Although antibodies protect against pathogens largely by activating complement- and Fc receptor (FcR)-dependent effector mechanisms, most IgG antibodies produced in mice are of the lgG1 isotype, which has limited ability to activate these mechanisms. We will test the hypothesis that lgG1 antibodies contribute to health by suppressing inflammation caused by foreign serum, infection and autoimmunity and will determine how they suppress inflammation. Our initial studies show that injecting wild-type mice with a goat antiserum to mouse IgD induces a large, rapid, predominantly lgG1 antibody response that eliminates the injected antiserum in <10 days without causing detectable immune complex disease. Mice that cannot produce lgG1 die from immune complex kidney disease when injected with the same antiserum, even though they make normal or increased amounts of other Ig isotypes. We will extend this observation by evaluating the relative importance of inhibition of the binding of pro-inflammatory Ig isotypes to antigen, stimulation of an inhibitory FcR, failure to activate specific stimulatory FcRs and failure to activate complement in lgG1 suppression of inflammation in mouse models of serum sickness, chronic infection, and autoimmune diseases in which immunopathology is antibody-dependent. These studies will use a C5a receptor antagonist, anti-FcR antibodies and mice deficient in lgG1, the C3 component of complement, all stimulatory FcRs, specific stimulatory FcRs and/or the inhibitory FcR to determine how lgG1 protects against inflammation. Studies will evaluate the importance of lgG1 antibodies in protecting against immune complex kidney disease caused by administration of foreign serum, worm infection and autoimmune graft vs. host disease, as well as hemolytic anemia caused by graft vs. host disease and weakness caused by immunization with acetylcholine receptors. Mouse chimera studies will evaluate whether lgG1 protects against immune complex kidney disease by suppressing inflammatory effects of immune complex binding to glomerular cells, bone marrow-derived cells, or both. These studies should elucidate the conditions under which lgG1 protects against antibody-dependent disease and the mechanisms responsible for this protection, and thus, provide a basis for administering or inducing human Ig isotypes that poorly activate complement and FcRs as a therapy for human antibody-mediated disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072040-05
Application #
8115194
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2007-08-15
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$369,933
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
Strait, Richard T; Thornton, Sherry; Finkelman, Fred D (2016) C?1 Deficiency Exacerbates Collagen-Induced Arthritis. Arthritis Rheumatol 68:1780-7
Strait, Richard T; Posgai, Monica T; Mahler, Ashley et al. (2015) IgG1 protects against renal disease in a mouse model of cryoglobulinaemia. Nature 517:501-4
Huda, Ruksana; Strait, Richard T; Tüzün, Erdem et al. (2015) IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice. J Neuroimmunol 281:68-72
Strait, Richard T; Mahler, Ashley; Hogan, Simon et al. (2011) Ingested allergens must be absorbed systemically to induce systemic anaphylaxis. J Allergy Clin Immunol 127:982-9.e1
Morris, Suzanne C; Heidorn, Stephanie M; Herbert, De'Broski R et al. (2009) Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. J Immunol 182:1429-38