Primary deficiencies of the complement system

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

2. 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

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

4. Complement activation pathways

5. 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)

6. Primary complement deficienciesclinical 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

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

8. Primary complement deficiencies

9. Primary complement deficienciesin ESID registry from Czech republic

10. 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 Table 1.Group of patients with primarycomplement deficiencies

11. C1 inhibitor deficiency Table 2. C1 inhibitor deficiency Patient Nr. 1 Patient Nr. 2 Patient Nr. 3 Patient Nr. 4 Patient Nr. 5 Sex Male Male Female Male Male Age (years) 43 18 11 26 10 Family Nr. 1 1 1 2 3 Family history Edema of upper airways (mother died), oncle, son Recurrent edema of the upper airways (grand mother, father Frequent respiratory infection Glomerullonephritis Frequent respiratory infection, sinusitis Clinical expression Frequent respiratory infections, abdominal pain, edema Frequent respiratory infections, abdominal pain Frequent respiraotry infections Edema of cheeksafter stomatologic treatment Recurrent respiratory infections, abdominal pain Laboratory C3 C4 not detecable C1 INHnot detecable CH100 0 CIK normal IgA  IgG,IgM normal C3 normal C4 not detecable C1 INH not detecable CH100 0 CIK normal IgA, IgG  IgM normal C3 normal C4 not detecable C1 INH not detecable CH100 0 CIK normal IgA  IgG,IgM normal C3 normal C4 not detecable C1 INH not detecable CH100 0 CIK normal IgA  IgG,IgM normal C3 normal C4 not detecable C1 INH not detecable CH100 0 CIK normal IgA  IgG,IgM normal Therapy Danazol C1 inhibitor C1 inhibitor C1 inhibitor Danazol, C1 inhibitor C1 inhibitor

12. Patient Nr.1 Patient Nr.2 Patient Nr.3 Patient Nr.4 Patient Nr.5 Sex Female Female Female Female Female Clinical course No clinical manifestation Meningitis in newborn age Neonatal infection Girl died at the age 1 month due to meningitis Otitis, sinusitis, recurrent meningitis Laboratory investigation IgG, IgA, IgE , C3, C4 normal, C2, CH 100 normal IgG, IgA, IgM normal, IgE , C3,C4 normal, CH 100 normal IgG , IgA not detecable, IgM normal, C3,C4 normal, CH 100 normal IgG, IgG1-3 , IgM, IgA , C3,C4 normal CH 100  IgG, IgA, IgM IgG1-4 normal, C3, C4 normal, CH 100 , C2  Genotypisation C2 180/152 28 bp deletion C2 180/152 28 bp deletion Not performed Not performed Deletion 28 bp not verified Therapy - Antimicrobial drugs Antimicrobial drugs, plasma Antimicrobial drugs Antimicrobial drugs, vaccciination Pneumokok, Haemofilus, Meningokok Table 3. C2 deficiencies

13. Patient Nr. 1. Patient Nr. 2 Patient Nr.2 Pateint Nr.4 Sex Female Female Female Female Age 8 54 5 31 Clinical course Transposition of great arteries, chronic acute hepatitis with delayed antibody formation Rheumatic fever, meningitis, lupus like skin disease, arthralgias, Anemia of chronic infection, recurrent pyodermia Septic infection in newborn age Meningitis Recurrent pyodermias Lupus erythematodes, autoimmune cytopenia Laboratory investigation CH100 normal C3 normal C4 not detecable IgG, IgA, Ana, ANCA, dsDNA, ASMA, LKNM negative HbsAg positive, HbeAg positive C3 C4 antigen normal C4 hemolytic  MBL normla CH100  Factor B normal Nephritic factor negative Facor H normal Factor I normal C3 normal C4, CH100 normal IgG, IgA, IgM normal ANCA type p positive IgG kappa positive ANCA ELISA method normal C3 normal, C4, CH100 , IgG, IgA, IgM normal ENA SS-B positive Cardiolipin antibodies positive Coombs test positive Genetic phenotypisation C4A3AQ0 B2B2 C4A3A3B1BQ0 C4B Q0 heterozygous C4AQ0C4BQ0 Therapy Interferon A Antimicrobial therapy Corticosteroids, vaccination (Pneumococcus, Meningiciccus, Haemophilus) Table 4. C4 deficiencies CH100

14. Primary complement deficienciesConclusions • Relatively uncommon diagnosed group of diseases • Can be the underlying disease in autoimmunity and recurrent infections • Laboratoty investigation of complement components is not easy, but C3 and C4 is normal available • Most frequent is C2 deficiency • Angioedema in C1 inhibitor deficiency appears in more generations in one family, differential diagnosis to allergy