Protease Found Crucial for First-Line Immune Defense Complement Activation Pathway
By LabMedica International staff writers Posted on 04 Dec 2012 |
Scientists have established a lectin-associated protease to be central to the complement pathway activation. The discovery answers a long-standing question in immunology and opens new possibilities for manipulating the immune system in medical therapy.
In an international collaboration with scientists in the USA and Turkey, scientists at Denmark’s Aarhus University (Aarhus, Denmark) led the study mapping the mechanism underlying the lectin-pathway central to complement pathway activation. Activation of the lectin pathway of complement has been thought to occur via recognition of pathogens via mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine proteases (MASPs).
Using blood samples from a unique patient harboring a rare genetic syndrome, the researchers have now established that it is the enzyme MASP-1 that is key to activation of the complement system. In mice, MASP-1 and MASP-3 had been previously reported to be central also to alternative pathway function. The patient in the current study harbors a nonsense mutation in the common part of the MASP1 gene and hence is deficient in both MASP-1 and MASP-3. Surprisingly, the researchers found that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, they found that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. Additional findings further established the central role of MASP-1. MASP-1 is able to efficiently auto-activate, for example when it senses a bacterium; it then activates MASP-2, which in turn activates the rest of the complement system cascade that attacks the bacteria.
The discovery may have implications for the treatment of various medical conditions, including cancer and stroke patients. "For example this system is important for the survival of patients undergoing chemotherapy, because this treatment suppresses other functions of the immune system - so in their case it is beneficial to "rev up" the system.
But following a heart attack there may be reasons to instead dampen the system. The complement system has an unfortunate tendency to attack tissues that have suffered damage due to deprivation of oxygen, and thereby it exacerbates the damage already done to the heart,” explained Dr. Soeren Egedal Degn, first author and postdoc at Aarhus University.
The findings were published October 15, 2012, in the Journal of Immunology.
Related Links:
Aarhus University
In an international collaboration with scientists in the USA and Turkey, scientists at Denmark’s Aarhus University (Aarhus, Denmark) led the study mapping the mechanism underlying the lectin-pathway central to complement pathway activation. Activation of the lectin pathway of complement has been thought to occur via recognition of pathogens via mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine proteases (MASPs).
Using blood samples from a unique patient harboring a rare genetic syndrome, the researchers have now established that it is the enzyme MASP-1 that is key to activation of the complement system. In mice, MASP-1 and MASP-3 had been previously reported to be central also to alternative pathway function. The patient in the current study harbors a nonsense mutation in the common part of the MASP1 gene and hence is deficient in both MASP-1 and MASP-3. Surprisingly, the researchers found that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, they found that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. Additional findings further established the central role of MASP-1. MASP-1 is able to efficiently auto-activate, for example when it senses a bacterium; it then activates MASP-2, which in turn activates the rest of the complement system cascade that attacks the bacteria.
The discovery may have implications for the treatment of various medical conditions, including cancer and stroke patients. "For example this system is important for the survival of patients undergoing chemotherapy, because this treatment suppresses other functions of the immune system - so in their case it is beneficial to "rev up" the system.
But following a heart attack there may be reasons to instead dampen the system. The complement system has an unfortunate tendency to attack tissues that have suffered damage due to deprivation of oxygen, and thereby it exacerbates the damage already done to the heart,” explained Dr. Soeren Egedal Degn, first author and postdoc at Aarhus University.
The findings were published October 15, 2012, in the Journal of Immunology.
Related Links:
Aarhus University
Latest BioResearch News
- Genome Analysis Predicts Likelihood of Neurodisability in Oxygen-Deprived Newborns
- Gene Panel Predicts Disease Progession for Patients with B-cell Lymphoma
- New Method Simplifies Preparation of Tumor Genomic DNA Libraries
- New Tool Developed for Diagnosis of Chronic HBV Infection
- Panel of Genetic Loci Accurately Predicts Risk of Developing Gout
- Disrupted TGFB Signaling Linked to Increased Cancer-Related Bacteria
- Gene Fusion Protein Proposed as Prostate Cancer Biomarker
- NIV Test to Diagnose and Monitor Vascular Complications in Diabetes
- Semen Exosome MicroRNA Proves Biomarker for Prostate Cancer
- Genetic Loci Link Plasma Lipid Levels to CVD Risk
- Newly Identified Gene Network Aids in Early Diagnosis of Autism Spectrum Disorder
- Link Confirmed between Living in Poverty and Developing Diseases
- Genomic Study Identifies Kidney Disease Loci in Type I Diabetes Patients
- Liquid Biopsy More Effective for Analyzing Tumor Drug Resistance Mutations
- New Liquid Biopsy Assay Reveals Host-Pathogen Interactions
- Method Developed for Enriching Trophoblast Population in Samples