Celiac disease: pathogenesis of a model immunogenetic disease

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Abstract

Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. Although celiac disease is predicted by screening studies to affect approximately 1% of the population of the United States and is seen both in children and in adults, 10%-15% or fewer of these individuals have been diagnosed and treated. This article focuses on the role of adaptive and innate immune mechanisms in the pathogenesis of celiac disease and how current concepts of immunopathogenesis might provide alternative approaches for treating celiac disease.

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Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.

Bertrand Meresse, Zhangguo Chen, Cezary Ciszewski … (2004)

A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells. These findings may not only explain previous reports of transformation of CTL into NK-like "lymphokine-activated killers" (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases.

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Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer

L.M. Sollid, H. Gjerde, J Ek … (1989)

Typing of DNA from 94 unrelated children with celiac disease (CD) with HLA-DQA1 and -DQB1 allele-specific oligonucleotide probes revealed that all but one (i.e., 98.9%) may share a particular combination of a DQA1 and a DQB1 gene. These genes are arranged in cis position on the DR3DQw2 haplotype and in trans position in DR5DQw7/DR7DQw2 heterozygous individuals. Thus, most CD patients may share the same cis- or trans- encoded HLA-DQ alpha/beta heterodimer.

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The diagnostic accuracy of serologic tests for celiac disease: a systematic review.

Navaaz Saloojee, Ann Cranney, Margaret Sampson … (2005)

Clinicians are increasingly utilizing noninvasive serologic tests for the diagnosis and screening of celiac disease (CD). The aim of this study was to conduct a systematic review of the diagnostic performance of serologic tests for the diagnosis and screening of CD. Standard systematic review methodology was used. A literature search was conducted in MEDLINE (1966 to October 2003) and EMBASE (1974 to December 2003) databases. A weighted mean of the sensitivity and specificity along with 95% confidence intervals and summary receiver operating characteristic (ROC) curves were calculated. The pooled specificity of endomyseal antibody (EMA)-monkey esophagus (ME) or EMA-human umbilical cord (HU) was close to 100% in adults and children. The pooled specificity of transglutaminase antibody (tTG)-guinea pig (GP) and tTG-human recombinant (HR) were between 95% and 99%. IgA-EMA-ME demonstrated sensitivities of 96% and 97% in children and adults, respectively. EMA-HU demonstrated a similar sensitivity of 97% in children but 90% in adults. The pooled sensitivity of tTG-GP in adults and children was 90% and 93%, respectively. The sensitivity of tTG-HR was 98% and 96%, respectively. The performance of antigliadin antibody was inferior to that of EMA and tTG. EMA and tTG offer high sensitivity and specificity. The sensitivity of these tests appears to be lower than reported when milder histologic grades are used to define CD (below 90%). If true, the nearly perfect negative predictive value of these tests would drop. The positive predictive value of these tests is likely lower than reported when the tests are applied in low-prevalence populations.