Terminal Complement Pathway Deficiency

The membrane attack complex (MAC), which is formed by complement proteins, plays a crucial role in the eradication of bacterial infections, especially Neisseria species and other encapsulated bacteria, by attaching to the bacterial plasma membrane and forming pores that eventually lead to cell lysis. Patients with terminal complement pathway deficiency may present with recurrent and severe neisserial infections as they are unable to synthesize MAC because of a deficiency in one of its components (e.g., late complement proteins). Treatment is antibiotics for the infection and vaccination against encapsulated bacteria.

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Etiology and Pathophysiology

Epidemiology and etiology

  • Genetic disorder with autosomal recessive inheritance 
  • Deficiency of 1 of the terminal complement proteins
  • Most common deficiencies in the United States: C5, C6, or C8

Pathophysiology

Membrane attack complex (MAC) structure and function:

  • Structure: ring-like structure formed by activated terminal complement proteins (C5b, C6, C7, C8, and C9)
  • Function:
    • Attaches to the bacterial membrane to create pores
    • Produces free diffusion between the intracellular and extracellular components, leading to microorganism lysis
  • Pathophysiology:
    • Decreased ability to create bacterial cell membrane pores leads to poor microorganism lysis.
    • Increased susceptibility to encapsulated organisms
Complement pathway

Membrane attack complex (MAC) formation:

When the first protein in the complement series is activated (typically by an antibody that has locked on to an antigen), it sets in motion a domino effect. Each component takes its turn in a precise chain of steps known as the complement cascade. The end product is a cylinder (MAC) inserted into (and puncturing a hole in) the cell’s wall. With fluids and molecules flowing in and out, the cell swells and bursts.

Image: “Complement pathway” by DO11.10. License: Public Domain

Clinical Presentation

Most patients are asymptomatic.

Symptomatic patients present with:

  • Recurrent encapsulated bacterial infections:
    • Meningococcal infections
    • Gonococcal infections 
  • Severe, disseminated neisserial infection:
    • Meningococcemia 
    • Sepsis and septic shock

Diagnosis and Management

Diagnosis

Total complement activity (CH50) is used for screening. If CH50 is low/undetectable, measurement of the serum protein level for complement proteins should be ordered. Findings include:

  • CH50: undetectable to low
  • C3 level: normal 
  • C4 level: normal 
  • ≥ 1 of the late complement proteins is deficient.

Management

  • Treat infections aggressively with antibiotics.
  • Vaccination against encapsulated bacteria: 
    • Pneumococcus 
    • Meningococcus 
    • Haemophilus influenzae type b

Differential Diagnosis

  • Bacterial sepsis/septic shock: a life-threatening syndrome that can be caused by bacterial infections. Sepsis is a generalized immune response that may result in organ dysfunction or failure. The best/fastest way to assess organ dysfunction in patients with a possible infection is the “quick Sequential Organ Failure Assessment (qSOFA).
  • Hypogammaglobulinemia: refers to a laboratory finding (low IgG) that may be asymptomatic or that can be related to a number of clinical situations with different causes and manifestations if it’s more severe. Hypogammaglobulinemia can be caused by a primary immune deficiency or can be secondary to other diseases. The main feature of symptomatic hypogammaglobulinemia is repeated infections that normally are prevented by antibody responses.
  • Meningococcemia: defined as dissemination of meningococci (Neisseria meningitidis) into the bloodstream. Patients with acute meningococcemia may present with meningitis, meningitis with meningococcemia, or meningococcemia without clinically apparent meningitis.

References

  1. Liszewski, M.K., et al. (2020). Inherited disorders of the complement system. In Schur, P.H., et al. (Ed.), UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/inherited-disorders-of-the-complement-system
  2. Liszewski, M.K., et al. (2020). Overview and clinical assessment of the complement system. In Schur, P.H., et al. (Ed.), UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/overview-and-clinical-assessment-of-the-complement-system
  3. Fischer, A. (2018). Primary immune deficiency diseases. Chapter 344 of Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.

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