A role for HHV-6A/B has been proposed in several autoimmune disorders, including multiple sclerosis (MS), autoimmune connective tissue diseases, and Hashimoto’s thyroiditis. In an article published this month, researchers from Italy discuss the potential mechanisms by which HHV-6A/B may contribute to the development of autoimmune diseases such as those listed above.
Given the currently available information, the authors propose primarily two independent mechanisms by which HHV-6 may play a role in the disease pathogenesis of MS. First, the authors outline a hypothesis for a model of HHV-6A-induced MS, whereby reactivation of HHV-6A has the potential to trigger autoimmunity and tissue damage associated with MS lesion development. The second proposed hypothesis details the potential for a CD46-HHV-6A interaction whereby HHV-6A could participate in neuroinflammatory processes through binding to the cellular receptor CD46 during infection.
Autoimmune Connective Tissue Disease
As the authors point out, “autoimmune connective tissue diseases (ACTD) encompass a very large group of diseases, including systemic sclerosis or scleroderma (SSc), systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), dermatomyositis (DM), rheumatoid arthritis (RA), and other conditions causing chronic inflammation that can affect many organs and systems.” The article mentions four pathogenic hypotheses that have been proposed as potential mechanisms by which viruses may induce ACTDs, including molecular mimicry, endothelial cell damage, super-antigen stimulation, and microchimerism. Although several connections have recently been made between ACTDs and HHV-6A/B, the authors caution that definitive evidence of a direct association is still lacking. The authors go on to suggest that HHV-6A/B may induce ACTD through molecular mimicry of host proteins. However, more likely is the idea that these viruses may induce autoimmunity by cell death, primarily through increasing the rate of apoptosis and thus resulting in the enhanced release of self-antigens.
Recent evidence suggests that HHV-6 may induce Hashimoto’s Thyroiditis (HT) via de novo expression of HLA class II molecules in thyrocytes, which may thus behave as functional antigen presenting cells for CD4+ T lymphocytes. The study found that HHV-6A was detected significantly more frequently among thyroid fine needle aspirates (FNA) from HT individuals than controls (82% versus 10%, resp.), and low-grade acute infection was identified in all HHV-6 positive HT samples compared to 0% of controls. Furthermore, the presence of HHV-6A infection was found localized mainly to thyrocytes, rather than in lymphocytes infiltrating the lesion, and increased prevalence of latent HHV-6A infection was seen in PBMCs overall. In addition, the group demonstrated that thyroid cells infected with both HHV-6A and HHV-6B became susceptible to NK-mediated killing, providing evidence of a potential mechanism for HHV-6A/B induced autoimmunity. These findings are consistent with the possibility that the thyroid of HT patients may constitute a site of active HHV-6A/B infection/replication.