Complement Male, Immunology, 2006 Zipfel, Nature, 2009 Mobeen Syed ب Dr. Yıldıran1

Objectives You should say: Basic functions How works Its place and importance in immune reactions Dr. Yıldıran2

Non-specific immunity (Innate) Specific immunity (Adaptive) Immune System Delayed reaction MEMORY! Fast reaction Dr. Yıldıran3

Immune Response Abbas, 2003 Dr. Yıldıran4

Serum vs Plasma If you wait blood in a glass tube, blood coagulated, serum separated It does not contain fibrinogen Dr. Yıldıran5

Complement System Many plasma proteins, nine are essential. 10% of plasma proteins as pro-enzymes It was named as ‘Complement’ in 19th century because of thinking about it completes bactericidal feature of serum. Dr. Yıldıran6

Complement Proteins C1, C2, C3, C4, C5, C6, C7, C8, C9 Underlined parts do not cleaved When cleaved; C2b (big part) and C2a (anaphylaxis part) C6, C7, C8, C9 are not enzymes C6, C7, C8 binded with C9 Main activating molecule is C3 Dr. Yıldıran7

Basic Function Recognizing and clearing the FOREIGN For this, Complement –Starts and increases inflammation –Increases chemotaxis and phagocytosis –Cleares immune complexes –Activates cells –Kills directly –Provides antibody response. Dr. Yıldıran8

Functions in Inflammation C3b Dr. Yıldıran9

Four Plasma Cascades Pain Plug DIC Inflam. Dr. Yıldıran10

Simple Mechanism IgG and IgM C1 C4  Innate arm Spontaneous activation Endotoxin C3 and B C3  Adaptive arm Antibody activation Dr. Yıldıran11

Dr. Yıldıran12 EDEMA

C1qrs Electron Microscobe Dr. Yıldıran13

Membran activating complex Elektron Mikroskobu ile Dr. Yıldıran14

Some Functions C5a → Chemotaxis, inflammation C3a and C5a (Anaphylotoxins) → Mast cell and basophil activation (Anaphylaxis), inflammation C3b → –Opsonisation, –Clearing immune complexes, –B cell activation –Clearing apopitotic cells –Asplenic patients can not grab C3b-bacteria complex –Increases plasma cell antibody secretion MAC → Lysis of Gr negative (Especially Neisseria) some viruses Dr. Yıldıran15

Clinical evaluation C3 ( g/L) C4 ( g/L) CH50 → Classical pathway AH50 → Alternative pathway Dr. Yıldıran16

Control of Complement System IF not Autoimmunity Dr. Yıldıran17

CD18CD11b,c PNH Dr. Yıldıran18

Regulation P (Properdin)stabilizes C3bBb and prevent inactivation by H,I D cleaves B to Bb Properdin and Factor D deficiencies are PID Factor H binds C3b Factor I destroys C3b-factor H complex C1 inh, regulates classical pathway inhibiting C1q and s Dr. Yıldıran19

In disease Atypical HUS (no diarrhea): heterozygot factor H mutation Dense deposite disease (MPGN II): homozygot or compound heterozygot C3 or factor B (C3 convertase stage), otoantikor oluşumu (C3 nephritic factor) Age-related macular degeneration: retinal Bruch membrane or glomerule basal membrane; factor H or C3 mutation Dr. Yıldıran20

Autoimmune diseases C1q and C4 deficiency: clearing of apopitotic cells impairs. Homozygot defects in C1q, C1r, C1s, C2, C3 or C4 genes: rheumatic diseases, especially SLE. C1qinh defect → Hereditary angioedema Dr. Yıldıran21

Tumors In some tumors, inhibitors of complement on cell membrane (CD46, CD55, CD59) changed. soluble regulators (factor H, factor I, C4BP) expression increased on lung, ovary, glial and bowel cancer cell membranes and plasma. Namely, tumor cells hide from CD8 cytotoxic cells. Dr. Yıldıran22

Eculizumab C5 monoclonal antibody Inhibits complement system on C5 convertase. Dr. Yıldıran23

Hereditary angioedema Dr. Yıldıran24

Neonatal Lupus Dermatology.cdlib.org Dr. Yıldıran25

Meningococcemia Dr. Yıldıran26