Applied nutritional investigationHMGB1 as a new biomarker of celiac disease in children: A multicenter study
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)
- et al.
Celiac disease and autoimmunity in the gut and elsewhere
Gastroenterol Clin North Am
(2008) - et al.
HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice
Gastroenterology
(2002) - et al.
Sputum high mobility group box-1 in asthmatic children: A noninvasive sensitive biomarker reflecting disease status
Ann Allergy Asthma Immunol
(2015) - et al.
Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: High-mobility group box 1 (HMGB1) between inflammation and infection
Clin Microbiol Infect
(2015) - et al.
Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer
Biochem Biophys Res Commun
(2007) - et al.
Extracellular high mobility group box-1 (HMGB1) inhibits enterocyte migration via activation of Toll-like receptor-4 and increased cell-matrix adhesiveness
J Biol Chem
(2010) - et al.
Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium
Am J Pathol
(2002) - et al.
Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease
Lancet
(2003) - et al.
The spectrum of celiac disease: Epidemiology, clinical aspects and treatment
Nat Rev Gastroenterol Hepatol
(2010) - et al.
The Oslo definitions for coeliac disease and related terms
Gut
(2013)
European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease
J Pediatr Gastroenterol Nutr
Serum markers in the clinical management of celiac disease
Dig Dis
Alarmin(g) news about danger: Workshop on innate danger signals and HMGB1
EMBO Rep
Requirement of HMGB1 for stromal cell-derived factor-1/CXCL12-dependent migration of macrophages and dendritic cells
J Leukoc Biol
HMGB1 is an endogenous immune adjuvant released by necrotic cells
EMBO Rep
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HMGB1 is related to disease activity in children with celiac disease
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2018, Digestive and Liver DiseaseCitation Excerpt :HMGB1 is a protein included in a group of endogenous molecules (also known as alarmins or damage-associated molecular patterns) with intestinal and systemic pro-inflammatory properties when secreted in the extracellular milieu [9]. HMGB1 serum levels have recently been shown to have increased in CD at diagnosis helping to characterize patients according to their phenotypical subtype [10]. In this preliminary report we investigated the usefulness of faecal HMGB1 as a non-invasive marker in the diagnosis and in the follow-up of children with CD.
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2017, NutritionCitation Excerpt :Recently, high mobility group box 1 (HMGB1) has been proposed as biomarker potentially able to elucidate the causative relationship between the immune system and gut mucosal inflammation and onset and progression of gastrointestinal (GI) diseases [13]. First, we investigated HMGB1 in patients with CD, and we found this alarmin to be upregulated at diagnosis in all children with CD, especially in typical form, reflecting the histologic severity of disease as well as correlating with the Marsh-Oberhuber (MO) classification [14]. Therefore, HMGB1 appeared to reflect faithfully the different CD phenotypes.
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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.