Research Article: Usp18 Driven Enforced Viral Replication in Dendritic Cells Contributes to Break of Immunological Tolerance in Autoimmune Diabetes

Date Published: October 24, 2013

Publisher: Public Library of Science

Author(s): Nadine Honke, Namir Shaabani, Dong-Er Zhang, George Iliakis, Haifeng C. Xu, Dieter Häussinger, Mike Recher, Max Löhning, Philipp A. Lang, Karl S. Lang, Matthias G. von Herrath.


Infection with viruses carrying cross-reactive antigens is associated with break of immunological tolerance and induction of autoimmune disease. Dendritic cells play an important role in this process. However, it remains unclear why autoimmune-tolerance is broken during virus infection, but usually not during exposure to non-replicating cross-reactive antigens. Here we show that antigen derived from replicating virus but not from non-replicating sources undergoes a multiplication process in dendritic cells in spleen and lymph nodes. This enforced viral replication was dependent on Usp18 and was essential for expansion of autoreactive CD8+ T cells. Preventing enforced virus replication by depletion of CD11c+ cells, genetically deleting Usp18, or pharmacologically inhibiting of viral replication blunted the expansion of autoreactive CD8+ T cells and prevented autoimmune diabetes. In conclusion, Usp18-driven enforced viral replication in dendritic cells can break immunological tolerance and critically influences induction of autoimmunity.

Partial Text

Autoimmune diabetes in humans is characterized by immunological destruction of beta islet cells in the pancreas; this cellular destruction leads to hyperglycemia [1]. T cells specific for beta islet cell antigens play an important role in the development of the disease and have been found to arise after exposure to viruses that contain cross-reactive epitopes [2]–[4]. Viruses known to contain cross-reactive epitopes are enterovirus, rubella virus, and rotavirus. Infection with these viruses is often found during the onset of diabetes [5]–[7]. Recent evidence of the ability of viruses to induce diabetes comes from epidemiological and genetic analyses, which have shown that functional polymorphisms in interferon-regulating genes are strongly associated with autoimmune diabetes [8]–[10]. Thus, viral infection is associated with the onset of autoimmune diabetes in humans, and molecular mimicry is an obvious explanation for the immunological destruction of pancreatic beta cells. Besides viruses, several other pathogens and environmental proteins, such as bovine serum albumin (BSA) and beta-casein, carry cross-reactive epitopes to beta islet cells [11]–[13]. Because both substances are found in cow milk, many people are exposed to those antigens. However, this exposure is not strongly linked to the induction of autoreactive T cells or to the occurrence of autoimmune diabetes [14], [15]. Several bacterial species (e.g. Escherichia coli, Pseudomonas species, and Campylobacter) are known to carry epitopes that are cross-reactive to beta islet cells [16], [17]. Although infection with these opportunistic pathogens will lead to presentation of cross-reactive beta islet antigens in combination with high amounts of bacterial Toll-like receptor (TLR) ligands, the contribution of these bacteria to the incidence of diabetes remains uncertain [18]. Thus, cross-reactive viruses, are more efficient than other cross-reactive antigens in breaking immunologic tolerance.

In this study we examined why replicating self-antigen is much more efficient in breaking autoimmune tolerance than the exposure to nonreplicating self-antigen. Our findings emphasize that the development of autoimmune diabetes requires active autoantigen replication in specialized APCs that are characterized by the expression of Usp18, a known inhibitor of type I interferon signaling [32]. Since Usp18 expressing APCs are not responsive to the antiviral actions of type I interferons, they act as endogenous “replicators” of autoantigen.




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