KOMPLEMENT RENDSZER.

Az előadások a következő témára: "KOMPLEMENT RENDSZER."— Előadás másolata:

1 KOMPLEMENT RENDSZER

2 az immunválasz végrehajtásában komplementál,
A KOMPLEMENT RENDSZER az immunválasz végrehajtásában komplementál, humorális immunválaszt egészíti ki Complement activation, kinin generation, blood coagulation, and fibrinolysis are physiologic processes that occur through sequential cascade-like activation of enzymes normally present in their inactive forms in plasma. Although these four distinct systems perform different functions, they interact with one another and with various cell membrane proteins. The first two—complement and kinins—are critical elements of the innate immune system, promoting inflammation and, in the case of complement, providing a first line of defense against infection.

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4 Az antitestek specifikusan az antigénekhez kötődnek
Antigén + antitest: Immunkomplex - az esetek egy részében semlegesítik őket - az esetek nagyobb részében az antitestmolekulák nagyméretű antigénekkel együtt immunkomplexet alkotnak A megsemmisítésükhöz vezető folyamatban játszik szerepet a komplement rendszer

5 A komplementrendszer:
- Ősi - Az immunválaszban effektor = végrehajtószerepet tölt be - Nem antigénspecifikus - Főleg az extracelluláris patogének eltávolításában játszik szerepet

6 A komplementrendszer háromféle módon fejti ki hatását:
Komplement aktiváció A patogének lízise Opszonizáció A fagociták odavonzása The third function of the complement proteins is the generation of peptide fragments that regulate features of the inflammatory and immune responses. These proteins play a role in vasodilatation at the site of inflammation, in adherence of phagocytes to blood vessel endothelium, in egress of the phagocytes from the vessel, in directed migration of phagocytic cells into areas of inflammation, and, ultimately, in clearing infectious agents from the body.

7 A rendszer a plazmában szolubilisan előforduló fehérjék összessége
Fő tagjai proenzimek: egymást láncreakciószerűen aktiválják Hatásuk felerősödik: egy patogén által aktiválódott molekula a rendszer számos következő tagjának aktiválódását váltja ki The proteins of each pathway interact in a precise sequence. When a protein is missing, as occurs in some of the genetic deficiencies, the sequence is interrupted at that point.

8 központi szerep: C3 C3 molekulának az aktiválása kulcslépése minden komplement által mediált folyamatnak

9 Az aktiválódásnak három lehetséges útját ismerjük
klasszikus lektin alternatív Az aktiválódásnak három lehetséges útját ismerjük C3 konvertáz

10 1. KLASSZIKUS AKTIVÁCIÓ Főleg IgM első antitest Elsődleges immunválasz

11 KLASSZIKUS AKTIVÁCIÓS ÚT
Antigén felszín Antigén felszín C1q + C1r,C1s

12 Klasszikus C3 konvertáz
antigén-antitest komplex + C1  C4  C4b + C4a C1  C2 C2b + C2a C4b + C2b  C2bC4b Klasszikus C3 konvertáz C2bC4bC  C3  C3b + C3a

13 Alternatív C3 konvertáz
ALTERNATÍV AKTIVÁCIÓS ÚT Spontán keletkező C3b C3b + B  C3bBb + Ba  D-faktor Alternatív C3 konvertáz C3bBb  C3  C3b +C3a C3 not only serves as a pivotal component of the classical pathway but also is the key component of the alternative complement pathway. Circulating plasma C3 undergoes spontaneous hydrolysis of its thioester bond to form a conformationally altered species called C3(H2O) as water slowly penetrates to the thioester group. Once the thioester group has opened, C3(H2O) acts like C3b (described earlier). In the presence of magnesium ions it can bind the C2-like protein, factor B, and interact with the C1-like protein, factor D, to form the alternative pathway convertase that cleaves C3, just as the classical convertase cleaves C3 . If these reactions happen to occur near a foreign particle, however, some C3b fragments may become covalently bound to its surface The alternative pathway C3 convertase (C3bBb) is extremely unstable and would ordinarily dissociate rapidly. In the blood, however, a protein called properdin binds to this convertase and stabilizes it, thus slowing its decay and allowing it to continue the complement cascade.

