Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy.
BACKGROUND:Pathophysiological mechanisms are still incompletely understood for leprosy, an urgent public health issue in Brazil. Complement receptor 1 (CR1) binds complement fragments C3b/C4b deposited on mycobacteria, mediating its entrance in macrophages. We investigated CR1 polymorphisms, gene ex...
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ftdoajarticles:oai:doaj.org/article:88c591e6d1894eecb4511d36345d32d8 2023-05-15T15:10:54+02:00 Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy. Gabriela Canalli Kretzschmar Luana Caroline Oliveira Renato Mitsunori Nisihara Thirumalaisamy P Velavan Sérvio Túlio Stinghen Ewalda R S Stahlke Maria Luiza Petzl-Erler Iara José T de Messias-Reason Angelica Beate Winter Boldt 2018-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006705 https://doaj.org/article/88c591e6d1894eecb4511d36345d32d8 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC6103516?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006705 https://doaj.org/article/88c591e6d1894eecb4511d36345d32d8 PLoS Neglected Tropical Diseases, Vol 12, Iss 8, p e0006705 (2018) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2018 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006705 2022-12-31T12:07:05Z BACKGROUND:Pathophysiological mechanisms are still incompletely understood for leprosy, an urgent public health issue in Brazil. Complement receptor 1 (CR1) binds complement fragments C3b/C4b deposited on mycobacteria, mediating its entrance in macrophages. We investigated CR1 polymorphisms, gene expression and soluble CR1 levels in a case-control study with Brazilian leprosy patients, aiming to understand the role of this receptor in differential susceptibility to the disease. METHODOLOGY:Nine polymorphisms were haplotyped by multiplex PCR-SSP in 213 leprosy patients (47% multibacillary) and 297 controls. mRNA levels were measured by qPCR and sCR1 by ELISA, in up to 80 samples. PRINCIPAL FINDINGS:Individuals with the most common recombinant haplotype harboring rs3849266*T in intron 21 and rs3737002*T in exon 26 (encoding p.1408Met of the York Yka+ antigen), presented twice higher susceptibility to leprosy (OR = 2.43, p = 0.017). Paucibacillary patients with these variants presented lower sCR1 levels, thus reducing the anti-inflammatory response (p = 0.040 and p = 0.046, respectively). Furthermore, the most ancient haplotype increased susceptibility to the multibacillary clinical form (OR = 3.04, p = 0.01) and presented the intronic rs12034383*G allele, which was associated with higher gene expression (p = 0.043), probably increasing internalization of the parasite. Furthermore, there was an inverse correlation between the levels of sCR1 and mannose-binding lectin (initiator molecule of the lectin pathway of complement, recognized by CR1) (R = -0.52, p = 0.007). CONCLUSIONS:The results lead us to suggest a regulatory role for CR1 polymorphisms on mRNA and sCR1 levels, with haplotype-specific effects increasing susceptibility to leprosy, probably by enhancing parasite phagocytosis and inflammation. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 12 8 e0006705 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Gabriela Canalli Kretzschmar Luana Caroline Oliveira Renato Mitsunori Nisihara Thirumalaisamy P Velavan Sérvio Túlio Stinghen Ewalda R S Stahlke Maria Luiza Petzl-Erler Iara José T de Messias-Reason Angelica Beate Winter Boldt Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND:Pathophysiological mechanisms are still incompletely understood for leprosy, an urgent public health issue in Brazil. Complement receptor 1 (CR1) binds complement fragments C3b/C4b deposited on mycobacteria, mediating its entrance in macrophages. We investigated CR1 polymorphisms, gene expression and soluble CR1 levels in a case-control study with Brazilian leprosy patients, aiming to understand the role of this receptor in differential susceptibility to the disease. METHODOLOGY:Nine polymorphisms were haplotyped by multiplex PCR-SSP in 213 leprosy patients (47% multibacillary) and 297 controls. mRNA levels were measured by qPCR and sCR1 by ELISA, in up to 80 samples. PRINCIPAL FINDINGS:Individuals with the most common recombinant haplotype harboring rs3849266*T in intron 21 and rs3737002*T in exon 26 (encoding p.1408Met of the York Yka+ antigen), presented twice higher susceptibility to leprosy (OR = 2.43, p = 0.017). Paucibacillary patients with these variants presented lower sCR1 levels, thus reducing the anti-inflammatory response (p = 0.040 and p = 0.046, respectively). Furthermore, the most ancient haplotype increased susceptibility to the multibacillary clinical form (OR = 3.04, p = 0.01) and presented the intronic rs12034383*G allele, which was associated with higher gene expression (p = 0.043), probably increasing internalization of the parasite. Furthermore, there was an inverse correlation between the levels of sCR1 and mannose-binding lectin (initiator molecule of the lectin pathway of complement, recognized by CR1) (R = -0.52, p = 0.007). CONCLUSIONS:The results lead us to suggest a regulatory role for CR1 polymorphisms on mRNA and sCR1 levels, with haplotype-specific effects increasing susceptibility to leprosy, probably by enhancing parasite phagocytosis and inflammation. |
format |
Article in Journal/Newspaper |
author |
Gabriela Canalli Kretzschmar Luana Caroline Oliveira Renato Mitsunori Nisihara Thirumalaisamy P Velavan Sérvio Túlio Stinghen Ewalda R S Stahlke Maria Luiza Petzl-Erler Iara José T de Messias-Reason Angelica Beate Winter Boldt |
author_facet |
Gabriela Canalli Kretzschmar Luana Caroline Oliveira Renato Mitsunori Nisihara Thirumalaisamy P Velavan Sérvio Túlio Stinghen Ewalda R S Stahlke Maria Luiza Petzl-Erler Iara José T de Messias-Reason Angelica Beate Winter Boldt |
author_sort |
Gabriela Canalli Kretzschmar |
title |
Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy. |
title_short |
Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy. |
title_full |
Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy. |
title_fullStr |
Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy. |
title_full_unstemmed |
Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy. |
title_sort |
complement receptor 1 (cr1, cd35) association with susceptibility to leprosy. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2018 |
url |
https://doi.org/10.1371/journal.pntd.0006705 https://doaj.org/article/88c591e6d1894eecb4511d36345d32d8 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 12, Iss 8, p e0006705 (2018) |
op_relation |
http://europepmc.org/articles/PMC6103516?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006705 https://doaj.org/article/88c591e6d1894eecb4511d36345d32d8 |
op_doi |
https://doi.org/10.1371/journal.pntd.0006705 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
12 |
container_issue |
8 |
container_start_page |
e0006705 |
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1766341833223307264 |