《动物免疫学》课程PPT教学课件（讲稿）主要的补体系统缺乏（Primary deficiencies of the complement system）

Primary deficiencies of the complement system Radana Zachova Institute of Immunology Faculty hospital Prague,Motol

Primary deficiencies of the complement system Radana Zachová Institute of Immunology Faculty hospital Prague, Motol

Complement system part of hummoral innate immune system group of serum and cell surface proteins important in antiinfectious and inflammatory immune response activated by a cascade of reactions during activation generates active components

Complement system • part of hummoral innate immune system • group of serum and cell surface proteins • important in antiinfectious and inflammatory immune response • activated by a cascade of reactions • during activation generates active components

Complement activation pathways Alternative pathway (pathogen surface) Mannan binding lectin pathway (pathogen surface) Classical pathway_(antigen-antibody complexes)

Complement activation pathways • Alternative pathway (pathogen surface) • Mannan binding lectin pathway (pathogen surface) • Classical pathway (antigen-antibody complexes)

Complement activation pathways Antigen-antibody complexes Microbial surfaces Microbial surfaces Classical pathway Mannanbinding lectir Alternativepathway pathway C1q MBL c3 C1r-C1s MASP1-MASP2 B C4 C4 0 c2 C2 C3 Opsonic fragments, Vasoactive and chemotactic C3b,ic3b cs fragments,C4a,C3a,C5a C6 C7 Immune response stimulating fragments, C3d 9 Membrane-attack complex (MAC)

Complement activation pathways

Primary complement deficiencies 1)Components of activation pathways C1q,C1r,C1s,C4,C2,C3,MBL,D,B,C5,C6,C7,C8,C9 2)Control proteins soluble control proteins C1 inhibitor,factor I,factor H,C4b binding protein,S protein, SP-40,40 membrane regulatory proteins CD 55(DAF),MCP CD 46,CD 59,HRF/C8bp 3)Receptors for complement C1q receptor,CR1(CD 35),CR2(CD21),CR3(CD11b/CD18),CR4 (CD11c-CD18)

Primary complement deficiencies 1) Components of activation pathways C1q, C1r,C1s,C4,C2,C3, MBL, D,B,C5,C6,C7,C8,C9 2) Control proteins • soluble control proteins C1 inhibitor, factor I, factor H,C4b binding protein,S protein, SP-40,40 • membrane regulatory proteins CD 55(DAF), MCP CD 46, CD 59, HRF/C8bp 3) Receptors for complement C1q receptor, CR1(CD 35), CR2 (CD21), CR3 (CD11b/CD18), CR4 (CD11c-CD18)

Primary complement deficiencies clinical manifestation Increased susceptibility to infections with systemic course-bacteremia+meningitis S.pneumoniae,S.pyogenes,H.influenzae (early components defect in opsonization) Neisseria meningitidis (defect in terminal components Autoimmune disorders defective immune complex clearance 。 Angioedema

Primary complement deficiencies clinical manifestation • Increased susceptibility to infections with systemic course - bacteremia+meningitis • S. pneumoniae, S.pyogenes, H.influenzae (early components , defect in opsonization) • Neisseria meningitidis (defect in terminal components ) • Autoimmune disorders defective immune complex clearance • Angioedema

Complement genes Complement system proteins members of various gene families Some groups of complement proteins are in close chromosomal linkage chromosome 1 chromosome 6

Complement genes • Complement system proteins – members of various gene families • Some groups of complement proteins are in close chromosomal linkage – chromosome 1 – chromosome 6

Primary complement deficiencies Component (or subunit) Gene symbol Chromosomal location C1q:a chain CIQA 1p34.1-p36.3 CIq:B chain 1●)PB 1p34.1-p36.3 C1q:Y chain C1OG 1p34.1-p36.3 C8:a chain C8A 1p32 C8:B chain C8B 1p32 C4 Binding Protein:a chain C4BPA 1q32 C4 Binding Protein:B chain C4BPB 1g32 Complement Receptor 1(CD 35) CRI 1q32 Complement Receptor 2(CD 21) CR2 1q32 Decay Accelerating Factor (CD 55) DAF 1q32 Membrane Cofactor Protein(CD 46) MCP 1q32 Factor H HF 1q32 Factor I IF 4q25 6 6 5p13 7 C7 5p13 C9 C9 5p13 C2 C2 6p21.3 Factor B BF 6p21.3 C4A (isotype) C4A 6p21.3 C4B (isotype) C4B 65p21.3 C8:y chain C8G 9a22.3-g32 C5 9a33 Mannose Binding Lectin MBL 10q11.2-q21 Perforin PRF1 10q22 Surfactant Proteins Al and A2 SFTPA1,A2 10g22-q23 Surfactant Protein D SFTPD 10q22-q23 Membrane Inhibitor of Reactive Lysis CD59 11p13 (MIRL,CD59) C1 Inhibitor CINH 11q11-q13.1 C1r CIR 12p13 CIs CIS 12p13 Complement Receptor 3:a chain, ITGAM 16p11.2 =a-M Integrin(CR3A,CD11A) Vitronectin (S-protein) VTN 17g11 C3 3 19p13,3-p13.2 CSa receptor 1 C5R1 19q13.3-q13.4 Leucocyte Adhesion Molecule:B chain, ITGB2 21q22.3 B-2 Integrin (LCAMB,CD18) Properdin PFC Xp11.4-p11.2

