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Terminal Complement Pathway Deficiency

The membrane attack complex Membrane attack complex A product of complement activation cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target cell membrane and cell lysis. It is formed by the sequential assembly of terminal complement components (complement C5b; complement C6; complement C7; complement C8; and complement C9) into the target membrane. The resultant C5b-8-poly-c9 is the 'membrane attack complex' or MAC. Type II Hypersensitivity Reaction (MAC), which is formed by complement proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, plays a crucial role in the eradication of bacterial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, especially Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria species and other encapsulated Encapsulated Klebsiella bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, by attaching to the bacterial plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products membrane and forming pores that eventually lead to cell lysis. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with terminal complement pathway deficiency may present with recurrent and severe neisserial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease as they are unable to synthesize MAC because of a deficiency in one of its components (e.g., late complement proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis). Treatment is antibiotics for the infection and vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination against encapsulated Encapsulated Klebsiella bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology.

Last updated: 9 May, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Etiology and Pathophysiology

Epidemiology and etiology

  • Genetic disorder with autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance 
  • Deficiency of 1 of the terminal complement proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
  • Most common deficiencies in the United States: C5, C6, or C8

Pathophysiology

Membrane attack complex Membrane attack complex A product of complement activation cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target cell membrane and cell lysis. It is formed by the sequential assembly of terminal complement components (complement C5b; complement C6; complement C7; complement C8; and complement C9) into the target membrane. The resultant C5b-8-poly-c9 is the ‘membrane attack complex’ or MAC. Type II Hypersensitivity Reaction (MAC) structure and function:

  • Structure: ring-like structure formed by activated terminal complement proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (C5b, C6, C7, C8, and C9)
  • Function:
    • Attaches to the bacterial membrane to create pores
    • Produces free diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis between the intracellular and extracellular components, leading to microorganism lysis
  • Pathophysiology:
    • Decreased ability to create bacterial cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane pores leads to poor microorganism lysis.
    • Increased susceptibility to encapsulated Encapsulated Klebsiella organisms
Membrane attack complex (mac) formation

Membrane attack complex Membrane attack complex A product of complement activation cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target cell membrane and cell lysis. It is formed by the sequential assembly of terminal complement components (complement C5b; complement C6; complement C7; complement C8; and complement C9) into the target membrane. The resultant C5b-8-poly-c9 is the ‘membrane attack complex’ or MAC. Type II Hypersensitivity Reaction (MAC) formation:
When the 1st protein in the complement series is activated (typically by an antibody locked onto an antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination), a domino effect is set into motion. Each component takes a turn in a precise chain of steps known as the complement cascade Complement cascade The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. C3 Deficiency. The end product Product A molecule created by the enzymatic reaction. Basics of Enzymes is the cylindrical MAC, which inserts into and punctures a hole in the cell’s wall. With fluids and molecules flowing in and out, the cell swells and bursts.

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Clinical Presentation

Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are asymptomatic.

Symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with:

  • Recurrent encapsulated Encapsulated Klebsiella bacterial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
    • Meningococcal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Gonococcal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 
  • Severe, disseminated neisserial infection:
    • Meningococcemia 
    • Sepsis and septic shock Sepsis and Septic shock Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and septic shock are medical emergencies and antibiotics are given within an hour of diagnosis. Sepsis and Septic Shock

Diagnosis and Management

Diagnosis

Total complement activity (CH50) is used for screening Screening Preoperative Care. If CH50 is low/undetectable, measurement of the serum protein level for complement proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis should be ordered. Findings include:

  • CH50: undetectable to low
  • C3 level: normal 
  • C4 level: normal 
  • ≥ 1 of the late complement proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis is deficient.

Management

  • Treat infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease aggressively with antibiotics.
  • Vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination against encapsulated Encapsulated Klebsiella bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology
    • Pneumococcus 
    • Meningococcus 
    • Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae type b

Differential Diagnosis

  • Bacterial sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock/ septic shock Septic shock Sepsis associated with hypotension or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include, but are not limited to lactic acidosis; oliguria; or acute alteration in mental status. Sepsis and Septic Shock: a life-threatening syndrome that can be caused by bacterial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. Sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock is a generalized immune response that may result in organ dysfunction or failure. Early identification Identification Defense Mechanisms is paramount so that proper therapy can be initiated with intravenous fluid resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome, antibiotics, and vasopressors Vasopressors Sepsis in Children (if needed).
  • Hypogammaglobulinemia Hypogammaglobulinemia Selective IgA Deficiency: refers to a laboratory finding (low IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis) 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 Hypogammaglobulinemia Selective IgA Deficiency can be caused by a primary immune deficiency or can be secondary to other diseases. The main feature of symptomatic hypogammaglobulinemia Hypogammaglobulinemia Selective IgA Deficiency is repeated infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease that normally are prevented by antibody responses.
  • Meningococcemia: defined as dissemination of meningococci ( Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria meningitidis) into the bloodstream. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with acute meningococcemia may present with meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis, meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis with meningococcemia, or meningococcemia without clinically apparent meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. 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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