The Immune System: Complement Activation

Study Notes

Complement System: A group of 20 plasma proteins activated by foreign substances.
Complement activation enhances and amplifies inflammation.
Bacteria and other cells are lysed by complement activation.
Complement activation enhances both innate and adaptive defenses.

Classical Pathway: Requires antibodies.
- Antibodies bind to a target (antigen).
- Complement protein C1 binds to the antibody-antigen complex (complement fixation).
Alternative Pathway: Complement factors interact with microorganism glycocalyx.
Lectin Pathway: Employs mannose-binding proteins.
All three pathways lead to a cascade of protein activation culminating in the activation of C3.

C3 is the starting point of the final common pathway.
C3 cleaves to form C3a and C3b.
C3a and C5a enhance inflammation by increasing histamine release, increasing vascular permeability, and stimulating chemotaxis.
C3b coats bacterial membranes, supplying adhesion points (opsonization).
C3b initiates the cascade forming the membrane attack complex (MAC).
The MAC forms a hole in the cell membrane, enhances Ca2+ influx, and causes cell lysis.

The complement system can damage tissues in response to abnormal stimuli.
In infectious or autoimmune conditions, complement's inflammatory or lytic effects may significantly contribute to disease pathology.
Complement activation can lead to intravascular thrombosis causing ischemic injury to tissues.

Low complement levels suggest recent excessive activation or consumption.
Genetic defects can cause an absence of a single complement component.
Absence of regulatory components can lead to inappropriate activation at the wrong time or location.
Excess activation can cause inflammation and cell lysis and deplete complement components.
Complement deficiency increases susceptibility to infections like Haemophilus influenzae and Streptococcus pneumoniae.

Rheumatic diseases: Systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, essential mixed cryoglobulinemia, glomerulonephritis, poststreptococcal type, and membranoproliferative type.
Infectious diseases: Subacute bacterial endocarditis, infected atrioventricular shunts, pneumococcal sepsis, Gram-negative sepsis, viremias (e.g., hepatitis B, measles), and parasitic infections (e.g., malaria).
Deficiencies of control proteins: C1 inhibitor deficiency (hereditary angioedema), Factor I deficiency, and Factor H deficiency.

Cytokines: Control various cellular responses, regulating the immune response.
- Interleukins: Regulate growth, mobility, and differentiation of lymphoid cells.
- Interferons: Interfere with viral replication.
- Tumor Necrosis Factor: Mediates acute inflammatory response to infectious microbes.
Hematopoietic stimulators: Stem cell factor, colony-stimulating factors, transforming growth factors, chemokines.
Other cytokines—TNF, variants of TNF (lymphotoxin), the CD40 ligand, the CD27 ligand, and the CD30 ligand

A group of glycoproteins associated with the acute-phase response.
Acute-phase proteins rise in varying levels in response to tissue injury (inflammation, infection, diseases, trauma, surgical procedures, drug response).
Increased synthesis of these proteins takes place shortly after trauma, initiated and sustained by proinflammatory cytokines.