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

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 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

Primary complement deficiencies

Primary complement deficiencies in ESID registry from Czech republic

Table 1.Group of patients with primary complement deficiencies Type of deficiency Number of families Number of patients MalesFemales C1 inhibitor deficiency 3541 C4 deficiency C4A*Q0 heterozygous 21-1 C4B*Q0 heterozygous 12-2 C4A*Q0 C4B*Q0 heterozygous 11-1 C2 deficiency I. type (28 bp deletion) 1--2 C2 deficiency II.type 11-1

C1 inhibitor deficiency Patient Nr. 1 Patient Nr. 2Patient Nr. 3Patient Nr. 4Patient Nr. 5 SexMale FemaleMale Age (years) Family Nr 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 expressi on Frequent respiratory infections, abdominal pain, edema Frequent respiratory infections, abdominal pain Frequent respiraotry infections Edema of cheeksafter stomatologic treatment Recurrent respiratory infections, abdominal pain Laborat ory C3  C4 not detecable C1 INH not detecable CH CIK normal IgA  IgG,IgM normal C3 normal C4 not detecable C1 INH not detecable CH CIK normal IgA, IgG  IgM normal C3 normal C4 not detecable C1 INH not detecable CH CIK normal IgA  IgG,IgM normal C3 normal C4 not detecable C1 INH not detecable CH CIK normal IgA  IgG,IgM normal C3 normal C4 not detecable C1 INH not detecable CH CIK normal IgA  IgG,IgM normal Therapy Danazol C1 inhibitor Danazol, C1 inhibitor C1 inhibitor Table 2. C1 inhibitor deficiency

Table 3. C2 deficiencies Patient Nr.1 Patient Nr.2 Patient Nr.3 Patient Nr.4 Patient Nr.5 Sex Female Clinical course No clinical manifestation Meningitis in newborn age Neonatal infecti on Girl died at the age 1 month due to meningitis Otitis, sinusitis, recurrent meningitis Laboratory investigatio n 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  Genotypisat ion C2 180/ bp deletion C2 180/ bp deletion Not performed Deletion 28 bp not verified Therapy - Antimicrobial drugs Antimicrobial drugs, plasma Antimicrobial drugs Antimicrobial drugs, vaccciination Pneumokok, Haemofilus, Meningokok

Table 4. C4 deficiencies CH 100  Patient Nr. 1. Patient Nr. 2 Pateint Nr.4 SexFemale Age Clinical courseTransposition 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 CH 100 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 CH 100  Factor B normal Nephritic factor negative Facor H normal Factor I normal C3 normal C4 , CH 100 normal IgG, IgA, IgM normal ANCA type p positive IgG kappa positive ANCA ELISA method normal C3 normal, C4 , CH 100 , IgG, IgA, IgM normal ENA SS-B positive Cardiolipin antibodies positive Coombs test positive Genetic phenotypisation C4A3AQ0 B2B2C4A3A3B1BQ0C4B Q0 heterozygous C4AQ0C4BQ0 TherapyInterferon AAntimicrobial therapy Corticosteroids, vaccination (Pneumococcus, Meningiciccus, Haemophilus)

Primary complement deficiencies Conclusions 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