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

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.

• Authors: Floriana Giorgio, Mariabeatrice Principi, Giuseppe Losurdo, Domenico Piscitelli, Andrea Iannone, Michele Barone, Annacinzia Amoruso, Enzo Ierardi, Alfredo Di Leo
• Journal: Nutrients (Nutrients) Vol. 7 Issue 9 Pg. 7486-504 (Sep 08 2015) ISSN: 2072-6643 [Electronic] Switzerland
• PMID: 26371035 (Publication Type: Journal Article, Review)

Chemical References

• Autoantibodies
• Biomarkers
• Immunoglobulins

Topics

• Animals
• Autoantibodies (blood)
• Biomarkers (blood)
• Celiac Disease (blood, diagnosis, diet therapy, immunology)
• Common Variable Immunodeficiency (blood, diagnosis, diet therapy, immunology)
• Diagnosis, Differential
• Diet, Gluten-Free
• Humans
• IgA Deficiency (blood, diagnosis, immunology)
• Immunoglobulins (blood, deficiency)
• Intestines (immunology)
• Predictive Value of Tests
• Serologic Tests