{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T23:32:04Z","timestamp":1782862324093,"version":"3.54.5"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011958","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Tuberculosis (TB) presents a serious health problem with approximately a quarter of the world\u2019s population infected with <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>M. tuberculosis<\/jats:italic>) in an asymptomatic latent state of which 5\u201310% develops active TB at some point in their lives. The antimicrobial protein cathelicidin has broad antimicrobial activity towards viruses and bacteria including <jats:italic>M. tuberculosis<\/jats:italic>. Vitamin D increases the expression of cathelicidin in many cell types including macrophages, and it has been suggested that the vitamin D-mediated antimicrobial activity against <jats:italic>M. tuberculosis<\/jats:italic> is dependent on the induction of cathelicidin. However, unraveling the immunoregulatory effects of vitamin D in humans is hampered by the lack of suitable experimental models. We have previously described a family in which members suffer from hereditary vitamin D-resistant rickets (HVDRR). The family carry a mutation in the DNA-binding domain of the vitamin D receptor (VDR). This mutation leads to a non-functional VDR, meaning that vitamin D cannot exert its effect in family members homozygous for the mutation. Studies of HVDRR patients open unique possibilities to gain insight in the immunoregulatory roles of vitamin D in humans. Here we describe the impaired ability of macrophages to produce cathelicidin in a HVDRR patient, who in her adolescence suffered from extrapulmonary TB. The present case is a rare experiment of nature, which illustrates the importance of vitamin D in the pathophysiology of combating <jats:italic>M. tuberculosis<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1038960","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T10:02:00Z","timestamp":1667556120000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Reduced vitamin D-induced cathelicidin production and killing of Mycobacterium tuberculosis in macrophages from a patient with a non-functional vitamin D receptor: A case report"],"prefix":"10.3389","volume":"13","author":[{"given":"Fatima A. H.","family":"Al-Jaberi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia Geisler","family":"Crone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lindenstr\u00f8m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai Skovbjerg","family":"Arildsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia S\u00e6derup","family":"Lindel\u00f8v","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Aagaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Gravesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Mortensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aase Bengaard","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Olgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Xin","family":"Hjaltelin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren","family":"Brunak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte Menn\u00e9","family":"Bonefeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kongsbak-Wismann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Geisler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"B1","volume-title":"Global tuberculosis report","year":"2021"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3230","article-title":"In search of a new paradigm for protective immunity to Tb","volume":"12","author":"Nunes-Alves","year":"2014","journal-title":"Nat Rev Microbiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12217","article-title":"Beyond macrophages: The diversity of mononuclear cells in tuberculosis","volume":"262","author":"Srivastava","year":"2014","journal-title":"Immunol Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2005.00612.x","article-title":"Characterization of the tuberculous granuloma in murine and human lungs: Cellular composition and relative tissue oxygen tension","volume":"8","author":"Tsai","year":"2006","journal-title":"Cell Microbiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1011624108","article-title":"T-Cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin d metabolism","volume":"107","author":"Edfeldt","year":"2010","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B6","doi-asserted-by":"publisher","first-page":"104ra2","DOI":"10.1126\/scitranslmed.3003045","article-title":"Vitamin d is required for ifn-Gamma-Mediated antimicrobial activity of human macrophages","volume":"3","author":"Fabri","year":"2011","journal-title":"Sci Transl Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12062","article-title":"Cd40 ligand and interferon-gamma induce an antimicrobial response against mycobacterium tuberculosis in human monocytes","volume":"139","author":"Klug-Micu","year":"2013","journal-title":"Immunology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1123933","article-title":"Toll-like receptor triggering of a vitamin d-mediated human antimicrobial response","volume":"311","author":"Liu","year":"2006","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1086\/525268","article-title":"Vitamin d deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from Sub-Saharan Africa","volume":"46","author":"Gibney","year":"2008","journal-title":"Clin Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dym247","article-title":"Low serum vitamin d levels and tuberculosis: A systematic review and meta-analysis","volume":"37","author":"Nnoaham","year":"2008","journal-title":"Int J Epidemiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3201\/eid1605.091693","article-title":"Vitamin d deficiency and tuberculosis progression","volume":"16","author":"Talat","year":"2010","journal-title":"Emerg Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2010.12.1097","article-title":"Circulating levels of 25-hydroxyvitamin d and human cathelicidin in healthy adults","volume":"127","author":"Bhan","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-5-575","article-title":"Positive correlation between circulating cathelicidin antimicrobial peptide (Hcap18\/Ll-37) and 25-hydroxyvitamin d levels in healthy adults","volume":"5","author":"Dixon","year":"2012","journal-title":"BMC Res Notes"},{"key":"B14","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.clim.2014.12.003","article-title":"Pulmonary tuberculosis patients with a vitamin d deficiency demonstrate low local expression of the antimicrobial peptide ll-37 but enhanced Foxp3+ regulatory T cells and igg-secreting cells","volume":"156","author":"Rahman","year":"2015","journal-title":"Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.758154","article-title":"Normal T and b cell responses against sars-Cov-2 in a family with a non-functional vitamin d receptor: A case report","volume":"12","author":"Kongsbak-Wismann","year":"2021","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-13-22","article-title":"Vitamin d accelerates clinical recovery from tuberculosis: Results of the succinct study [Supplementary cholecalciferol in recovery from tuberculosis]. a randomized, placebo-controlled, clinical trial of vitamin d supplementation in patients with pulmonary tuberculosis\u2019","volume":"13","author":"Salahuddin","year":"2013","journal-title":"BMC Infect Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-2014-0386","article-title":"Vitamin d: Immuno-modulation and tuberculosis treatment","volume":"93","author":"Selvaraj","year":"2015","journal-title":"Can J Physiol Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-012-1997-x","article-title":"Cathelicidins: Family of antimicrobial peptides","volume":"39","author":"Ko\u015bciuczuk","year":"2012","journal-title":"A Review Mol Biol Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.16.9541","article-title":"The peptide antibiotic ll-37\/Hcap-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface","volume":"95","author":"Bals","year":"1998","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.11.7190","article-title":"Ifn-gamma- and tnf-independent vitamin d-inducible human suppression of mycobacteria: The role of cathelicidin ll-37","volume":"178","author":"Martineau","year":"2007","journal-title":"J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-3284com","article-title":"Human cathelicidin antimicrobial peptide (Camp) gene is a direct target of the vitamin d receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3","volume":"19","author":"Gombart","year":"2005","journal-title":"FASEB J"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2007.04.023","article-title":"Complex regulation of human cathelicidin gene expression: Novel splice variants and 5\u2019utr negative regulatory element","volume":"45","author":"Elloumi","year":"2008","journal-title":"Mol Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.9.3086","article-title":"The human antimicrobial and chemotactic peptides ll-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations","volume":"96","author":"Agerberth","year":"2000","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2006.12.095","article-title":"Regulation of the camp gene by 1,25(Oh)2d3 in various tissues","volume":"103","author":"Gombart","year":"2007","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803736","article-title":"Vitamin d-directed rheostatic regulation of monocyte antibacterial responses","volume":"182","author":"Adams","year":"2009","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00656","article-title":"Vitamin d counteracts mycobacterium tuberculosis-induced cathelicidin downregulation in dendritic cells and allows Th1 differentiation and ifngamma secretion","volume":"8","author":"Rode","year":"2017","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.4.2060","article-title":"Vitamin d-mediated human antimicrobial activity against mycobacterium tuberculosis is dependent on the induction of cathelicidin","volume":"179","author":"Liu","year":"2007","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00151","article-title":"Impact of vitamin d on immune function: Lessons learned from genome-wide analysis","volume":"5","author":"Chun","year":"2014","journal-title":"Front Physiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jsbmb.2005.06.002","article-title":"Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts","volume":"97","author":"van