Citations

Abstract Spleen cells from a number of H-2 congenic mice were tested for their proliferative and/or cytolytic responses to partially purified products from CNBr cleavage of Sendai virus. In response to in vitro stimulation of Sendai-primed spleen cells with virus-infected cells, Sendai virus-specific cytolytic T lymphocytes restricted to H-2Kb, Kd, Kk, Kb, and Dd were generated. Of these, H-2Kb- and Kd-, but not H-2Kk-, Kb-, and Dd-, restricted cytolytic T cells were generated after stimulation with partially purified Sendai peptides. H-2Dd-restricted, virus-specific cytotoxicity was generated in response to unseparated products from CNBr cleavage of Sendai virus. Thus, the pool of partially purified peptides contains some but not all of the antigenic determinants that can stimulate a cytolytic response. These results suggest that each determinant on Sendai viral proteins may stimulate cytolytic T lymphocytes restricted to only a subset of the H-2K and D alleles which can be recognized by the sum of cytolytic T cells generated in response to all of the antigenic determinants on Sendai viral proteins. Thus, H-2K and D genes function as immune response genes regulating the cytolytic response to partially purified peptides and, by extension, possibly to individual antigenic determinants on Sendai viral proteins. Also, spleen cells from three mice differing only in the H-2I-S regions show differences in their proliferative responses to Sendai antigens. Only spleen cells from mice with the k haplotype in IA-IJ proliferate in response to partially purified peptides, whereas spleen cells from all three mice proliferate when virus is added to the cultures. These proliferating cells are sensitive to treatment with anti-Thy-1.2 and C, suggesting that immune response genes regulating T cell proliferative responses to individual viral determinants may also exist.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

ABSTRACT Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT ‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT , PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐ H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT ‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society