Complement System Disorders

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Hereditary angioedema is an autosomal dominant primary immunodeficiency disorder characterized by a C1 inhibitor deficiency. This deficiency leads to an overactive complement system, due to the lack of inhibition on C1, resulting in unchecked cleavage and activation of downstream C2 & C4. The deficiency in C1 inhibitor results in reduced inactivation of kallikrein, thereby causing uncontrolled bradykinin production. This cascade of events increases levels of C3a, C4a, & C5a. These complement proteins and bradykinin are vasoactive substances, and their cumulative effects result in vasodilation and increased vascular permeability.

Clinically, hereditary angioedema causes widespread angioedema—presenting as painless, non-pitting swelling affecting the face, neck, lips, and tongue. Additionally, angioedema of the GI tract can result in symptoms like abdominal pain, nausea/vomiting, & diarrhea. Lab findings include low C4 due to consumption by overactive complement. ACE inhibitors can exacerbate hereditary angioedema as ACE normally degrades bradykinin.

Complement deficiencies are primary immunodeficiencies affecting various components, such as C1, C2, C3, & C4 deficiencies. Among these, C2 deficiency is the most common. These deficiencies increase susceptibility to encapsulated bacteria, like Strep pneumo, H. influenzae, & N. meningitidis, as the early complement system is crucial for opsonization and phagocytosis of these pathogens. Additionally, deficiencies in C1, C2, and C4 increase the risk of systemic lupus erythematosus.

C5-9 deficiencies are associated with the absence or malfunctioning of the membrane attack complex (MAC), consisting of C5-C9. These deficiencies increase vulnerability to Neisseria species, especially N. meningitidis, as MAC is vital for killing this species of bacteria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a condition stemming from mutations in the PIG-A gene, leading to deficient GPI anchor protein and consequently decreased CD55 & CD59 complement inhibitors on the surface of red blood cells. This results in an overactive complement system, including MAC, resulting in intravascular hemolysis due to RBC lysis by the complement system.

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How does hereditary angioedema develop and what impact does it have on the complement system?

Hereditary angioedema arises due to a deficiency in the C1 inhibitor. This deficiency results in an uninhibited C1, leading to unchecked activation of downstream complement proteins, specifically C2 and C4. Consequently, the complement system becomes hyperactive because of the diminished inhibition of C1.

How does a deficiency in C1 inhibitor contribute to the pathophysiology and clinical manifestations of hereditary angioedema?

In hereditary angioedema, a deficiency in C1 inhibitor leads to a cascade of events that disrupt normal physiological processes. One of the primary consequences is the reduced inactivation of kallikrein, an enzyme that plays contributes to the production of bradykinin. The uncontrolled production of bradykinin, in turn, leads to increased vascular permeability and fluid leakage into surrounding tissues, causing episodes of swelling or angioedema. Additionally, the deficiency in C1 inhibitor results in elevated levels of complement proteins C3a, C4a, and C5a. This overactivation of the complement cascade contributes to the production of various vasoactive substances, further exacerbating the symptoms and potentially leading to life-threatening complications.

What clinical manifestations are associated with hereditary angioedema?

Individuals with hereditary angioedema often experience widespread angioedema, manifesting as painless, non-pitting swelling of areas like the face, neck, lips, and tongue. Other symptoms can encompass abdominal pain, nausea, vomiting, and diarrhea, all attributed to angioedema affecting the gastrointestinal tract. A common laboratory finding in these individuals is low C4 levels due to consumption by overactive complement.

Which complement system deficiencies increase the risk of infections from encapsulated bacteria?

Deficiencies in complement proteins C1, C2, C3, and C4 elevate the risk of infections from encapsulated bacteria, including Strep pneumo, H. influenzae, and N. meningitidis, due to the compromised ability of early complement to opsonize foreign pathogens for phagocytosis. Additionally, these deficiencies can also predispose individuals to systemic lupus erythematosus.

How does paroxysmal nocturnal hemoglobinuria (PNH) impact the complement system?

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by mutations in the PIG-A gene, leading to a deficiency in the GPI anchor protein. This deficiency results in decreased levels of complement inhibitors, specifically CD55 and CD59, on the surface of RBCs. The subsequent reduction in complement inhibitors prompts an overactive complement system, including the membrane attack complex (MAC), causing red blood cell lysis.