Lecture No 7. Soluable mediators of the immune system PDF

10/12/2021 I‐ THE COMPLEMENT Proteins  Consists of over 20 serum glycoproteins  Synthesized principally by hepatocytes (except C1).  The complement system is important for killing , recruitment of inflammatory cells, opsonization of pathogens, clearing immunocomplexes i...

10/12/2021 I‐ THE COMPLEMENT Proteins  Consists of over 20 serum glycoproteins  Synthesized principally by hepatocytes (except C1).  The complement system is important for killing , recruitment of inflammatory cells, opsonization of pathogens, clearing immunocomplexes it can be phagocytosed directly  Many of the complement components circulate in the serum as proenzymes (functionally inactive enzymes) that require proteolytic cleavage for activation.  Once a component is activated, it catalyses the next step of the pathway. Components remain in the activated state for only a short time this is not considered signaling because 1 there was no kinase involved Functions of the Complement System Three main physiologic activities of the complement system: 1.Host defense against infection 2.Interface between innate and adaptive immunity 3.Disposal of waste 1  10/12/2021 Complement system activation pathways mannose lectin pathway independent of the mannose and ab 3 Complement system activation pathways Classical C1q, C1r, C1s C4a ,C4b C4+C2 C2a, C2b Spontaneous C4b2b C3 (C3 convertase) C3a &C3b Properidin C4b2bC3b C5 (C5 convertase) C5a & C5b MB‐lectin MBL, MASP1 &MASP2 : Mannose associated serine proteases 1&2 aggregate C4a? and act as C1qrs they act as Alternative cytokines Spontaneous C3a C3 C3b Factor H Factor D Ba+Bb Factor B Pathogen components such as LPS inhibit factor H (C3b‐Bb)‐ properidin C3b + Bb or C3 convertase C3b‐Bb‐Factor D C5a & C5b or C5 convertase 2  10/12/2021 1‐ Classical pathway C1q, C1r, C1s C4a ,C4b C4+C2 C2a, C2b C4b2b C3 (C3 convertase) C3a &C3b C4b2a C4b2bC3b C5 (C5 convertase) C5a & C5b 1‐Classical pathway http://www.youtube.com/watch?v=vbWYz9XDtLw &feature=related C1q C1r C5 convertase Ag‐Ab complex C3 convertase Pathogen cell surface C4b2bC3b C5 C5a 6& C5b (C5 convertase) 3  10/12/2021 C3 convertase: C4b2a C5 convertase: C4b2a3b Properidin: stabilize C3B‐bB (C3 convertaste) Video: https://www.youtube.co m/watch?v=d6qFPegEYV0 7 Results of complement activation in parasitic infection and membrane attack complex allergic reactions C3a, C4a, C5a: mast cells and basophils C5a: neutrophils and monocyte 8 4  10/12/2021 Table 5‐2 Initiators of Three Complement Activation Pathways 9 Three Main Physiologic Activities of the Complement System autoimmune disease 10 the complexes could deposit anywhere which is why they MUST be cleared 5  10/12/2021 Alterations in Complement Levels  The complement system can cause significant tissue damage in response to abnormal stimuli.  Biologic effects of complement activation can occur as a reaction to persistent infection or an autoAbs response to “self” Ags.  The inflammatory or lytic effects of complement may one complement can do the function of another contribute significantly to the pathology of the disease.  Complement activation is also associated with intravascular thrombosis, which leads to ischemic injury to tissues Complement levels may be abnormal in certain disease states (e.g., RA, SLE) and in some genetic disorders. 11 Alterations in Complement Levels‐Con  Elevated Complement Levels  Increased complement levels are often associated with inflammatory conditions ,trauma, acute illness such as myocardial infarction because separate complement components (e.g., C3) are acute‐phase proteins.  Elevations of complement level are common and nonspecific. Therefore, increased levels are of limited clinical significance.  Decreased Complement Levels Low levels of complement suggest one of the following biologic effects: Complement has been excessively activated recently. Complement is currently being consumed. A single complement component is absent because of a genetic defect. complements could be exausted 12 6  10/12/2021 Control mechanisms of complement system: I. C1 inhibitor (C1INH): block C1 activities II. Anaphylatoxin inactivator (example Regulator Protein 4): compounds inactivates C4a, C3a, C5a by allergic reaction? removing single amino acid from them,. III. MAC inhibitors: S‐protein inactivate C5b‐7 IV. Complement receptor type I (CRI or CD35): inactivate C4b and C3b 13 14 7  10/12/2021 Alterations in Complement Levels‐Con  Deficiencies of complement account for a small percentage of primary immunodeficiencies (