Autoantibodies in the Extraintestinal Manifestations of Celiac Disease

Abstract

Increased antibody reactivity towards self-antigens is often indicative of a disruption of homeostatic immune pathways in the body. In celiac disease, an autoimmune enteropathy triggered by the ingestion of gluten from wheat and related cereals in genetically predisposed individuals, autoantibody reactivity to transglutaminase 2 is reflective of the pathogenic role of the enzyme in driving the associated inflammatory immune response. Autoantibody reactivity to transglutaminase 2 closely corresponds with the gluten intake and clinical presentation in affected patients, serving as a highly useful biomarker in the diagnosis of celiac disease. In addition to gastrointestinal symptoms, celiac disease is associated with a number of extraintestinal manifestations, including those affecting skin, bones, and the nervous system. Investigations of these manifestations in celiac disease have identified a number of associated immune abnormalities, including B cell reactivity towards various autoantigens, such as transglutaminase 3, transglutaminase 6, synapsin I, gangliosides, and collagen. Clinical relevance, pathogenic potential, mechanism of development, and diagnostic and prognostic value of the various identified autoantibody reactivities continue to be subjects of investigation and will be reviewed here.

The Effect of Gluten-Free Diet on Health and the Gut Microbiota Cannot Be Extrapolated from One Population to Others

“…In people with CD, a significantly enhanced autoantibody response to the transglutaminase 2 (TG2) enzyme, also known as tissue transglutaminase (tTG), is a hallmark of the pathogenic process that primarily affects the architecture of the enterocyte lining of the small intestine [ 15 ] but can also affect other organs such as the liver, kidney, lymph nodes and muscles [ 16 , 17 ]. Interestingly, other autoantibodies may also be involved, especially in extraintestinal manifestations, such as anti-ganglioside, anti-synapsin I and anti-actin antibodies [ 18 ]. Patients with CD present either typical or atypical symptoms [ 19 ] and CD is believed to perpetuate other maladies and often presents simultaneously with other autoimmune diseases [ 20 , 21 , 22 , 23 ].…”

Role of the gut microbiota in the pathogenesis of coeliac disease and potential therapeutic implications

“…Stimulated gluten-specific CD4 + T cells can result in the overactivation of the various immune functions-for example activated CD4 + T cells can further stimulate B cells to produce autoantibodies such as anti-gluten, transglutaminase 2 (TG2) and anti-tissue antibodies [22,31] that could induce changes in the cytoskeleton of enterocyte through actin redistribution and the consequent epithelial cell damage [32]. The CD4 + T cells can also produce a high level of pro-inflammatory cytokines and induce specific T H 1 cells leading to the production of excessive amounts of IL-21 and IFN-γ [33].…”

Neuroimmunogastroenterology: At the Interface of Neuroimmunology and Gastroenterology

“…Auto-antibodies to gangliosides have also been reported (100); the significance remains unclear but the generation of anti-ganglioside antibodies is speculated to be linked to the intestinal immune response to ingested gluten. Similar to ganglioside generation in acute immune-mediated neuropathies, where molecular mimicry between gangliosides and bacterial or viral oligosaccharides is proposed as a mechanism (101) in celiac disease as well (100). Following a gluten-free diet, which alleviates gastrointestinal symptoms of celiac disease, has mixed success in relieving the neurological manifestations of the disease (102)(103)(104)(105).…”

“…Overlapping nervous system autoimmunity may also contribute to neurological symptoms as anti-transglutaminase antibodies, a biomarker of celiac disease, have been reported in the CNS of celiac disease patients ( 98 ) Indeed, intraventricular injection of anti-transglutaminase antibodies into mice results in ataxia ( 99 ). Auto-antibodies to gangliosides have also been reported ( 100 ); the significance remains unclear but the generation of anti-ganglioside antibodies is speculated to be linked to the intestinal immune response to ingested gluten. Similar to ganglioside generation in acute immune-mediated neuropathies, where molecular mimicry between gangliosides and bacterial or viral oligosaccharides is proposed as a mechanism ( 101 ) in celiac disease as well ( 100 ).…”