# Wimpy antibody isotypes protect against antibody-mediated disease

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $365,342

## Abstract

IgG is the predominant circulating Ig class in most mammals. Both mouse and man have 4 IgG
isotypes, which differ in ability to induce effector mechanisms. Murine IgG1 activates complement poorly, has
the shortest IgG hinge region (which may limit immune complex (IC) formation) and binds to only 1 stimulatory
Fcγ receptor (FcγR). Human IgG4 has similar characteristics to mouse IgG1 and should have even less ability
to form ICs because it spontaneously forms univalent, bispecific molecules. These observations raise the
question of why mouse IgG1 and human IgG4 evolved, despite their likely reduced ability to damage
pathogens. We hypothesized that these isotypes provide a selective advantage by limiting host-damaging
responses and studied this by comparing development of antibody (Ab)-mediated disorders in γ1-sufficient and
deficient mice. Our results support our hypothesis: γ1-sufficient mice are not damaged by immunization with a
potent antigen, while identically immunized γ1-deficient mice die from complement- and FcγR-independent
obstruction of glomerular capillaries by large ICs. IgG1 Abs suppress large IC formation and do so more
potently than IgG2a or IgG2b, which have longer hinge regions. γ1-deficient mice also develop 2 complement-
and FcγR-dependent disorders, collagen induced arthritis and experimental autoimmune myasthenia gravis,
more frequently and more severely than γ1-sufficient mice on the same genetic background.
 Three important questions are suggested by these observations: (1) do differences in hinge region
length fully explain the greater ability of IgG1 than other IgG isotypes to disrupt formation of large ICs; (2) are
our observations with mouse IgG isotypes human-relevant; and (3) can mouse IgG1 ameliorate an established
Ab-mediated disease. These questions will be addressed by the following specific aims:
 1. Determine whether short hinge region length promotes the ability of mouse IgG to suppress Ab-
mediated disease. We will swap mouse IgG1 and IgG2b hinge regions and minimize and maximize IgG1 hinge
region length and use the chimeric monoclonal Abs produced to study whether a short hinge region limits
disease severity in complement-independent and complement-dependent disease models.
 2. Determine whether our observations with mouse IgG isotypes are human-relevant. Chimeric anti-TNP
mAbs that have human γ1, γ2, γ3 or γ4 constant regions, as well as an anti-TNP mAb that has a mutated
human γ4 constant region that prevents formation of univalent, bispecific Ab molecules, will be produced and
compared for ability to disrupt IC production in vitro and prevent IC kidney disease in vivo.
 3. Determine whether an Ab isotype that is relatively poor at inducing effector functions can suppress an
established Ab-mediated disorder. Studies will be performed with active and passive mouse models of
epidermolysis bullosa acquisita, a complement- and FcγR-dependent blistering skin disease caused by Abs to
collagen type VII (Col7), to ...

## Key facts

- **NIH application ID:** 9843095
- **Project number:** 5R01AI130103-04
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** FRED Douglass FINKELMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,342
- **Award type:** 5
- **Project period:** 2017-01-25 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843095

## Citation

> US National Institutes of Health, RePORTER application 9843095, Wimpy antibody isotypes protect against antibody-mediated disease (5R01AI130103-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843095. Licensed CC0.

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