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John Mountz, MD, PhD


The University of Alabama at Birmingham



B-cell control point dysregulation in African Americans in SLE

Dr. Mountz is investigating a new explanation for how lupus develops and the reason some people are at greater risk for flares and kidney disease. He found that patients with high levels of the molecule interferon beta (IFN-β) within their early developing (“baby”) B cells (the immune cells that grow to become autoantibody-producing cells) are more likely to have higher levels of autoantibodies and kidney disease. Among those individuals, African American patients, who are disproportionately affected by lupus, had higher levels IFN-β in these cells compared to Caucasian patients. Dr. Mountz will use his Distinguished Innovator Award to determine if the high level of IFN-β production within these baby B cells causes them to grow into adult autoantibody-producing B cells that trigger lupus.


What this study means for people with lupus:


The results of Dr. Mountz’ study will form a solid foundation to develop treatments that block IFN-β for use in people with lupus and the identification of biological markers to identify lupus patients, especially among the African American population, at high risk of flares and kidney disease, who may respond to interferon therapies.

The overall goal of this project is to test a paradigm shifting hypothesis that B cell over-expression of interferon-(IFN)-beta (IFNß) during the early stages of peripheral B-cell development is a primary and formative immune abnormality in SLE and particularly in African-American (AA) patients. Specifically, intrinsic overexpression of IFNß by early transitional (Tr) B cells is the primary event that promotes survival of ANA autoreactive B-cells, self-sustained TLR7 signaling competence, and collateral inflammation through subsequent induction of IFNa genes. This model has been developed based on application of unbiased analysis of expression of the type I IFN family in immune cells using PBMCs from patients with SLE in combination with analysis of the BXD2 mouse model of lupus. The data indicate that over-expression of IFNß in Tr B cells in patients with SLE correlates with sera titers of anti-DNA, anti-Sm, anti-SSA and renal disease. This Tr B cell-IFN-beta(hi) phenotype is over-represented in AA SLE patients. Single-cell gene expression analysis further suggests a previously undescribed network of IFNß-producing, IFNa producing, and responding Tr B cells. We propose to test this hypothesis in AA patients seen at the University of Alabama at Birmingham (UAB) as a discovery population to address the following specific goals: (1) To determine if B-cell expression of IFNß is a driver of SLE; (2) To determine if endogenous production of IFNß in SLE B cells is a primary abnormality; (3) To determine if single-cell sequencing identifies IFNß producer and responder signatures in Tr cells that correlate with development of IFNß(hi) B cells; and (4) To place this model in the context of the current concept of the role of IFNa in plasmacytoid dendritic cells (pDCs) and its implications in the design of effective, individualized IFN blockade versus pDC blockade strategies in vivo using a preclinical mouse model. To accomplish these goals, the PI has drawn on the expertise at UAB in terms of the diagnosis and treatment of AA SLE patients; analysis of B-cell dysregulation; and computational analysis of single-cell data. The lack of knowledge on the hierarchy of the network of sources of and subtypes of type I IFN in the development of SLE has inhibited the development of a coherent understanding of the primary abnormalities that can drive SLE pathogenesis. The premise of the proposed work is that rigorous studies at the single-cell level of individual cell production and response to IFNß and IFNa in B cells will facilitate development of effective precision medicine for individual SLE patients. The project should lead to identification of patients, especially within the AA population of SLE patients, that are more likely to respond to IFNß blockade. Such therapy may be effective in ablating autoreactive B-cell development, and ameliorating ANA-related flares and potentially renal disease.

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