Complement J Ochotn Complement system of about 30

Complement J. Ochotná

Complement § system of about 30 serum and membrane proteins (humoral component of nonspecific immunity) § complement components in serum are present in inactive form § complement activation has cascade character

§ complement proteins are synthesized in the liver, less by tissue macrophages and fibroblasts § the main complement components: C 1 -C 9 (C 3 is the central component) § other complement components: factor B, factor D, factor P § regulatory proteins: C 1 - inhibitor, factor I, factor H, C 4 bp, DAF, MCP, CR 1, factor S (vitronectin), CD 59 (protektin), inactivator of anafylatoxin

Functions of complement § Opsonization (C 3 b, C 4 b) § Chemotaxis (C 3 a, C 5 a) § Osmotic lysis (MAC C 5 b-C 9) § Anafylatoxins (C 3 a, C 4 a, C 5 a)

Complement activation § Alternative pathway § Classical pathway § Lektin pathway

Riedemann N. C.

Alternative pathway § C 3 component of complement rarely spontaneously breaks into C 3 b and C 3 a § C 3 b can covalently bind on the surface of a particle (own cell, microorganism) or reacts with water and inactivate § to bound C 3 b joins a factor B, which is cleaved by factor D to Ba and Bb, resulting complex C 3 b. Bb is stabilized by factor P and functions as an alternative C 3 convertase

§ C 3 convertase cleaves C 3 to C 3 a (chemotactic for phagocytes) and C 3 b, which binds to the surface of the particles (opsonization), or gives rise to other C 3 convertases § from some C 3 convertases form C 3 b. Bb. C 3 b that act as an alternative C 5 convertase, which cleaves C 5 to C 5 a (chemotaxis) and C 5 b (starts terminal lytic phase)

Classical pathway § can be initiated by antibodies (Ig. G, not by Ig. G 4; Ig. M) or so-called pentraxins (CRP, SAP - acute phase proteins) § after binding of antibodies to the bacteria surface, there is a change in its conformation and C 1 protein can bind § C 1 have to bind to the 2 molecules of antibodies, change their conformation and get proteolytic activity - will cleave proteins C 4 and C 2

§ fragments C 4 b and C 2 a bind to the surface of organism and create the classic C 3 convertase (C 4 b. C 2 a), which cleaves C 3 to C 3 a and C 3 b § then creates a classic C 5 convertase (C 4 b. C 2 a. C 3 b) that cleaves C 5 to C 5 a and C 5 b

Zde dřívější nomenklatura – záměna 2 a za 2 b

Lectin pathway § is initiated by serum mannose binding lectin (MBL) § MBL binds to carbohydrate structures on the surface of some microbes, after the binding starts cleave C 4 and C 2 § this way is similar to the classical pathway

Terminal (lytic) phase of the complement cascade § C 5 b fragments creates a complex with C 6, C 7 and C 8, the complex dive into the lipid membrane of the cell and attached to it into a circle 13 -18 molecules of C 9 (MAC – membrane attack complex), thus create in the membrane pores and cell can lysis (G-bacteria, protozoans, some viruses). § Most microorganisms are resistant to this lytic effect of complement (protection by cell wall).

Regulation of complement and protection of own cells § Activation of complement cascade is controlled by the plasma and membrane inhibitors. § C 1 inhibitor (C 1 -INH – inhibits C 1, when the deficit → HAE ) § DAF (decay-accelerating protein)-degradation of C 3 and C 5 convertase

§ factor I, MCP (membrane cofactor protein), CR 1, factor H – C 3 b cleavage § CD 59 (protectin) - prevents the polymerization of C 9 § factor S (vitronectin) – inhibits complex C 5 b. C 6 § inactivator of anafylatoxins - inactivates anafylatoxins (C 3 a, C 4 a, C 5 a)

Complement receptors § Bind fragments of complement components § CR 1 - on various cells - removing of immunecomplexes § CR 2 - on B lymphocytes and FDC - activation of B cells § CR 3, CR 4 - on phagocytes - participation in opsonization, adhesion

