Elsevier

Nutrition

Volume 37, May 2017, Pages 18-21
Nutrition

Applied nutritional investigation
HMGB1 as a new biomarker of celiac disease in children: A multicenter study

https://doi.org/10.1016/j.nut.2016.12.011Get rights and content

Highlights

  • Celiac disease is a gluten-induced enteropathy of the small intestine in genetically predisposed individuals.

  • Despite the availability of specific tests, a delayed celiac disease (CD) diagnosis is common.

  • High mobility group box 1 (HMGB1) is upregulated at diagnosis in all CD children.

  • HMGB1 seems to reflect the histologic severity of disease.

Abstract

Objective

Despite the availability of specific sierology and point-of-care tests, the phenotypic heterogeneity and the symptoms fluctuation as well as the “open-window” existing among the late and silent forms cause often a delayed celiac disease (CD) diagnosis. Recently, it has been reported that high mobility group box 1 (HMGB1) mediates inflammation and gastrointestinal barrier failure. The aim of this study was to detect serum HMGB1 levels at CD diagnosis and to evaluate the relationship between serum HMGB1 levels and clinical and histologic phenotypes.

Methods

49 CD children and 44 healthy children were enrolled. Specific antitissue transglutaminase type 2, antideaminated form of gliadin antibodies, serum HMGB1 levels, and typical histopathological changes in duodenal mucosa were performed in all patients. Mucosal lesions were classified according to Marsh classification. In relation to clinical presentation, we classified patients into: typical, atypical and silent forms.

Results

Serum HMGB1 levels were significantly higher in those with CD than those in the healthy control group (P < 0.001). Significant differences in serum HMGB1 levels were detected in children with typical CD form compared to both children with atypical CD form (P < 0.001) and children with silent CD form (P < 0.001). By using the Marsh classification, significant differences were found between subjects with grade 3 B-B1 and 3 C-B2 and villous atrophy, respectively (P < 0.05). On the contrary, no significant differences in serum HMGB1 levels in subgroups of children with grade 3 A compared to grade 3 B-B1 were detected.

Conclusions

HMGB1 is upregulated at diagnosis in all CD children, especially in typical form, and reflecting the histologic severity of disease.

Introduction

Celiac disease (CD) is a gluten-induced enteropathy of the small intestine in genetically predisposed individuals [1], affecting about 1 to 3% of population worldwide. Signs and symptoms due to chronic inflammation of the small intestinal mucosa include abdominal pain, chronic diarrhea, anemia, and malnutrition [2], [3]. Despite the availability of specific serology and point-of-care tests, and the use of case-finding strategies (e.g., HLA genotyping, gluten-dependent symptoms, antitissue transglutaminase type 2, antiendomysial antibody (EMA), antideaminated forms of gliadin, and specific histologic changes) identified by the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition [4], the diagnostic algorithm has greatly improved; however, the current literature suggests that these biomarkers are insufficiently sensitive to detect the presence and the grade of histologic damage in patients with CD because they do not correlate well with histologic findings or symptoms [5]. Recently, high mobility group box 1 (HMGB1) has been proposed as a biomarker potentially able to elucidate the causative relationship between the immune system and gut mucosal inflammation, onset, and progression of gastrointestinal diseases [6]. HMGB1, a 30 kDa nuclear and cytosolic ubiquitous protein, is a marker of inflammation that belongs to the alarmins family promoting an immediate immune response to tissue damage [7]. In particular, HMGB1 is one of the most important damage-associated molecular pattern molecules, initiating and perpetuating immune responses in noninfectious and/or infectious inflammatory processes [7]. Its role is indeed to act as a “danger signal” that orchestrates a homeostatic defensive response in challenged tissues [8].

As a consequence of infection or apoptosis [9], HMGB1 exerts both an intracellular nuclear function, with an important structural role and regulation of gene transcription, and an extracellular activity, secondary to either a passive release from necrotic cells or an active production of macrophages, dendritic cells, and natural killer cells [7]. Consequently, HMGB1, by binding with its specific receptors (Toll-like receptors [TLRs] 2 and 4, and the receptor for advanced glycation end-products [RAGE]) [10], contributes to strongly up-regulating the proinflammatory immune response [11]. The HMGB1 effects associated with several critical proinflammatory mediators have stimulated an increasing interest in the field of several inflammation-associated disorders including allergic [12], [13], [14], [15], hematological [16], infective [17], endocrine [18], and gastrointestinal [6], [19], [20] diseases. In particular, HMGB1, acting as a late-acting mediator, supports alterations in gut barrier function both by increasing the permeability in enterocyte monolayer and impairing intestinal barrier function and bacterial translocation [6].

