# Role of the immunoglobulin DQ52 DH gene segment in fetal immunosuppression

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $185,625

## Abstract

Project Summary
Our goal is to address the mechanisms that control the humoral immune response during embryonic and fetal
development. During ontogeny, the B cells that are needed to populate the various lymphoid tissues and organs
sequentially encounter an increasingly complex array of self-antigens as new cell types and non-lymphoid
tissues and organs appear. There is a significant risk that embryonic B cells producing potentially pathogenic
autoreactive immunoglobulins (Igs) could pass essential developmental checkpoints and thus survive to be
activated after these `neo' antigens are ultimately expressed. Unsurprisingly, there is strong evidence that the
humoral immune response is selectively suppressed in mammalian embryos and fetuses. Thus, although in
theory Ig and T cell receptor (TCR) repertoires appear to be generated in a strictly stochastic fashion through
random VDJ rearrangement and N addition; in practice both VDJ rearrangement and N addition are regulated in
utero to restrict Ig and TCR diversity. There are 27 functional DH gene segments in humans and 13 in BALB/c
mice. We previously showed that VDJ joins from both human and mouse embryonic B cell progenitors were
enriched for use of the DQ52 gene segment (D7-27 in human and D4-01 in mouse). After birth, however, both
species use DQ52 sparingly. Consequently, regulation of complementarity-determining region 3 of the Ig heavy
(H) chain (CDR-H3), which contains the DQ52 gene segment, does not occur by chance and must be a major
element of embryonic and early fetal repertoire control. Our prior research has shown that the sequence of the
diversity (D) gene segment both delimits the range of CDR diversity and directs, or even dictates, patterns of
epitope recognition and antibody production, thereby influencing host resistance to infection and autoimmune
disease. DQ52 is the most highly conserved DH between human in mouse. Interestingly, DQ52 differs
dramatically in amino acid content from the rest of the Ds, the most striking difference being the absence of
tyrosine and enrichment for glycine. In this regard, DQ52 is more similar to TCR Dβ than the other Ig DH, making
the in utero DQ52 CDR-H3 repertoire more like TCRβ CDR-B3 than adult Ig CDR-H3. TCRs function more like
polyreactive sensors than monospecific effectors. Thus, using DQ52 in CDR-H3 could have the effect of
reducing monospecificity and affinity for antigen, and reducing antibody production. These fundamental
observations led us to our hypothesis that the role of Ig DQ52 during ontogeny is to promote the production
of B cells while simultaneously serving as an immune suppressant DH. To test this hypothesis and to
provide proof-of-concept, we propose to (a) use CRISPR/Cas9 technology to create a mouse whose DH locus
contains only DQ52 (ΔD-DQ52), (b) test whether use of DQ52 facilitates B cell production, and (c) test whether
use of DQ52 results in reduced antibody production. These studies will fill a major gap in our knowl...

## Key facts

- **NIH application ID:** 10596627
- **Project number:** 5R21AI163555-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Harry William Schroeder
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $185,625
- **Award type:** 5
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596627

## Citation

> US National Institutes of Health, RePORTER application 10596627, Role of the immunoglobulin DQ52 DH gene segment in fetal immunosuppression (5R21AI163555-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10596627. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*