Complement deficiency

Abstract: The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

Abstract: Complete deficiency of C1q is almost invariably associated with the development of systemic lupus erythematosus. It has been suggested that this association may result from a generalized failure to clear Ag-Ab complexes. However, it has not been demonstrated how such a broad impairment results in this specific and consistent autoimmune phenotype, in which photosensitive skin disease is the most prominent manifestation. We believe there is another role for the classical pathway in maintaining immune tolerance. Surface blebs of apoptotic keratinocytes are concentrated sources of autoantigens, and these packages may define a novel immune context and challenge self-tolerance if not properly cleared and processed. We demonstrate here that when human keratinocytes are rendered apoptotic, they also develop the capacity to specifically and directly bind to C1q in the absence of Ab. C1q may mediate Ab-independent clearance of apoptotic keratinocytes, and prevent immunization with autoantigens of cutaneous origin.

Abstract: Complement has both beneficial and deleterious roles in the pathogenesis of systemic lupus erythematosus (SLE). On the one hand, patients with SLE present with decreased complement levels and with complement deposition in inflamed tissues, suggestive of a harmful role of complement in the effector phase of disease. On the other hand, homozygous deficiency of any of the classical pathway proteins is strongly associated with the development of SLE. There are two main hypotheses to explain these observations. The first invokes an important role for complement in the physiological waste-disposal mechanisms of dying cells and immune complexes. The second hypothesis is based around the role of complement in determining the activation thresholds of B and T lymphocytes, with the proposal that complement deficiency causes incomplete maintenance of peripheral tolerance. These two hypotheses are not mutually exclusive. In addition, there is evidence for a contribution from other genetic factors in determining the phenotype of disease in the absence of complement.

Abstract: There are many links between the complement system and the autoimmune disease systemic lupus erythematosus (SLE). Soon after the identification of antinuclear antibodies, the major serological hallmark of the disease, it was discovered that complement proteins are deposited in the tissues of patients. An association was found between the degree of complement activation in blood samples from patients and the level of disease activity. Complement proteins were discovered to be co-located with antibodies in inflamed tissues, such as the glomeruli of patients with glomerulonephritis. These data suggested that the formation or deposition of immune complexes in tissues leading to complement and leukocyte activation could cause the pathogenesis of the tissue injury of SLE. However, it was also discovered that the presence of antibodies and complement in tissues was not sufficient to cause inflammatory injury. Clinically normal tissues from patients with SLE (e.g., the skin) also contained deposited antibodies and complement proteins. Indeed, the presence of these proteins at the dermoepidermal junction in nonlesional skin was found to be a moderately specific diagnostic test for SLE, named the lupus band test. As the spectrum of autoantibodies characterized in SLE increased, it was discovered that about one third of patients with the disease have autoantibodies to complement proteins, especially to C1q. A reduction was also discovered in the expression of a complement receptor on erythrocytes, CR1, which plays a role in binding immune complexes in the circulation. Each of these links between complement and SLE, which we discuss in detail below, may be explained on the basis that the autoantibodies of SLE, on binding autoantigen, activate complement. Downstream events following complement activation could explain the development of autoantibodies to complement and to erythrocyte CR1 consumption. However, the links between complement and SLE are much more complicated and curious. It was found that inherited complement deficiency is strongly associated with the development of SLE. Indeed, the very rare inherited homozygous deficiency of the first protein of the classical