Integrative Molecular Analyses of Inflammatory and Autoimmune Signals in Cardiac Sarcoidosis
Abstract
BACKGROUND: Cardiac sarcoidosis (CS) is an enigmatic disorder characterized by unexplained patchy, sterile granulomas intermixed with preserved myocardium and fibrotic regions without granuloma. CS causes arrhythmias, sudden cardiac death, and heart failure. The mechanisms producing this remarkable histopathology and disease progression remain unexplained. METHODS: Using comprehensive single-cell and spatial transcriptomic analyses, we characterized the cellular composition and gene expression in preserved, granulomatous, and fibrotic regions of human CS hearts. From unexpectedly identified clonally expanded cardiac B cells with rearranged immunoglobulin sequences, we reconstructed antibodies and screened libraries comprising the human peptidome or microbial and allergen peptides to define reactive epitopes in CS hearts. RESULTS: Cellular composition and gene expression differed substantially in CS tissues with preserved, granulomatous, or fibrotic histopathology. Cardiomyocytes upregulated arrhythmogenic and inflammasome transcripts associated with pyroptosis. Cardiomyocytes and fibroblasts activated chemoattractant cytokines that sustained myeloid and lymphoid infiltration. Granulomas contained abundant macrophages expressing modulators of cell–cell fusion, along with Th17-skewed T cells that upregulated B-cell–activating factor, thereby promoting antibody production. Fibrotic regions, without active granulomas, exhibited tertiary lymphoid structures, with clonal expansion of mature B and plasma cells. Reconstructed antibodies derived from expanded B-cell clones were inert to microbial and allergen peptides, but reacted to PPL (periplakin), a desmosome protein, and other peptides expressed on cardiac cells. CONCLUSIONS: Progressive inflammatory signals in CS are mediated by chemoattractant genes in cardiomyocytes and fibroblasts within preserved myocardium, cell–cell fusion modulators in activated macrophages within granulomatous regions, and tertiary lymphoid structures in fibrotic regions that produce patient-specific autoimmune antibodies. Identification of PPL as a CS autoantigen may account for shared clinical manifestations in CS and arrhythmic desmosomal cardiomyopathies. CS autoantigens may underlie enigmatic histopathologic findings, perpetuate disease, and contribute to adverse outcomes. Uncovering an intracardiac humoral autoimmune axis in CS provides specific therapeutic opportunities to limit granuloma formation and B-cell activation, which may reduce arrhythmogenicity and progressive dysfunction. Parallel analytic strategies have potential to define autoantigens in other enigmatic cardiac immune disorders.
Article Details
Authors (27)
Meraj Neyazi
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Gabriela Venturini
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Kemar J. Brown
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Youjung Choi
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Joshua M. Gorham
Olivia G. Layton
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Arjun Verma
Adam J. Wang
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Ryan T. Gross
Departments of Surgery (R.T.G., M.M.P., D.E.B.), Duke University, Durham, NC.
Barbara A. McDonough
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Michelle Mendiola Pla
Anissa Viveiros
Division of Cardiology, Department of Medicine and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada (A. Viveiros, G.Y.O.).
Daniel M. DeLaughter
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Steven R. DePalma
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Yuri Kim
Cardiovascular Division, Brigham and Women’s Hospital
Daniel Reichart
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Hiroko Wakimoto
Department of Genetics (M.N., G.V., K.J.B., Y.C., J.M.G., O.G.L., A. Verma, A.J.W., B.A.M., D.M.D., S.R.D., D.R., H.W., S.J.E., J.G.S., C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Stephen J. Elledge
Sanjay Divakaran
Richard N. Mitchell
Department of Pathology (R.N.M.), Brigham and Women’s Hospital, Boston, MA.
Jiwon Koh
Department of Pathology (J.K.), Seoul National University Hospital, Republic of Korea.
Jun-Bean Park
Dawn E. Bowles
Carolyn Glass
Pathology (C.G.), Duke University, Durham, NC.
Gavin Y. Oudit
Division of Cardiology, Department of Medicine, University of Alberta
Jonathan G. Seidman
Christine E. Seidman