# Role of HLA Class-II Polymorphism in the Regulation of Host-Microbiota Symbiosis

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

Both HLA class-II polymorphism and gut microbiota had been linked with the regulation of host immunity and
pathobiology of multiple sclerosis (MS) However, it is not known whether there is a crosstalk between HLA
class-II molecules and gut microbiota in the regulation of host immunity which can influence disease outcome
in people with MS (PwMS). Thus, there is a critical unmet need to understand mechanism(s) through which
interaction between HLA class-II polymorphism and gut microbiota modulate disease phenotypes in MS. Our
long-term goal is to determine mechanism(s) through which gut bacteria and their metabolites influence
protection from or predisposition/progression to MS so that we can harness the enormous potential of gut
microbiome as diagnostic and/or therapeutic agent. Previously, we have utilized transgenic mice expressing
MS linked HLA-DR and -DQ alleles in experimental autoimmune encephalomyelitis (EAE), an animal model of
MS to validate the significance of HLA in MS. We have shown that while HLA-DR3 transgenic mice are
susceptible and HLA-DQ8 transgenic mice are resistant to EAE, the presence of HLA-DQ8 allele on a disease
susceptible HLA-DR3 transgenic mice (HLA-DR3.DQ8) results in severe disease. Our data showing that
cytokine and gut microbiota profile being more similar between HLA-DQ8 and HLA-DR3.DQ8 mice than HLA-
DR3 mice suggest a role of HLA-DQ8 restricted gut microbiota and Th17 response in modulation of disease.
Additionally, weaning reaction defined by a period in newborn mammals when expansion of gut microbiota
during early life induces a vigorous immune response, had been shown to play a critical role in maintaining
immune homeostasis through induction of immune imprinting. Based on these observations we hypothesize
that HLA class-II molecules modulate host immunity through regulation of host microbiome during early life and
adulthood and perturbation of the same might lead to predisposition/exacerbation of inflammatory disease
such as MS. We propose to determine the significance of HLA class-II polymorphism in disease resistance vs
susceptibility through its influence on neonatal and adult gut microbiota in two aims. In aim-1, we will determine
significance of HLA class II polymorphism in regulating adult gut microbiota and disease pathogenesis by
characterizing APCs and CD4+ T cells function (cytokine signature) in disease susceptible HLA-DR3 vs. disease
resistance HLA-DQ8 mice in conventional or pseudo-Germ-free mice (antibiotic depleted gut microbiota). We will
also perform microbiome transplantation from disease resistance to susceptible strain and vice versa or
colonization with specific bacteria identified in microbiome analysis to determine whether adult gut microbiome
alone can transfer the immune and disease phenotype. In aim-2, we will determine effect of HLA class II
polymorphism on the selection of neonatal gut microbiota and weaning reaction on immune-imprinting and
disease susceptibility to EAE in adultho...

## Key facts

- **NIH application ID:** 10694591
- **Project number:** 1I01BX006112-01A1
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Ashutosh Kumar Mangalam
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694591

## Citation

> US National Institutes of Health, RePORTER application 10694591, Role of HLA Class-II Polymorphism in the Regulation of Host-Microbiota Symbiosis (1I01BX006112-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694591. Licensed CC0.

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