Immunodeficiency due to a classical component pathway complement deficiency

Immunodeficiency due to a classical component pathway complement deficiency is a group of rare primary immunodeficiency disorders caused by deficiencies in one or more proteins of the classical complement pathway, including C1q, C1r, C1s, C2, and C4. The classical complement pathway is a critical part of the innate immune system that helps the body recognize and destroy pathogens, clear immune complexes, and regulate inflammatory responses. When components of this pathway are missing or dysfunctional, patients become susceptible to recurrent and severe bacterial infections, particularly with encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. The immune system's ability to opsonize bacteria and clear immune complexes is significantly impaired. A hallmark feature of classical pathway complement deficiencies is a strong association with autoimmune diseases, particularly systemic lupus erythematosus (SLE) or SLE-like syndromes. This association is especially pronounced in C1q deficiency, where the vast majority of affected individuals develop lupus, and in C4 and C2 deficiency. Patients may present with skin rashes, glomerulonephritis, arthritis, and other autoimmune manifestations in addition to recurrent infections. C2 deficiency is the most common classical pathway complement deficiency in individuals of European descent. Management focuses on prevention and early treatment of infections, including vaccination against encapsulated bacteria, prophylactic antibiotics when appropriate, and prompt antibiotic therapy for acute infections. Autoimmune manifestations are treated with standard immunosuppressive therapies. Fresh frozen plasma has been used in some cases to temporarily replace missing complement components. There is currently no definitive cure, and long-term follow-up with immunology specialists is essential. Genetic counseling is recommended for affected families.

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