Complement Receptors in Inflammation

Complement was first discovered in 1889 as a bactericidal protein, distinct from heat stable antibodies present in normal serum. Since that time, it has been shown that the complement system is a biochemical cascade, comprised of more than 30 fluid phase and membraneassociated proteins, normally present as inactive forms. The complement system can be activated by different sequential cascades of enzymatic reactions (described below) in which proteins are sequentially cleaved and activated. The resulting effector molecules, C3a and C5a (also known as anaphylatoxins) are the most potent complement activation products, showing diverse activities on many cell types ranging from chemoattraction to apoptosis. The main target cells carry specialized complement receptors through which anaphylatoxins participate in host defense, inflammatory processes, and immune responses. The complement system plays an essential role in innate immunity by defending the host against bacterial, viral, and parasitic invasion. Complement proteins promote opsonisation and/or phagocytosis and intracellular killing of these pathogens by immune effector cells such as macrophage and neutrophils. Complement proteins, particularly those of the classical pathway, aid in the processing of immune complexes and in protection against the development of immune complex diseases such as systemic lupus erythematosus (SLE). Recently, it has become evident that the complement system also regulates adaptive immunity involving B and T cells that help in the elimination of pathogens. Furthermore, the engagement of complement receptors on antigen-presenting cells (APC) and other immune cells leads to production of immunoregulatory cytokines. Not only is complement involved in innate and adaptive immunity, it is also involved in pathological conditions. For example, in allergic disease complement proteins participate in the development of an inflammatory reaction. The complement pathways are also activated in patients with sepsis, allergic rhinitis, allergic asthma, and allergic skin conditions such as urticaria. This chapter will outline how complement proteins, C3a and C5a, and their complement receptors regulate inflammation.