Download Primary deficiencies of the complement system

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
Component (or subunit)
Gene symbol
Chromosomal location
C1q:  chain
C1q:  chain
C1q:  chain
C8:  chain
C8:  chain
C4 Binding Protein:  chain
C4 Binding Protein:  chain
Complement Receptor 1 (CD 35)
Complement Receptor 2 (CD 21)
Decay Accelerating Factor (CD 55)
Membrane Cofactor Protein (CD 46)
Factor H
Factor I
C6
C7
C9
C2
Factor B
C4A (isotype)
C4B (isotype)
C8:  chain
C5
Mannose Binding Lectin
Perforin
Surfactant Proteins A1 and A2
Surfactant Protein D
Membrane Inhibitor of Reactive Lysis
(MIRL, CD59)
C1 Inhibitor
C1r
C1s
Complement Receptor 3:  chain,
= -M Integrin (CR3A, CD11A)
Vitronectin (S-protein)
C3
C5a receptor 1
Leucocyte Adhesion Molecule:  chain,
= -2 Integrin (LCAMB, CD18)
Properdin
C1QA
C1QB
C1QG
C8A
C8B
C4BPA
C4BPB
CR1
CR2
DAF
MCP
HF
IF
C6
C7
C9
C2
BF
C4A
C4B
C8G
C5
MBL
PRF1
SFTPA1, A2
SFTPD
CD59
1p34.1-p36.3
1p34.1-p36.3
1p34.1-p36.3
1p32
1p32
1q32
1q32
1q32
1q32
1q32
1q32
1q32
4q25
5p13
5p13
5p13
6p21.3
6p21.3
6p21.3
6p21.3
9q22.3-q32
9q33
10q11.2-q21
10q22
10q22-q23
10q22-q23
11p13
C1NH
C1R
C1S
ITGAM
11q11-q13.1
12p13
12p13
16p11.2
VTN
C3
C5R1
ITGB2
17q11
19p13.3-p13.2
19q13.3-q13.4
21q22.3
PFC
Xp11.4-p11.2
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)
11%
2%
2%
Antibody deficiencies (n=424)
7%
T cell or Combined Deficiencies (n=39)
Phagocytic Disorders (n=13)
Complement deficiencies (n=63)
78%
Other Primary Immunodeficiencies (n=9)
Table 1.Group of patients with primary
complement deficiencies
Type of deficiency
Number of
families
Number of
patients
Males
Females
3
5
4
1
C4A*Q0 heterozygous
2
1
-
1
C4B*Q0 heterozygous
1
2
-
2
C4A*Q0 C4B*Q0
heterozygous
1
1
-
1
I. type (28 bp deletion)
1
-
-
2
C2 deficiency
II.type
1
1
-
1
C1 inhibitor deficiency
C4 deficiency
C2 deficiency
C2 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
Frequent
respiratory
infection
Glomerullonephritis
Frequent
respiratory
infection, sinusitis
Clinical
expressi
on
Frequent
respiratory
infections,
abdominal pain,
edema
Frequent
respiraotry
infections
Edema of
cheeksafter
stomatologic
treatment
Recurrent
respiratory
infections,
abdominal pain
Laborat
ory
Therapy
Recurrent edema
of the upper
airways
(grand mother,
father
Frequent
respiratory
infections,
abdominal pain
C3
C4 not detecable
C1 INH not
C3 normal
C4 not detecable
C1 INH not
C3 normal
C4 not detecable
C1 INH not
C3 normal
C4 not detecable
C1 INH not
C3 normal
C4 not detecable
C1 INH not
detecable
detecable
detecable
detecable
detecable
CH100 0
CIK normal
Danazol
IgA 
C1 inhibitor
IgG,IgM
normal
CH100 0
CIK normal
IgA, IgG 
C1 inhibitor
IgM normal
CH100 0
CIK normal
IgA 
C1 inhibitor
IgG,IgM normal
CH100 0
CIK normal
C1
IgADanazol,

inhibitor
IgG,IgM
normal
CH100 0
CIK normal
IgA 
C1 inhibitor
IgG,IgM normal
Table 3. C2 deficiencies
Sex
Patient
Nr.1
Female
Patient
Nr.2
Female
Patient
Nr.3
Female
Patient
Nr.4
Female
Patient
Nr.5
Female
Clinical
course
No clinical
manifestation
Meningitis in
newborn age
Neonatal
infection
Otitis,
sinusitis,
recurrent
meningitis
Laboratory
investigatio
n
IgG, IgA,
IgE , C3, C4
normal,
C2, CH 100
normal
C2 180/152
28 bp
deletion
IgG, IgA,
IgM normal,
IgE , C3,C4
normal,
CH 100
normal
C2 180/152
28 bp
deletion
IgG , IgA
not
detecable,
IgM normal,
C3,C4
normal,
Not
CH
100
performed
normal
Girl died at the
age 1 month
due to
meningitis
IgG, IgG1-3
, IgM, IgA
, C3,C4
normal
CH 100 
Not
performed
IgG, IgA, IgM
IgG1-4
normal, C3,
C4 normal,
CH 100 
,Deletion
C2  28
bp not
verified
-
Antimicrobial
drugs
Antimicrobial
drugs, plasma
Antimicrobial
drugs
Antimicrobial
drugs,
vaccciination
Pneumokok,
Haemofilus,
Meningokok
Genotypisat
ion
Therapy
Table 4. C4 deficiencies
Patient Nr. 1.
Patient Nr. 2
Patient Nr.2
Pateint Nr.4
Sex
Female
Female
Female
Female
Age
8
54
5
31
Transposition of great
arteries, chronic
acute hepatitis with
delayed antibody
formation
CH100 normal
C3 normal
C4 not detecable
IgG, IgA, Ana,
ANCA, dsDNA,
ASMA, LKNM
negative
C4A3AQ0
B2B2
HbsAg
positive,
HbeAg positive
Interferon A
Rheumatic fever,
meningitis, lupus like
skin disease,
arthralgias,
Anemia of chronic
C3
C4
antigen
normal
infection,
recurrent
C4
hemolytic
pyodermia 
MBL normla
CH100 
Factor B normal
Nephritic factor
C4A3A3B1BQ0
negative
Facor H normal
Antimicrobial
therapy
Factor I normal
Clinical course
CH100 
Laboratory
investigation
Genetic
phenotypisation
Therapy
Septic infection in
newborn age
C3 normal
C4, CH100 normal
IgG, IgA, IgM normal
ANCA type p positive
IgG kappa positive
ANCA ELISA method
normal
C4B Q0
heterozygous
Meningitis
Recurrent
pyodermias
Lupus
erythematodes,
C3
normal, C4,
autoimmune
CH
cytopenia
100 ,
IgG, IgA, IgM normal
ENA SS-B positive
Cardiolipin antibodies
positive
Coombs test positive
C4AQ0C4BQ0
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