B cells, CD4 T cells, and myeloid cells play a critical role in the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and can be engaged in a pathologic stimulatory network of autoantibody and cytokine production, tissue damage, and activation by released self-antigens. Our proposal is centered on CD4 T- and myeloid- cells in autoimmune diseases. New techniques have increased our understanding of the genetic basis of diseases like SLE and helped identify robust susceptibility loci, such as MHC. Recent whole genome sequencing has revealed a detailed catalog of the human genetic variation with a very high occurrence of ~12,000 gene variants per person. Much less robust is our knowledge of dysregulated signaling pathways in immune cells in SLE or other autoimmune diseases and how gene variants (non-synonymous SNPs) may underpin abnormal immune features. Here we combine molecular-, cellular-, and in vivo- approaches to understand the autoimmune features of CD4 T cells, how these T cells are entangled in a stimulatory loop with myeloid cells, and how subtle monoallelic, non-synonymous SNPs in patients can result in robust autoimmune phenotypes. In Preliminary Results, we present a novel mouse model, Rasgrp1Anaef, with a point mutation in the Ras activator Rasgrp1 that causes an autoimmune phenotype. Thorough characterization of T cell development demonstrates that Rasgrp1Anaef T cells develop effectively and Rasgrp1Anaef mice are not lymphopenic. Instead, CD44hiCXCR5+PD1+ CD4+ T cells aberrantly accumulate due to increased basal Rasgrp1Anaef- mTOR signaling, numbers of myeloid cell subsets increase, and mice show ANA (anti-nuclear antibodies) and proteinuria. Rasgrp1Anaef/WT heterozygous mice also demonstrate autoimmune pathology, thus one Rasgrp1WT allele cannot compensate for Rasgrp1Anaef. We present a recently published crystal structure of an autoinhibitory Rasgrp1 dimer and demonstrate that Rasgrp1Anaef can form a dimer with a Rasgrp1WT protein, presenting a mechanism of action for how monoallelic RasGRP1 variants, reported in patients with SLE, autoimmune (Type 1) diabetes, and Graves disease, can have a biological effect. Here we will investigate the immune character of the aberrantly accumulating Rasgrp1Anaef T cells (Aim 1), the intimate interaction between T-, B-, and myeloid cells and the role of Rasgrp1Anaef myeloid cells in the Rasgrp1Anaef autoimmune features (Aim 2), and how this Rasgrp1Anaef mouse model may serve as a paradigm for monoallelic, non-synonymous RasGRP1 SNP alleles (Aim 3). Results from the strongly related but independent aims will increase our understanding of how T cells and myeloid cells with seemingly innocent and subtle SNP variants can drive autoimmunity through a pathological stimulatory network, and how monoallelic genetic SNP events in RasGRP1 may cause autoimmune pathology.

Public Health Relevance

Development of autoimmune diseases such as systemic lupus erythematosus (SLE) involves abnormal activation of several types of immune cells, including B cells, CD4 T cells, and myeloid cells engaged in a stimulatory loop of autoantibody production, tissue damage, and immune activation by released self-antigens. The goal of this project is to determine how subtle genetic variants of signaling molecules that constitute a major form of human variation underlie aberrant activation of immune cells entangled in a pathological stimulatory network. Results obtained from the proposed research will provide mechanistic insights how subtle genetic variants in autoimmune patients can results in immune pathology driven by myeloid-, B-, and T- cells and will be of relevance to the mission of the NIH and of interest to a broad audience of researchers studying lymphocyte development and autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Rothermel, Annette L
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University of California San Francisco
Anatomy/Cell Biology
Schools of Medicine
San Francisco
United States
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