Peripheral Blood Th40 cells Reflect Disease Progression and Are Controlled by Rituximab in Human Multiple Sclerosis

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Abstract Multiple Sclerosis (MS) is a neuro-degenerative autoimmune disease, progressive in nature, that lacks biomarkers for diagnosis or progression. We described a population of CD4+ T cells that express the CD40 receptor, Th40 cells, which proved causal in murine models of autoimmunity. Hypothesis Peripheral blood Th40 numbers reflect MS progression and their control correlates with improvement. Peripheral blood and cerebral spinal fluid from MS patients and disease controls were examined for HLA haplotype and PBMC were characterized by flow cytometry. Random sampling of CIS, RRMS, SPMS and PPMS patients demonstrated diverse HLA haplotypes; DR2 / DQ6 were highly represented but surprisingly DR4, DR3 and DQ2 were prominent. In antigen recall, each HLA haplotype preferred unique myelin-based antigens when presenting to Th40 cells. Percentages of Th40 cells in peripheral blood of CIS and RRMS had a wide range while the range in PPMS and SPMS was tight yet significantly elevated. CSF from RRMS patients had Th40 cell percentages mirroring peripheral blood. RRMS subjects had elevated B cells that surprisingly were the major source of IL-17. Rituximab treated subjects demonstrated a significant but temporal reduction in Th40 cell numbers; FoxP3+ cells were elevated while Th40 inflammatory-cytokine production was reduced. Conclusions The wide range of Th40 cell numbers in CIS and RRMS but universally high numbers in SPMS suggest that Th40 cell number expansions in MS reflect progression. Th40 cells in CSF demonstrate access to the CNS and an important correlation between peripheral blood and CNS. Antigen recall to myelin demonstrates Th40 pathogenicity. Rituximab treatment ablates B cells that then affect pathogenic effector Th40 cells.