Component (or subunit) Gene symbol Chromosomal location C1q:  chain C1QA 1p34.1-p36.3 C1q:  chain C1QB 1p34.1-p36.3 C1q:  chain C1QG 1p34.1-p36.3 C8:  chain C8A 1p32 C8:  chain C8B 1p32 C4 Binding Protein:  chain C4BPA 1q32 C4 Binding Protein:  chain C4BPB 1q32 Complement Receptor 1 (CD 35) CR1 1q32 Complement Receptor 2 (CD 21) CR2 1q32 Decay Accelerating Factor (CD 55) DAF 1q32 Membrane Cofactor Protein (CD 46) MCP 1q32 Factor H HF 1q32 Factor I IF 4q25 C6 C6 5p13 C7 C7 5p13 C9 C9 5p13 C2 C2 6p21.3 Factor B BF 6p21.3 C4A (isotype) C4A 6p21.3 C4B (isotype) C4B 6p21.3 C8:  chain C8G 9q22.3-q32 C5 C5 9q33 Mannose Binding Lectin MBL 10q11.2-q21 Perforin PRF1 10q22 Surfactant Proteins A1 and A2 SFTPA1, A2 10q22-q23 Surfactant Protein D SFTPD 10q22-q23 Membrane Inhibitor of Reactive Lysis (MIRL, CD59) CD59 11p13 C1 Inhibitor C1NH 11q11-q13.1 C1r C1R 12p13 C1s C1S 12p13 Complement Receptor 3:  chain, = -M Integrin (CR3A, CD11A) ITGAM 16p11.2 Vitronectin (S-protein) VTN 17q11 C3 C3 19p13.3-p13.2 C5a receptor 1 C5R1 19q13.3-q13.4 Leucocyte Adhesion Molecule:  chain, = -2 Integrin (LCAMB, CD18) ITGB2 21q22.3 Properdin PFC Xp11.4-p11.2 Primary complement deficiencies

Primary complement deficiencies in ESID registry from Czech republic Patients with primary immunodeficiencies in ESID registry Czech republic 1.1.2002 Population 10,000,000 inhabitants(n=548) 2% 11% 2% 7% Antibody deficiencies(n=424) T cell or Combined Deficiencies (n=39) Phagocytic Disorders(n=13) Complement deficiencies(n=63) 78% Other Primary Immunodeficiencies(n=9)

Primary complement deficiencies in ESID registry from Czech republic Patients with primary immunodeficiencies in ESID registry Czech republic 1.1.2002 Population 10,000,000 inhabitants (n=548) 78% 7% 2% 11% 2% Antibody deficiencies (n=424) T cell or Combined Deficiencies (n=39) Phagocytic Disorders (n=13) Complement deficiencies (n=63) Other Primary Immunodeficiencies (n=9)

Table 1.Group of patients with primary complement deficiencies Type of deficiency Number of Number of Males Females families patients C1 inhibitor deficiency 3 5 C4 deficiency C4A*Q0 heterozygous C4B*Q0 heterozygous C4A*Q0 C4B*Q0 heterozygous C2 deficiency C2 deficiency I.type(28 bp deletion) C2 deficiency ll.type

Table 1.Group of patients with primary complement deficiencies Type of deficiency Number of families Number of patients Males Females C1 inhibitor deficiency 3 5 4 1 C4 deficiency C4A*Q0 heterozygous 2 1 - 1 C4B*Q0 heterozygous 1 2 - 2 C4A*Q0 C4B*Q0 heterozygous 1 1 - 1 C2 deficiency C2 deficiency I. type (28 bp deletion) 1 - - 2 C2 deficiency II.type 1 1 - 1