Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ
Background CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequenc...
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| creator | Cabral-Marques, Otavio, PhD Ramos, Rodrigo Nalio, PhD Schimke, Lena F., MD Khan, Taj Ali, PhD Amaral, Eduardo Pinheiro, PhD Barbosa Bomfim, Caio César, MSc Junior, Osvaldo Reis, MSc França, Tabata Takahashi, MSc Arslanian, Christina, BSc Carola Correia Lima, Joanna Darck, MSc Weber, Cristina Worm, MD Ferreira, Janaíra Fernandes, MD Tavares, Fabiola Scancetti, MD Sun, Jing, MD D'Imperio Lima, Maria Regina, PhD Seelaender, Marília, PhD Garcia Calich, Vera Lucia, PhD Marzagão Barbuto, José Alexandre, MD, PhD Costa-Carvalho, Beatriz Tavares, MD, PhD Riemekasten, Gabriela, MD Seminario, Gisela, MD Bezrodnik, Liliana, MD Notarangelo, Luigi, MD Torgerson, Troy R., MD, PhD Ochs, Hans D., MD Condino-Neto, Antonio, MD, PhD |
| description | Background CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. Objectives We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. Methods After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. Results Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin in macrophages from both control subjects and patients. Conclusion Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency. |
| doi_str_mv | 10.1016/j.jaci.2016.07.018 |
| format | Article |
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Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. Objectives We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. Methods After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. Results Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin in macrophages from both control subjects and patients. Conclusion Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2016.07.018</identifier><identifier>PMID: 27554817</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Allergy and Immunology ; CD40 ligand ; CD40 Ligand - deficiency ; Cells, Cultured ; Child ; Child, Preschool ; Humans ; IFN-γ ; Immunologic Deficiency Syndromes - genetics ; Immunologic Deficiency Syndromes - immunology ; Immunologic Deficiency Syndromes - metabolism ; Interferon-gamma - pharmacology ; Macrophages ; Macrophages - drug effects ; Macrophages - immunology ; Macrophages - metabolism ; Macrophages - physiology ; Male ; Monocytes - cytology ; Mycobacterium tuberculosis ; opportunistic infections ; Phagocytosis ; Transcriptome - drug effects ; Young Adult</subject><ispartof>Journal of allergy and clinical immunology, 2017-03, Vol.139 (3), p.900-912.e7</ispartof><rights>American Academy of Allergy, Asthma & Immunology</rights><rights>2016 American Academy of Allergy, Asthma & Immunology</rights><rights>Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-e13a8269d589db41de71527646d816c97ba336c79b473a609af9c75413c4a5003</citedby><cites>FETCH-LOGICAL-c488t-e13a8269d589db41de71527646d816c97ba336c79b473a609af9c75413c4a5003</cites><orcidid>0000-0001-7006-3101</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0091674916308053$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27554817$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cabral-Marques, Otavio, PhD</creatorcontrib><creatorcontrib>Ramos, Rodrigo Nalio, PhD</creatorcontrib><creatorcontrib>Schimke, Lena F., MD</creatorcontrib><creatorcontrib>Khan, Taj Ali, PhD</creatorcontrib><creatorcontrib>Amaral, Eduardo Pinheiro, PhD</creatorcontrib><creatorcontrib>Barbosa Bomfim, Caio César, MSc</creatorcontrib><creatorcontrib>Junior, Osvaldo Reis, MSc</creatorcontrib><creatorcontrib>França, Tabata Takahashi, MSc</creatorcontrib><creatorcontrib>Arslanian, Christina, BSc</creatorcontrib><creatorcontrib>Carola Correia Lima, Joanna Darck, MSc</creatorcontrib><creatorcontrib>Weber, Cristina Worm, MD</creatorcontrib><creatorcontrib>Ferreira, Janaíra Fernandes, MD</creatorcontrib><creatorcontrib>Tavares, Fabiola Scancetti, MD</creatorcontrib><creatorcontrib>Sun, Jing, MD</creatorcontrib><creatorcontrib>D'Imperio Lima, Maria Regina, PhD</creatorcontrib><creatorcontrib>Seelaender, Marília, PhD</creatorcontrib><creatorcontrib>Garcia Calich, Vera Lucia, PhD</creatorcontrib><creatorcontrib>Marzagão Barbuto, José Alexandre, MD, PhD</creatorcontrib><creatorcontrib>Costa-Carvalho, Beatriz Tavares, MD, PhD</creatorcontrib><creatorcontrib>Riemekasten, Gabriela, MD</creatorcontrib><creatorcontrib>Seminario, Gisela, MD</creatorcontrib><creatorcontrib>Bezrodnik, Liliana, MD</creatorcontrib><creatorcontrib>Notarangelo, Luigi, MD</creatorcontrib><creatorcontrib>Torgerson, Troy R., MD, PhD</creatorcontrib><creatorcontrib>Ochs, Hans