Abdomen, Pelvis, and Perineun

The Complement System

This system consists of about 20 plasma proteins and their products, which can be activated by way of the classic, alternate, or lectin pathways to form a final product—the membrane attack complex (MAC).

Each pathway is activated by a different mechanism.

The major goal of all three cascades is the deposition of substantial quantities of C3b on a target (opsonization), which marks it for elimination.

01. Classic Pathway

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Alternate pathway

This pathway is initiated directly by nonimmunologic stimuli, such as invading microorganisms, and, like the classic pathway, leads to cleavage products that cause cell lysis. It bypasses the initial stages of the classic pathway. This pathway contains factor B, properdin, and factor D.
Lectin pathway

This pathway is initiated by mannose or other carbohydrates on the microbial surface. It is important in the destruction of microbial pathogens, including gram-negative bacteria, fungi, viruses, and protozoa.
Other diseases associated with complement include:
1. C6-C9 deficiency—These individuals have an increased susceptibility to disseminated Neisseria infections.
2. Paroxysmal nocturnal hemoglobinuria—These individuals have a mutation in the phosphatidylinositol glycan complementation group A gene in a myeloid stem cell clone that results in a defect in the anchoring of inhibitors of complement (CD55 [decay accelerating factor] and CD59) on the surface of red blood cells, polymorphonuclear leukocytes, and platelets. Therefore, complement-mediated intravascular lysis of those cells occurs, leading to pancytopenia.

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●Functions of complement – In pathologic conditions featuring autoantibodies and immune complexes, complement activation contributes to cell and tissue damage. In acute injury states (membrane damage, apoptosis, necrosis) and with deposition of debris (lipids, proteins, pigments, crystals), the system plays an important role in the host's response to altered self. Failure of this clearance role predisposes to autoimmunity, particularly systemic lupus erythematosus (SLE). (See 'Functions of the complement system' above.)

●Assessing complement function – Complement levels can be evaluated either by antigenic or functional assays. The CH50 is a functional assay that requires all nine components of the classical pathway (C1 through C9) for a normal result. A homozygous deficiency of classical pathway components is indicated by an extremely low CH50 value (≤10 units/mL). Less dramatic reductions in CH50 are seen in pathologic processes secondary to immune complex formation. A low CH50 can also result from laboratory error and "cold activation." (See 'CH50' above.)

●C3 and C4 – The measurement of C3 and/or C4 can assist in the diagnosis of certain diseases (especially SLE), as well as in monitoring the course of the disease. Other diseases featuring autoantibodies leading to immune complex formation are the antiphospholipid syndrome, mixed cryoglobulinemia, Sjögren syndrome, and membranoproliferative glomerulonephritis. Low C4 and C3 or low C3 alone can indicate the presence of any of these disorders. (See 'Serum C3 and C4 levels' above.)

●Complement deficiencies – Genetic deficiencies (usually haploinsufficiency of complement inhibitory proteins) leading to excessive activation of the alternative pathway have been identified in atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy, and age-related macular degeneration (AMD). Genetic variation in the copy number of C4 genes in the brain is associated with increased risk of schizophrenia. (See 'Alternative pathway activation' above.)

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Reference

https://www.ncbi.nlm.nih.gov/books/NBK27100/#:~:text=The%20complement%20system%20is%20made,themselves%20activated%20by%20proteolytic%20cleavage.

Other diseases associated with complement include:
1. C6-C9 deficiency—These individuals have an increased susceptibility to disseminated Neisseria infections.
2. Paroxysmal nocturnal hemoglobinuria—These individuals have a mutation in the phosphatidylinositol glycan complementation group A gene in a myeloid stem cell clone that results in a defect in the anchoring of inhibitors of complement (CD55 [decay accelerating factor] and CD59) on the surface of red blood cells, polymorphonuclear leukocytes, and platelets. Therefore, complement-mediated intravascular lysis of those cells occurs, leading to pancytopenia.

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Convertase refers to a group of enzyme complexes that play a crucial role in the complement system, which is a part of the immune system involved in enhancing the ability of antibodies and phagocytic cells to clear pathogens from an organism. Convertases are central to the activation and amplification of the complement cascade.

### Types of Convertases:

1. **C3 Convertase:**
- **Function:** C3 convertase cleaves the complement protein C3 into two fragments: C3a and C3b.
- **Pathways:**
- **Classical Pathway:** The C3 convertase in the classical pathway is formed by the complex of C4b and C2a (C4b2a).
- **Alternative Pathway:** The C3 convertase in the alternative pathway is formed by the complex of C3b and Bb (C3bBb).
- **Lectin Pathway:** The lectin pathway also forms a C3 convertase similar to that of the classical pathway (C4b2a).

- **Role:** The generation of C3b is a critical step in opsonization (marking pathogens for destruction) and in the formation of C5 convertase, which leads to the activation of the terminal complement pathway and the formation of the membrane attack complex (MAC).

2. **C5 Convertase:**
- **Function:** C5 convertase cleaves the complement protein C5 into C5a and C5b.
- **Pathways:**
- **Classical and Lectin Pathways:** The C5 convertase in these pathways is formed by the complex of C4b, C2a, and C3b (C4b2a3b).
- **Alternative Pathway:** The C5 convertase in the alternative pathway is formed by the complex of C3b, Bb, and an additional C3b molecule (C3bBbC3b).

- **Role:** C5b initiates the assembly of the membrane attack complex (MAC), which forms a pore in the membrane of the target cell, leading to cell lysis and death.

### Clinical Significance:
- **Complement Deficiencies:** Deficiencies or dysfunctions in convertases or other complement components can lead to increased susceptibility to infections, particularly with encapsulated bacteria, and can also contribute to autoimmune diseases.
- **Therapeutic Targets:** Convertases, especially C3 and C5 convertases, are targets for therapeutic interventions in diseases where excessive complement activation plays a role, such as certain autoimmune disorders and inflammatory diseases.

Convertases are essential for the proper functioning of the complement system, and their regulation is vital for maintaining immune homeostasis and preventing tissue damage from excessive immune responses.