bred to B6 .Sle1b mice to identify the region mediating ANA suppression . One BAC carrying Cd84 and Ly108 suppressed autoantibody production . We then generated BAC transgenic mice carrying the lupus -susceptible (129 ) and lupus -resistant (B6 ) alleles of Ly108 on the B6 and B6 .Sle1b genetic background , respectively . The B6 allele of Ly108 suppresses ANA production on the lupus -susceptible B6 .Sle1b background while the 129 allele induces ANA on the lupus -resistant B6 genome . Taken together , these data identify Ly108 as a causative gene in Sle1b . While Ly108 is needed to mediate the breach in tolerance , we have also identified other SLAM family members as genetic modifiers necessary to recapitulate fully penetrant , high titer ANA production as seen in Sle1b . We found that in vitro stimulation of B6 .Sle1b CD4 T cells led to altered cytokine production , such as decreased IL4 production . Interestingly , these phenotypes have also been reported in knockouts of SLAM /CD2 family members as well as in the absence of the SLAM family adaptor , SAP . Our data indicates that the presence of the Sle1b haplotype , derived from either NZM2410 or 129 , recapitulates these phenotypes , independent of the absence of these molecules . While recent reports have suggested a role for SAP in ANA development , we find that the breach in tolerance in Sle1b mice is SAP -independent . However , SAP is necessary to potentiate the autoantibody production . ANAs is an important biomarker for autoimmune diseases including , Systemic Lupus Erythematosus (SLE ) , and potentially identifies an autoimmune -prone state . We have identified genes which contribute to the production of ANAs . Elucidating the pathways these genes dysregulate will provide critical insight into our understanding of tolerance and how tolerance can be breached .
URI: http : / /hdl .handle .net /2152 .5 /618
Date: 2008-05-12

Citation

In Vivo Identification of SLE1B: LY108 Mediates Autoantibody Production. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /618 .

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