Confirming these findings, experimental and human studies conducted on models with gastrointestinal diseases (inflammatory bowel disease and colitis) [21], [22], reported that HMGB1, secreted in large quantities by inflamed intestinal tissues, once released, behaves as a cytokine-like proinflammatory molecule by up-regulating other proinflammatory mediators [23] and it also mediates inflammation and gastrointestinal barrier failure, leading to increased cell-matrix adhesiveness and impaired cellular migration [23]. Moreover, neutralizing HMGB1 activity, trough administration of natural neutralizing chemicals [24], or anti-HMGB1 antibodies [25], attenuates colon injury, reduces weight loss, and improves colon scores in experimental models of colitis.

Therefore, in light of the above-mentioned studies, suggesting that HMGB1 is an important target in proinflammatory gastrointestinal diseases, we firstly postulated that HMGB1 might also be useful as a new biomarker in CD diagnosis.

Section snippets

Subjects and experimental design

Clinical and laboratory findings of CD patients and healthy controls are summarized in Table 1.

Physical examination of each child was performed by a physician. Demographic data and other clinical characteristics of the study subjects were collected using questionnaires.

The diagnosis of CD was performed according to the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition criteria updated in 2012 [4]: Presence of specific anti-tTG-IgA or anti-DGP-IgG antibodies (in the case

Results

Serum HMGB1 levels were significantly higher in CD than in a healthy control group (serum HMGB1 levels 16.4 ± 4.2 ng/mL versus 6.23 ± 2.64 ng/mL; P < 0.001) (Table 2).

With reference to the characterization of phenotypes, significant differences in serum HMGB1 levels in children with typical CD form respective to both children with atypical CD form (22.03 ± 5.97 ng/mL versus 14.83 ± 6.11 ng/mL; P < 0.001) and children with silent form CD were detected (22.03 ± 5.97 ng/mL versus

Discussion

The aim of this study was to detect serum HMGB1 levels at CD diagnosis and to evaluate the relationship between serum HMGB1 levels and both clinical phenotype and tissue damage grade.

Although the etiology of CD is not yet clearly known, injury to epithelial cells, which act as a barrier to environmental factors invasion, could be the first step in the inflammatory process. The damage and alteration in permeability of the intestinal mucosa allows gluten molecules to penetrate inside the mucosal

Conclusions

Our data suggest that HMGB1, a proinflammatory molecule regulating innate and adaptive immune response, is upregulated and linked with severity of the histologic damage in CD. Although further studies are required to confirm these data, we believe that our findings could represent a significant contribution to clinical practice. It would be possible to hazard the hypothesis that asymptomatic children only with positive familiar history and abnormal serum anti-tTG-IgA levels as well as normal

References (30)

  • S. Husby et al.

    European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease

    J Pediatr Gastroenterol Nutr

    (2012)
  • M. Adriaanse et al.

    Serum markers in the clinical management of celiac disease

    Dig Dis

    (2015)
  • H.E. Harris et al.

    Alarmin(g) news about danger: Workshop on innate danger signals and HMGB1

    EMBO Rep

    (2006)
  • L. Campana et al.

    Requirement of HMGB1 for stromal cell-derived factor-1/CXCL12-dependent migration of macrophages and dendritic cells

    J Leukoc Biol

    (2009)
  • P. Rovere-Querini et al.

    HMGB1 is an endogenous immune adjuvant released by necrotic cells

    EMBO Rep

    (2004)
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    Study concept, design, analysis of data, and drafting of the manuscript: Leonardi S, Manti S, Cuppari C, Tardino L, Parisi G, Spina M; critical revision of the manuscript: Leonardi S, Salpietro C. All the authors are agreed to submit the paper in this version, confirming that the material is original and that it has been neither published elsewhere nor submitted for publication simultaneously. This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Conflict of interests: None.

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