# Host's and microbiota's contribution to sexual dimorphism of autoimmunity

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $545,958

## Abstract

Many of major autoimmune diseases are sexually dimorphic. Systemic Lupus Erythematosus (SLE),
scleroderma, multiple sclerosis, Sjogren's syndrome, and some forms of Type 1 diabetes (T1D) are primarily
occurring in females. It has been attributed to multiple factors including expression of the genes encoded by
sex chromosomes, hormonal regulation of gene expression, and lately to unexpected regulation by commensal
microbiota. Thus, understanding of sexual dimorphism of diseases requires that the problem be approached by
a combination of different strategies. In this proposal, we take advantage of our abilities to perform state of the
art experiments using genetically modified and gnotobiotic animals with original and constantly developing
computational methods. Our preliminary data demonstrates the efficiency of such an integrative approach to
the problem. We have suggested a `dual signal' model of autoimmunity involving regulation by microbes and
sex hormones. Accordingly, hormonal and microbial influences do not have to be simultaneous: they may be
important at different stages of development or disease progression. We already identified a number of genes
that are regulated by hormone (androgen) receptors and are now posed to elucidate the connection between
such regulation and autoimmunity. Given the complexity of the problem, we plan to pursue several carefully
selected goals that will lay foundation for the future expansion of research in this important area.
Aim 1: Test the dual signal model of microbial involvement in sexual dimorphism of autoimmunity.
We will test whether gene expression patterns and chromatin status in T cells and macrophages are regulated
by hormones independently of the microbiota.
Aim 2: Elucidate specific mechanisms involved in hormonal regulation of immunity
We will study the mechanisms of hormone and microbe-dependent regulation of IFNγ production: we will test
the hypothesis that a long non-coding RNA termed NeST controls the gender bias of IFNγ production, and test
its relevance to the gender bias in Type 1 Diabetes (T1D).
We will study the role of sex hormones in contribution to expression of regulatory phosphatase Ptpn22 and its
role in T1D.
Aim 3: The role of microbiota in sexual dimorphism of systemic autoimmunity
To determine how general the role of microbiota is in sexual dimorphism, we will test a model of systemic
autoimmunity with well-established sexual dimorphism -B6.NZM mice- in SPF and GF conditions.
We will determine a role of model genes regulated by androgens (NeST and Ptpn22) we will manipulate
hormone-responsive elements in their promoters and test the consequences in Systemic Lupus Erythematosus
(SLE).

## Key facts

- **NIH application ID:** 10216963
- **Project number:** 5R01AI127411-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** ALEXANDER V CHERVONSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $545,958
- **Award type:** 5
- **Project period:** 2017-08-16 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216963

## Citation

> US National Institutes of Health, RePORTER application 10216963, Host's and microbiota's contribution to sexual dimorphism of autoimmunity (5R01AI127411-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216963. Licensed CC0.

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