Systemic lupus erythematosus (SLE) is a common multisystem autoimmune disease that is estimated to affect more than 500,000 Americans. Our goal is to gain a better understanding of the mechanisms that normally prevent expression of the self-reactive antibodies that cause the disease as well as to better understand where and how these mechanisms fail. Research into fundamental causes of disease in humans is often impossible due to ethical considerations. Decades of medical research attest to the usefulness of mouse models as a means to identify root causes as well as new avenues for treatment and prevention. The presence of the sle1, sle2, and/or sle3/5 NZM2410 lupus loci in C57BL/6 mice promotes development of an autoantibody driven disorder that shares many of the features of human SLE. It is our hypothesis that failure to properly regulate one specific part of the antibody, CDR-H3, in susceptible individuals facilitates production of anti-DNA antibodies and triggers disease. CDR-H3 is critical because it is created de novo by VDJ joining and it lies at the very center of the antigen binding site. In the past funding period, we finished creating a novel set of D- altered mouse strains, each of which incorporates one of three different DH alleles, each limited to a single DH gene segment. The first contains a single, normal DH as a control for the loss of the rest of the DH locus. This DH incorporates tyrosine and glycine in preferred reading frame 1 (RF1). The second forces use of inverted RF1, replacing tyrosine and glycine residues with arginine. The third forces use of RF2, replacing tyrosine and glycine residues with valine instead of arginine. We created these alleles in BALB/c, and then bred them onto C57BL/6 (N22). We showed that the sequence of the DH has a dominant effect on CDR-H3 content, B cell development and antibody production. In previously supported studies, we have documented that enrichment for arginine in the DH enhances expression of arginine in CDR-H3 and, with aging, promotes the development of IgG anti-dsDNA antibodies in BALB/c mice. We now propose to use our D-altered mice to test whether genes within the sle1, sle2, and/or sle3/5 NZM2410 lupus loci alter regulation of the amino acid content of CDR-H3 and/or the development of B cells that express charged CDR-H3 intervals. We will test whether early and enhanced expression of arginine in CDR-H3 in the presence of one or more of the sle1, sle2, and/or sle3/5 NZM2410 lupus loci in C57BL/6 mice will promote early expression of IgG anti-dsDNA antibodies and accelerate the development of autoimmune disease. We will then breed our D-altered mice onto B6 mice congenic for individual susceptibility genes or sub-intervals within the sle1, sle2, and/or sle3/5 loci in order to identify the specific genes, and byextension, the mechanisms that regulate CDR-H3 content and anti-dsDNA activity and assess their relationship to the development of nephritis. We predict that the information we glean from our studies will help us learn how to prevent lupus, as well as control humoral responses to pathogens, vaccines, and altered-self antigens.
In systemic lupus erythematosus and other autoimmune diseases, mature B cells expressing antibodies with uncommon and dangerous binding characteristics appear to thrive. Using mice whose immunoglobulin genes have been altered to encourage the production of potentially pathogenic autoantibodies, we propose to determine whether, which, and how individual lupus susceptibility genes can alter normal tolerance and permit abnormal antibody production and B cell development. Insights gleaned from these studies could allow us to better regulate abnormal autoantibody responses.
|Khass, Mohamed; Schelonka, Robert L; Liu, Cun Ren et al. (2017) Alterations in B cell development, CDR-H3 repertoire and dsDNA-binding antibody production among C57BL/6 ?D-iD mice congenic for the lupus susceptibility loci sle1, sle2 or sle3. Autoimmunity 50:42-51|
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|Westerink, M A Julie; Schroeder Jr, Harry W; Nahm, Moon H (2012) Immune Responses to pneumococcal vaccines in children and adults: Rationale for age-specific vaccination. Aging Dis 3:51-67|
|Lange, Hans; Hecht, Oliver; Zemlin, Michael et al. (2012) Immunoglobulin class switching appears to be regulated by B-cell antigen receptor-specific T-cell action. Eur J Immunol 42:1016-29|
|Vale, A M; Foote, J B; Granato, A et al. (2012) A rapid and quantitative method for the evaluation of V gene usage, specificities and the clonal size of B cell repertoires. J Immunol Methods 376:143-9|
|Mahmoud, Tamer I; Schroeder Jr, Harry W; Kearney, John F (2011) Limiting CDR-H3 diversity abrogates the antibody response to the bacterial polysaccharide ? 1?3 dextran. J Immunol 187:879-86|
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