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Nutrients 2015, 7(9), 7486-7504; doi:10.3390/nu7095350

Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg?

1
Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
2
Section of Pathology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
*
Author to whom correspondence should be addressed.
Received: 28 May 2015 / Revised: 27 August 2015 / Accepted: 2 September 2015 / Published: 8 September 2015
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
View Full-Text   |   Download PDF [138 KB, uploaded 8 September 2015]

Abstract

In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten “challenge” are the most reliable markers. Immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of SNCD patients may be useful. In our experience, tTG-mRNA was similarly increased in seropositive celiac disease (CD) and suspected SNCD, and strongly correlated with the IELs count. This increase is found even in the IELs’ range of 15–25/100 enterocytes, suggesting that there may be a “grey zone” of gluten-related disorders. An immune deregulation (severely lacking B-cell differentiation) underlies the association of SNCD with immunoglobulin deficiencies. Therefore, CD may be linked to autoimmune disorders and immune deficits (common variable immunodeficiency (CVID)/IgA selective deficiency). CVID is a heterogeneous group of antibodies dysfunction, whose association with CD is demonstrated only by the response to a gluten-free diet (GFD). We hypothesized a familial inheritance between CD and CVID. Selective IgA deficiency, commonly associated with CD, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare (<300 cases) and associated to CD in 5% of cases. We diagnosed SNCD in a patient affected by sIgMD using the tTG-mRNA assay. One-year GFD induced IgM restoration. This evidence, supporting a link between SNCD and immunoglobulin deficiencies, suggests that we should take a closer look at this association. View Full-Text
Keywords: seronegative celiac disease; tissue-transglutaminase mRNA; common variable immunodeficiency; selective IgA deficiency; selective IgM deficiency; gluten-free diet seronegative celiac disease; tissue-transglutaminase mRNA; common variable immunodeficiency; selective IgA deficiency; selective IgM deficiency; gluten-free diet
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Giorgio, F.; Principi, M.; Losurdo, G.; Piscitelli, D.; Iannone, A.; Barone, M.; Amoruso, A.; Ierardi, E.; Di Leo, A. Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg? Nutrients 2015, 7, 7486-7504.

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