Research Square · Sep 14, 2026
Universal seropositivity, markers of recurrent reactivation, and a convergent T-cell response implicate cytomegalovirus in Susac syndrome
By Schwab N, Dawin E, Schneider-Hohendorf T et al.
Susac syndrome (SuS) is a rare brain, retina, and inner ear endotheliopathy, in which CD8⁺ T cells are thought to target the microvascular endothelium. We applied unbiased, HLA-restricted antigen-specificity annotation of T-cell receptor beta-chain repertoires, followed by targeted serology, virology, and single-cell profiling, to a multicenter German cohort of 72 patients with definite SuS. Repertoires showed increased clonality and convergent expansion of CMV-specific clusters positively associated with age, alongside expansion of adaptive NKG2C⁺ natural killer cells. T cells converged on the immediate-early-1 epitope CRVLCCYVL in carriers of HLA-C*07:02, an allele nominally enriched in this cohort, together indicating recurrent antigen exposure. Every tested patient with SuS was CMV IgG-positive (70 of 70), and 37% of patients were CMV IgM-positive or DNAemic at one or more time points. This was confirmed at diagnosis in an untreated Belgian validation cohort with 100% CMV IgG-positivity (13 of 13) and 31% IgM-positivity. Serum DNAemia, but not IgM, coincided with disease activity. Single-cell profiling of a patient with SuS, hospitalized for CMV disease eleven months before disease onset, showed the same antigenic focus alongside a CMV reactivation phenotype resembling that of allogeneic transplant recipients. These findings implicate recurrent CMV reactivation in the pathogenesis of SuS, support further prospective evaluation of diagnostic CMV testing, and provide a foundation for assessment of treatment strategies combining antiviral and immunomodulatory effects.