The complement system antigens Martin Lika The complement

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The complement system, antigens Martin Liška

The complement system, antigens Martin Liška

The complement system • A complex consisting of at least 20 serum proteins, which,

The complement system • A complex consisting of at least 20 serum proteins, which, once activated, acts like a part of the innate immune defense • The complement components are present in serum in inactive form • The complement is activated in a cascading manner (= each protein activates that following) and it has widespread physiologic and pathophysiologic effects • Complement proteins are synthesized mainly in the liver, but tissue macrophages and fibroblasts can synthesize some complement proteins as well

The complement system nomenclature • • C 1 q, C 1 r, C 1

The complement system nomenclature • • C 1 q, C 1 r, C 1 s, C 2 -9 Factor B, Factor D Properdin Regulatory proteins (C 1 -inhibitor, Factor I, C 4 b. BP, Factor H, S protein, anaphylatoxin inactivator)

The classical pathway of complement activation • The pathway is activated through antigenantibody complexes:

The classical pathway of complement activation • The pathway is activated through antigenantibody complexes: initially, C 1 component binds to a site on the Fc fragment of Ig (Ig. G (but not Ig. G 4) or Ig. M); however, native Ig molecules do not interact with C 1 • C 1 component – contains three polypeptides (C 1 q, C 1 r, C 1 s); C 1 q attaches first to Ig (for initiation of complement activation, C 1 q has to interact with two or more Ig monomers) → C 1 q activates proenzyme C 1 r → C 1 r cleaves proenzyme C 1 s → C 1 s is able to cleave C 4 component

The classical pathway of complement activation • Activated C 1 s cleaves C 4

The classical pathway of complement activation • Activated C 1 s cleaves C 4 to C 4 a (an anaphylatoxin) + C 4 b → C 4 b binds to cell membranes → the next component becomes susceptible to enzymatic attack by activated C 1 • C 4 b + C 2 + C 1 s → removal of C 2 a → enzymatically active molecular complex C 4 b 2 b (= C 3 convertase of the classical pathway) • Formation of C 3 convertase represents the nodal point for all pathways of complement system activation

The alternative pathway of complement activation • The alternative pathway is considered to be

The alternative pathway of complement activation • The alternative pathway is considered to be a primitive „bypass“ mechanism, that does not require C 1, C 2 and C 4 • The pathway is activated through reaction of the complement system and some substances of microbial origin (polysaccharides – e. g. lipopolysaccharides of G negative bacteria, teichoic acid of G positive bacteria, zymosan from yeast cell walls, surface components of some animal parasites) or other foreign materials

The alternative pathway of complement activation • C 3 cleaves into C 3 a

The alternative pathway of complement activation • C 3 cleaves into C 3 a + C 3 b spontaneously; however, these are inactive under standard conditions • In this case, C 3 b binds to microbial surface → it reacts with factor B → removal of Ba (it is chemotactic for neutrophils) → C 3 b. Bb (= C 3 convertase of the alternative pathway) – it is stabilized by properdin (P)

The lectin pathway of complement activation • The pathway is activated through binding of

The lectin pathway of complement activation • The pathway is activated through binding of MBL (mannose-binding lectin) to microbial surface → C 4 a is released + C 4 b → C 4 b reacts with C 2 → C 2 b is released → C 4 b 2 a complex (= C 3 convertase)

Further events of complement activation process C 3 convertase causes generation of: a/ C

Further events of complement activation process C 3 convertase causes generation of: a/ C 3 a, C 4 a, C 5 a fragments - C 3 a and C 4 a act as peptide mediators of inflammation - C 5 a is chemotactic for phagocytes b/ C 3 b - it binds to complement receptors and causes opsonization of microbes and immunocomplexes

Further events of complement activation process c/ MAC (membrane attack complex) - formed from

Further events of complement activation process c/ MAC (membrane attack complex) - formed from terminal complement components (C 5 b, C 6, C 7, C 8, C 9); it attacks membrane of cells (e. g. microbes), causing their osmolysis

Complement receptors • Fragments of complement components can bind to complement receptors, which are

Complement receptors • Fragments of complement components can bind to complement receptors, which are expressed on the surface of different cells. • CR 1 – erythrocytes, granulocytes, monocytes and B cells - important for IC clearance • CR 2 – B cells and follicular dendritic cells - immunoregulation • CR 3, CR 4 – phagocytes - opsonization

Regulatory mechanisms of the complement system • Some serum proteins enzymatically attack complement components,

Regulatory mechanisms of the complement system • Some serum proteins enzymatically attack complement components, thereby inactivating them (factor I inactivates C 3 b; anaphylatoxin inactivator inactivates anaphylatoxins (C 3 a, C 4 a, C 5 a)) • Some serum proteins bind to, and thus inhibit, complement components (C 1 -INH inhibits C 1; C 1 INH deficiency → HAE = recurrent episodes of local edema; factor H acts with factor I the inhibition of C 3 b; S protein binds to C 5 b 67 → prevention of MAC binding to cell membrane)

Regulatory mechanisms of the complement system • Regulatory proteins in cell membranes (DAF (decay-accelerating

Regulatory mechanisms of the complement system • Regulatory proteins in cell membranes (DAF (decay-accelerating factor) – it has the same function as factor H → the inactivation of C 3 b and C 4 b; membrane cofactor protein – it serves as a cofactor for inactivation of C 4 b and C 3 b)

Functions of the complement system • C 3 a, C 5 a – anaphylatoxins

Functions of the complement system • C 3 a, C 5 a – anaphylatoxins (= they cause release of histamine and other vasoactive compounds from basophils and mast cells, increasing capillary permeability) • C 3 b, C 4 b – opsonization (they bind IC to macrophages and neutrophils, enhancing phagocytosis; also binds complexes to erythrocytes, facilitating removal by the liver and spleen) • C 5 a – chemotaxis (attracts phagocytic cells to sites of inflammation and increases their overall activity)

