Complement Deficiencies



Complement Deficiencies


Jerry A. Winkelstein



The complement system is composed of a series of plasma proteins and cellular receptors that, when functioning in an ordered and integrated fashion, serve as important mediators of host defense and inflammation. Although the complement system was first described at the turn of the twentieth century, it was not until 1960 that the first patient with a genetically determined complement deficiency was identified. Since then, deficiencies have been described for nearly all components of the complement system (Table 429.1).


CLINICAL MANIFESTATIONS AND COMPLICATIONS

Individuals with genetically determined complement deficiencies have a variety of clinical presentations. Most patients present with an increased susceptibility to infection, some with a variety of rheumatic diseases, others with angioedema and, in some instances, some patients may be asymptomatic.


Increased Susceptibility to Infection

An increased susceptibility to infection is a prominent clinical finding in most patients with complement deficiencies. The kinds of infections relate to the biologic functions of those components that are missing. For example, the third component of complement (C3) is an important opsonic ligand. Therefore, patients with a deficiency of C3, or of a component of either of the two pathways that activate C3, are more susceptible to infections caused by encapsulated bacteria for which opsonization is the primary host defense (e.g., Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae). Similarly, C5 through C9 form the membrane attack complex and are responsible for the bactericidal functions of complement. Thus, patients with deficiencies of C5, C6, C7, C8, or C9 are susceptible to gram-negative bacteria, notably Neisseria species, because serum bactericidal activity is an important host defense against these organisms.

A number of studies have examined groups of patients with specific infectious diseases to determine the frequency of complement deficiencies in these infections and to evaluate the utility of screening for complement deficiencies. Between 5% and 15% of unselected patients with systemic meningococcal infections have a genetically determined complement deficiency. The differing estimates may reflect differences in populations examined. In general, the prevalence is higher if the patient has had recurrent meningococcal disease, has a positive family history for meningococcal disease, or is infected with an uncommon meningococcal serotype. Therefore, it seems reasonable to screen children with systemic meningococcal infections for the presence of a complement deficiency. In contrast, although many patients with complement deficiencies present with systemic pneumococcal or H. influenzae infections, the prevalence of complement deficiencies in patients with these specific infections appears to be quite low. Therefore, recommending routine screening for complement deficiencies in patients with bacteremia or meningitis caused by pneumococcus or H. influenzae is more difficult to justify.


Rheumatic Diseases

Patients with complement deficiencies also have a variety of clinical conditions that can be described best as rheumatic diseases. These include disorders that resemble systemic lupus
erythematosus (SLE) as well as glomerulonephritis, dermatomyositis, anaphylactoid purpura, and vasculitis. The prevalence of these inflammatory disorders is highest in those patients with deficiencies of the classical activating pathway (C1, C4, and C2) and of C3. The pathophysiologic basis for the occurrence of these diseases in complement-deficient patients may relate in part to the physiologic role of the complement system in processing immune complexes or its role in the clearance of apoptotic cells.








TABLE 429.1. GENETICALLY DETERMINED COMPLEMENT DEFICIENCIES






























































Deficiency Inheritance Major Clinical Manifestation
C1q Autosomal recessive Rheumatic disorders and pyogenic infections
C1r/s Autosomal recessive Rheumatic disorders
C4 Autosomal recessive Rheumatic disorders and pyogenic infections
C2 Autosomal recessive Rheumatic disorders and pyogenic intections
C3 Autosomal recessive Pyogenic infections
C5 Autosomal recessive Meningococcal sepsis and meningitis
C6 Autosomal recessive Meningococcal sepsis and meningitis
C7 Autosomal recessive Meningococcal sepsis and meningitis
C8 Autosomal recessive Meningococcal sepsis and meningitis
C9 Autosomal recessive Meningococcal sepsis and meningitis
Factor I Autosomal recessive Pyogenic infections
Factor H Autosomal recessive Hemolytic uremic syndrome
Properdin X-linked recessive Meningococcal sepsis and meningitis
C1 esterase inhibitor Autosomal dominant Angioedema

Some important differences exist between the rheumatic diseases seen in complement-deficient patients and their counterparts in non–complement-deficient individuals. For example, the SLE-like illness seen in complement-deficient individuals often is characterized by onset in childhood, skin lesions resembling discoid lupus, and relatively limited renal and pleuropericardial involvement. In addition, complement-deficient individuals with the lupus-like syndrome may have absent or low titers of antinuclear antibodies and negative lupus preparations. In contrast, their incidence of anti-Ro antibodies is significantly higher than in non–complement-deficient patients with lupus. Thus, complement-deficient patients with the lupus-like syndrome resemble a subgroup of lupus patients who have subacute, cutaneous lupus.


Angioedema

Patients with a deficiency of one of the control proteins of the classical pathway, C1 esterase inhibitor, usually present with angioedema of the skin or mucous membranes (see following discussion). No large studies have examined the prevalence of C1 esterase inhibitor deficiency in patients with angioedema.


Asymptomatic

Some patients with genetically determined complement deficiencies are relatively asymptomatic, never having developed a serious infection or a rheumatic disorder. These asymptomatic patients usually are ascertained as a consequence of screening family members of complement-deficient patients who themselves have been ascertained because of clinically significant problems.


SPECIFIC DISORDERS


Complement Deficiencies


C1q Deficiency

Two distinct forms of C1q deficiency exist. In one form, C1q cannot be detected through either functional or immunochemical analysis. In the other form, immunochemical C1q is present, but it lacks functional activity (i.e., it is dysfunctional). The dysfunctional C1q is antigenically deficient, and it does not interact with either IgG or C1r and C1s. The most common clinical presentation of either form of C1q deficiency has been a lupus-like syndrome. Some patients also have had an increased susceptibility to infection, manifested by bacterial sepsis or meningitis.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Complement Deficiencies
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