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 Fc? receptor (Fc?R). 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 ?1-sufficient and deficient mice. Our results support our hypothesis: ?1-sufficient mice are not damaged by immunization with a potent antigen, while identically immunized ?1-deficient mice die from complement- and Fc?R-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. ?1-deficient mice also develop 2 complement- and Fc?R-dependent disorders, collagen induced arthritis and experimental autoimmune myasthenia gravis, more frequently and more severely than ?1-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 ?1, ?2, ?3 or ?4 constant regions, as well as an anti-TNP mAb that has a mutated human ?4 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 Fc?R-dependent blistering skin disease caused by Abs to collagen type VII (Col7), to determine whether IgG1 anti-Col7 Abs can cause established disease to regress.

Public Health Relevance

If our hypothesis is correct, human IgG4 Abs should help to prevent or limit the severity of Ab-mediated disease. Consequently, approaches that influence the human immune system to produce more IgG4 and less IgG1 or IgG3 may be useful for suppressing these disorders when it is not possible or safe to prevent autoAb production entirely. In addition, our elucidation of the mechanisms by which some IgG isotypes limit disease should assist the design of Ab reagents that can be used to suppress established Ab-mediated disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI130103-03
Application #
9619034
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Ferguson, Stacy E
Project Start
2017-01-25
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221