{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:27:49Z","timestamp":1787729269170,"version":"build-2784847793"},"reference-count":107,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2015,9,8]],"date-time":"2015-09-08T00:00:00Z","timestamp":1441670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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 \u201cchallenge\u201d 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\u2019 range of 15\u201325\/100 enterocytes, suggesting that there may be a \u201cgrey zone\u201d 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 (&lt;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.<\/jats:p>","DOI":"10.3390\/nu7095350","type":"journal-article","created":{"date-parts":[[2015,9,8]],"date-time":"2015-09-08T11:59:54Z","timestamp":1441713594000},"page":"7486-7504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg?"],"prefix":"10.3390","volume":"7","author":[{"given":"Floriana","family":"Giorgio","sequence":"first","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariabeatrice","family":"Principi","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7038-3287","authenticated-orcid":false,"given":"Giuseppe","family":"Losurdo","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Piscitelli","sequence":"additional","affiliation":[{"name":"Section of Pathology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Iannone","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8284-5127","authenticated-orcid":false,"given":"Michele","family":"Barone","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annacinzia","family":"Amoruso","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Ierardi","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2026-1200","authenticated-orcid":false,"given":"Alfredo","family":"Di Leo","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1001\/archinte.163.3.286","article-title":"Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study","volume":"163","author":"Fasano","year":"2003","journal-title":"Arch. 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