Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mannose-binding lectin (MBL) is the most intensively studied human collectin. It is recognized to be a versatile macro-molecule with many of the functional characteristics of IgM, IgG and Clq. In the presence of calcium the protein can bind to a wide spectrum of oligosaccharides through multiple lectin domains. Such binding to the repeating sugar arrays on microbial surfaces may result in direct uptake by one or more collectin receptors on phagocyte surface or may trigger the activation of a pro-serine protease complex (MASP 1 and MASP 2) leading to cleavage of C4 and C2 of the classical complement pathway. Although serum levels of MBL are normally rather low (1500 micrograms/litre) there is increasing evidence that the protein plays an important role in immune defence, particularly during the phase of primary contact with a microorganism. This is suggested by the observed association of an increased incidence of infections in individuals with structural mutations in exon 1 of the MBL gene. A cluster of such mutations in codons 52, 54 and 57 lead to secondary structural abnormalities of the collagenous triple helix and a failure to form biologically functional higher order oligomers. The codon 54 mutation has been identified in several Eurasian populations whereas the codon 57 mutation is characteristic of sub-Saharan populations. One intriguing paradox arising from the MBL genotyping studies is the observation that in many populations there are surprisingly high frequencies of either the codon 54 or codon 57 mutation, suggesting that there may be some biological advantage associated with absence of the protein. Nevertheless, various groups have reported either low serum levels of MBL or an increased frequency of the structural gene mutations in patients with suspected immunodeficiencies, those with frequent unexplained infections and those with systemic lupus erythematosus. There is also evidence that the rate of progression of AIDS in HIV positive men is faster in those with such mutations. A recently published study of a consecutive series of admissions to a paediatric unit suggests that children presenting with an infectious aetiology are significantly more likely to have a MBL mutation. Moreover, this association was independent of age. Prospective studies are underway to address the questions raised by these findings.
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PMID:Mannose-binding lectin (MBL) in health and disease. 977 16

The ficolins and mannose-binding lectin (MBL) create complexes with three different serine proteases (MASP-1, MASP-2 and MASP-3) and a truncated non-enzymatic form of MASP-2 (sMAP). MASP-2 is able to activate complement by cleavage of C4 and C2, while the physiological functions of MASP-1, MASP-3 and sMAP still are debated. MASP-1 and MASP-3 are alternative spliced forms of the same MASP gene. To gain insight in the molecular variation in the MASP-1/3 gene, we undertook a systematic study of the protein coding sequences of the MASP-1/3 gene. The coding regions of the MASP-1/3 gene were sequenced in 92 healthy Caucasian donors. A total of six nucleotide substitutions were detected. Five were detected only once. One polymorphism identified in exon 10 at position +50074 (rs 38343199) relative to the transcription start site resulting in the amino acid substitution of a glycine (GGG) with a glutamic acid residue (GAG) in the second complement control protein domain was observed. The frequency of this allele in 305 blood donors, 90 patients with systemic lupus erythematosus and 234 patients with the systemic inflammatory response syndrome (SIRS) and/or sepsis was 0.03, 0.017 and 0.03 respectively. No significant differences in genotype frequencies between the groups were observed (P > 0.45). However, the SIRS/sepsis group deviated from the Hardy-Weinberg expectations due to one variant allele homozygote (P = 0.07), which was not observed in the other groups. In conclusion, the MASP1/3 gene harbours a low-frequent polymorphic site resulting in an amino acid substitution, which may influence the function of the gene product.
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PMID:A novel mannose-binding lectin-associated serine protease 1/3 gene variant. 1744 53

The complement system, composed of the three activation pathways, has both protective and pathogenic roles in the development of systemic lupus erythematosus (or lupus), a prototypic autoimmune disease. The classical pathway contributes to the clearance of immune complexes (ICs) and apoptotic cells, whereas the alternative pathway (AP) exacerbates renal inflammation. The role of the lectin pathway (LP) in lupus has remained largely unknown. Mannose-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with humoral pattern recognition molecules (MBL or ficolins), are the enzymatic constituents of the LP and AP. MASP-1 encoded by the Masp1 gene significantly contributes to the activation of the LP. After the binding of MBL/ficolins to pathogens or self-altered cells, MASP-1 autoactivates first, then activates MASP-2, and both participate in the formation of the LP C3 convertase C4b2a, whereas, MASP-3, the splice variant of the Masp1 gene, is required for the activation of the zymogen of factor D (FD), and finally participates in the formation of the AP C3 convertase C3bBb. To investigate the roles of MASP-1 and MASP-3 in lupus, we generated Masp1 gene knockout lupus-prone MRL/lpr mice (Masp1/3-/- MRL/lpr mice), lacking both MASP-1 and MASP-3, and analyzed their renal disease. As expected, sera from Masp1/3-/- MRL/lpr mice had no or markedly reduced activation of the LP and AP with zymogen forms of complement FD. Compared to their wild-type littermates, the Masp1/3-/- MRL/lpr mice had maintained serum C3 levels, little-to-no albuminuria, as well as significantly reduced glomerular C3 deposition levels and glomerular pathological score. On the other hand, there were no significant differences in the levels of serum anti-dsDNA antibody, circulating ICs, glomerular IgG and MBL/ficolins deposition, renal interstitial pathological score, urea nitrogen, and mortality between the wild-type and Masp1/3-/- MRL/lpr mice. Our data indicate that MASP-1/3 plays essential roles in the development of lupus-like glomerulonephritis in MRL/lpr mice, most likely via activation of the LP and/or AP.
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PMID:Essential Roles for Mannose-Binding Lectin-Associated Serine Protease-1/3 in the Development of Lupus-Like Glomerulonephritis in MRL/lpr Mice. 2989 4

Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with community-acquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.
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PMID:Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway. 3182 94