Innate immunity and autoimmunity

Lead Research Organisation: MRC Immunochemistry Unit

Abstract

Animals defend themselves against microorganisms by a range of mechanisms. Proteins of the innate immune system recognise and bind to many microorganisms. The major proteins of innate immunity are the Complement system proteins, which are found in body fluids and tissues.Complement proteins recognise and bind to bacteria, viruses, fungi and to damaged host cells. Recognition occurs by interactions with charged and uncharged regions of the target surface. Once complement proteins bind, the system is activated, and a C3b, a protein, is deposited on the target surface. C3b and its derivatives are recognised by receptors on phagocytes, which destroy the target. Complement proteins may attack the hosts own tissues, causing inflammation and tissue damage. Such damage is associated with rheumatoid diseases, forms of kidney malfunction, and transplant rejection. The system has many regulatory proteins, which prevent excessive activation. A major research topic of the laboratory is to investigate the structure and activity of the regulatory proteins and receptors. This is achieved by in vitro studies with isolated proteins and cultured cells, and by investigation of genetic defects in regulatory proteins.

Technical Summary

The major part of this research programme is to investigate the structure and function of the complement and related proteins in human plasma. Complement is a major part of the immune system, and consists of about 35 soluble and cell-bound proteins which interact together to recognise invading microorganisms and damaged (apoptotic or necrotic) host cells and cell debris. Once recognition has occurred, complement proteins react to opsonise the targets, and to facilitate their clearance by phagocytic cells. Complement proteins are of major interest in many diseases, including infectious diseases, autoimmune diseases such as systemic lupus erythematosus, inflammatory tissue damage syndromes such as rheumatoid arthritis and ischaemia-reperfusion injury (stroke). Complement deficiencies are linked to a number of conditions: those of particular interest to us are haemolytic-uraemic syndrome (HUS) and acquired angio-oedema. Since 2001, we have made rapid progress in investigating aspects of how the complement system is activated by the recognition protein MBL (mannose binding lectin) which binds to targets via interaction with neutral sugars (e.g. mannose, glucosamine). Once MBL is bound, proteases named the MASPs are activated. Of these, MASP2 activates other complement proteins, but another, MASP1, does not. We have shown that MASP1 may activate the coagulation system, suggesting that localised coagulation may be contribute to innate immunity in humans, as it is known to do in invertebrates. Assay systems for both MASP enzymes have been developed in collaboration with Dr. Peter Gal (Budapest), and a convenient assay for complement system activation via MBL has been developed as an EU collaboration with Prof. M. R. Daha, Leiden. Complement proteins can recognise targets such as bacteria directly, or they may recognise antibodies already bound to the target. This is so for MBL. We have surveyed the glycan compositions of the human immunoglobulin classes, and have shown that IgG and IgA glycoforms can bind MBL as does a small subset of IgM, but IgE and IgD do not. The enzymology of another complement protease, factor I has been explored. Synthetic substrates have been identified for the first time, and the activity of the isolated serine protease domain demonstrated. Crystals of factor I have been obtained with Dr. S. Lea, Oxford, and crystallisation will be optimised to work towards structure determination. Additional collaborative work is being done to examine complement activation in stroke, mechanisms of complement activation by particulate materials, including nanomaterials and infectious microorganisms, and the mechanism by which complement factor H deficiency contributes to HUS.

Publications

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