4 basic complement functions § Opsonization (C 3 b, C 4 b) § Chemotaxis (C 3 a, C 5 a) § Osmotic lysis (MAC C 5 b-C 9) § Anafylatoxins (C 3 a, C 4 a, C 5 a)

Antigens

Antigen (immunogen) § substance that the immune system recognizes and responds to it § usually proteins or polysaccharides (lipids and nucleic acids only in the combination with proteins or polysaccharides) § molecules <5 k. Da can´t trigger an immune response, the optimal size of the antigen molecules to initiate immune response is about 40 k. Da

Hapten § small molecules, that are able to induce specific immune response only after the establishment to the macromolecular carrier § separate haptens are not immunogenic § typically drugs (eg penicillin antibiotics, hydralazin)

Epitope § = a part of the antigen which is recognized by immune system (lymphocytes- BCR, TCR, Ig) § linear epitope (AA sequence) - critical is amino acid composition § conformational epitope - critical is tertiary structure § cross-reactive antigens - shares one or more identical or similar epitopes

Interaction antigen – antibody § Binding site of antibody (paratop) form non-covalent complexes with the corresponding part on antigen molecule (epitope) § participation: the hydrogen bonds, electrostatic and hydrophobic interactions, van der Waals forces § antigen-antibody complex is reversible

Antigen § endogenous antigens - autoantigens (self Ag) § exogenous antigens - foreign substances from the environment § allergen is exoantigen that in the susceptible individuals can cause pathological (allergic) immune response

Antigen features § immunogenicity proteins> carbohydrates> macromolecule complexes (glycoproteins, nucleoproteins, and glycolipids)> lipids § specificity

Factors affecting the immunogenicity § Physical: solubility - insoluble more immunogenic molecular weight - ideal 5 -40 k. Da § Chemical: structure - the number of determinants degradability - "ease" of uncovering the determinants in antigen presenting cells (APC cell) § Biological: biological heterogeneity genetic and physiological disposition of the body

Degree of foreignness § Autogeneic - antigens of the same individual § Syngeneic - antigens of genetically identical individuals (eg twins) § Allogeneic (alloantigens) - antigens genetically different individuals of the same species § Xenogeneic (heterologous) - antigens derived from individuals of different species (eg monkey kidney transplant man)

Types of antigens according to antigen presentation § thymus dependent antigens § thymus independent antigens

Thymus dependent antigens § more frequently, mostly protein Ag § for specific humoral immune response to antigen is necessary to cooperate with TH lymphocytes (or response isn´t enough effective) § assistance implemented in the form of cytokines produced by TH lymphocytes

Thymus independent antigens § in a small number of antigens can be induced antibodies production directly without the participation of T lymphocytes § this are mainly a bacterial polysaccharides, lipopolysaccharides and polymer forms of proteins (e. g. Haemophilus, Str. pneumoniae)

Superantigens § proteins (microbial products) which have 2 binding sites, one interacts with the epitope presented on all MHCgp. II, second interacts with other structures presented in many different TCR molecules (connection of T lymphocyte with APC) § stimulate polyclonaly and massively § massive activation of T lymphocytes can cause shock § e. g. bacterial toxins (Staph. aureus, Str. pyogenes, Pseud. aeruginosa)

Differcence between antigen and superantigen binding

Sequestered antigens § autoantigens that are normally hidden to immune system and therefore unknow (e. g. brain, the lens of the eye , testes) § if they are "uncovered" by demage, exposed to the immune system, are recognized as foreign (one of theories of autoimmune processes)

Immunologically privileged sites § Some tissues in allogeneic transplant are far less rejected (eg CNS, cornea, gonads) § Mechanisms of protection from the immune system: § isolation from the immune system (blood-brain barrier) § preferences Th 2 and suppression of Th 1 -response active protection against effector T-lymphocytes § This privileged position is not absolute

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