# Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $348,700

## Abstract

Project Summary: “Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity”
 The prototypical autoimmune disease systemic lupus erythematosus (SLE) is characterized by anti-
nuclear autoantibodies (ANAs) that serve not only as critical biomarkers of disease, but also play a central role
in pathogenesis. Surprisingly, despite central tolerance mechanisms such as receptor editing and deletion of
autoreactive B cells during bone marrow development, up to 30% of mature human B cells nevertheless harbor
some degree of ANA-reactivity. This suggests that additional peripheral tolerance mechanisms must keep such
potentially dangerous clones in check. We have recently characterized a novel fluorescent reporter mouse line,
Nur77-eGFP, that is sensitive to antigen-dependent B cell receptor (BCR) signaling in vivo. The most highly
fluorescent naïve B cells from these mice have recognized endogenous antigen, and are enriched for ANA-
reactivity. The Nur77-eGFP reporter thus identifies ANA-reactive B cells in a diverse, normal repertoire,
enabling us to track and isolate such cells. We have shown that these ANA-reactive B cells down-regulate
expression of the IgM isotype BCR, resulting in dampened responses to IgM stimulation. However, naïve B
cells uniquely express a second BCR isotype, IgD, with the same epitope-binding domain as IgM. In contrast to
IgM, IgD expression and signaling in ANA-reactive B cells are unperturbed. How does IgM downregulation limit
autoimmune responses to self-antigens despite high IgD expression? Each BCR isotype alone is capable of
mediating B cell development and responses to immunization with model antigens. In contrast to such
apparent redundancy, we have new preliminary data to show that B cells lacking IgM and expressing only IgD
are completely prevented from contributing to autoantibody production in a mouse model of SLE. It has
recently been shown that IgM, but not IgD, is uniquely sensitive to monovalent antigens. However, relevant
nucleic acid-associated autoantigens in SLE are thought to be membrane associated and multivalent
suggesting that other distinctive properties of IgM may be important for autoantibody production. In this
proposal we intend to identify the mechanisms by which IgM and IgD differentially regulate B cells in the
context of health and disease. To do so: (1) We will take advantage of mice deficient for either IgM or IgD to
explore how B cells expressing each isotype alone are recruited to secrete pathogenic autoantibodies in two
models of systemic autoimmunity with distinct disease mechanisms (Lyn-/- and BAFF Tg). (2) We will
determine how the IgM and IgD BCRs traffic to endosomal compartments to recruit costimulatory signals via
TLRs7/9 and via MHCII presentation of antigen to T cells. (3) We will explore how differential coupling of IgM
and IgD to B cell stimulatory and inhibitory co-receptors alters downstream signaling and contributes to B cell
tolerance. Together these studies...

## Key facts

- **NIH application ID:** 9899730
- **Project number:** 5R01AR069520-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JULIE ZIKHERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,700
- **Award type:** 5
- **Project period:** 2016-06-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899730

## Citation

> US National Institutes of Health, RePORTER application 9899730, Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity (5R01AR069520-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899730. Licensed CC0.

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