Immunodeficiency: Complement disorders

Abstract

The complement system is an important component of innate and adaptive immunity that consists of three activation pathways. The classic complement pathway plays a role in humoral immunity, whereas the alternative and lectin pathways augment the innate response. Impairment, deficiency, or overactivation of any of the known 50 complement proteins may lead to increased susceptibility to infection with encapsulated organisms, autoimmunity, hereditary angioedema, or thrombosis, depending on the affected protein. Classic pathway defects result from deficiencies of complement proteins C1q, C1r, C1s, C2, and C4, and typically manifest with features of systemic lupus erythematosus and infections with encapsulated organisms. Alternative pathway defects due to deficiencies of factor B, factor D, and properdin may present with increased susceptibility to Neisseria infections. Lectin pathway defects, including Mannose-binding protein-associated serine protease 2 (MASP2) and ficolin 3, may be asymptomatic or lead to pyogenic infections and autoimmunity. Complement protein C3 is common to all pathways, deficiency of which predisposes patients to severe frequent infections and glomerulonephritis. Deficiencies in factor H and factor I, which regulate the alternative pathway, may lead to hemolytic uremic syndrome. Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9). Diagnosis of complement deficiencies involves screening with functional assays (i.e., total complement activity [CH50], alternative complement pathway activity [AH50], enzyme-linked immunosorbent assay [ELISA]) followed by measurement of individual complement factors by immunoassay. Management of complement deficiencies requires a comprehensive and individualized approach with special attention to vaccination against encapsulated bacteria, consideration of prophylactic antibiotics, treatment of comorbid autoimmunity, and close surveillance.

ROLE OF COMPLEMENT IN INNATE AND ADAPTIVE IMMUNITY

There are ∼50 proteins recognized in the complement cascade.¹ The complement system plays a crucial role in both innate and adaptive immunity. As a part of the innate immune system, complement exerts effector functions that can directly destroy microbes. The three main effector functions of the complement system include cellular lysis via the membrane attack complex (MAC); stimulation of the inflammatory response via anaphylatoxins generated by the cleavage of C3, C4, and C5; and opsonization and phagocytosis by activation of macrophages and neutrophils.²

As a part of the adaptive immune system, the complement system enhances the function of B cells and T cells, which makes it critical for both humoral and cell-mediated immunity. Complement enhances B-cell signaling (via CD19/CD21 complex) that results in decreasing thresholds for B cells encountering opsonized antigen.² Although its exact function in cell-mediated immunity remains unclear, the complement system has been shown to be important for T-cell priming and may play a role in co-stimulation and differentiation of naive CD4⁺ T cells.²

COMPLEMENT PATHWAYS

Complement activation occurs via three pathways with distinct triggers that converge to MAC formation (Fig. 1). The classic pathway is initiated through binding of complement protein C1 to antigen-bound immunoglobulins. Once activated, C1, composed of C1q, C1r, and C1s subunits, cleaves C4 and incorporates C4b. This complex then cleaves C2, forming C4bC2a (also called C4bC2b), known as C3 convertase.³

Figure 1.

Overview of the complement system. The central events of the three complement pathways, classic pathway (CP), alternative pathway (AP), and lectin pathway (LP), can be summarized by four important steps: (1) initiation of complement activation, (2) formation of C3 convertase, (3) formation of C5 convertase, and (4) late steps (i.e., terminal pathway).

The lectin pathway is initiated through binding of microbial surface carbohydrates to mannose-binding lectin (MBL) or ficolins, which are then complexed to MBL-associated serine proteases (MASP) 1–3. These activated complexes are structurally and functionally analogous to the C1 protein and cleave C4.³ The remaining steps of this pathway are identical to those in the classic pathway.

