Complement Activation in Health and Disease

Under physiological conditions, complement is activated upon recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), including signals released by apoptotic or necrotic cells. Activation of the CP, LP, and AP enables broad surveillance and robust amplification of immune responses. Anaphylatoxins such as C3a and C5a, generated during activation, are potent inflammatory mediators that recruit and activate leukocytes, increase vascular permeability, trigger mast cell degranulation, and enhance phagocyte function.

Nonetheless, complement activation can also drive pathology. The system is controlled by a diverse set of regulators; genetic variants, deficiencies, or autoantibodies targeting complement proteins can result in inadequate or excessive activation. Insufficient control may lead to host tissue injury, while loss of function can predispose to severe infections. For example, dysregulation of AP control proteins contributes to atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), diseases characterized by disproportionate complement activation, MAC deposition in the glomeruli, and eventually progression to end-stage kidney disease. Deficiencies in proteins such as properdin, factor I, or MASP-2 increase susceptibility to meningitis and sepsis. The first complement-inhibiting therapy approved for clinical use targeted paroxysmal nocturnal hemoglobinuria (PNH), a clonal hematopoietic stem cell disorder marked by uncontrolled AP-mediated hemolysis, bone marrow failure, and thrombophilia. Autoantibodies such as anti-C1q can aberrantly activate complement and contribute to autoimmune diseases, including systemic lupus erythematosus (SLE).

Key Functions of Complement Activation in Immunity

Complement activation enables recognition, elimination, and clearance of pathogens and cellular debris while coordinating broader immune responses. Major functions include:

• Direct pathogen killing: C5b incorporation initiates assembly of the C5b-9 MAC, which forms lytic pores in microbial membranes of particularly in Gram-negative bacteria and can neutralize viruses by preventing their spread.
• Opsonization: Complement fragments such as C3b and C4b coat microbes or foreign particles, promoting recognition by complement receptors on phagocytes (e.g. via CR1 on macrophages and neutrophils) thereby enhancing phagocytic clearance and strengthen the immune response.
• Inflammation: Cleavage products C3a and C5a act as potent anaphylatoxins, recruiting and activating immune cells and amplifying local inflammatory responses.
• Clearance of apoptotic cells and immune complexes: C3b tagging facilitates removal of apoptotic debris and antigen–antibody complexes by the liver and spleen, preventing tissue damage and autoimmunity.

Bridging innate and adaptive immunity: Complement is a dynamic regulator integrating early immune sensing with adaptive responses. For example, B cells respond to complement-decorated antigens via CR1 and CR2, enhancing activation and antibody production, while C3a and C5a modulate T-cell responses and cytokine profiles.