Virus infection, antiviral immunity, and autoimmunity

Abstract

Summary As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved. Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self-tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity.

Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes

“…However, in most cases the mechanism does not seem to be via a general breakdown in thymic deletion or peripheral regulatory mechanisms, but rather is related to MHC allele-specific antigen presentation. In this regard, there have been several mechanisms suggested, including differential gene expression in the thymus versus periphery (36,37), posttranslational modifications (38)(39)(40), and activation by molecular mimicry [e.g., high-affinity cross-reactive peptides from inflammatory microorganisms (41)]. Without excluding other mechanisms, our data raise the possibility that this third mechanism might be at work in T1D.…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Host‐inherent anti‐viral responses comprise a meticulously regulated mounting of the immune system. Erroneous and faulty progression of such antiviral responses may lead to subsequent break‐down of self‐tolerance with concomitant epitope spreading and recognition of auto‐antigens60 (Fig. 2).…”

“…2). Other potential virus‐mediated mechanisms include bystander activation and immortalization of low‐affinity autoaggressive effector cells due to unphysiological exposure and subsequent presentation of self‐antigens in the context of a strong antiviral response 60. Despite considerable effort, so far no virus could be isolated and amplified from affected muscle tissue of IBM patients and no conclusive evidence for a viral trigger of this myopathy exists 3, 61.…”

Dealing with Garbage is the Immune System’s Main Job

“…Instead of performing the status quo clean up of normal cellular or tissue debris, these signals override normal regulatory signals so that host peptides on MHC I and MHC II molecules from the debris are presented to T cells with the same infection warning as for the microbe. This gives the T cells and subsequently the B cells permission to activate cytolytic and inflammatory immune responses against cells expressing these self proteins to create an autoimmune response [8,9]. Fortunately, this does not happen to everybody, only to those people who have the MHC I or MHC II molecules that can bind and display peptides from certain normal tissue proteins.…”