The Role of Viral Infections in the Onset of Autoimmune Diseases

Abstract

Autoimmune diseases (AIDs) are the consequence of a breach in immune tolerance, leading to the inability to sufficiently differentiate between self and non-self. Immune reactions that are targeted towards self-antigens can ultimately lead to the destruction of the host's cells and the development of autoimmune diseases. Although autoimmune disorders are comparatively rare, the worldwide incidence and prevalence is increasing, and they have major adverse implications for mortality and morbidity. Genetic and environmental factors are thought to be the major factors contributing to the development of autoimmunity. Viral infections are one of the environmental triggers that can lead to autoimmunity. Current research suggests that several mechanisms, such as molecular mimicry, epitope spreading, and bystander activation, can cause viral-induced autoimmunity. Here we describe the latest insights into the pathomechanisms of viral-induced autoimmune diseases and discuss recent findings on COVID-19 infections and the development of AIDs.

Keywords: COVID-19; autoimmunity; bystander activation; central tolerance; epitope spreading; molecular mimicry; multiple sclerosis; peripheral tolerance; rheumatoid arthritis; systemic lupus erythematosus; type 1 diabetes.

Figure 1

Mechanisms by which virus infections cause autoimmune diseases. (a) Epitope spreading. 1. Viruses infect the host´s cells. 2. Viral antigens are presented to T-helper cells by APCs. 3. T-helper cells release cytokines, which can affect cytotoxic T lymphocytes (CTLs). 4. CTLs release granzymes, which attack infected cells. 5. Hidden self-antigens leak from damaged cells. 6. APCs present these antigens to autoreactive T cells. 7. Therefore, autoreactive T cells attack other uninfected cells carrying these self-antigens. (b) Molecular mimicry. T cell receptors (TCR) can recognize and react towards both viral antigens and self-antigens that have structural or sequential homology. (c) Bystander activation. Infected cells present viral antigens to virus-specific T cells. T cells identify infected cells and release cytotoxic granules, causing cell death of infected and nearby, uninfected cells. The inflammatory milieu leads to the activation of bystander cells within the tissue.

Figure 2

Virus-induced rheumatoid arthritis. (a) Synovium, bone and cartilage damage in RA. The activated CD4⁺ T cells against viruses stimulate the release of cytokines, such as IL-1, IL-6 and TNFα, from monocytes and macrophages. These cytokines lead to the increased release of proteolytic enzymes which cause damage of the synovium, cartilage and underlying bone. (b) Antibodies against proteins. Post-translationally changed proteins through citrullination (ACPA) and carbamylation (anti-CarP antibodies) can be identified by autoantibodies. (c) Molecular mimicry mechanism in RA. Antibodies reactive towards the primary epitope p107 of the EBV-encoded EBNA-1 antigen cross-react with keratin and denatured collagen.

Figure 3

Demyelination in MS. CD4⁺ T cells (T helper 1/17 cells) and CTLs can pass through the blood–brain barrier (BBB) by endocytosis or diapedesis. Self-antigens can be presented by APCs to CTLs, Th1 or Th17 cells. Th1 cells release cytokines such as IFNγ and TNFα, whereas Th17 cells release IL-17, IL-21, IL-22 and IFNγ cytokines. These cytokines affect CTLs and increase granzyme and perforin production and release which leads to myelin destruction.