Demyelinating Disease In Patients Research Articles

Mouse polyomavirus-specific CD8+ T cells establish a brain-resident memory population during persistent infection (VIR6P.1174)

Abstract Human JC polyomavirus (JCV) causes progressive multifocal leukoencephalopathy (PML), a rare but life-threatening demyelinating disease in patients under profound immunosuppression and those receiving therapeutic immunomodulation for autoimmune and inflammatory disorders. Using persistent mouse polyomavirus (MPyV) infection in mice, we are developing a model of PyV-induced CNS disease to elucidate the role of immunosuppression in PML pathogenesis. Histology revealed corpus callosum demyelination in 100% of persistently infected mice. Following intracerebral injection with MPyV, immunocompetent C57BL/6 mice showed robust infiltration by MPyV-specific CD8 T cells with minimal contraction. During persistent CNS infection, a significant population of CD8 T cells exhibited a tissue-resident memory (Trm) phenotype (CD103+CD69+CD62Llo), as reported for acute VSV and latent HSV-1 infections, and incorporated BrdU in situ, suggesting capacity for self-renewal. Furthermore, these Trm cells develop and survive independently of replenishment by circulating antiviral CD8 T cells or CD4 T cell help. Unlike in the spleen, MPyV-specific CD8 T cells are PD-1hi upon infiltration of the brain without evidence of exhaustion. Interestingly, levels of CD8 and T cell receptor also increase on cells in the brain over time. Whether brain-infiltrating T cells exhibit higher sensitivity to antigen due to higher affinity and/or functional avidity is currently under investigation.

Idiopathic inflammatory demyelinating disease of the central nervous system in patients with inflammatory bowel disease: retrospective analysis of 9095 patients

Anti-TNFα biologics induce and maintain remission in inflammatory bowel disease (IBD). Also, they have been reported to induce or unmask idiopathic inflammatory demyelinating disease of the central nervous system (IIDD). To determine if anti-TNFα biologics increased the risk of IIDD in a large cohort of patients with IBD. We retrospectively identified adult patients referred to the Mayo Clinic, Rochester, MN for management of IBD from a five state capture area (Minnesota, Wisconsin, North Dakota, South Dakota and Iowa) between 1996 and 2010. IIDDs were identified in both Crohn's disease (CD) and ulcerative colitis (UC) patients with and without anti-TNFα exposure using the 2010 McDonald MRI criteria. The risk of IIDDs in patients with and without anti-TNFα exposure was estimated for IBD; CD and UC groups separately. A total of 9095 patients with IBD were identified (4342 CD and 4753 UC). Four patients with CD with exposure to anti-TNFα agents (4/2054) and five patients with CD without anti-TNFα exposure (5/2288) developed a confirmed IIDD. One patient with UC with exposure to anti-TNFα agents (1/1371) and five patients with UC without anti-TNFα agents developed a confirmed IIDD (5/3382). The per cent of IIDDs in patients with and without anti-TNFα exposure was; IBD: 0.15% and 0.18% (RR=0.83, 95% CI: 0.28-2.42; P=0.729); CD: 0.19% and 0.22% (RR=0.89, 95% CI: 0.24-3.31; P=0.863); UC: 0.07% and 0.15% (RR=0.49, 95% CI: 0.06-4.22; P=0.510). Anti-TNFα biologics do not appear to impact the risk of developing clinical idiopathic inflammatory demyelinating disease in patients with inflammatory bowel disease.