Functions of the complement system • C 8, C 9 – components of MAC

Functions of the complement system • C 8, C 9 – components of MAC • Ba – neutrophil chemotaxis • Bb – macrophage activation

Functions of the complement system - overview • Inflammation (mast cell degranulation, chemotaxis, increases

Functions of the complement system - overview • Inflammation (mast cell degranulation, chemotaxis, increases vascular permeability, margination and diapedesis of polymorphonuclears, smooth muscle contraction, activation of polymorphonuclears, NK cells and macrophages) • Clearance of immune complexes • Cell lysis (G negative bacteria, Protozoa, some viruses) • Viral neutralization • Opsonization

The complement system - overview • The alternative and lectin pathways are clear components

The complement system - overview • The alternative and lectin pathways are clear components of innate immune system, whereas the classical pathway depends on addaptive immune response (it is triggered through antigen-antibody reaction) • Three functions of the complement system: 1/ C 3 b coats microbes and promotes the binding of these microbes to phagocytes (by receptors for C 3 b)

The complement system - overview 2/some breakdown products of complement proteins are chemoattractants for

The complement system - overview 2/some breakdown products of complement proteins are chemoattractants for neutrophils and monocytes and promote inflammation at the site of complement activation 3/ complement activation results to the formation of a polymeric protein complex (MAC), causing osmolysis or apoptosis of microbes

Antigen • A substance, which is recognized by immune system and induces the immune

Antigen • A substance, which is recognized by immune system and induces the immune response • It comes from environment (exoantigen), or from individual’s own structures (autoantigen) • Usually proteins or polysaccharides (lipids and nucleic acids can act as antigens when combined with proteins or polysaccharides)

Haptens • Small and well-defined chemical structures, which are not immunogenic themselves, but can

Haptens • Small and well-defined chemical structures, which are not immunogenic themselves, but can add a new epitope when combined to an existing antigen • The antibody directed against the new epitope will react with the free hapten as well as the haptenepitope site in the altered antigen • Typically drugs (e. g. penicillin ATB, hydralazine)

Epitope • The portion of antigen, which is recognized by the immune system (lymphocytes,

Epitope • The portion of antigen, which is recognized by the immune system (lymphocytes, Ig) • Epitopes may be linear (amino acid sequence important), conformational (space conformation important) • Some epitopes are on the antigen’s surface, others are internal • Cross-reactive antigens – share one or more identical or similar epitopes

Antigen-antibody reaction • Binding sites of antibodies (paratope) interract with the corresponding sites of

Antigen-antibody reaction • Binding sites of antibodies (paratope) interract with the corresponding sites of the antigen (epitope) • The bonds that hold the antigen-antibody complex are non-covalent (hydrogen, electrostatic and hydrophobic bonds, Van der Waals forces) • Antigen-antibody complex is reversible

T cell dependent and independent antigens 1/ T cell dependent antigens - more common,

T cell dependent and independent antigens 1/ T cell dependent antigens - more common, typically contain protein component - a help from T helper cells is necessary for specific humoral immune response generating, otherwise the response is not so effective - the help comes in form of cytokines secreted by the T cell

T cell dependent and independent antigens 2/ T cell independent antigens - in some

T cell dependent and independent antigens 2/ T cell independent antigens - in some antigens, antibody production can be induced directly, without help from T cells - bacterial lipopolysaccharides and polymeric forms of proteins (e. g. Haemophilus, Str. pneumoniae)

Superantigens • Antigenic structures, capable to induce response of T cells by external binding

Superantigens • Antigenic structures, capable to induce response of T cells by external binding to MHC molecules (i. e. outside of the usual binding site) • The stimulation is polyclonal and extensive • Some bacterial toxins (Staph. aureus, Str. pyogenes, Pseud. aeruginosa)

Sequestered antigens • The antigens, which are normally hidden from the immune system at

Sequestered antigens • The antigens, which are normally hidden from the immune system at privileged sites, and thus the immune system cannot identify them (e. g. lens, testes) • However, if these allergens are released (injury), the immune system could response to them (the potential mechanism of autoimmunity development)

Immunologically privileged tissue • In allogeneic transplantation, some tissues are rejected less frequently (e.

Immunologically privileged tissue • In allogeneic transplantation, some tissues are rejected less frequently (e. g. CNS, cornea, gonades). • The mechanisms of protection from the immune system: separation from the immune system (haematoencephalic barrier); the preference of Th 2 - and suppression of Th 1 -reactions; active protection from effector T cells • The privileged status is not absolute (see MS)

Molecular size of antigens • Molecules < 5 k. Da are not able to

Molecular size of antigens • Molecules < 5 k. Da are not able to induce immune response, the optimal molecular size for immune response induction is approximately 40 k. Da

Degree of foreignness • An antigen must be foreign or alien to the host

Degree of foreignness • An antigen must be foreign or alien to the host • The greater the phylogenetic difference, the more foreign something becomes; based on this fact, we can distinguish the following types of antigens:

Degree of foreignness • Autologous – are found within the same individual (e. g.

Degree of foreignness • Autologous – are found within the same individual (e. g. a skin graft from an individual’s thigh to his chest); that is, they are not foreign • Syngeneic – are found in genetically identical individuals (e. g. identical twins); that is, they are not foreign • Allogeneic (alloantigens) – are found in genetically dissimilar members of the same species (e. g. a kidney transplant from mother to daughter); it is foreign • Xenogeneic (heterogeneic) – are found in different species (e. g. a transplant of monkey kidneys to human); it is foreign