Viral triggers for autoimmunity: is the 'glass of molecular mimicry' half full or half empty?

Abstract

In this review we want to consider some of the requirements for autoimmune disease to develop and how this may be reproduced in animal models. Besides a genetic predisposition, environmental triggering factors seem to play a central role in the etiology of many autoimmune diseases. In theory, a structural similarity or identity between the host and an invading pathogen might cause the immune system of the host to react not only to the pathogen but also to self-components. However, in order for such a process of molecular mimicry to induce autoimmunity the mechanisms of maintaining tolerance or ignorance to the self-components need to be circumvented. Subsequently, in order to advance autoimmunity to overt autoimmune disease the frequency and avidity of autoaggressive lymphocytes has to be of sufficient magnitude. Intuitively, one would assume that tolerance might be stronger to identical structures than to structures that just share a certain degree of similarity. Self-reactive lymphocytes with high-avidity are more likely to be deleted or functionally silenced by central and/or peripheral tolerance mechanisms. Thus, perfect mimicry between identical structures might fail in inducing autoimmunity because of efficient tolerance mechanisms. In contrast, imperfect mimicry between similar but not identical structures might on one hand circumvent tolerance but on the other hand result in the generation of lymphocytes with only low- to intermediate avidity. Here we examine animal models that use the concept of molecular mimicry as a potential mechanism for inducing or accelerating autoimmunity. We focus on the RIP-LCMV model for type 1 diabetes and the novel cytochrome P450 2D6 (CYP2D6) model for autoimmune hepatitis, which use either identical or similar triggering and target antigens.

Figure 1. RIP-LCMV model: Thymic expression of the target antigen influences onset of autoimmune disease

LCMV-GP in exclusively expressed in the pancreas of RIP-LCMV-GP mice (C57BL/6 background). In contrast, LCMV-NP is expressed in the thymus of RIP-LCMV-NP mice (Balb/c background) as well, which results in the deletion of the higher avidity LCMV-NP-specific CD8 T cells. The remaining LCMV-NP118-specific CD8 T cells are of low avidity and cause delayed-onset of T1D after LCMV-infection of RIP-LCMV-NP mice when compared to RIP-LCMV-GP mice. In addition, RIP-LCMV-NP mice require ‘help’ of LCMV-NP-specific CD4 T cells for the development of T1D.

Figure 2. RIP-LCMV model: Molecular mimicry boosts the frequency of autoaggressive CD8 T cells and accelerates autoimmune disease

Infection of RIP-LCMV-NP mice with Pichinde virus, which confers molecular mimicry to a subdominant LCMV-NP epitope (NP205) fails to induce autoimmune disease. In contrast, heterologous virus infection with LCMV followed by Pichinde virus expands LCMV-NP205-specific CD8 T cells. The presence of high frequencies of both LCMV-NP396- and LCMV-NP205-specific CD T cells rushes the ongoing autoimmune process to overt autoimmune disease.

Figure 3. CYP2D6 model: Molecular mimicry induces a higher frequency of autoaggressive lymphocytes than molecular identity

The CYP2D6 model for autoimmune hepatitis uses an Adenovirus expressing the natural human autoantigen CYP2D6 as a trigger. Infection wildtype FVB mice expressing the mouse homologues of CYP2D6 only develop massive form of chronic autoimmune hepatitis. In contrast, transgenic CYP2D6 mice, which in addition to the similar mouse CYP2D6 homologues express the identical human CYP2D6 in the liver, develop a significantly milder form of hepatitis with a delayed kinetics. Most strikingly, CYP2D6 mice generate a 10-20 times lower frequencies of CYP2D6-specific CD8 and CD4 T cells.