The alternative pathway is initiated by the spontaneous hydrolysis of the C3 thioester bond. Hydrolyzed C3 can bind factor B, which may then be cleaved by factor D, forming a free C3 convertase in the form of C3Bb. The free C3 convertase cleaves C3 to C3b, which then binds to a microbe and factor B. Complexed factor B is then cleaved by factor D, creating a microbe-bound C3 convertase (C3bBb).³

C3 convertases from any pathway can bind C3b to form a C5 convertase that cleaves C5, creating C5b. C5b binds to C6, C7, C8, and multiple C9 proteins to form the MAC.³

EPIDEMIOLOGY

Inherited complement deficiencies (CD) have an estimated prevalence of 0.03% but are likely underdiagnosed.⁴ It is estimated that they comprise 2 to 10% of all inborn errors of immunity.⁴ CDs have a higher prevalence among patients with characteristic disease manifestations, such as meningitis and autoimmunity. The incidence and reported cases of individual CDs range from one case of factor B deficiency to 2–7% of the population with MBL deficiency.⁵ CDs have been found in almost 6% of patients with systemic lupus erythematosus (SLE) and as many as 25% of adults with bacterial meningitis.⁶

CDs are most often inherited as autosomal recessive (AR) traits, with some exceptions. C1 inhibitor (C1-INH) deficiency is autosomal dominant (AD), whereas factor H and CD46 deficiencies are either AD or AR.⁷ Another notable exception is properdin deficiency, which is X-linked recessive. Given the rarity of CDs, much of the literature is limited to case reports, which makes it difficult to gather demographic data. The largest described cohort to date was of 273 patients with CDs diagnosed in the French health-care system from 1988 to 2018. Most patients have defects in the terminal pathway (56%), followed by the classic pathway (27%), and, finally, the alternative pathway (17%).⁸ There is a slight male predominance (56%), possibly due to 12 cases of properdin deficiency in the group. The median age of diagnosis is 15 years.⁸

CLASSIC PATHWAY DEFECTS

Most classic complement pathway defects are inherited in an AR pattern with variable expressivity. Classic pathway complement defects may result in impaired infection control and accumulation of immune complexes. This phenomenon is seen in defects of C1 subunits (C1q, C1r, or C1s).⁸ Patients with deficiency of C1 subunits, C4, or C2, have symptoms similar to SLE, likely due to poor complement-mediated clearance of immune complexes and inflammatory debris.⁸ Quantitative or functional defects of C1-INH result in hereditary angioedema type 1 or 2, which is characterized by abnormal swelling episodes.³

Inflammatory manifestations are not observed in all patients with CDs. Instead, most CDs, particularly C2, C3, and C4, are characterized by susceptibility to infections due to encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae.⁵ Defects in early complement components, e.g., C2 (and, more rarely, C3 or C4), manifest with severe infections early in life.⁹

ALTERNATIVE PATHWAY DEFECTS

The alternative pathway of complement activation is phylogenetically older than the classic pathway. There have been human deficiencies identified with all three proteins that are unique to this pathway, viz., factor B, factor D, and properdin. Few cases of factor B and factor D deficiencies have been reported, whereas properdin deficiency is comparatively more common. Patients with properdin deficiency have increased susceptibility to Neisseria meningitidis infections.⁷ Two unique features of properdin deficiency include that it is the only X-linked CD and it is the only positive regulator of complement.³ Fewer than 10 patients with factor D deficiency have been identified in the literature, all of whom were children of consanguineous parents.⁹ These patients are susceptible to meningococcal sepsis. There is only one reported case of factor B deficiency. This patient had pneumococcal and meningococcal infections due to increased susceptibility to encapsulated organisms.¹⁰

Deficiencies of several of the regulatory proteins of the complement pathways have also been described. These include factor H, factor I, membrane cofactor protein (CD46), decay-accelerating factor (CD55), and CD59. Deficiencies in factor H, factor I, and CD46 are all associated with an increased risk of recurrent infections with S. pneumoniae and, to a lesser extent, H. influenzae or N. meningitidis, which resemble a similar phenotype of patients with C3 deficiency. In addition, patients with abnormalities in these regulatory proteins are prone to episodes of atypical hemolytic uremic syndrome.³ Factor H and factor I deficiencies, additionally, are associated with C3 glomerulopathy and age-related macular degeneration, respectively.⁸ Deficiencies in CD55 and CD59 are associated with paroxysmal nocturnal hemoglobinuria.³

