Biallelic TLR4 deficiency in humans
<h3>Background </h3><p dir="ltr">Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins. </p>&...
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2023
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| _version_ | 1864513507102294016 |
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| author | Melania Capitani (17238355) |
| author2 | Ahmad A. Al-Shaibi (19482409) Sumeet Pandey (7010018) Lisa Gartner (19482412) Henry Taylor (6737321) Satanay Z. Hubrack (19482415) Nourhen Agrebi (14151222) Muneera Jassim Al-Mohannadi (14166138) Saad Al Kaabi (18112780) Thomas Vogl (125044) Johannes Roth (125060) Daniel Kotlarz (6473711) Christoph Klein (157998) Adrian K. Charles (15084250) Vinayan Vijayakumar (19482418) Mohammed Yousuf Karim (8602092) Bruce George (19482421) Simon P. Travis (19482424) Mamoun Elawad (438979) Bernice Lo (3441317) Holm H. Uhlig (8163909) |
| author2_role | author author author author author author author author author author author author author author author author author author author author |
| author_facet | Melania Capitani (17238355) Ahmad A. Al-Shaibi (19482409) Sumeet Pandey (7010018) Lisa Gartner (19482412) Henry Taylor (6737321) Satanay Z. Hubrack (19482415) Nourhen Agrebi (14151222) Muneera Jassim Al-Mohannadi (14166138) Saad Al Kaabi (18112780) Thomas Vogl (125044) Johannes Roth (125060) Daniel Kotlarz (6473711) Christoph Klein (157998) Adrian K. Charles (15084250) Vinayan Vijayakumar (19482418) Mohammed Yousuf Karim (8602092) Bruce George (19482421) Simon P. Travis (19482424) Mamoun Elawad (438979) Bernice Lo (3441317) Holm H. Uhlig (8163909) |
| author_role | author |
| dc.creator.none.fl_str_mv | Melania Capitani (17238355) Ahmad A. Al-Shaibi (19482409) Sumeet Pandey (7010018) Lisa Gartner (19482412) Henry Taylor (6737321) Satanay Z. Hubrack (19482415) Nourhen Agrebi (14151222) Muneera Jassim Al-Mohannadi (14166138) Saad Al Kaabi (18112780) Thomas Vogl (125044) Johannes Roth (125060) Daniel Kotlarz (6473711) Christoph Klein (157998) Adrian K. Charles (15084250) Vinayan Vijayakumar (19482418) Mohammed Yousuf Karim (8602092) Bruce George (19482421) Simon P. Travis (19482424) Mamoun Elawad (438979) Bernice Lo (3441317) Holm H. Uhlig (8163909) |
| dc.date.none.fl_str_mv | 2023-03-03T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.jaci.2022.08.030 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Biallelic_TLR4_deficiency_in_humans/26830192 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Inflammatory bowel disease primary immunodeficiency |
| dc.title.none.fl_str_mv | Biallelic TLR4 deficiency in humans |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background </h3><p dir="ltr">Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins. </p><h3>Objective </h3><p dir="ltr">We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency. </p><h3>Methods </h3><p dir="ltr">We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays. </p><h3>Results </h3><p dir="ltr">We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). A third individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact. </p><h3>Conclusions </h3><p dir="ltr">Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Allergy and Clinical Immunology<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.jaci.2022.08.030" target="_blank">https://dx.doi.org/10.1016/j.jaci.2022.08.030</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_8a30036c972447b4e38b3283a17684ee |
| identifier_str_mv | 10.1016/j.jaci.2022.08.030 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26830192 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Biallelic TLR4 deficiency in humansMelania Capitani (17238355)Ahmad A. Al-Shaibi (19482409)Sumeet Pandey (7010018)Lisa Gartner (19482412)Henry Taylor (6737321)Satanay Z. Hubrack (19482415)Nourhen Agrebi (14151222)Muneera Jassim Al-Mohannadi (14166138)Saad Al Kaabi (18112780)Thomas Vogl (125044)Johannes Roth (125060)Daniel Kotlarz (6473711)Christoph Klein (157998)Adrian K. Charles (15084250)Vinayan Vijayakumar (19482418)Mohammed Yousuf Karim (8602092)Bruce George (19482421)Simon P. Travis (19482424)Mamoun Elawad (438979)Bernice Lo (3441317)Holm H. Uhlig (8163909)Biological sciencesGeneticsBiomedical and clinical sciencesClinical sciencesImmunologyInflammatory bowel diseaseprimary immunodeficiency<h3>Background </h3><p dir="ltr">Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins. </p><h3>Objective </h3><p dir="ltr">We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency. </p><h3>Methods </h3><p dir="ltr">We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays. </p><h3>Results </h3><p dir="ltr">We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). A third individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact. </p><h3>Conclusions </h3><p dir="ltr">Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Allergy and Clinical Immunology<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.jaci.2022.08.030" target="_blank">https://dx.doi.org/10.1016/j.jaci.2022.08.030</a></p>2023-03-03T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.jaci.2022.08.030https://figshare.com/articles/journal_contribution/Biallelic_TLR4_deficiency_in_humans/26830192CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/268301922023-03-03T03:00:00Z |
| spellingShingle | Biallelic TLR4 deficiency in humans Melania Capitani (17238355) Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Inflammatory bowel disease primary immunodeficiency |
| status_str | publishedVersion |
| title | Biallelic TLR4 deficiency in humans |
| title_full | Biallelic TLR4 deficiency in humans |
| title_fullStr | Biallelic TLR4 deficiency in humans |
| title_full_unstemmed | Biallelic TLR4 deficiency in humans |
| title_short | Biallelic TLR4 deficiency in humans |
| title_sort | Biallelic TLR4 deficiency in humans |
| topic | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Inflammatory bowel disease primary immunodeficiency |