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C3 Deficiency

Complement component 3 (C3) deficiency is the absence, reduction, or dysfunction of complement factor C3 and its fragments, C3a and C3b. Complement factors are key components of the innate immune system Immune system The body's defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs. Reduced levels of C3b increase the probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability of developing 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 with encapsulated Encapsulated Klebsiella organisms (e.g., Pneumococcus, 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 influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, 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), especially respiratory 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, due to reduced opsonization. Individuals with C3 deficiencies are also more susceptible to type III hypersensitivity reactions because a reduced clearance of antigen-antibody C3b complexes from the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment causes an increased risk of hypersensitivity reactions.

Last updated: Sep 19, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Epidemiology

Complement component 3 (C3) deficiency is part of the larger category of complement deficiencies:

  • Complement deficiencies are rare: They make up 5% of all immune deficiencies.
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency varies by geographic location.
  • No gender Gender Gender Dysphoria or ethnic propensity reported.

Etiology

  • Hereditary C3 deficiency:
    • Encoded on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 19 by the C3 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
    • 17 mutations in C3 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics prevent C3 protein from forming: commonly affects fragment C3b
    • 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
  • Acquired C3 deficiency:
    • Increased consumption of C3 during infection:
      • C3 overactivation by immune complexes
      • Seen in lepromatous leprosy Leprosy Leprosy, also known as Hansen’s disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy, bacterial endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis, malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Plasmodium/Malaria, infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as “the kissing disease,” is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis, dengue Dengue An acute febrile disease transmitted by the bite of aedes mosquitoes infected with dengue virus. It is self-limiting and characterized by fever, myalgia, headache, and rash. Severe dengue is a more virulent form of dengue. Dengue Virus hemorrhagic fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and acute hepatitis Acute Hepatitis Autoimmune Hepatitis B
    • Consumption of C3 due to medical conditions:
      • Lupus
      • Membranoproliferative glomerulonephritis Membranoproliferative Glomerulonephritis Membranoproliferative glomerulonephritis (MPGN) is also known as mesangiocapillary glomerulonephritis. Membranoproliferative glomerulonephritis is a pattern of glomerular injury characterized by mesangial hypercellularity, endocapillary proliferation, and thickening of the glomerular basement membrane (double contour formation). Membranoproliferative Glomerulonephritis

Pathophysiology

  • Complement cascade (3 pathways converging in common pathway Common pathway Hemostasis):
    1. Classical pathway Classical pathway Complement activation initiated by the binding of complement C1 to antigen-antibody complexes at the complement C1q subunit. This leads to the sequential activation of complement C1r and complement C1s subunits. Activated C1s cleaves complement C4 and complement C2 forming the membrane-bound classical C3 convertase (c4b2a) and the subsequent C5 convertase (c4b2a3b) leading to cleavage of complement C5 and the assembly of complement membrane attack complex. Innate Immunity: Barriers, Complement, and Cytokines (C1qrs, C2, C4)
    2. Alternative pathway Alternative pathway Complement activation initiated by the interaction of microbial antigens with complement C3b. When complement factor B binds to the membrane-bound C3b, complement factor d cleaves it to form alternative C3 convertase (c3bbb) which, stabilized by complement factor p, is able to cleave multiple complement C3 to form alternative C5 convertase (c3bbb3b) leading to cleavage of complement C5 and the assembly of complement membrane attack complex. Innate Immunity: Barriers, Complement, and Cytokines (C3, factor B, properdin)
    3. Lectin pathway Lectin pathway Complement activation triggered by the interaction of microbial polysaccharides with serum mannose-binding lectin resulting in the activation of mannose-binding protein-associated serine proteases. As in the classical pathway, masps cleave complement C4 and complement C2 to form C3 convertase (c4b2a) and the subsequent C5 convertase (c4b2a3b) leading to cleavage of complement C5 and assembly of complement membrane attack complex. Innate Immunity: Barriers, Complement, and Cytokines ( mannan-binding lectin Mannan-binding lectin A subclass of lectins that are specific for carbohydrates that contain mannose. Innate Immunity: Barriers, Complement, and Cytokines (MBL))
  • C3 deficiency results in malfunction of complement cascade: 
    • Decreased levels of opsonin C3b → impaired opsonization of pathogens (especially 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
    • Leads to reduced clearance of immune complexes
    • Increased risk of pyogenic 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
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. 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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Diagnosis

Clinical presentation

  • Recurrent 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 during childhood, especially encapsulated Encapsulated Klebsiella organisms:
    • Upper respiratory tract 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
    • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
    • 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
  • Generalized 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 and 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 can occur similar to Bruton agammaglobulinemia: 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 with Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus, Pneumococcus, or 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
  • Also associated with autoimmune diseases Autoimmune diseases Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides. Selective IgA Deficiency:
    • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
    • Type III hypersensitivity reactions
    • 25% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship develop glomerulonephritis.

Laboratory testing

Clinical testing directed by pattern of infection:

  • Bacterial types
  • Location of infection

Management

Management of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with C3 deficiency centers on prevention of illness.

Prevention of infection

  • Promotion of hygiene and frequent hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy washing
  • Monitor closely for early signs of illness.
  • 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: meningococcal, pneumococcal, and H. influenzae H. influenzae A species of Haemophilus found on the mucous membranes of humans and a variety of animals. The species is further divided into biotypes I through VIII. Haemophilus vaccines are critical.
  • Prophylactic antibiotic Prophylactic antibiotic Autosomal Dominant Hyperimmunoglobulin E Syndrome:
    • Chronic prophylaxis Prophylaxis Cephalosporins is controversial.
    • May be indicated in select individuals based on severity, frequency, and kind of infection

Treatment of infection

  • Antibiotic therapy directed by 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 isolated
  • Complement infusion: indicated with acute illness

References

  1. Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014 Oct. 61(2):110-117
  2. Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev. 1991 Jul;4(3):359-95. doi: 10.1128/cmr.4.3.359. PMID: 1889047; PMCID: PMC358203.
  3. Botto M, Kirschfink M, Macor P, Pickering MC, Würzner R, Tedesco F. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol. 2009 Sep;46(14):2774-83. doi: 10.1016/j.molimm.2009.04.029. Epub 2009 May 28. PMID: 19481265.

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