Post-streptococcal Autoimmunity and Its Relevance to Epstein–Barr virus as the Potential Cause of Multiple Sclerosis

There is mounting evidence that Epstein–Barr virus (EBV) infection is the potential cause of multiple sclerosis (MS) [1]. Epstein–Barr virus exposure is necessary, but insufficient, to develop MS, which explains why most people infected with EBV do not develop MS. Immunologists currently favor molecular mimicry to explain how EBV may cause MS. Arguably, the most well-documented infectious agent to trigger autoimmunity is group A beta-hemolytic streptococcus (GAS) or Streptococcus pyogenes. It is the established cause of acute rheumatic fever (ARF), Sydenham's chorea, glomerulonephritis, arthritis, and vasculitis [2]. We hypothesize that EBV drives MS disease activity, similar to how GAS infection drives attacks of ARF. The first attack of MS is asymptomatic in the majority of people who develop MS and is likely to occur relatively soon after primary EBV exposure. Multiple sclerosis manifests later, when a subsequent attack or lesion forms in a pathway that results in neurological symptoms. This explains why most people who develop MS have preexisting old white matter lesions on their brain MRI when presenting with their first clinical attack. Epstein–Barr virus differs from GAS because it establishes a latent infection that reactivates intermittently. This intermittent asymptomatic reactivation of EBV (latent-lytic cycling) likely drives MS disease activity [1]. In contrast, GAS tends to cause repeated symptomatic infections. However, asymptomatic colonization with GAS is associated with elevated anti-streptolysin (ASO) titers and other serological markers of GAS infection. Similarly, people with MS have increased titers and responsiveness to a broader array of EBV epitopes in their antibody and T-cell receptor repertoires compared to healthy controls [1], supporting the latent-lytic cycling hypothesis as the driver of MS disease activity [1].