Immunopathology of the optic nerve in multiple sclerosis.

Optic neuritis, a primary clinical manifestation commonly observed in multiple sclerosis (MS), is a major factor leading to permanent loss of vision. Despite decreased vision (optic neuritis), diplopia, and nystagmus, the immunopathology of the optic nerve in MS is unclear. Here, we have characterized the optic nerve pathology in a large cohort of MS cases (n = 154), focusing on the immune responses in a sub-cohort of MS (n = 30) and control (n = 6) cases. Immunohistochemistry was used to characterize the myeloid (HLA-DR, CD68, Iba1, TMEM119, and P2RY12) and adaptive immune cells (CD4, CD8, and CD138) in the parenchyma, perivascular spaces, and meninges in optic nerve tissues from MS and control cases. Of the 154 MS cases, 122 (79%) reported visual problems; of which, 99 (81%) optic nerves showed evidence of damage. Of the 31 cases with no visual disturbances, 19 (61%) showed evidence of pathology. A pattern of myeloid cell activity and demyelination in the optic nerve was similar to white matter lesions in the brain and spinal cord. In the optic nerves, adaptive immune cells were more abundant in the meninges close to active and chronic active lesions, and significantly higher compared with the parenchyma. Similar to brain tissues in this Dutch cohort, B-cell follicles in the meninges were absent. Our study reveals that optic nerve pathology is a frequent event in MS and may occur in the absence of clinical symptoms.

Cigarette Smoke Directly Promotes Pulmonary Arterial Remodeling and Kv7.4 Channel Dysfunction.

Rationale: Cigarette smoke is considered the chief leading cause of chronic obstructive pulmonary disease (COPD). Its impact on the progressive deterioration of airways has been extensively studied, but its direct effects on the pulmonary vasculature are less known. Objectives: To prove that pulmonary arterial remodeling in patients with COPD is not just a consequence of alveolar hypoxia but also due to the direct effects of cigarette smoke on the pulmonary vascular bed. Methods: We have used different molecular and cell biology approaches, as well as traction force microscopy, wire myography, and patch-clamp techniques in human cells and freshly isolated pulmonary arteries. In addition, we relied on in vivo models and human samples to analyze the effects of cigarette smoke on pulmonary vascular tone alterations. Measurements and Main Results: Cigarette smoke extract exposure directly promoted a hypertrophic, senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to an increase in the proliferative potential of nonexposed cells. Interestingly, these effects were significantly reversed by antioxidants. Furthermore, cigarette smoke extract affected cell contractility and dysregulated the expression and activity of the voltage-gated K+ channel Kv7.4. This contributed to the impairment of vasoconstriction and vasodilation responses. Most importantly, the levels of this channel were diminished in the lungs of smoke-exposed mice, smokers, and patients with COPD. Conclusions: Cigarette smoke directly contributes to pulmonary arterial remodeling through increased cell senescence, as well as vascular tone alterations because of diminished levels and function in the Kv7.4 channel. Strategies targeting these pathways may lead to novel therapies for COPD.