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Complement system
-main humoral mechanism of nonspecific immunity
- > 40 glykoproteins
- blood
- on the surface of immune cells
- Complement components inter-react be precise and regulated manner
to eliminate microbs, foreign cells or material.
-Charles Bordet 1896 - fresh serum of immunized animals agglutinate in
vitro and lyse bacteria used for immunization
- serum heated to 60oC agglutinate bacteria, but do
not lyse
- system responsible for lysis was named alexin
Complement components
Classical pathaway
C1q, C1r, C1s, C2, C3, C4
Alternative pathway
C3, faktor B, D, I, H, P
Lactin pathway
C3, MBP, MASP
MAC
C5, C6, C7, C8, C9
Abnormálne proteíny
C3 – nefritický faktor
Regulatory functions
C1-inhibitor, C4-binding factor, I factor, H factor, S- protein,
properdin, inactivator of anaphylaxis, DAF, MCP, MIRL
Receptors of C
CR1- binds C3b, CR3 – binds iC3b, ...
Biosynthesis of Complement
1. Hepatocytes
2. Mononuclear phagocytes – inflammatory site
3. Epithelial cells
Genetics of Complemet System
1. Isolated genes
- C3
- chromosome 19
- I factor - chromosome 4
- C1-INH - chromosome 11
2. Genes in clusters
chromosome 6 - C2, C4, B factor
chromosome 1 - C4 bp, H factor, CR1, CR2, DAF, MCP
Activation of Immune System
-
Complemets of components are innactive in serum
3 pathways of activation
1. Classical pathway
2. Alternative pathway
3. Lectin pathway
Cascade system of activation – active component serve as enzyme
and activate (split) following component
Activation of Complement
Classical pathway
Activation signals:
1. Immune complexes
complex Ag + Ab (IgM, IgG3, IgG1)
2. CRP – C-reactive protein
During inflammation rise its
concentration 100 times.
CRP binds polysaccharides of bacteria,
fungi, parasites and viruses.
Its binding to Ag is non specific
3. Aggregated IgG
4. Polycationic and polyanionic compounds
5. RNA, DNA
6. LPS G- bacteria
7. Some viral proteins
Activation of Complement
Classical pathway
C1 – macromolecular complex
- 3 subunitsC1q, C1r, C1s
Recognition function - C1q
Effector functions
- tetramolecular complex (C1r, C1s)2
C1q - 3 types of chains (A, B,C)
- triplet of chains A+B+C form subunit with binding site for
- CH2 domain IgG
- CH4 domain IgM
Activation signal = binding of C1q to immunocomplex
( IgM, IgG + Ag)
Activation of Complement
Classical pathway
Binding of C1q to immune complex
 auto-catalytic splitting of proenzyme C1r for active enzyme C1r
 conversion of C1s for active serine protease C1s
 splitting of C2 na C2a a C2b
and C4 na C4a a C4b
 C4b2a = C3 convertase – split C3 for C3a a C3b
 C4b2a3b = C5 convertase – split C5 C5a a C5b
Activation of Complement
Alternative pathway
Activation signals :
1. Aggregated IgG4, IgA1, IgA2, IgE
2. Polysaccharides
3. LPS of bacteria (low content of sialic acid)
4. Various components of viruses, fungi, protozoa,
cancer cells
Spontaneous conversion of C3 for C3b.
C3b rapidly inactivated (H factor) binding to sialc (typical for cells MAO)
Cells with low content of sialic acid (MIO) cause low affinity of H factor
to C3b. C3b persist and binds B factor – further activation of C3
alternative pathway of activation
Activation of Complement
Lectin pathway
Resemble of classical pathway – 2 differences
A) C1q is supplied by MBP (mannose binding protein) –
strucrurally close to C1q
B) MASP (MBP asssociated serine protease) –
strucrurally close to C1r a C1s
After binding of MBP to mannose or N-acetylglukoseamin – activation of
MASP – splitting C4 a C2
Activation of Complement
MAC
Biological funcions
1.
2.
3.
4.
5.
6.
Lysis
Opsonization – C3b, C3bi
Chemotaxis – C5a
Inflammation - anaphylatoxins: C3a, C4a, C5a
Modulation of immune complexes
Immunoregulation
Deficiences
C3 – inherited >> susceptibility to bacterial infections
C2 - immune complex diseases
- autoimmune disseases Systemic lupus
erythematosus (SLE)
C1INH - hereditary angioneurotic oedem (HANE).