The Ancient Complement System: Role in Physiology and Defense

Abstract

The Ancient Complement System: Role in Microbial Clearance, Lipid Transport and Prevention of Autoimmunity This study concentrates on the complement system, which is part of the nonspecific or ‘innate’ immune system. The complement system may be considered a primordial enzyme system that was, before enhancing cytolysis, primarily involved in the enhancement of transportation of ‘opsonized’ (C3b-laden) particles through the circulation towards eliminatory organs in the human body. In primates, adherence of opsonized particles to the cellular C3b-receptor (CR1) is called ‘immune adherence’. Although erythrocytes carry low numbers of CR1s on their surface, their receptors are clustered in such a way that erythrocyte ‘immune adherence’ is more efficient than on e.g. neutrophils. Because 95% of CR1s in the circulation are erythrocyte-bound, the role of erythrocytes in transport and elimination of microbes, immune complexes and tumor cells is indispensable. Our studies concerned the investigation of lectin and classical pathway proteins mannose-binding lectin (MBL) and complement factor C4. The prevalence of MBL deficiency in the Dutch population was investigated (chapter 3). The development of a hemolytic MBL assay is described, which may be of great value for the further analysis of MBL and/or MBL-associated protein deficiency (chapter 4). By adapting this functional MBL assay, microorganism-induced MBL activation could be investigated, leading to a new way of looking at MBL-activating potencies of microbes (chapter 5). As Legionella pneumophila was found capable of activating the MBL pathway, the question arose as to what the role of MBL in legionellosis might be (chapter 6). Complement factor C4 is shared by the lectin and classical complement pathways. Although synthesized mainly in the liver, the thyroid and adrenals also produce C4 transcripts for, as yet, unknown reasons. Possibly, the link between (auto)immunity and endocrine systems can be sought at the level of the diseased organ (chapter 8). By now, it is clear that the lectin and alternative pathways are the most ancient complement pathways. Possibly, these pathways constitute intimately linked parts of a single pathway, whereas the antibody-dependent ‘classical’ pathway must have evolved about 450 million years ago, when antibodies developed. Other targets of opsonization by these complement pathways may be lipoproteins and DNA. Apolipoprotein B activates the complement system via the lectin pathway, followed by lipid particle opsonization and immune adherence (chapter 7). Hypothetically, DNA may have been the target of the primitive immune system via MBL binding to pentose sugars. The complement system does not only play an important role in the immunological and microbiological field but it may be one of the key players in endocrinology and lipidology. Further research needs to be done to prove the hypotheses raised by our results.