D., MD</creatorcontrib><creatorcontrib>Condino-Neto, Antonio, MD, PhD</creatorcontrib><title>Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>Background CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. Objectives We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. Methods After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. Results Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin in macrophages from both control subjects and patients. Conclusion Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Allergy and Immunology</subject><subject>CD40 ligand</subject><subject>CD40 Ligand - deficiency</subject><subject>Cells, Cultured</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Humans</subject><subject>IFN-γ</subject><subject>Immunologic Deficiency Syndromes - genetics</subject><subject>Immunologic Deficiency Syndromes - immunology</subject><subject>Immunologic Deficiency Syndromes - metabolism</subject><subject>Interferon-gamma - pharmacology</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - physiology</subject><subject>Male</subject><subject>Monocytes - cytology</subject><subject>Mycobacterium tuberculosis</subject><subject>opportunistic infections</subject><subject>Phagocytosis</subject><subject>Transcriptome - 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Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cabral-Marques, Otavio, PhD</au><au>Ramos, Rodrigo Nalio, PhD</au><au>Schimke, Lena F., MD</au><au>Khan, Taj Ali, PhD</au><au>Amaral, Eduardo Pinheiro, PhD</au><au>Barbosa Bomfim, Caio César, MSc</au><au>Junior, Osvaldo Reis, MSc</au><au>França, Tabata Takahashi, MSc</au><au>Arslanian, Christina, BSc</au><au>Carola Correia Lima, Joanna Darck, MSc</au><au>Weber, Cristina Worm, MD</au><au>Ferreira, Janaíra Fernandes, MD</au><au>Tavares, Fabiola Scancetti, MD</au><au>Sun, Jing, MD</au><au>D'Imperio Lima, Maria Regina, PhD</au><au>Seelaender, Marília, PhD</au><au>Garcia Calich, Vera Lucia, PhD</au><au>Marzagão Barbuto, José Alexandre, MD, PhD</au><au>Costa-Carvalho, Beatriz Tavares, MD, PhD</au><au>Riemekasten, Gabriela, MD</au><au>Seminario, Gisela, MD</au><au>Bezrodnik, Liliana, MD</au><au>Notarangelo, Luigi, MD</au><au>Torgerson, Troy R., MD, PhD</au><au>Ochs, Hans D., MD</au><au>Condino-Neto, Antonio, MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2017-03-01</date><risdate>2017</risdate><volume>139</volume><issue>3</issue><spage>900</spage><epage>912.e7</epage><pages>900-912.e7</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><abstract>Background CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. Objectives We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. Methods After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. Results Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin in macrophages from both control subjects and patients. Conclusion Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27554817</pmid><doi>10.1016/j.jaci.2016.07.018</doi><orcidid>https://orcid.org/0000-0001-7006-3101</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0091-6749 |
| ispartof | Journal of allergy and clinical immunology, 2017-03, Vol.139 (3), p.900-912.e7 |
| issn | 0091-6749 1097-6825 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1877843618 |
| source | MEDLINE; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adolescent Adult Allergy and Immunology CD40 ligand CD40 Ligand - deficiency Cells, Cultured Child Child, Preschool Humans IFN-γ Immunologic Deficiency Syndromes - genetics Immunologic Deficiency Syndromes - immunology Immunologic Deficiency Syndromes - metabolism Interferon-gamma - pharmacology Macrophages Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Macrophages - physiology Male Monocytes - cytology Mycobacterium tuberculosis opportunistic infections Phagocytosis Transcriptome - drug effects Young Adult |
| title | Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T22%3A50%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Human%20CD40%20ligand%20deficiency%20dysregulates%20the%20macrophage%20transcriptome%20causing%20functional%20defects%20that%20are%20improved%20by%20exogenous%20IFN-%CE%B3&rft.jtitle=Journal%20of%20allergy%20and%20clinical%20immunology&rft.au=Cabral-Marques,%20Otavio,%20PhD&rft.date=2017-03-01&rft.volume=139&rft.issue=3&rft.spage=900&rft.epage=912.e7&rft.pages=900-912.e7&rft.issn=0091-6749&rft.eissn=1097-6825&rft_id=info:doi/10.1016/j.jaci.2016.07.018&rft_dat=%3Cproquest_cross%3E1877843618%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1859714967&rft_id=info:pmid/27554817&rft_els_id=S0091674916308053&rfr_iscdi=true |