Complemento fallas

mpleComplement disorders and hereditary angioedema
Michael M. Frank, MD Durham, NC

The term complement was introduced more than 100 years ago to refer to a group of plasma factors important in host defense and in the destruction of microorganisms. We now know that there are 3 separate activation pathways that appeared at different times in evolution: the classical, alternative, and lectinpathways. Two of these appear before the evolution of the adaptive immune system and do not require antibody for initiation. All pathways come together to activate C3, the principle opsonic protein of the complement cascade, and all continue together to the generation of biologically active factors, such as C5a, and to lysis of cells and microbes. In general, complete deficiencies of complementproteins are rare, although partial or complete deficiencies of one of the proteins that initiates the lectin pathway, mannose-binding lectin, are far more common. Although genetically controlled complement defects are rare, defects in the proteins in the circulation and on cell membranes that downregulate complement so as to limit uncontrolled inflammation are more common. A number of these arediscussed, and because new methods of treatment are currently being introduced, one of these defects, CI inhibitor deficiency associated with hereditary angioedema, is discussed in some detail. (J Allergy Clin Immunol 2010;125:S262-71.) Key words: Complement, complement deficiencies, hereditary angioedema, atypical hemolytic uremic syndrome

Abbreviations used C1-INH: C1 inhibitor C’: complement FDA: USFood and Drug Administration HAE: Hereditary angioedema iC3b: Inactivated C3b MASP: Mannose-binding lectin–associated serine protease MBL: Mannose-binding lectin MCP: Membrane cofactor protein PNH: Paroxysmal nocturnal hemoglobinuria

Complement is a term originally introduced a hundred years ago to define a group of factors present in fresh plasma that, when activated by a specific antibody, wereable to kill microorganisms.1 Later work showed the bacteria studied were lysed and that the killing principle was heat labile. We now define complement as a collective term for a group of about 30 known proteins and protein regulators, some of which circulate in the blood and some of which are cell membrane bound. The complement proteins play a major role in host defense and innate immunity.Although all of the early studies focused on the role of complement in host defense, in recent years, we have learned that complement is also important in the generation of a normal immune response. Phylogenetically, the complement proteins are ancient, serving a host defense function even in primitive animals in the absence of any adaptive immune system. The adaptive immune system appears in evolutionat the level of the fish, and by this point in evolution, all the various complement proteins are arrayed to produce their regulatory and host defense functions.2 We have come to recognize 3 pathways of complement activation (Fig 1).3,4 The first pathway was defined almost a
From the Department of Pediatrics, Duke University Medical Center. Disclosure of potential conflict of interest: M. Frank is aconsultant for Viropharma, CSL Behring, and Dyax. Received for publication July 13, 2009; revised October 1, 2009; accepted for publication October 7, 2009. Reprint requests: Michael Frank, MD, Box 2611 Room 131 MSRB, Duke University Medical Center, Durham NC, 27710. E-mail: frank007@mc.duke.edu. 0091-6749/$36.00 Ó 2010 American Academy of Allergy, Asthma & Immunologydoi:10.1016/j.jaci.2009.10.063

century ago and, for this reason, is termed the classical pathway. This pathway is usually activated by antibody and was the first pathway identified because of its ability to kill antibody-sensitized bacteria. A second pathway, now termed the alternative pathway, was first observed in the 1950s but was studied in detail in the 1970s and 1980s.5 The alternative pathway has been shown to be...