The Role of Viral Infections in the Onset of Autoimmune Diseases.

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.

T Cell Receptor Sequences Amplified during Severe COVID-19 and Multisystem Inflammatory Syndrome in Children Mimic SARS-CoV-2, Its Bacterial Co-Infections and Host Autoantigens.

Published hypervariable region V-beta T cell receptor (TCR) sequences were collected from people with severe COVID-19 characterized by having various autoimmune complications, including blood coagulopathies and cardiac autoimmunity, as well as from patients diagnosed with the Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C). These were compared with comparable published v-beta TCR sequences from people diagnosed with KD and from healthy individuals. Since TCR V-beta sequences are supposed to be complementary to antigens that induce clonal expansion, it was surprising that only a quarter of the TCR sequences derived from severe COVID-19 and MIS-C patients mimicked SARS-CoV-2 proteins. Thirty percent of the KD-derived TCR mimicked coronaviruses other than SARS-CoV-2. In contrast, only three percent of the TCR sequences from healthy individuals and those diagnosed with autoimmune myocarditis displayed similarities to any coronavirus. In each disease, significant increases were found in the amount of TCRs from healthy individuals mimicking specific bacterial co-infections (especially Enterococcus faecium, Staphylococcal and Streptococcal antigens) and host autoantigens targeted by autoimmune diseases (especially myosin, collagen, phospholipid-associated proteins, and blood coagulation proteins). Theoretical explanations for these surprising observations and implications to unravel the causes of autoimmune diseases are explored.

Induction of T Cell Senescence by Cytokine Induced Bystander Activation.

As people around the world continue to live longer, maintaining a good quality of life is of increasing importance. The COVID-19 pandemic revealed that the elderly are disproportionally vulnerable to infectious diseases and Immunosenescence plays a critical role in that. An ageing immune system influences the conventional activity of T cells which are at the forefront of eliminating harmful foreign antigens. With ageing, unconventional end-stage T cells, that exhibit a senescent phenotype, amass. These senescent T cells deviate from T cell receptor (TCR) signaling toward natural killer (NK) activity. The transition toward innate immune cell function from these adaptor T cells impacts antigen specificity, contributing to increased susceptibility of infection in the elderly. The mechanism by which senescent T cells arise remains largely unclear however in this review we investigate the part that bystander activation plays in driving the change in function of T cells with age. Cytokine-induced bystander activation may offer a plausible explanation for the induction of NK-like activity and senescence in T cells. Further understanding of these specific NK-like senescent T cells allows us to identify the benefits and detriments of these cells in health and disease which can be utilized or regulated, respectively. This review discusses the dynamic of senescent T cells in adopting NK-like T cells and the implications that has in an infectious disease context, predominately in the elderly.

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens.

In our continuing examination of the role of exposomes in autoimmune disease, we use this review to focus on pathogens. Infections are major contributors to the pathophysiology of autoimmune diseases through various mechanisms, foremost being molecular mimicry, when the structural similarity between the pathogen and a human tissue antigen leads to autoimmune reactivity and even autoimmune disease. The three best examples of this are oral pathogens, SARS-CoV-2, and the herpesviruses. Oral pathogens reach the gut, disturb the microbiota, increase gut permeability, cause local inflammation, and generate autoantigens, leading to systemic inflammation, multiple autoimmune reactivities, and systemic autoimmunity. The COVID-19 pandemic put the spotlight on SARS-CoV-2, which has been called "the autoimmune virus." We explore in detail the evidence supporting this. We also describe how viruses, in particular herpesviruses, have a role in the induction of many different autoimmune diseases, detailing the various mechanisms involved. Lastly, we discuss the microbiome and the beneficial microbiota that populate it. We look at the role of the gut microbiome in autoimmune disorders, because of its role in regulating the immune system. Dysbiosis of the microbiota in the gut microbiome can lead to multiple autoimmune disorders. We conclude that understanding the precise roles and relationships shared by all these factors that comprise the exposome and identifying early events and root causes of these disorders can help us to develop more targeted therapeutic protocols for the management of this worldwide epidemic of autoimmunity.

Effect of inactivated influenza vaccination on human coronavirus infection: Secondary analysis of a randomized trial in Hutterite colonies.

BACKGROUND: Although influenza vaccines provide protection against influenza viruses, concern has been raised that they may increase susceptibility to non-influenza respiratory viruses. As pandemic lockdowns end, temporal overlap of circulation of seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expected. Understanding the impact of influenza vaccination on risk of coronavirus infection is therefore of considerable public health importance. METHODS: We performed a secondary analysis of a randomized trial where children and adolescents in Canadian Hutterite colonies were randomly assigned by colony to receive the 2008-2009 seasonal inactivated trivalent influenza vaccine (TIV) or a control hepatitis A (HepA) vaccine. All 3273 colony members (vaccinated children and nonvaccine recipients) were followed for the primary outcome of RT-PCR confirmed seasonal coronavirus infection. Serum collected pre- and post-vaccination was analyzed for titers of IgG antibodies towards human coronaviruses (HCoV). RESULTS: The incidence of coronavirus infection was 0·18/1000 person-days in the colonies that received TIV vs 0.36/1000 person-days in the control group, hazard ratio (HR) 0.49 [0.21-1.17]. The risk reduction among non-vaccine recipients in the TIV group compared to the control group was HR 0.55 [0.24-1.23]. There was an increase in the geometric mean fold change of HCoV-OC43 antibody titers following TIV compared to HepA vaccine (mean difference 1.2 [0.38-2.06], p = 0.007), and an increase in geometric mean HCoV-NL63 antibody titers post-TIV (262.9 vs 342.9, p = 0.03). CONCLUSION: The influenza vaccine does not increase the risk of a coronavirus infection. Instead, the influenza vaccine may reduce the rate of coronavirus infections by inducing cross-reactive anti-coronavirus IgG antibodies.