Complement deficiency

The complement system is part of the innate immune system consisting of about 30 proteins. An intact complement system is required for protection against infection and for maintaining the internal inflammatory homeostasis.

The immune system is divided in the innate immunity and the adaptive immunity. The adaptive immunity is specific in its action allowing for a defense against particular pathogens and provides the immune system with the ability to recognize and remember specific pathogens. This form of immunity is constantly developing throughout life in response to and as an adaption to different pathogenic organisms. In contrast, the innate immunity is inherited and acts as a first line of defense. The innate immunity includes cells and mechanisms that defend against a variety of pathogens in a non-specific mode. The complement system is an important part of part of the innate immune system.

The complement system

The complement system consists of about 30 different proteins, generally synthesized by the liver and normally circulating as inactive precursors. Stimulation by one of several trigger molecules will initiate an amplifying cascade of proteolytic cleavages. The complement can be activated by three pathways. The classical pathway is typically activated when natural or elicited antibodies (Fc) bind to antigen, but can also be activated independently of antibodies. Activation of the lectin pathway is initiated by mannose binding lectin (MBL) or ficolins recognising structures on bacteria, often carbohydrates. The alternative pathway can be activated by foreign substances such as different microbial cell wall/surface components. The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex (MAC). Complement may also act through other important mechanisms such as opsonization and chemotaxis.

Complement deficiency and infection

Deficiencies in complement predispose patients to infection basically via 2 mechanisms: (1) ineffective opsonization and (2) defects in lytic activity (defects in MAC formation). Individuals with complement deficiencies that hinder opsonization present with frequent recurrent infections and a high rate of morbidity and mortality. Deficiency of C3, the major opsonin, results in recurrent pyogenic infections, particularly with encapsulated bacteria.

Patients with a defect in formation of the MAC have a somewhat lesser degree of morbidity and mortality than, for example, patients with a defect in C3. A deficiency in a lytic component of the complement cascade is believed to actually have some protective effect against the generation of full-blown sepsis. These patients are at high risk for recurrent infection with Neisseria gonorrhoeae or Neisseria meningitidis. Severe pyogenic infections and sepsis occur in children and neonates who have a deficiency of a MAC component.

Inherited complement deficiency is a rare condition with an estimated frequency of 0.03%; excluding the lectin pathway which is much more common. Among C1-C9 components, C2 deficiency is the most common, with an incidence of 1 per 10,000 population. There is no simple and straightforward association between race and complement deficiency although ethnic predispositions have been described for certain complement deficiencies. Deficiency in C9 has been associated with an Asian racial background and is actually the most common complement deficiency in Japan (excluding the lectin pathway) with a frequency of about 0.095%.
Complement and autoimmune diseases.

In addition to susceptibility to infections there are a number of pathological conditions and diseases that are suggested to be affected by the complement system. Deficiency of the classical pathway is associated with an increased risk of developing Systemic Lupus Erythematosus (SLE). Individuals with C1q deficiency have a 93% chance of developing SLE. In Henoch-Scönlein purpura (HSP) it has been shown that complement, in particular the classical and lectin pathways, are involved in the development of the disease. Activation of the lectin pathway may contribute to the development of advanced glomerular injury in patients with HSP nephritis.

The complement system has been suggested to be involved in the pathogenesis of the ANCA –associated vasculitides (AAV). The alternative pathway, through factor C5a has been suggested to form an amplification loop for ANCA mediated neutrophil activation culminating in severe necrotizing inflammation of the blood vessels. The anti-phospholipid syndrome (APS) is a clinical condition characterized by arterial and venous thrombosis and pregnancy complications. In this autoimmune condition, complement activation plays an essential role in pregnancy loss and fetal growth restriction. Complement deficiency may counteract the effects of APS autoantibodies such as fetal injury.

Rheumatoid arthritis (RA) is affected by complement and although activation is potentially related to the occurrence of inflammation, complement deficiency may induce RA. Deficiency in the lectin pathway (MBL) seems to be associated with disease severity.  Overactivity of the alternative pathway, due to deficient complement inhibitor activity, has been implicated as a main cause of the seemingly unrelated pathologies of hemolytic uremic syndrome (HUS) and age-related macular degeneration (AMD).

In addition, complement activity may have significant effect on the appearance and development/course in a variety of different diseases such as glomerulonephritis, atherosclerosis, Crohn’s disease, Alzheimer’s disease, cardiac disease etc.  Moreover, complement activity is of significant importance in states of immune suppression resulting from transplantation and chemotherapy. The interest in complement and complement activity has grown exponentially over the last few years as a result of the increased awareness of its important implications on a large variety of diseases and clinical conditions. Accordingly, the interest in simple and accurate test methods for the assessment of complement function has grown significantly.

Relevant Literature

Literature Complement

Bouwman LH et al: Mannose-binding lectin: clinical implications for infection, transplantation, and autoimmunity. Human Immunology 67 (2006), 247-256

Ceribelli A et al. Complement Cascade in Systemic Lupus Erythematosus. Analyses of the Three Activation Pathways. Contemporary Challenges in Autoimmunity.  Ann. N.Y. Acad. Sci. 2009; 1173: 427–434

Chen M et al: The complement system in systemic autoimmune disease. J Autoimmunity, 2009

Damman J et al: Complement and renal transplantation: from donor to recipient. Transplantation 85 (2008), 923-927

Grimnes G et al: Recurrent meningococcal sepsis in a presumptive immunocompetent host shown to be complement C5 deficient—a case report. APMIS  2011

Harboe M et al. Advances in assay of complement function and activation.Advanced Drug Delivery Reviews 2011.

Manuel, O et al: Meningococcal disease in a kidney transplant recipient with mannose-binding lectin deficiency. Transplant Infectious Disease 2007;9; 214-218

Orth D et al. EspP, a Serine Protease of Enterohemorrhagic Escherichia coli Impairs Complement Activation by Cleaving Complement Factors C3/C3b and C5. Infect Immun 2010; 78

Qin X, Gao B: The complement system in Liver diseases. Cellular & Molecular Immunology, 3 (2006) 333-340

Sjöholm et al: Complement deficiency and disease: An update. Molecular Immunology 43 (2006), 78-85

Ficolin 3

Estrid Hein et al: Functional Analysis of Ficolin-3 Mediated Complement Activation. PLoS ONE | 1 November 2010 | Volume 5 | Issue 11 | e15443

Muller et al. Congenital H-ficolin deficiency in premature infants with severe necrotising enterocolitis. Gut 2011;60:1438-1439

Munthe-Fog L et al: Immunodeficiency associated with FCN3 mutation and Ficolin-3 deficiency. NEJM, 360 (2009), 2637-44

Schlapbach LJ et al: H-Ficolin serum concentration and susceptibility to fever and neutropenia in paediatric cancer patients. Clin Exp Immunol 157 (2009), 83-89