LECTIN PATHWAY DEFECTS

MBL deficiency, originally discovered as an opsonization defect in pediatric patients with recurrent pyogenic infections, is the most common CD.⁹ An estimated 5% of the population has MBL deficiency, with most being asymptomatic.⁹ Although most patients may be asymptomatic, MBL deficiency can be associated with an increased frequency of autoimmune conditions, including SLE and rheumatoid arthritis.³ The increased frequency of autoimmunity suggests an inability to clear apoptotic nuclear debris, which facilitates autoantibody production.³ MASP2 deficiency is usually asymptomatic but may present with autoimmunity and recurrent respiratory and pyogenic infections.⁷ Ficolin-3 deficiency has eight known cases and is notable for recurrent respiratory infections, abscesses, and impaired polysaccharide vaccine response.¹¹

TERMINAL PATHWAY DEFECTS

Deficiencies in terminal complement components, including C5, C6, C7, C8αβγ, and C9, impair MAC formation. The only consistent clinical manifestation is recurrent infection with Neisseria species, although results of recent work suggest a possible risk of disseminated herpes simplex virus infection.^2,12

ACQUIRED CDs

Acquired CDs are more common than inherited CDs.¹³ Acquired deficiencies in complement proteins most commonly occur through accelerated consumption of complement proteins by immune complexes and less commonly by decreased hepatic synthesis or protein-losing nephropathies. Several complement components are affected, and acquired deficiencies are commonly associated with autoimmune conditions, e.g., SLE, which is characterized by low C3 and C4.

The autoantibody C3 nephritic factor stabilizes the alternative pathway C3 convertase (C3Bb), which results in uncontrolled C3 activation and consumption of complement proteins. The resultant ongoing complement activation can lead to membranoproliferative glomerulonephritis due to complement-containing deposits in the glomerular basement membrane.³

Acquired C1-INH deficiency presents with similar symptoms as hereditary angioedema. This acquired form of angioedema is caused by decreased C1-INH levels, either by increased consumption or increased activation of C1-INH. Decreased quantitative or functional C1-INH levels, low C1q, and no notable family history is diagnostic of acquired C1-INH deficiency. This disorder is often associated with B-cell lymphoproliferative disorders and rarely with autoimmune conditions.¹⁴

Terminal complement inhibitors eculizumab and ravulizumab bind to C5 with high affinity and prevent C5 cleavage to C5a and C5b, thereby inhibiting the formation of the MAC complex. These monoclonal antibodies are used in the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to prevent terminal complement-mediated intravascular hemolysis.^15,16 Patients on these medications are at increased risk of serious infections from N. meningitidis.¹⁵

DIAGNOSIS OF CDs

Diagnostic evaluation of CDs involves screening the function of each activation pathway, measuring individual protein concentrations, and measuring functional activity of the component in question.^3,17 With recent expansion in the field of complement analysis, novel assays have been developed to better detect complement activation products and genetic mutations associated with defined diseases.¹⁸

When evaluating a suspected CD, screening begins with functional assays.¹⁹ Currently, total hemolytic complement (CH50) and alternative complement activity pathway (AH50) assays are commercially available to detect total complement activity for the classic and alternative pathways, respectively (Table 1).^3,18 Functional enzyme-linked immunosorbent assay (ELISA) assays are available for screening the lectin pathway. C1-INH functional assay and quantitative levels of C1-INH, C4, and C1q are used to screen for hereditary angioedema.³ Blood samples should be properly collected and stored because inappropriately handled specimens can limit complement evaluation, potentially leading to falsely low results.¹⁸ If functional testing with CH50 and AH50 are normal, then further testing is usually not indicated.

