Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice

Abstract

We recently reported that mice deficient in the programmed cell death-1 (PD-1) immunoinhibitory coreceptor develop autoimmune dilated cardiomyopathy (DCM), with production of high-titer autoantibodies against a heart-specific, 30-kDa protein. In this study, we purified the 30-kDa protein from heart extract and identified it as cardiac troponin I (cTnI), encoded by a gene in which mutations can cause familial hypertrophic cardiomyopathy (HCM). Administration of monoclonal antibodies to cTnI induced dilatation and dysfunction of hearts in wild-type mice. Monoclonal antibodies to cTnI stained the surface of cardiomyocytes and augmented the voltage-dependent L-type Ca2+ current of normal cardiomyocytes. These findings suggest that antibodies to cTnI induce heart dysfunction and dilatation by chronic stimulation of Ca2+ influx in cardiomyocytes.

Establishment of NOD-Pdcd1-/-mice as an efficient animal model of type I diabetes

“…We then examined whether PD-1 deficiency induced production of autoantibodies against the pancreas, as previously shown in dilated cardiomyopathy in BALB͞c-Pdcd1 Ϫ/Ϫ mice (13). Compared with C57BL͞6-Pdcd1 Ϫ/Ϫ mice, which have been reported to have higher levels of IgA, IgG2b, and IgG3 (20), serum Ig levels of NOD-Pdcd1 Ϫ/Ϫ mice were not different from NOD WT mice at 6 weeks of age (Fig.…”

“…The NOD (nonobese diabetic) mouse, an animal model of type I diabetes, greatly contributed to the understanding of the genetic basis of type I diabetes (4-6). So far, 28 susceptible loci 4.1, 4.2, 5.1, 5.2,[6][7][8] 9.1, 9.2, 9.3,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] have been identified on the NOD chromosomes by several different crosses and generation of congenic mice.Although many diabetes-susceptible loci have been identified by using NOD mice, the identification of their responsible genes and͞or the analyses of the immunological function of each locus have not been carried out smoothly. The difficulty is likely due in part to the late onset and the low penetrance of type I diabetes in NOD mice (40-70% and 20-40% at 30 weeks of age for females and males, respectively) and also to the involvement of many genes.…”

“…PD-1 knockout mice (Pdcd1 Ϫ/Ϫ mice) develop various autoimmune diseases depending on the genetic background. C57BL͞6-Pdcd1 Ϫ/Ϫ mice develop lupus-like glomerulonephritis and arthritis (11); BALB͞c-Pdcd1 Ϫ/Ϫ mice produce anti-cardiac troponin I autoantibodies, which are responsible for dilated cardiomyopathy (12,13). The development of different kinds of autoimmune disease on different genetic backgrounds by PD-1 deficiency lead us to assume that PD-1 deficiency may exaggerate the genetic predisposition of autoimmune diseases such as diabetes in NOD mice.…”

PD‐L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for VH11/VH12 and phosphatidylcholine binding

“…Surface levels of PD-1 are upregulated by BCR stimulation and down-regulated by cytokines generally grouped as "danger" signals [14]. Because of the wide distribution of the ligand for PD-1, B7-H1 (PD-L1: programmed death-ligand 1), it has been suggested that PD-1 acts as a "fail-safe" means of downmodulating aberrantly activated autoreactive lymphocytes, and PD-1 deficiency in mice leads to autoimmunity [15,16]. The PD-1 pathway not only plays a pivotal role in preventing autoimmunity but also plays an important role in regulating viral and parasite infection [17].…”

Contribution of Acquired Factors to the Pathogenesis of Dilated Cardiomyopathy - The Cause of Dilated Cardiomyopathy: Genetic or Acquired? (Acquired-Side) -

“…When this antibody was administered repeatedly to healthy mice for 12 weeks, DCM-like lesions were reproduced. 44 After 270 days of immunization of A/J mice with troponin I and an adjuvant, DCM-like changes were also induced, along with troponin I autoantibody production.…”