Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4+ T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints. Transcriptome analysis of GCA-affected temporal arteries revealed low expression of the coinhibitory ligand programmed death ligand-1 (PD-L1) concurrent with enrichment of the programmed death-1 (PD-1) receptor. Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA patients were PD-L1 lo
Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In the autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (TH1) and TH17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating expression of the Notch ligand Jagged1. Vascular endothelial growth factor (VEGF), abundantly present in GCA patients’ blood, induced Jagged1 expression, allowing mvECs to regulate effector T cell induction via the Notch-mTORC1 (mammalian target of rapamycin complex 1) pathway. We found that circulating CD4 T cells in GCA patients have left the quiescent state, actively signal through the Notch pathway and differentiate into TH1 and TH17 effector cells. In an in vivo model of large vessel vasculitis, exogenous VEGF functioned as an effective amplifier to recruit and activate vasculitogenic T cells. Thus, systemic VEGF co-opts endothelial Jagged1 to trigger aberrant Notch signaling, biases responsiveness of CD4 T cells, and induces pathogenic effector functions. Adventitial microvascular networks function as an instructive tissue niche, which can be exploited to target vasculitogenic immunity in large vessel vasculitis.
Summary The absence of the optic chiasm is an extraordinary and extreme abnormality in the nervous system. The abnormality produces highly atypical functional responses in the cortex, including overlapping hemifield representations and bilateral population receptive fields in both striate and extrastriate visual cortex. Even in the presence of these large functional abnormalities, the effect on visual perception and daily life is not easily detected. Here we demonstrate that in two achiasmic humans the gross topography of the geniculo-striate and occipital callosal connections remains largely unaltered. We conclude that visual function is preserved by reorganization of intra-cortical connections instead of large-scale reorganizations of the visual cortex. Thus developmental mechanisms of local wiring within cortical maps compensate for the improper gross wiring to preserve function in human achiasma.
Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.
This was a serial SD-OCT quantification of acute and chronic changes following experimental AION, which revealed changes in the GCC similar to that of human AION, but over a time frame of weeks rather than months.
Voltage-gated Ca 2؉ channels (VGCCs) are membrane proteins that determine the activity and survival of neurons, and mutations in the P/Q-type VGCCs are known to cause cerebellar ataxia. VGCC dysfunction may also underlie acquired peripheral and central nervous system diseases associated with small-cell lung cancer, including Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar ataxia (PCA). The pathogenic role of anti-VGCC antibody in LEMS is well established. Although anti-VGCC antibody is also found in a significant fraction of PCA patients, its contribution to PCA is unclear. Using a polyclonal peptide antibody against a major immunogenic region in P/Q-type VGCCs (the extracellular Domain-III S5-S6 loop), we demonstrated that such antibody was sufficient to inhibit VGCC function in neuronal and recombinant VGCCs, alter cerebellar synaptic transmission, and confer the phenotype of cerebellar ataxia. Our data support the hypothesis that anti-VGCC antibody may play a significant role in the pathogenesis of cerebellar dysfunction in PCA.Lambert-Eaton myasthenic syndrome ͉ paraneoplastic ͉ P/Q-type ͉ N-type ͉ neurotransmission T he association between anti-voltage-gated Ca 2ϩ channel (VGCC) antibody and paraneoplastic cerebellar ataxia (PCA) dates back several decades to clinical observations of the coexistence of small-cell lung cancer with either cerebellar ataxia, Lambert-Eaton myasthenic syndrome (LEMS), or both (1, 2). The majority of these cancer patients with neurological symptoms have antibody against different types of VGCCs, especially P/Q-and N-type (3-5). The presence of different antibodies may be the consequence of an autoimmune response against the cancer cells (6, 7), known to express different VGCCs (8). There is conclusive evidence that the peripheral disease LEMS is caused by anti-VGCC antibodies, which diminish the availability of P/Q-type channels of the motor nerve terminals (9, 10).In contrast, much less is known about the origin of cerebellar ataxia associated with anti-VGCC antibody, although VGCCs are prominent in cerebellar neurons (11,12), and mutations in the P/Q-type VGCC cause ataxia (13). PCA patients have a high titer of anti-VGCC antibody (14-17) and undergo a selective loss of P/Q-type VGCC-containing cerebellar neurons (2, 18). Sera from LEMS patients, known to contain anti-VGCC antibodies, reduce P/Q-type VGCC surface expression in cerebellar granule and Purkinje neurons (19), consistent with an overlap of clinical syndromes between LEMS and PCA and, possibly, of pathogenic mechanism. There is no evidence to date that passive transfer of sera from LEMS or PCA patients is sufficient to cause central nervous system disease. Based on epitope mapping of antibody repertoire in patients with paraneoplastic neurological syndromes and small-cell lung cancer, we generated an antibody against a major epitope in the P/Q-type VGCC and evaluated its ability to affect cerebellar VGCC function and motor behavior. ResultsFunctional Effects of Anti-VGCC Antibody. We looked for...
The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
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