14 LEKTIN ÚT Mannóz kötő lektin (MBL) a patogén mannóztartalmú részeihez köt MBL+ MASP  C2, C4  C2bC4b C3  C3b MBL is present in mammals and birds and belongs to a family of molecules termed collectins. Nonimmunologic Classical Pathway Activators A number of nonimmunologic activators of the classical pathway exist. Certain bacteria (eg, certain Escherichia coli and Salmonella strains of low virulence), viruses (eg, parainfluenza virus, human immunodeficiency virus), and even apoptotic cells interact with C1q directly, causing C1 activation and, in turn, classical pathway activation in the absence of antibody. Such an interaction in most cases aids the natural defense process of the host. Other structures, such as the surface of urate crystals, myelin basic protein, denatured DNA, bacterial endotoxin, and polyanions (such as heparin) also may activate the classical pathway directly. Such activation by urate crystals is thought to contribute to the inflammation and pain associated with gout.

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16 In summary, the early steps of the complement cascade lead to the generation of a series of enzymatically active peptides and peptide complexes. As each complex is formed, it has a different specificity from the preceding complex and interacts with the next protein in the complement cascade. Each enzyme interacts with multiple molecules of the next substrate protein in the cascade of reactions either until it decays, as occurs with the C3 and C5 convertases, or until it is inhibited by regulatory proteins present on cells or in plasma. Thus, there is a potential for considerable biologic amplification: A limited number of antigen-antibody complexes lead to the activation of large numbers of complement molecules. C5b

17 MAC

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19 OPSZONIZÁCIÓ C3b also has a
strong tendency to interact with nearby IgG molecules, and the dimer formed by C3b and IgG is a more potent opsonin than is C3b alone. C3b reacts with water to form the conformationally altered inactive species C3b(H2O); this rapid inactivation helps to ensure that the reactive form of C3b is destroyed and does not produce unwanted activation. The regulation and degradation of bound C3b depend on interaction with the circulating factors H and I. In the presence of these factors, C3b is cleaved to iC3b, which continues to act as an opsonin through complement receptor 3 (CR3). However, iC3b can no longer activate the terminal components of the complement cascade. The product iC3b undergoes further cleavage in the presence of CR1 and factor I to C3dg. C3dg and C3d, the final degradation product, interact with complement receptor 2

20 KOMPLEMENT RECEPTOROK
CR1 - immunkomplex szállítása - fagocitózis The fourth function of complement is to help regulate the biologic activity of cells. Complement binding to cells may cause their activation and even cause them to divide. Complement binding to antigens may facilitate their binding to receptors on antigen- presenting cells and thereby render them far more "antigenic." CR1 plays a role in the opsonization and phagocytosis of particles coated with C3b. CR1 enhances the phagocytosis of IgG and C3b-coated particles by monocytes and neutrophils. Here phagocytosis requires simultaneous triggering of two receptors on the phagocyte surface. Activated monocytes (C3b and Fcg) can phagocytose C3b-coated targets in the absence of IgG. CR1 expressed on erythrocytes aids in the transport of immune complexes to the liver for degradation by Kupffer cells Organisms have also subverted the complement peptides to their own ends. For example, Epstein-Barr virus (EBV) produces a surface protein that mimics the C3 fragment C3d, thereby gaining entry to B cells by binding to CR2 (CD21), the B-cell C3d receptor.

21 - B-sejt pozitív kostimuláció
CR2 - B-sejt pozitív kostimuláció Ag Ig/Ig Complement elem CR2 B-sejt IgM

22 2. C3 konvertáz szabályozás
INHIBITOROK Szolubilis plazma / integráns membrán fehérjék C1 inhibitor 1. Kezdeti kontroll: C1 inhibitor 2. C3 konvertáz szabályozás C1 inhibitor (C1INH), is a serine protease inhibitor (serpin) that recognizes activated and and destroys their activity. This glycoprotein also acts as an inhibitor of activated Hageman factor (see section on Proteins of the Kinin Cascade), of activated kallikrein, of clotting protein XIa, and of plasmin. Thus, C1INH regulates enzymes formed during activation of the kinin-generating system, the clotting system, the fibrinolytic system, and the complement cascade. Decay-accelerating factor . Membrane cofactor protein, MCP is expressed on nearly every cell type except for erythrocytes and is believed to play a significant role in preventing complement-mediated damage to host cells. MCP is of particular interest because it has proven to be the receptor for measles virus, allowing the infection of cells. In the control of complement attack against host tissue, it would be beneficial if complement proteins such as C3b were rapidly degraded when bound to host cells but not degraded when bound to the surface of a microorganism. A process for accomplishing this goal has evolved. When deposited on a microorganism, C3b is often in a "protected site," which is protected from the action of the control proteins factors H and I. The C3b persists to activate the alternative pathway and destroy the organism. In contrast, on host cells C3b interacts with factors H and I and is degraded. The biochemical basis for this protection of C3b on an organism surface is not yet completely understood but appears to relate to the presence of charged carbohydrates such as sialic acid on mammalian cells, which may facilitate the binding of factor H. is a physiologic analog of C3b in this reptile. Cobra venom factor, when added to human plasma, functions just like human C3b to activate the alternative pathway. As described later on, endogenous C3b is under tight regulatory control by other plasma proteins. By contrast, cobra venom factor is not inhibited by these regulators and therefore can induce massive complement activation. The MBL pathway is regulated by C1 inhibitor and a2-macroglobulin. 3. MAC szabályozás

