Complement C6

Complement component C6 is important in the immune system by forming the membrane attack complex (MAC), which helps protect the body against infections. 

Complement C6 deficiency (C6D) significantly increases susceptibility to infections like meningococcal meningitis, with particular prevalence among African-American populations due to specific genetic mutations.

What is Complement C6?

Complement component C6 is a key protein in the complement system. It is essential for forming the membrane attack complex (MAC), which disrupts pathogens by creating pores in their cell membranes. 

C6 is produced from a 934-amino acid polypeptide, encoded by the C6 gene located on chromosome 5p13. 

Complement component C6 consists of two major domains: C6a, which shares similarities with C9 and perforin, and C6b, which is related to complement regulatory proteins like factor H. These domains are connected by disulfide bonds, contributing to C6's structural stability.

C6 is glycosylated with two oligosaccharide chains, and mutations in the C6 gene can lead to complement deficiencies, particularly C6 deficiency (C6D), which is inherited in an autosomal recessive manner. 

Complement C6 and the Membrane Attack Complex

Complement component C6 is a vital protein in the immune system’s complement cascade, which helps form the membrane attack complex (MAC) that creates pores in pathogen membranes. 

The MAC is assembled in a specific order: C5b first binds C6, followed by C7, C8, and multiple C9 molecules. C6 is the first to join the complex and consists of several domains that help regulate the assembly process.

C6 starts in a closed, inactive state, stabilized by its auxiliary domains. When it binds to C5b, it undergoes changes that allow it to interact with C7, kickstarting the MAC formation. This process continues as C8 binds, followed by the addition of C9, each contributing to the growing pore. 

Importance in Immune Defense Against Neisseria Infections

One of the key roles of C6 is in defending against infections caused by Neisseria species, such as Neisseria meningitidis, which causes meningitis, and Neisseria gonorrhoeae, responsible for gonorrhea. 

Individuals with a deficiency in C6 are particularly vulnerable to these infections due to the impaired ability to form the MAC, which is necessary for the lysis of Neisseria bacteria.

Complement C6 Deficiency

C6D increases susceptibility to Neisseria infections, notably meningococcal meningitis, and is more prevalent among African Americans, with specific mutations such as 1195delC and 1936delG being more common in this group. 

Understanding C6's molecular structure and genetic variations helps in diagnosing and managing C6D, particularly in populations with a higher prevalence of the condition. The evolutionary implications of C6 deficiency, especially in African Americans, remain an area of ongoing research.

Who Should Get Complement C6 Tested?

Testing for Complement C6 should be considered in a variety of clinical scenarios.

Individuals with Recurrent Neisseria Infections (Meningitis, Gonorrhea)

If a patient experiences recurrent or severe infections caused by Neisseria, particularly Neisseria meningitidis or Neisseria gonorrhoeae, C6 testing may be indicated. A deficiency in C6 can significantly increase the risk of these infections, making early diagnosis and intervention essential.

Individuals with Suspected Complement Deficiency

C6 testing can be part of the broader diagnostic evaluation for complement deficiencies, which may manifest as increased susceptibility to various infections. Complement deficiencies are also associated with autoimmune diseases and angioedema, so C6 testing may be considered in these contexts as well.

Individuals with Systemic Lupus Erythematosus (SLE) or Other Autoimmune Diseases

While C6 testing is not a primary diagnostic tool for autoimmune diseases like SLE, it can be part of a comprehensive assessment of complement activity in patients with autoimmune conditions. 

Measuring C6 levels may provide additional insights into the immune system's functionality in these individuals.

Family Members of Individuals with Known C6 Deficiency

Family screening may be recommended for individuals with a known C6 deficiency. This helps identify potential carriers or other affected family members, particularly since C6 deficiency is inherited in an autosomal recessive pattern.

Testing Procedure and Preparation

Complement C6 is typically assessed in serum, which requires a blood draw. Fasting is preferred.

In some cases, practitioners may prefer genetic testing for the complement C6 gene.

Normal Reference Ranges

Reference ranges may vary depending on the laboratory company used; always consult the laboratory company for their recommended reference ranges.

A normal genetic test result is considered to be without any mutations that can cause dysfunctional proteins. 

What Do Low Complement C6 Levels Mean?

Low or absent Complement C6 levels are diagnostic of C6 deficiency. This condition can significantly impair the body's ability to form the MAC, leading to an increased susceptibility to infections, particularly those caused by Neisseria species. 

Individuals with C6 deficiency are at a notably higher risk of developing meningococcal meningitis, and these patients require careful monitoring and preventive measures, such as vaccination and prophylactic antibiotics.

In rare cases, C6 deficiency may be associated with certain autoimmune diseases or angioedema. However, these associations are less common and should be considered only after other potential causes are excluded.

What Do High Complement C6 Levels Mean?

Elevated C6 levels are not typically associated with specific diseases or conditions. In most cases, high C6 levels are transient and reflect an acute-phase response to inflammation. 

As such, elevated C6 is generally not a primary diagnostic indicator, but rather a non-specific marker of an ongoing inflammatory process. C6 levels should be interpreted in the context of the patient's clinical presentation and other laboratory findings.