MASP1 and MASP2

Boldt, Angelica Beate Winter; Boschmann, Stefanie Epp; Catarino, Sandra Jeremias; Andrade, Fabiana Antunes; Messias-Reason, Iara José de

doi:10.1007/978-3-319-67199-4_101714

Cited by 2 publications

(1 citation statement)

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“…MASP-1 generates bradykinin from the cleavage of high-molecular-weight kininogen (28). It also cleaves PAR4 (protease-activated receptor 4) on endothelial cells and induces MAPKp38 (mitogen activated protein kinase protein 38) and NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) proinflammatory signaling (reviewed by (29) and (30)).…”

Section: Introductionmentioning

confidence: 99%

AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

Mendes

Boldt

Stahlke

et al. 2019

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38 39 Background: Deposition of complement factors on Mycobacterium leprae 40 may enhance phagocytosis. Such deposition may occur through the lectin 41 pathway of complement. Three proteins of the lectin pathway are produced 42 from the gene MASP1: Mannan-binding lectin-associated serine protease 1 43 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 44 kDa (MAp44). Despite their obvious importance, the roles played by these 45 proteins have never been investigated in leprosy disease. Methodology: We 46 haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR 47 (intronic rs7609662*G>A and rs13064994*C>T, exon 12 3'-untranslated 48 rs72549262*C>G, rs1109452*C>T and rs850314*G>A) and measured 49 MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, 50 lepromatous) and 193 controls. Principal findings: Lower MASP-3 and 51 MAp44 levels were observed in patients, compared with controls (P=0.000252 and P<0.0001, respectively) and in lepromatous, compared with non-53 lepromatous patients (P=0.008 and P=0.002, respectively). Higher MASP-3 54 levels occurred in controls carrying variants/haplotypes associated with 55 leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG 56 and rs850314*A: OR=0.5-0.6, Pcorr=0.01-0.04). Controls with rs1109452*T, 57 included in susceptibility haplotypes (GT_GTG/GT_CTG: OR=2.0, 58 Pcorr=0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those 59 with GC_CCG, presented increasing susceptibility (OR=1.7, Pcorr=0.006) and 60 had higher MAp44 levels (P=0.015). MASP-3 expression decreased in 61 patients, compared with controls carrying rs1109452_rs850314*CA or CG 62 (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-63 3181 mRNA binding. Conclusion: Polymorphisms regulating MASP-3/MAp44 64 availability in serum modulate leprosy susceptibility, underlining the 65 importance of lectin pathway regulation against pathogens that exploit 66 phagocytosis to parasitize host macrophages. 67 68 Author summary 3 69Since immemorial times, Mycobacterium leprae inflicts permanent injuries in 70 human kind, within a wide symptomatic spectrum ranging from insensitive 71 skin patches to disabling physical lesions. Innate resistance to this parasite is 72 well recognized, but poorly understood. The complement system is one of the 73 most important arms of the innate response, and several lines of evidence 74 indicate that it may be usurped by the parasite to enhance its entrance into 75 host cells. These include our recent work on genetic association of the 76 disease with lectin pathway components and the complement receptor CR1, 77 whose polymorphisms modulate susceptibility to infection and clinical 78 presentation. Here, we add another pivotal piece in the leprosy parasite-host 79 interaction puzzle: polymorphisms and serum levels of three different lectin 80 pathway proteins, all encoded by the same gene, namely mannan-binding 81 lectin-associated serine protease 1 (MASP1). We found lower levels of two of 82 these ...

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Section: Introductionmentioning

confidence: 99%

AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

Mendes

Boldt

Stahlke

et al. 2019

Preprint

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Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus

et al. 2018

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Skin blisters of pemphigus foliaceus (PF) present concomitant deposition of autoantibodies and components of the complement system (CS), whose gene polymorphisms are associated with susceptibility to different autoimmune diseases. To investigate these in PF, we evaluated 992 single-nucleotide polymorphisms (SNPs) of 44 CS genes, genotyped through microarray hybridization in 229 PF patients and 194 controls. After excluding SNPs with minor allele frequency <1%, out of Hardy–Weinberg equilibrium in controls or in strong linkage disequilibrium (r2 ≥ 0.8), 201 SNPs remained for logistic regression. Polymorphisms of 11 genes were associated with PF. MASP1 encodes a crucial serine protease of the lectin pathway (rs13094773: OR = 0.5, p = 0.0316; rs850309: OR = 0.23, p = 0.03; rs3864098: OR = 1.53, p = 0.0383; rs698104: OR = 1.52, p = 0.0424; rs72549154: OR = 0.55, p = 0.0453). C9 (rs187875: OR = 1.46, p = 0.0189; rs700218: OR = 0.12, p = 0.0471) and C8A (rs11206934: OR = 4.02, p = 0.0323) encode proteins of the membrane attack complex (MAC) and C5AR1 (rs10404456: OR = 1.43, p = 0.0155), a potent anaphylatoxin-receptor. Two encode complement regulators: MAC-blocking CD59 (rs1047581: OR = 0.62, p = 0.0152) and alternative pathway-blocking CFH (rs34388368: OR = 2.57, p = 0.0195). One encodes opsonin: C3 (rs4807895: OR = 2.52, p = 0.0239), whereas four encode receptors for C3 fragments: CR1 (haplotype with rs6656401: OR = 1.37, p = 0.0382), CR2 (rs2182911: OR = 0.23, p = 0.0263), ITGAM (CR3, rs12928810: OR = 0.66, p = 0.0435), and ITGAX (CR4, rs11574637: OR = 0.63, p = 0.0056). Associations reinforced former findings, regarding differential gene expression, serum levels, C3, and MAC deposition on lesions. Deregulation of previously barely noticed processes, e.g., the lectin and alternative pathways and opsonization-mediated phagocytosis, also modulate PF susceptibility. The results open new crucial avenues for understanding disease etiology and may improve PF treatment through additional therapeutic targets.

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MASP1 and MASP2

Cited by 2 publications

References 106 publications

AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus

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