23 C3 konvertáz szabályozása
Klasszikus C4BP C2bC4b  C3 C3b+C3a Alternatív H - faktor C3bBb  C3 C3b+C3a

24 KIS KOMPLEMENT-FRAGMENSEK
All of these small activation peptides have anaphylatoxic activity: They cause smooth muscle contraction and degranulation of mast cells and basophils, with consequent release of histamine and other vasoactive substances that induce capillary leakage. C5a is the most potent of these anaphylatoxins. C5a has profound effects on phagocytic cells. By interacting with specific cell membrane C5a receptors, (C5aR) it is strongly chemotactic for neutrophils and mononuclear phagocytes, inducing their migration along a concentration gradient toward the site of generation. It increases neutrophil adhesiveness and causes neutrophil aggregation. In addition, it dramatically stimulates neutrophil oxidative metabolism and the production of reactive oxygen species, and it triggers lysosomal enzyme release from a variety of phagocytic cells. Cellophane membranes used in renal dialysis machines, and membrane oxygenators may activate the alternative pathway with C5a generation. This, in turn, may lead to neutrophil aggregation, embolization of the aggregates to the lungs, and pulmonary distress. It is suspected that C5a generation plays an important deleterious role in the development of adult respiratory distress syndrome.

25 MHC III: C3 konvertázok The genes for C4, C2, and factor B are
located within the major histocompatibility locus on the short arm of chromosome 6 in humans and are termed class III histocompatibility genes. C2 is highly homologous to factor B and may have arisen as a gene duplication of factor B. The significance of the intimate colocalization of histocompatibility genes and complement genes is unknown at present. MHC III: C3 konvertázok

26 KOMPLEMENT-HIÁNYOS BETEGSÉGEK
HANO Immunkomplex betegségek . A relative deficiency occurs in patients with hereditary angioedema, who have a defect in one of the two genes responsible for formation of C1INH. These patients have one half to one third the normal level of C1INH and have frequent attacks of angioedema—painless swelling of deep cutaneous tissues—whose cause is still uncertain. It may arise from activation of the kinin-generating system or from activation of the complement system, with generation of peptides that cause vascular leakage. DAF, HRF, and CD59 are each bound to the cell surface by a phosphoinositide glycosidic linkage rather than by a transmembrane domain within the amino acid backbone of the protein. This phosphoinositide linkage is reported to give the protein far greater lateral mobility within the cell membrane, increasing its ability to intercept damage-causing complement complexes. In patients with paroxysmal nocturnal hemoglobinuria, phosphoinositide-linked proteins are incorrectly assembled or inserted into cellular membranes of hematologic cells due to a specific enzyme defect, rendering these cells exquisitely sensitive to complement-mediated lysis. A Neisseria meningitidis (meningococcusok) egy Gram-negatív coccus-baktérium, amelynek az ember a természetes gazdája. A meningococcusok megfertőzhetik az agy és a gerincvelő burkait (meningitisz),s a vért, és felelősek lehetnek egyéb súlyos gyermek- és felnőttkori fertőzésekért. A invazív meningococcus betegség okozója egy baktérium, a „Neisseria meningitidis", másnéven meningococcus. E baktériumnak több típusa van (A, B, C, Y, W135 stb.), Magyarországon a leggyakoribb a B és a C szerocsoportú kórokozó. E baktérium gyakran kimutatható az egészsége emberek orrüregének és garatjának nyálkahártyáján. A betegség a téli időszakban gyakoribb, de megjelenése nem zárható ki a melegebb hónapokban sem. A Neisseria gonorrhoeae szintén gram-negatív coccus, amelynek az ember a természetes gazdája, gonorreát (kankó, tripper) egy szexuálisan terjedő betegséget okoz, mely megfertőzheti a húgycsövet, a hüvelyt és a végbelet, valamint ráterjedhet az ízületekre.n Sok egyéb Neisseria törzs honos rendes körülmények között a torokban, szájban, hüvelyben és a belekben, de ezek ritkán okoznak betegséget. Visszatérő bakteriális fertőzések Visszatérő Neisseria fertőzések