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  • Review Article
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Tissue-mediated control of immunopathology in coeliac disease

Key Points

  • Coeliac disease is a T cell-mediated enteropathy that has an autoimmune component and is induced by dietary wheat gluten. The ability to access to the targeted tissue during active (from patients on a gluten-containing diet) and non-active (from patients on a gluten-free diet) disease conditions makes it a unique human model to obtain insights into autoimmune disorders.

  • Coeliac disease is a multigenic complex immune disorder. The main genetic factors associated with coeliac disease are the MHC class II genes that encode HLA-DQ2 and HLA-DQ8. They contribute to at least 30% of the genetic heritability of the disease; the non-HLA genes identified to date contribute to only 3–4%.

  • The tissue enzyme transglutaminase 2 requires inflammatory signals to become activated in the tissue environment. Once it is activated, it deamidates gluten peptides, introducing negative charges that increase the binding affinity of the gluten peptides for HLA-DQ2 and HLA-DQ8.

  • Resistance to proteolytic cleavage and post-translational modifications of gluten, combined with particular physicochemical properties of HLA-DQ2 and HLA-DQ8 molecules, provide the basis for the association of coeliac disease with HLA-DQ2 or HLA-DQ8.

  • The presence of inflammatory mediators in the tissue environment may explain why intestinal dendritic cells induce an inflammatory response instead of a regulatory gluten-specific immune response; their presence may also explain why effector T cells become resistant to the inhibitory effects of regulatory T cells.

  • Intraepithelial cytotoxic lymphocytes require signals from target tissue cells to become licensed killer cells and to mediate tissue damage. In particular, interleukin-15 and non-classical MHC molecules expressed by intestinal epithelial cells reduce the activation threshold and promote the lytic activity of cytotoxic T cells by upregulating and activating natural killer cell receptors.

Abstract

Coeliac disease is an inflammatory disorder with autoimmune features that is characterized by destruction of the intestinal epithelium and remodelling of the intestinal mucosa following the ingestion of dietary gluten. A common feature of coeliac disease and many organ-specific autoimmune diseases is a central role for T cells in causing tissue destruction. In this Review, we discuss the emerging hypothesis that, in coeliac disease, intestinal tissue inflammation — induced either by infectious agents or by gluten — is crucial for activating T cells and eliciting their tissue-destructive effector functions.

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Figure 1: Effects of gluten on intestinal epithelial cells and antigen-presenting cells.
Figure 2: The importance of threshold for induction of pathogenic gluten-specific CD4+ T cells.
Figure 3: Induction of an inflammatory anti-gluten immune response following gluten ingestion may result from alteration of intestinal dendritic cells by inflammatory tissue signals.
Figure 4: Gluten-specific CD4+ T cells contribute to the inflammatory environment required for activation of pathogenic intraepithelial cytotoxic T lymphocytes.
Figure 5: Intraepithelial cytotoxic T lymphocytes require a second hit in the intestinal environment to become licensed killer cells.

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Acknowledgements

We thank patients with coeliac disease and their family members for their support of our research. We also thank the present and former members of our laboratories for their contributions to the work cited. Thanks are especially extended to V. Abadie for help with preparation of the figures. The work was supported by the US National Institutes of Health (grants RO1DK063158, RO1DK58727, P30DK42086), the Research Council of Norway, the European Commission FP7 programme, the South-Eastern Norway Regional Health Authority, the Juvenile Diabetes Research Foundation and the Norwegian Foundation for Health and Rehabilitation.

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Glossary

Gluten

Wheat proteins that are not tolerated by people with coeliac disease. Similar proteins exist in barley and rye. Gluten consists of proline- and glutamine-rich gliadin and glutenin subcomponents.

Villi

Projections into the lumen that have an outer layer that mainly consists of mature, absorptive enterocytes and also contain mucus-secreting goblet cells.

Crypts

Tubular invaginations of the intestinal epithelium. At the base of the crypts there are paneth cells, which produce bactericidal defensins, and stem cells, which continuously divide and are the source of all intestinal epithelial cells.

Regulatory T (TReg)cell

A specialized subpopulation of CD4+ T cells that can suppress the effector responses of other T cells. They are characterized by the expression of the transcription factor forkhead box P3 (FOXP3).

Linkage disequilibrium

The nonrandom association of alleles at distinct loci owing to close physical proximity of the loci and a lack of recombination between them.

T helper 1 cell

(TH1 cell). CD4+ T cells that produce interferon and tumour necrosis factor and support cell-mediated immunity.

Mesenteric lymph nodes

Lymph nodes located at the base of the mesentery. They collect lymph (including cells and antigens) draining from the intestinal mucosa.

Intraepithelial lymphocyte

(IEL). A T cell that resides in the basolateral side of the intestinal epithelium. IELs express either an αβ T cell receptor (TCR) or a γδ TCR.

Interleukin-15

(IL-15). A pro-inflammatory cytokine that is trans-presented by the IL-15 receptor α-chain to neighbouring cells that express the IL-2 or IL-15 receptor β-chain and common γ-chain (γc). It is best known for its role in the development and/or survival of natural killer cells and memory CD8+ T cells. However, it is now recognized that IL-15 also enhances the effector functions of natural killer and cytotoxic T cells.

Leader peptides

(Also known as signal sequences). Hydrophobic amino acid sequences that signal for proteins to translocate to the endoplasmic reticulum. The leader peptide is cleaved before a protein is transported from the cell.

HLA-E

A human non-classical MHC class I molecule that is composed of the HLA-E heavy chain, β2-microglobulin, and a peptide that is often derived from the leader peptides of other MHC class I polypeptides or from certain microbial pathogens. HLA-E is recognized by CD94–NKG2 receptors.

CD94–NKG2C

An activating C-type lectin natural killer cell receptor that is expressed by natural killer cells (under normal conditions) and some T cells (under pathological conditions).

Polyinosinic–polycytidylic acid

(PolyI:C). A substance that is used as a mimic of viral double-stranded RNA.

Non-obese diabetic (NOD) mice

A strain of mouse that spontaneously develops idiopathic autoimmune diabetes that closely resembles type 1 diabetes in humans and involves autoreactive T cell-mediated destruction of pancreatic β-islet cells. The main component of susceptibility is the MHC haplotype H2g7.

Oral tolerance

Induction of peripheral immune tolerance by oral administration of antigen. Oral tolerance is now linked to the induction of forkhead box P3 (FOXP3)+ regulatory T cells.

Lamina propria

The layer of mucosal tissue directly beneath the mucosal epithelial cell surface, in which effector cells for mucosal immunity reside.

Plasmacytoid dendritic cell

(Plasmacytoid DC). An immature DC with a morphology that resembles that of a plasma cell. Plasmacytoid DCs produce large quantities of type I interferons (that is, interferon-α and interferon-β) after activation: for example, when stimulated through Toll-like receptors.

Intraepithelial cytotoxic T lymphocytes

(Intraepithelial CTLs). Cytotoxic CD8+ T cells found in the epithelial layer that lines mucosal surfaces. Their main role is to maintain the integrity of the mucosa by eliminating infected epithelial cells.

Immune complex

Complexes of antigen bound to antibody and, sometimes, components of the complement system. The levels of immune complexes are increased in many autoimmune disorders, in which they become deposited in tissues and cause tissue damage.

NKG2D

(Natural killer group 2, member D). A co-activating C-type lectin natural killer cell receptor that is expressed by human cytotoxic T cells, innate-like T cells and NK cells.

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Jabri, B., Sollid, L. Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 9, 858–870 (2009). https://doi.org/10.1038/nri2670

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