Table 1.

Diagnosis of complement defects based on laboratory evaluation*

Low CH50, Normal AH50	Normal CH50, Low AH50	Low CH50, Low AH50
C1q deficiency	Factor B deficiency	C3 deficiency
C1r deficiency	Factor D deficiency	C5 deficiency
C1s deficiency	Properdin deficiency	C6 deficiency
C2 deficiency		C7 deficiency
C4 deficiency		C8α deficiency
C1 inhibitor deficiency		C8β deficiency
		C8γ deficiency
		C9 deficiency
		Factor H deficiency
		Factor I deficiency

CH50 = Total hemolytic complement; AH50 = alternative complement activity pathway.

*Adapted from Refs. 3 and 16.

Once a defect is confirmed, further analysis should commence to determine whether the defect is from a component deficiency, regulator deficiency, or a consequence of activation and consumption of products. To confirm a specific component or regulator deficiency, individual factor concentrations can be measured via immunoassays. Currently available techniques include immunoprecipitation, ELISA, or Western blot.^3,17 Measurement of split products and macromolecular complexes, e.g., the C5-9 terminal complex, can also be used to detect activation products.³ However, testing for individual complement components, with the exception of C2, C3, and C4, is typically available only in reference laboratories.

Lastly, one can use genetic analysis to detect a CD associated with a genetic variant.⁸ A genetic diagnosis is important for reproductive counseling and informing blood relatives.

MANAGEMENT OF CDs

Curative therapy for CDs does not exist.¹⁷ Management of inborn errors of the complement system depends on both the specific component and pathway affected as well as the clinical manifestations noted in a particular patient case. Given that CDs may lead to infectious susceptibility, autoimmunity, or both, appropriate treatment requires an individualized approach. Patients should be counseled on vigilance for early signs of infection and told to seek immediate medical care when symptoms such as fever, headache, or neck stiffness are noticed. In addition to all routinely recommended vaccines, patients who are complement deficient should be immunized as early in life as possible with protein-conjugate vaccines targeting encapsulated bacteria such as S. pneumoniae, H. influenzae, and all serotypes of N. meningitidis.¹⁷ The treating physician should consider repeated immunization against these specific pathogens at a frequency beyond routinely recommended intervals throughout life to ensure maintenance of longitudinal protection, although there are no prospective trials on vaccine efficacy in this patient population.¹⁷ Some patients may benefit from antibiotic prophylaxis, although such treatment is often not required.¹⁷ Penicillin prophylaxis has specifically demonstrated efficacy in terminal CDs.²⁰ Neither immunoglobulin replacement therapy nor infusion with plasma to replenish absent complement proteins is generally recommended.¹⁷ Although replacement of deficient complement protein(s) via infusion has been successfully used in the acute setting, there is an associated risk of antibody formation and anaphylaxis.²¹ Patients should be routinely monitored for autoimmunity, and autoimmune diseases in patients with CDs are usually managed per standard of care for the specific disease.¹⁷ Additional novel targeted therapies are being developed for the treatment of complement-related disorders. Recent examples include danicopan and iptacopan, which inhibit factor D and factor B, respectively, and were approved for the treatment of paroxysmal nocturnal hemoglobinuria in 2024.^22,23

CLINICAL PEARLS AND PITFALLS

• Complement plays an important role in the adaptive and innate immune responses through involvement in the classic, alternative, and lectin pathways

• CDs represent ∼2–10% of inborn errors of immunity

• Clinical presentations of CDs vary, depending on the affected pathway(s), including increased susceptibility to certain infections (i.e., N. meningitidis, H. influenzae, S. pneumoniae) and autoimmune disorders

• The diagnostic evaluation of CDs should involve initial screening with CH50 and AH50, followed by measurement of individual complement proteins and genetic sequencing as indicated

• Management of CDs necessitates an individualized approach with immunization against encapsulated bacteria, consideration of antibiotic prophylaxis, and management of autoimmune complications