Complement deficiency

Overview

Complement deficiency refers to a group of rare immunodeficiency disorders involving the complement system—a critical part of the immune system that helps clear pathogens, damaged cells, and promotes inflammation. The complement system includes over 30 proteins that work in a cascade to defend against bacterial and viral infections. When one or more of these components are absent or dysfunctional, it can impair immune responses and increase susceptibility to infections and autoimmune diseases. Complement deficiencies can affect any of the three activation pathways: classical, lectin, or alternative.

Causes

Complement deficiencies are primarily caused by inherited genetic mutations in the genes that encode complement proteins or regulatory factors. These deficiencies are usually inherited in an autosomal recessive pattern, meaning both copies of the gene must be defective for symptoms to appear. Less commonly, complement deficiencies can be acquired as a result of autoimmune conditions, infections, or consumption of complement proteins in diseases like systemic lupus erythematosus (SLE) or cryoglobulinemia.

Symptoms

Symptoms of complement deficiency vary depending on which part of the complement cascade is affected, but common features include:

• Recurrent bacterial infections: Particularly with encapsulated bacteria such as Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae

• Meningitis and sepsis: Especially in individuals with terminal complement component deficiencies (C5–C9)

• Autoimmune disorders: Such as lupus-like disease, especially in deficiencies of early classical pathway components (C1q, C2, C4)

• Angioedema: Seen in hereditary angioedema due to C1 inhibitor deficiency (a regulatory protein)

• Glomerulonephritis: In some alternative pathway or regulatory protein deficiencies

Some individuals may be asymptomatic and only diagnosed after an infection or autoimmune event.

Diagnosis

Diagnosis of complement deficiency involves a combination of clinical suspicion, laboratory testing, and genetic analysis. Key diagnostic steps include:

• CH50 assay: A functional test measuring the activity of the classical complement pathway; a low CH50 suggests a deficiency in C1–C9

• AH50 assay: Assesses function of the alternative pathway

• Specific component testing: To measure levels of individual complement proteins (e.g., C3, C4, C5)

• C1 inhibitor assay: For suspected hereditary angioedema

• Genetic testing: To identify mutations in complement-related genes

• Autoimmune panels: May be used to detect associated conditions like SLE

Treatment

Treatment of complement deficiency is focused on preventing infections, managing autoimmune complications, and replacing deficient proteins when possible. Strategies include:

• Vaccinations: Pneumococcal, meningococcal, and Haemophilus influenzae type B vaccines are crucial for protection against encapsulated organisms

• Antibiotic prophylaxis: Daily or episodic use of antibiotics to prevent recurrent infections, especially in patients with terminal complement deficiencies

• Plasma-derived therapies: C1 inhibitor replacement therapy for hereditary angioedema (Berinert, Cinryze)

• Immunosuppressive therapy: For autoimmune manifestations such as lupus nephritis

• Gene counseling and family screening: Particularly in inherited forms

• Monitoring and supportive care: Regular follow-up with immunologists and infectious disease specialists

Prognosis

The prognosis for individuals with complement deficiency depends on the specific type and how early the condition is diagnosed. With appropriate vaccinations, prophylactic antibiotics, and monitoring, many individuals can lead relatively normal lives. However, those with unrecognized or untreated deficiencies are at risk for life-threatening infections and severe autoimmune complications. Early detection, patient education, and preventive care are key to improving outcomes and quality of life.