Modelling of HLA-DQ2 and its interaction with gluten peptides to explain molecular recognition in celiac disease

Costantini, Susan; Rossi, Mauro; Colonna, Giovanni; Facchiano, Angelo

doi:10.1016/j.jmgm.2004.12.002

Cited by 35 publications

(21 citation statements)

References 41 publications

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“…HLA-DQ8 is formed by an α-chain encoded by HLA-DQ A1*03/01 and a β-chain encoded by HLA-DQ B1*0302. DQ2 and DQ8 chains had 91% of sequence identity for both chains (Constantini et al 2005). HLA-DQ2 is present in the vast majority of CD patients (90-95%).…”

Section: Adaptive Immune Systemmentioning

confidence: 99%

“…Recent studies on various native and modified peptides from α/β-gliadins and γ-gliadins extended the knowledge basis for understanding the binding Qiao et al 2005). The computer modeling of HLA-DQ2 and its interaction with gluten peptides could distinguish which substitutions improve the binding and showed that Glu residues interact with specific positively charged amino acids of HLA-DQ2 (Constantini et al 2005). Rather less is known about the binding motif for HLA-DQ8.…”

Section: Adaptive Immune Systemmentioning

confidence: 99%

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The Biochemical Basis of Celiac Disease

2008

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Cereal Chem. 85(1):1-13Celiac disease (CD) is an inflammatory disorder of the upper small intestine triggered by the ingestion of wheat, rye, barley, and possibly oat products. The clinical feature of CD is characterized by a flat intestinal mucosa with the absence of normal villi, resulting in a generalized malabsorption of nutrients. The prevalence of CD among Caucasians is now thought to be in a range of 1:100-300. There is a strong genetic association with human leukocyte antigens (HLA-)DQ2 and DQ8 and currently unknown non-HLA genes. During the last decade, intense biochemical studies have contributed to substantial progress in understanding the general principles that determine the pathogenesis of CD. The precipitating factors of toxic cereals are the storage proteins, termed gluten in the field of CD (gliadins and glutenins of wheat, secalins of rye, and hordeins of barley). There is still disagreement about the toxicity of oat avenins. The structural features unique to all CD toxic proteins are sequence domains rich in Gln and Pro. The high Pro content renders these proteins resistant to complete proteolytic digestion by gastrointestinal enzymes. Consequently, large Pro-and Gln-rich peptides are cumulated in the small intestine and reach the subepithelial lymphatic tissue. Depending on the amino acid sequences, these peptides can induce two different immune responses. The rapid innate response is characterized by the secretion of the cytokine interleukin-15 and the massive increase of intraepithelial lymphocytes. The slower adaptive response includes the binding of gluten peptides (native or partially deamidated by tissue transglutaminase) to HLA-DQ2 or -DQ8 of antigen presenting cells and the subsequent stimulation of T-cells accompanied by the release of proinflammatory cytokines such as interferon-γ and the activation of matrix metalloproteinases. Both immune responses result in mucosal destruction and epithelial apoptosis. Additionally, stimulated T-cells activate B-cells that produce serum IgA and IgG antibodies against gluten proteins (antigen) and tissue transglutaminase (autoantigen). These antibodies can be used for noninvasive screening tests to diagnose CD. The current essential therapy of CD is a strict lifelong adherence to gluten-free diet. Dietetic gluten-free foods produced for CD patients underlie the regulations of the Codex Alimentarius Standard for Gluten-Free Foods. The "Draft Revised Codex Standard" edited in March 2006 proposes a maximum level of 20 mg of gluten/kg for naturally gluten-free foods (e.g., based on rice or corn flour) and 200 mg/kg for foods rendered gluten-free (e.g., wheat starch). Numerous analytical methods for gluten determination have been developed, mostly based on immunochemical assays, mass spectrometry, or polymerase chain reaction. So far, only two enzyme-linked immunosorbent assays have been successfully ring-tested and are commercially available. During the last decade, future strategies for prevention and treatment of CD have been proposed. They are based...

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Section: Adaptive Immune Systemmentioning

confidence: 99%

Section: Adaptive Immune Systemmentioning

confidence: 99%

The Biochemical Basis of Celiac Disease

2008

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“…In particular, for example, HLA-DQA1*0501 is strongly associated with celiac disease, in which a specific deamidated gliadin peptide binds preferentially to the antigenbinding pocket created by HLA-DQA1*0501 and HLA-DQB1*0201 from where the antigen is most efficiently presented to T cells. 13 Thus, the rarity of membranous nephropathy might be the result not of rare PLA2R1 polymorphisms but of the infrequent concurrence of common PLA2R1 variants in individuals predisposed to autoimmunity and positive for an HLA-DQ2 haplotype that includes particular alleles of HLA-DQA1 and HLA-DRB1 or HLA-DQB1.…”

Section: Nonementioning

confidence: 99%

Genetic Variants in Membranous Nephropathy

Salant

2013

Journal of the American Society of Nephrology

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“…The CVFF force field within the Discover module of Insight II was used to assign potentials and charges, and a mild energy minimization was applied, by performing 500 steps under the conjugate gradient algorithm, in order to optimise the interaction between the two sea bream protein chains and avoid sterical clashes according to the procedure used in our previous similar work [29].…”

Section: Modelling Of Sea Bream Cd8aa Homodimermentioning

confidence: 99%

Molecular modelling of co-receptor CD8αα and its complex with MHC class I and T-cell receptor in sea bream (Sparus aurata)

Costantini

Buonocore

Facchiano

2008

Fish & Shellfish Immunology

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T-cells are the main actors of cell-mediated immune defence; they recognize and respond to peptide antigens associated with MHC class I and class II molecules. In this paper, we investigated by molecular modelling methods in the teleost sea bream (Sparus aurata) the interaction among the molecules of the tertiary complex CD8/MHC-I/TCR, which determines the T-cell-mediated immunological response to foreign molecules. First, we predicted the three-dimensional structure of CD8 alpha alpha dimer and MHC-I, and, successively, we simulated the CD8 alpha alpha/MHC-I complex. Finally, the 3D structure of the CD8/MHC-I/TCR complex was simulated in order to investigate the possible changes that can influence TCR signalling events.

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Modelling of HLA-DQ2 and its interaction with gluten peptides to explain molecular recognition in celiac disease

Cited by 35 publications

References 41 publications

The Biochemical Basis of Celiac Disease

The Biochemical Basis of Celiac Disease

Genetic Variants in Membranous Nephropathy

Molecular modelling of co-receptor CD8αα and its complex with MHC class I and T-cell receptor in sea bream (Sparus aurata)

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