Giorgos Pitsas

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by immune-mediated demyelination and neurodegeneration. Although the exact cause of MS remains unclear, accumulating epidemiological and immunological evidence strongly implicates Epstein–Barr virus (EBV) infection as a major environmental factor associated with disease development. Nearly all individuals with MS are EBV seropositive, and longitudinal studies have demonstrated that EBV infection precedes MS onset, supporting a causal relationship. EBV establishes lifelong latency in B cells and can profoundly influence host immune responses, providing several potential mechanisms through which it may contribute to autoimmunity. In this review, we summarize current knowledge of EBV biology and discuss epidemiological findings linking EBV infection with MS risk. We then examine alterations in EBV-specific immune responses observed in MS, including dysregulated humoral and cellular immunity. Particular attention is given to molecular mimicry involving the Epstein–Barr nuclear antigen 1 (EBNA1) and central nervous system proteins, which may promote cross-reactive autoimmune responses. Finally, we discuss evidence for the presence and potential role of EBV-infected immune cells within the MS brain and highlight key unanswered questions that remain critical for understanding EBV-driven neuroinflammation.

The intronic biallelic AAGGG expansion in the replication factor C subunit 1 (RFC1) gene was recently associated with a phenotype combining cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, as well as with late-onset ataxia. Following this discovery, studies in multiple populations extended the phenotypic and genotypic spectrum of this locus. Multiple benign and additional pathogenic configurations are currently known. Our main objectives were to study the prevalence of the pathogenic AAGGG expansion in the Cypriot population, to further characterize the RFC1 repeat locus allele distribution, and to search for possible novel repeat configurations. Cypriot undiagnosed patients, in the majority presenting at least with cerebellar ataxia and non-neurologic disease controls, were included in this study. A combination of conventional methods was used, including standard PCR flanking the repeat region, repeat-primed PCR, long-range PCR, and Sanger sequencing. Bioinformatics analysis of already available in-house short-read whole-genome sequencing data was also performed. A large group of undiagnosed patients (n = 194), mainly presenting with pure ataxia or with ataxia accompanied by neuropathy or additional symptoms, as well as a group of non-disease controls (n = 100), were investigated in the current study. Our findings include the diagnosis of 10 patients homozygous for the pathogenic AAGGG expansion and a high percentage of heterozygous AAGGG carriers in both groups. The benign AAAAG_n, AAAGG_n, and AAGAG_n configurations were also identified in our cohorts. We also report and discuss the identification of 2 recently reported novel and possibly benign repeat configurations, AAAGGG_n and AAGAC_n, thus confirming their existence in another distinct population, and we highlight an increased frequency of the AAAGGG_n in the patient group, including a single case of homozygosity. Our findings indicate the existence of genetic heterogeneity regarding the RFC1 repeat configurations and that the AAGGG pathogenic expansion is a frequent cause of ataxia in the Cypriot population.