{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:30:58Z","timestamp":1788571858807,"version":"build-2803163510"},"reference-count":27,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"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>Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin D deficiency; this is especially true for female patients. We have already been able to show that vitamin D increases the antibody-dependent cytotoxicity (ADCC) of NK cells in a sex-dependent manner, but it is unclear how vitamin D makes NK cells more efficient. Methods: Healthy individuals with vitamin D deficiency were supplemented with vitamin D to sufficient levels. NK cells were isolated from blood samples before and after vitamin D saturation. For transcriptome analysis, we used the Affymetrix Gene-Chip 2.0\u2122. Gene expression analysis as well as supervised and unsupervised pathway analysis were performed. Results: Among others the \u201cNK cell-associated cytotoxicity pathway\u201d increased after vitamin D substitution. Five IFN-\u03b1 subtypes (2, 4, 6, 7 and 10) and IFN-\u03ba were more highly expressed and are mainly responsible in these pathways. In contrast, the pathway \u201cinterferon-gamma response\u201d, as well as other sets in cytokine production and chemotaxis showed a reduction. Toll-like receptor genes (TLR-8, TLR-7, TLR-2) were downregulated and, therefore, are responsible for the decline of these pathways. The same could be shown for the \u201cubiquitin-ligase\u201d pathway. Conclusions: Increased expression of several IFN-\u03b1 subtypes may explain the increased ADCC of NK cells in vitamin D-replenished and otherwise healthy subjects. Other regulators of interferon production and ADCC are compensatory upregulated in compensation, such as Toll-like receptors and those of the ubiquitin ligase, and normalize after vitamin D substitution.<\/jats:p>","DOI":"10.3390\/nu15163498","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:38:59Z","timestamp":1691498339000},"page":"3498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Vitamin D Enhances Immune Effector Pathways of NK Cells Thus Providing a Mechanistic Explanation for the Increased Effectiveness of Therapeutic Monoclonal Antibodies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0308-388X","authenticated-orcid":false,"given":"Konstantinos","family":"Christofyllakis","sequence":"first","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Bewarder","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenz","family":"Thurner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8832-252X","authenticated-orcid":false,"given":"Dominic","family":"Kaddu-Mulindwa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor Age","family":"Kos","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Lesan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3864-8315","authenticated-orcid":false,"given":"Joerg Thomas","family":"Bittenbring","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1056\/NEJMra070553","article-title":"Vitamin D Deficiency","volume":"357","author":"Holick","year":"2007","journal-title":"N. 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