Autoantibodies in the Extraintestinal Manifestations of Celiac Disease

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

Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease

Objective: Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy. Design: Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components. Results: Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals. Conclusions: These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease

Associations Between Subclass Profile of IgG Response to Gluten and the Gastrointestinal and Motor Symptoms in Children with Cerebral Palsy

OBJECTIVE. Gastrointestinal problems are often seen in children with cerebral palsy, although the etiology and underlying mechanisms are not fully understood. Recent data point to significantly elevated levels of IgG antibody to dietary gluten in cerebral palsy independent of celiac disease, a gluten-mediated autoimmune enteropathy. We aimed to further characterize this antibody response by examining its subclass distribution and target reactivity in the context of relevant patient symptom profile. METHODS. In a previous study, we investigated whether an elevated frequency of celiac disease might partially explain the observed weight and height impairment among children with CP. Serum IgG antibody to gluten was investigated for subclass distribution, pattern of reactivity towards target proteins, and relationship with gastrointestinal symptoms and motor function. RESULTS. The anti-gluten IgG antibody response in the cerebral palsy cohort was comprised of all four subclasses. However, in comparison with celiac disease, IgG1, IgG2, and IgG3 subclasses were significantly lower, whereas the IgG4 response was significantly higher in cerebral palsy. Within the cohort of cerebral palsy patients, levels of anti-gluten IgG1, IgG3, and IgG4 were greater in those with gastrointestinal symptoms, and the IgG3 subclass antibody correlated inversely with gross motor function. The anti-gluten IgG antibodies targeted a broad range of gliadin and glutenin proteins. CONCLUSION. These findings reveal an anti-gluten IgG subclass distribution in cerebral palsy that is significantly different from that in celiac disease. Furthermore, the observed association between IgG subclass and symptom profile is suggestive of a relationship between the immune response and disease pathophysiology that may indicate a role for defects in gut immune and barrier function in cerebral palsy. [Table: see text

Associations Between Subclass Profile of IgG Response to Gluten and the Gastrointestinal and Motor Symptoms in Children With Cerebral Palsy

OBJECTIVE: Gastrointestinal problems are often seen in children with cerebral palsy, although the etiology and underlying mechanisms are not fully understood. Recent data point to significantly elevated levels of IgG antibody to dietary gluten in cerebral palsy independent of celiac disease, a gluten-mediated autoimmune enteropathy. We aimed to further characterize this antibody response by examining its subclass distribution and target reactivity in the context of relevant patient symptom profile. METHODS: Study participants included children with cerebral palsy (n = 70) and celiac disease (n = 85), as well as unaffected controls (n = 30). Serum IgG antibody to gluten was investigated for subclass distribution, pattern of reactivity towards target proteins, and relationship with gastrointestinal symptoms and motor function. RESULTS: The anti-gluten IgG antibody response in the cerebral palsy cohort was constituted of all 4 subclasses. In comparison with celiac disease, however, IgG1, IgG2, and IgG3 subclasses were significantly lower, whereas the IgG4 response was significantly higher in cerebral palsy. Within the cohort of cerebral palsy patients, levels of anti-gluten IgG1, IgG3, and IgG4 were greater in those with gastrointestinal symptoms, and the IgG3 subclass antibody correlated inversely with gross motor function. The anti-gluten IgG antibodies targeted a broad range of gliadin and glutenin proteins. CONCLUSIONS: These findings reveal an anti-gluten IgG subclass distribution in cerebral palsy that is significantly different from that in celiac disease. Furthermore, the observed association between IgG subclass and symptom profile is suggestive of a relationship between the immune response and disease pathophysiology that may indicate a role for defects in gut immune and barrier function in cerebral palsy

Pseudomonas aeruginosa Uses Dihydrolipoamide Dehydrogenase (Lpd) to Bind to the Human Terminal Pathway Regulators Vitronectin and Clusterin to Inhibit Terminal Pathway Complement Attack.

The opportunistic human pathogen Pseudomonas aeruginosa controls host innate immune and complement attack. Here we identify Dihydrolipoamide dehydrogenase (Lpd), a 57 kDa moonlighting protein, as the first P. aeruginosa protein that binds the two human terminal pathway inhibitors vitronectin and clusterin. Both human regulators when bound to the bacterium inhibited effector function of the terminal complement, blocked C5b-9 deposition and protected the bacterium from complement damage. P. aeruginosa when challenged with complement active human serum depleted from vitronectin was severely damaged and bacterial survival was reduced by over 50%. Similarly, when in human serum clusterin was blocked by a mAb, bacterial survival was reduced by 44%. Thus, demonstrating that Pseudomonas benefits from attachment of each human regulator and controls complement attack. The Lpd binding site in vitronectin was localized to the C-terminal region, i.e. to residues 354-363. Thus, Lpd of P. aeruginosa is a surface exposed moonlighting protein that binds two human terminal pathway inhibitors, vitronectin and clusterin and each human inhibitor when attached protected the bacterial pathogen from the action of the terminal complement pathway. Our results showed insights into the important function of Lpd as a complement regulator binding protein that might play an important role in virulence of P. aeruginosa

Serologic Markers of Systemic Immune Activation and Intestinal Cell Damage in Non-Celiac Wheat Sensitivity

Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy. Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components. Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals. These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease

Markers of non-coeliac wheat sensitivity in patients with myalgic encephalomyelitis/chronic fatigue syndrome

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