MAdCAM-1-Mediated Intestinal Lymphocyte Homing Is Critical for the Development of Active Experimental Autoimmune Encephalomyelitis

Abstract

Lymphocyte homing into the intestine is mediated by binding of leukocytes to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), expressed on endothelial cells. Currently, the immune system of the gut is considered a major modulator not only of inflammatory bowel disease, but also of extra-intestinal autoimmune disorders, including multiple sclerosis (MS). Despite intense research in this field, the exact role of the intestine in the pathogenesis of (neuro-)inflammatory disease conditions remains to be clarified. This prompted us to investigate the role of MAdCAM-1 in immunological processes in the intestine during T cell-mediated autoimmunity of the central nervous system (CNS). Using the experimental autoimmune encephalomyelitis model of MS, we show that MAdCAM-1-deficient (MAdCAM-1-KO) mice are less susceptible to actively MOG 35−55 -induced disease. Protection from disease was accompanied by decreased numbers of immune cells in the lamina propria and Peyer's patches as well as reduced immune cell infiltration into the spinal cord. MOG 35−55 -recall responses were intact in other secondary lymphoid organs of MAdCAM-1-KO mice. The composition of specific bacterial groups within the microbiome did not differ between MAdCAM-1-KO mice and controls, while MAdCAM-1-deficiency severely impaired migration of MOG 35−55 -activated lymphocytes to the gut. Our data indicate a critical role of MAdCAM-1 in the development of CNS inflammation by regulating lymphocyte homing to the intestine, and may suggest a role for the intestinal tract in educating lymphocytes to become encephalitogenic.

Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease

“…ICAM-2 also mediates leukocyte-endothelial adhesion in cerebral vasculature ( 94 ), and neurons upregulate ICAM-2 with the formation of tau NFTs ( 95 ). Tau burden and cerebrovascular pathology also appeared to additively interact with regard to microvascular expression of MAdCAM-1, a leukocyte adhesion molecule that is upregulated in the CNS following chronic vascular inflammation ( 96 – 98 ). Since MAdCAM-1 detection was variable across samples, future studies in a larger cohort are warranted to clarify the relationship between MAdCAM-1, tau pathology, and cerebrovascular pathologies.…”

RETRACTED: Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19

“…Although the findings of the VIOLET trial strongly suggest that Vitamin D supplementation alone has no benefit as an intervention in the critically ill, our inclusion of Vitamin D in COVID-19 treatment, aside from the evidence suggesting the possibility of a more potent therapeutic role in both viral syndromes and COVID-19 (likely few patients with viral syndromes were included in the VIOLET study), is largely based on the therapeutic enhancement of corticosteroid effect when co-administered with Vitamin D, similar to the synergistic effects of corticosteroids with Vitamin C. 155 Investigators have demonstrated that Vitamin D up-regulates glucocorticoid receptors which leads to increased T-cell apoptosis while it can also enhance the corticosteroid effect on and suppression of cytokine production in peripheral blood cell monocytes. 156 -158…”

“…Although the findings of the VIOLET trial strongly suggest that Vitamin D supplementation alone has no benefit as an intervention in the critically ill, our inclusion of Vitamin D in COVID-19 treatment, aside from the evidence suggesting the possibility of a more potent therapeutic role in both viral syndromes and COVID-19 (likely few patients with viral syndromes were included in the VIOLET study), is largely based on the therapeutic enhancement of corticosteroid effect when co-administered with Vitamin D, similar to the synergistic effects of corticosteroids with Vitamin C. 155 Investigators have demonstrated that Vitamin D up-regulates glucocorticoid receptors which leads to increased T-cell apoptosis while it can also enhance the corticosteroid effect on and suppression of cytokine production in peripheral blood cell monocytes. [156][157][158] Recently, in a pilot RCT of Vitamin D therapy in hospitalized COVID-19 patients using calcifediol, the direct precursor to the active form of Vitamin D in the serum, patients were treated on the day of admission with an oral dose of 0.532 mg (roughly equivalent in potency to a dose of 68,000 IU of Vitamin D 3 ), then they gave half the dose on day 3, day 7, and weekly thereafter. They found that of the 50 patients treated with calcifediol, one required admission to the ICU (2%) while of 26 untreated patients, 13 required admission to the ICU (50%), p < .001, OR 0.02 [0.002-0.17].…”

Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca2+ Influx in Nkx2-3 Knock-out Mice

“…Along with its role in the development of intestinal lymphoid tissues. Nkx2-3 is crucial for the expression and regulation of the mucosal addressin cell adhesion molecule-1 (MADCAM-1) on the spleen sinus lining cells and on high endothelial venules of the mesenteric lymph nodes and Peyer’s patches [ 17 , 18 , 19 , 20 ]. Nkx2-3 has an important role in spleen organization and function, since it controls the correct micro-environment for B cell maturation and T-cell-dependent (TD) immune reaction [ 14 , 21 ].…”