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 Innate immune system Innate immunity, the 1st protective layer of defense, is a system that recognizes threatening microbes, distinguishes self-tissues from pathogens, and subsequently eliminates the foreign invaders. The response is nonspecific and uses different layers of protection: barriers such as the skin, pattern recognition receptors (PRRs) as well as circulating proteins, and immune cells that help eliminate the microbe. Cells of the Innate Immune System. 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 with encapsulated 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, 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 causes an increased risk of hypersensitivity reactions.

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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 varies by geographic location.
  • No gender or ethnic propensity reported.

Etiology

  • Hereditary C3 deficiency:
    • Encoded on chromosome 19 by the C3 gene
    • 17 mutations in C3 gene 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 Inheritanceinheritance
  • 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. 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 Dengue is an infection caused by the Dengue virus (DENV), a small, positive-sense, single-stranded RNA virus of the genus Flavivirus. The majority of infections are asymptomatic. Symptomatic individuals may progress through 3 stages of the disease, with severe manifestations occurring in those with previous infections. 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 B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus
    • 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):
    1. Classical pathway (C1qrs, C2, C4)
    2. Alternative pathway (C3, factor B, properdin)
    3. Lectin pathway (mannan-binding lectin (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: Overview
    • Leads to reduced clearance of immune complexes
    • Increased risk of pyogenic bacterial infections
C3 deficiency

Complement cascade

Image: “Complement pathway” by Perhelion. License: Public Domain

Diagnosis

Clinical presentation

  • Recurrent bacterial infections during childhood, especially encapsulated organisms:
    • Upper respiratory tract infections
    • 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 and sepsis Sepsis 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. Sepsis and Septic Shock can occur similar to Bruton agammaglobulinemia: infections 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:
    • 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 develop glomerulonephritis.

Laboratory testing

Clinical testing directed by pattern of infection:

  • Bacterial types
  • Location of infection

Management

Management of patients 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 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 vaccines are critical.
  • Prophylactic antibiotic:
    • Chronic prophylaxis 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: Overview 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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