title: 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.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. flomic@libero.it.
authors.forename: Floriana
authors.initials: F
authors.lastname: Giorgio
authors.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. b.principi@gmail.com.
authors.forename: Mariabeatrice
authors.initials: M
authors.lastname: Principi
authors.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. giuseppelos@alice.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Losurdo
authors.affiliation: Section of Pathology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. domenico.piscitelli@uniba.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Piscitelli
authors.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. ianan@hotmail.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Iannone
authors.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. michele.barone@uniba.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Barone
authors.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. annacinzia.amoruso@uniba.it.
authors.forename: Annacinzia
authors.initials: A
authors.lastname: Amoruso
authors.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. ierardi.enzo@gmail.com.
authors.forename: Enzo
authors.initials: E
authors.lastname: Ierardi
authors.affiliation: Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy. alfredo.dileo@uniba.it.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Di Leo
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002446:Celiac Disease / Q000097:blood / Q000175:diagnosis / Q000178:diet therapy / Q000276:immunology*; D017074:Common Variable Immunodeficiency / Q000097:blood / Q000175:diagnosis / Q000178:diet therapy / Q000276:immunology*; D003937:Diagnosis, Differential; D055050:Diet, Gluten-Free; D006801:Humans; D017098:IgA Deficiency / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D007136:Immunoglobulins / Q000097:blood / Q000172:deficiency*; D007422:Intestines / Q000276:immunology*; D011237:Predictive Value of Tests; D012698:Serologic Tests
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D007136:Immunoglobulins
keywords: common variable immunodeficiency; gluten-free diet; selective IgA deficiency; selective IgM deficiency; seronegative celiac disease; tissue-transglutaminase mRNA