Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A‐induced hepatitis

Abstract

SummaryWe previously demonstrated the immunosuppressive activity of anti-histone H1 autoantibody induced in experimental and clinical liver allograft tolerance. This study aimed to explore the immunological aspects of anti-histone H1 autoantibody in liver injury induced by concanavalin A (Con A). To establish a Con A-hepatitis model, 20 mg/kg Con A was intravenously injected into rats, after which liver function and histopathological analyses were performed. In this model, anti-histone H1 autoantibody was transiently induced in the sera during the natural recovery stage, 3-7 days after Con A injection. To evaluate the therapeutic significance of anti-histone H1 autoantibody, a polyclonal antibody against histone H1 was intraperitoneally injected immediately after Con A injection. We found that injection of antihistone H1 antibody could reduce Con A-induced liver damage. Further mechanical analyses revealed that anti-histone H1 antibody altered the intracellular activation of mitogen-activated protein kinase, nuclear factor-jB and calcineurin via T-cell receptor signalling, suggesting that anti-histone H1 antibody may protect the liver from Con A-induced injury by inhibiting activation of effector T cells. These findings suggest that anti-histone H1 autoantibody may be a natural immune regulatory factor that protects inflamed livers suffering from autoimmune hepatitis and may lead to T-cell unresponsiveness through the selective regulation of mitogen-activated protein kinase/ nuclear factor-jB and calcineurin signalling.

Nuclear Antigens and Auto/Alloantibody Responses: Friend or Foe in Transplant Immunology

“…In the field of liver transplantation, the induction of autoantibodies (e.g., antinuclear antibody, smooth muscle antibody, and liver-kidney microsomal antibody) has often been observed, particularly in pediatric recipients [36], while the incidence of de novo autoimmune hepatitis in children with elevated serum autoantibodies and liver function tests, hypergammaglobulinemia, and liver pathology showing necroinflammatory disease and fibrosis has been found to be just 1%–7% [37–39]. We also confirmed the significance of antinuclear antibody for protection and recovery from the concanavalin A-(Con A-) induced liver injury mimic of autoimmune hepatitis [40]. Therefore, the induction of autoantibodies in most recipients after liver transplantation may not be associated with any clinical manifestations of autoimmune disorders.…”

“…The therapeutic potential of anti-HMGB1 antibody, soluble RAGE, and anti-RAGE neutralizing antibody has been demonstrated in experimental sepsis [73, 74], liver ischemia/reperfusion injury [75], Con-A-induced hepatic injury [76], traumatic brain injury [77], and organ transplantation [78, 79]. The therapeutic potential of antihistone H1 polyclonal antibody for overcoming rejection and liver inflammation was also confirmed by our group [19, 40]. We also confirmed the great potential of histone H1 vaccination in transplant recipients for tolerance induction [80, 81].…”

“…In addition, our previous study strongly suggested the binding of antihistone H1 Abregs to histone H1-like molecules, which may be transiently expressed on the cell membrane of splenocytes [19]. We have also demonstrated that antihistone H1 Abregs may selectively suppress the MAPK, NF- κ B, and calcineurin-NFAT signaling pathways during T-cell activation [40], coordinate the Th1/Th2 balance [81], and induce CD4 + CD25 + T cells [65]. Recent evidence suggests that antihistone H1 Abregs negatively regulate the harmful T-cell response, in part through collaboration with Tregs [93].…”

Hepatoprotective effects of early pentoxifylline administration on hepatic injury induced by concanavalin A in rat

“…Induction of liver fibrosis followed the methods of Nakano et al (2010), and was induced by intravenous (i.v.) injection of Con A.…”

Theophylline, an old drug with multi-faceted effects: Its potential benefits in immunological liver injury in rats

“…In studying immune system-mediated liver injury the concanavalin A (Con A)-induced hepatitis model has been widely used [18]. The pathogenesis of this hepatitis model resembled chronic HCV infection in humans to a certain extent [27,33]. Con A induces hepatic activation of CD 4 T cells, natural killer T (NKT) cells and Kupffer cells which secrete large amounts of hepatotoxic cytokines such as interferon-γ (IFN-γ) [11].…”