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Open AccessReview

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