This proposal is directed at carrying out the initial exploratory studies to define the immune quantitative traits, or endophenotypes, that are regulated by TNIP1, a gene which has been associated with a variety of autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, and psoriasis, and more recently rheumatoid arthritis. We have recently reported a remarkably strong association with Myasthenia Gravis (OR, 1.91;p =3.2x10-10) that implicates an amino acid change of Pro to Ala at codon 151 as a possible causative variant. While TNIP1 has been clearly shown to be involved in the negative regulation of NFkB signaling(6), more recent studies have implicated other pathways, involving transcriptional regulation through C/EBPb as well as interactions with nuclear receptors such as PPAR/RAR(7-9). At a minimum, both B cell and myeloid phenotypes regulated by TNIP1 are likely to be relevant to risk for autoimmunity. This proposal will take advantage of unique population resources to explore the functional effects of autoimmune disease associated TNIP1 risk haplotypes, with an emphasis on immune quantitative traits in B cells.
Specific aim 1. We will examine the effects of risk haplotypes on TNIP1 expression in a range of primary human peripheral blood cell subsets of the immune system, with a particular emphasis on transitional, naive and memory B cells, as well as monocytes and in vitro monocyte derived macrophages and dendritic cells. Allele specific expression will also be investigated in major T cell subsets. An internal resource of 5,000 genotyped normal individuals in the Genotype and Phenotype Registry (GaP) will be utilized for these studies.
Specific aim 2. We will examine the influence of TNIP1 risk haplotypes on functional parameters in immune cell subsets. Our major focus will be on B cells, since preliminary data suggest an influence on memory B cell function. Proliferative responses, activation markers, differentiation and cytokine and immunoglobulin production will be examined in order to establish genotype phenotype correlations with TNIP1 risk haplotypes.
Specific aim 3. We will examine candidate regulatory pathways that may regulate B cell or other immune endophenotypes. We will focus our studies particularly on the potential involvement of TNIP1 regulation of nuclear receptor function in the PPAR/RAR family.
This proposal will study the functional effects of genetic variation in a gene, TNIP1, that is strongly associated with risk for various autoimmune diseases. The studies will lead to the identification of the particular components of the human immune system that are controlled by this genetic variation, and thereby offer an insight into how those immune components may be modified to prevent and/or treat human autoimmune disorders.