Etten","year":"2005","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-011-9195-z","article-title":"Vitamin d metabolism and signaling in the immune system","volume":"13","author":"White","year":"2012","journal-title":"Rev Endocr Metab Disord"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1186\/s12865-014-0035-2","article-title":"Vitamin d-binding protein controls T cell responses to vitamin d","volume":"15","author":"Kongsbak","year":"2014","journal-title":"BMC Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa218","article-title":"Vitamin d-regulated gene expression profiles: Species-specificity and cell-specific effects on metabolism and immunity","volume":"162","author":"Dimitrov","year":"2021","journal-title":"Endocrinology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/nrendo.2013.226","article-title":"Vitamin d and energy homeostasis: Of mice and men","volume":"10","author":"Bouillon","year":"2014","journal-title":"Nat Rev Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/bonekey.2014.5","article-title":"Mutations in the vitamin d receptor and hereditary vitamin d-resistant rickets","volume":"3","author":"Feldman","year":"2014","journal-title":"Bonekey Rep"},{"key":"B35","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.ymgme.2013.10.014","article-title":"Vitamin d receptor mutations in patients with hereditary 1,25-dihydroxyvitamin d-resistant rickets","volume":"111","author":"Malloy","year":"2014","journal-title":"Mol Genet Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxaa380","article-title":"Lessons learned from hereditary 1,25-dihydroxyvitamin d-resistant rickets patients on vitamin d functions","volume":"151","author":"Tiosano","year":"2021","journal-title":"J Nutr"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3858","article-title":"The role of vitamin d receptor in innate and adaptive immunity: A study in hereditary vitamin d-resistant rickets patients","volume":"98","author":"Tiosano","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B38","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.bone.2014.08.005","article-title":"A human vitamin d receptor mutation causes rickets and impaired Th1\/Th17 responses","volume":"69","author":"van der Eerden","year":"2014","journal-title":"Bone"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.684015","article-title":"Impaired vitamin d signaling in T cells from a family with hereditary vitamin d resistant rickets","volume":"12","author":"Al-Jaberi","year":"2021","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3201\/eid0807.010482","article-title":"Persistent high incidence of tuberculosis in immigrants in a low-incidence country","volume":"8","author":"Lillebaek","year":"2002","journal-title":"Emerg Infect Dis"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/nu12092602","article-title":"Seasonal antimicrobial activity of the airway: Post-hoc analysis of a randomized placebo-controlled double-blind trial","volume":"12","author":"Vargas Buonfiglio","year":"2020","journal-title":"Nutrients"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.15326\/jcopdf.2021.0220","article-title":"Bronchoalveolar lavage and plasma cathelicidin response to 25-hydroxy vitamin d supplementation: A pilot study","volume":"8","author":"Sanders","year":"2021","journal-title":"Chronic Obstr Pulm Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-1759(97)00084-7","article-title":"An Elisa for hcap-18, the cathelicidin present in human neutrophils and plasma","volume":"206","author":"Sorensen","year":"1997","journal-title":"J Immunol Methods"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096695","article-title":"Vitamin d up-regulates the vitamin d receptor by protecting it from proteasomal degradation in human Cd4+ T cells","volume":"9","author":"Kongsbak","year":"2014","journal-title":"PloS One"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003407","article-title":"Vitamin d induces interleukin-1\u03b2 expression: Paracrine macrophage epithelial signaling controls m. tuberculosis infection","volume":"9","author":"Verway","year":"2013","journal-title":"PloS Pathog"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.5.2909","article-title":"Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression","volume":"173","author":"Wang","year":"2004","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-021-09679-5","article-title":"Infections and immunity","volume":"23","author":"Ismailova","year":"2021","journal-title":"Rev Endocr Metab Disord"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005810","article-title":"Convergence of il-1beta and vdr activation pathways in human Tlr2\/1-induced antimicrobial responses","volume":"4","author":"Liu","year":"2009","journal-title":"PloS One"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1038960\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T10:02:04Z","timestamp":1667556124000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1038960\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,3]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2022.1038960"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1038960","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,3]]},"article-number":"1038960"}}