Sex/gender differences exist for most chronic inflammatory diseases such as cardiovascular and autoimmune diseases. Men have a higher incidence and severity of cardiovascular diseases (CVDs) including myocarditis/dilated cardiomyopathy (DCM) and heart failure than women. The reason why men progress more frequently from myocarditis to DCM is unclear. Clear evidence for complement activation and immune complex (IC) deposition in the heart is observed in myocarditis/DCM patients, and a recent proteomics study found that 2 of the top 3 pathways in myocarditis/DCM patients involved the classical and alternative complement pathways. In preliminary studies we show that the classical and alternative complement pathways are activated during myocarditis/DCM in mice and humans of both sexes but that men with myocarditis/DCM have higher levels of proinflammatory complement C3 in their sera than women, that sex differences exist in anti-inflammatory complement receptor (CR)1 expression with testosterone reducing CR1/2 during coxsackievirus B3 (CVB3) myocarditis resulting in increased Th1, C3, CD11b/CR3 inflammation, DCM and heart failure in male mice, and that interleukin (IL)-4/Th2 increases CR1/2 expression on cardiac macrophages and T cells during CVB3 myocarditis/DCM in female mice. This is the first report, to our knowledge, that sex hormone-driven differences in complement and CR expression influence susceptibility to myocarditis/DCM in patients and mice. Considering the importance of complement in activating and regulating inflammation and antibody/autoantibody levels during autoimmune and cardiovascular diseases, knowledge of how sex hormones influence complement-mediated inflammation and IC deposition will greatly impact our understanding of the pathogenesis of these diseases in profound and lasting ways. Innovation Our autoimmune model of CVB3-induced myocarditis, which uses heart-passaged CVB3 containing infectious virus and heart proteins, provides a unique model to gain better insight into sex differences in complement pathways that regulate chronic inflammation and remodeling in the heart. We have known that all major chronic inflammatory diseases, including autoimmune and cardiovascular diseases, display marked sex differences in prevalence, presentation, symptoms and response to therapy, but the reason for these sex differences has not been a research priority. We are poised for a paradigm shift in how we view chronic inflammation based on the effect of sex hormones. With an increased interest in developing personalized medicine, the biological basis for sex differences in CVD will need to be better understood and remains an important frontier for discovery.
Specific Aims Based on findings from our mouse model, we hypothesize that estrogen increases CR1 levels via Th2 cytokines like IL-4 allowing regulation of myocarditis in females, while testosterone increases Th1-type cytokines and inhibits CR1 resulting in increased complement-induced CD11b+ inflammation in males. To investigate this hypothesis we will determine in Aim 1) how estrogen and testosterone alter complement/CR pathway expression and in Aim 2) determine whether sex hormones regulate complement pathways indirectly via Th1 and Th2 cytokines (e.g. IL-4, IFN- ) during myocarditis/DCM in mice and humans. Collectively, these studies will help define sex differences in complement and CRs that regulate inflammation and remodeling during myocarditis/DCM. This research will provide further insight into the function of complement pathways that applies to other cardiovascular and autoimmune diseases that are influenced by sex/gender.

Public Health Relevance

Men have a higher incidence and severity of cardiovascular diseases including myocarditis, dilated cardiomyopathy and heart failure than women. The reason why men progress more frequently from myocarditis to dilated cardiomyopathy is unclear. This project will define sex differences in complement pathways that regulate inflammation and heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL111938-05
Application #
9270289
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wong, Renee P
Project Start
2012-06-15
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Batton, Kyle A; Austin, Christopher O; Bruno, Katelyn A et al. (2018) Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease. Biol Sex Differ 9:15
Coronado, Michael J; Fairweather, DeLisa; Bruno, Katelyn A (2017) Sex Determines Cardiac Myocyte Stretch and Relaxation. Circ Cardiovasc Genet 10:
Serie, Daniel J; Crook, Julia E; Necela, Brian M et al. (2017) Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial. Pharmacogenet Genomics 27:378-385
Myers, Jennifer M; Cooper, Leslie T; Kem, David C et al. (2016) Cardiac myosin-Th17 responses promote heart failure in human myocarditis. JCI Insight 1:
Brandt, Jessica E; Priori, Roberta; Valesini, Guido et al. (2015) Sex differences in Sjögren's syndrome: a comprehensive review of immune mechanisms. Biol Sex Differ 6:19
Heaney, Christopher D; Kmush, Brittany; Navas-Acien, Ana et al. (2015) Arsenic exposure and hepatitis E virus infection during pregnancy. Environ Res 142:273-80
Cooper Jr, Leslie T; Fairweather, DeLisa (2015) Nano-scale treatment for a macro-scale disease: nanoparticle-delivered siRNA silences CCR2 and treats myocarditis. Eur Heart J 36:1434-6
Root-Bernstein, Robert; Fairweather, DeLisa (2015) Unresolved issues in theories of autoimmune disease using myocarditis as a framework. J Theor Biol 375:101-23
Penta, Kayla L; Fairweather, DeLisa; Shirley, Devon L et al. (2015) Low-dose mercury heightens early innate response to coxsackievirus infection in female mice. Inflamm Res 64:31-40
Root-Bernstein, Robert; Fairweather, DeLisa (2014) Complexities in the relationship between infection and autoimmunity. Curr Allergy Asthma Rep 14:407

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