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Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function.
Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2012 Oct 15; Vol. 189 (8), pp. 3957-69. Date of Electronic Publication: 2012 Sep 10. - Publication Year :
- 2012
-
Abstract
- The lectin pathway of complement is an important component of innate immunity. Its activation has been thought to occur via recognition of pathogens by mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generating the C3 convertase. MASP-1 and MASP-3 are related proteases found in similar complexes. MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage. In mice, MASP-1 and MASP-3 have been reported to be central also to alternative pathway function through activation of profactor D and factor B. In this study, we present functional studies based on a patient harboring a nonsense mutation in the common part of the MASP1 gene and hence deficient in both MASP-1 and MASP-3. Surprisingly, we find that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, we find that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. We show that, although MASP-2 is able to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at physiological conditions through direct activation of MASP-2. We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that such cocomplexes are found in serum, providing a scenario for transactivation of MASP-2. Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s of the classical pathway.
- Subjects :
- Abdominal Muscles abnormalities
Abdominal Muscles enzymology
Abdominal Muscles immunology
Abnormalities, Multiple genetics
Abnormalities, Multiple immunology
Animals
Blepharoptosis genetics
Blepharoptosis immunology
Codon, Nonsense
Complement Pathway, Alternative genetics
Complement Pathway, Mannose-Binding Lectin genetics
Craniofacial Abnormalities genetics
Craniofacial Abnormalities immunology
Craniosynostoses genetics
Craniosynostoses immunology
Cryptorchidism genetics
Cryptorchidism immunology
Developmental Disabilities enzymology
Developmental Disabilities genetics
Developmental Disabilities immunology
Eye Abnormalities genetics
Eye Abnormalities immunology
Heart Defects, Congenital genetics
Heart Defects, Congenital immunology
Hip Dislocation, Congenital genetics
Hip Dislocation, Congenital immunology
Humans
Mannose-Binding Protein-Associated Serine Proteases genetics
Strabismus genetics
Strabismus immunology
Transcriptional Activation genetics
Transcriptional Activation immunology
Abnormalities, Multiple enzymology
Blepharoptosis enzymology
Complement Pathway, Alternative immunology
Complement Pathway, Mannose-Binding Lectin immunology
Craniofacial Abnormalities enzymology
Craniosynostoses enzymology
Cryptorchidism enzymology
Eye Abnormalities enzymology
Heart Defects, Congenital enzymology
Hip Dislocation, Congenital enzymology
Mannose-Binding Protein-Associated Serine Proteases physiology
Strabismus enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 189
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 22966085
- Full Text :
- https://doi.org/10.4049/jimmunol.1201736