3. The complement system
• Heat labile plasma proteins
• consists of several plasma proteins that work together
» normally inactive
» activated only under particular conditions
• Important effector mechanism of innate immunity
• One of the major effector mechanisms of humoral immunity
Abbas.Cellular and molecular immunology 7th edition
4. The most important biological functions
of the complement system
1. innate host defense:
– Opsonization
– initiation of an inflammatory response
– clearance of apoptotic debris
– direct lysis of gram negative bacteria
2. adaptive responses
– B cell activation
– T cell priming
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
7. Pathways of Complement Activation
• 3 major pathways
Pathways Activator
1. Classical -Ab bound to Ag (IC)
-Pentraxins (CRP,SAP, PTX3)
-SIGN R-1
-Apoptotic cell
2. Alternative Microbial cell surfaces (absence of Ab) ex. LPS
3. Lectin mannose residues on microbe
Abbas.Cellular and molecular immunology 7th edition
8. Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
- Alternative and lectin : effector
mechanisms of innate immunity
- Classical : major mechanism of
adaptive humoral immunity
Abbas.Cellular and molecular immunology 7th edition
16. Lectin pathways
• MBL and ficolins associate with MBL-associated
serine proteases (MASPs)
• MASP proteins
– structurally homologous to the C1r and C1s
proteases
– serve a similar function : cleavage of C4 and C2
Abbas.Cellular and molecular immunology 7th edition
Subsequent events in this pathway are
identical to those that occur in the
classical pathway
22. Complement receptors
Complement receptor of the immunoglobulin
family (CRIg)
• express on surface of macrophages in the liver (Kupffer cells)
• binds C3b and iC3b
• involved in the clearance of opsonized bacteria and other
blood-borne pathogens
Abbas.Cellular and molecular immunology 7th edition
29. Functions (cont.)
• Promote solubilization of immune complexes and their
clearance by phagocytes
• C3d protein binds to CR2 on B cells facilitates B cell
activation and initiation of humoral immune responses
Abbas.Cellular and molecular immunology 7th edition
31. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
32. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
33. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
34. COMPLEMENT DEFICIENCIES
• Deficiencies in classical pathway components
• Deficiencies in alternative pathway components
• Deficiencies in lectin pathway components
• Deficiencies in the terminal complement components
• Deficiencies in complement regulatory proteins
• Deficiencies in complement receptors
35. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in classical pathway components
36. C1q DEFICIENCY
• strongest known genetic risk factor for lupus
• early- onset SLE
• lupus seen in C1qD individuals is less steroid responsive
• increased rate of infection
– compromised opsonization
– mild decrease in B cell co-stimulation
• initial symptoms in the C1qD patients are more often
cutaneous symptoms of autoimmune disease than
infections
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
37. C1r,C1s DEFICIENCY
• Deficiencies of C1r and/or C1s are extremely rare
• frequently combined
• few cases of selective deficiencies
• Glomerulonephritis and lupus have been found in C1r/C1s
deficient patients
• 60% develop SLE or similar disease
• infections mainly due to encapsulated bacteria are frequent
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
38. C4 DEFICIENCY
• C4A deficiency
– 1–2% of general population
– up to 15% of patients with SLE
– risk factor for SLE
– severity of the disease is often less in patients with C4A
deficiency compared to complement sufficient hosts
• C4B deficiency
– 1–2% of population
– up to 15% of patients with invasive bacterial disease :
– impaired opsonization and a modestly compromised B cell
response to antigen
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
39. C2 DEFICIENCY
– most common of inherited classical complement
component deficiencies in Caucasians
– most common cause of death : sepsis
– most common organisms : S. pneumoniae and H.
influenzae
– Asymptomatic
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
40. C3 DEFICIENCY
• rarest of the 4 early component deficiencies
• most severe phenotype
– neutrophil dysfunction (abscesses)
– humoral deficiencies (sinopulmonary disease)
– complement deficiencies (sepsis, meningitis)
• 1/3 : Membranoproliferative glomerulonephritis
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
41. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in Alternative pathway components
42. FACTOR B DEFICIENCY
• A single case has been reported : meningococcemia
FACTOR D DEFICIENCY
• Neisserial infections : most common manifestation
• Systemic streptococcal infections have also been seen
• Other complement levels are typically normal
Deficiencies in Alternative pathway
components
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
43. PROPERDIN DEFICIENCY
• only X-linked complement deficiency
• occurs largely in Caucasians
• one or more episodes of meningococcal disease
• Other bacterial infections are also seen (less common)
• high fatality rate in meningococcal disease in contrast to
patients with terminal complement component deficiencies
Deficiencies in Alternative pathway
components
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
44. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in Lectin pathway components
45. MBL deficiency
• minimally to susceptibility to infections
• combination with other primary or secondary
immunodeficiency MBL deficiency has been
shown to be a risk factor in particular for respiratory
tract infections
– ex. C2 deficiency , CVID
• Also increased risk of cardiovascular disease
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in Lectin pathway components
46. MASP2 DEFICIENCY (mannose-binding protein-associated serine protease 2)
• combination of autoimmune symptoms and recurrent
respiratory infections
• more severe course of disease in MASP-2-deficient patient as
compared to MBL-deficient individuals
Ficolin-3 deficiency
• first case of ficolin-3 deficiency was described
– recurrent respiratory infections since early childhood and later in life
cerebral abscesses and several episodes of pneumonia
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in Lectin pathway components
47. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in terminal complement
components
- only with meningococcal infection with high recurrence rate
-rarely fatal (ǂ Properdin)
-C9 deficience : CH50 is diminished but not absent
48. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in complement regulatory
proteins& complement receptor
49. WAO Journal 2012; 5:182–199)
3 forms of HAE
(1) HAE-1
- C1-INH deficiency : low antigenic and functional C1- INH levels
(2) HAE-2
- C1-INH dysfunction : normal (or elevated) antigenic but low functional C1-INH
levels
(3) HAE-3
- normal C1-INH antigenic and functional levels
51. Type 3 HAE
• HAE with normal C1-INH
• very rare disease
• The symptoms are very similar to HAE-1/2
• A subset of HAE-3 patients exhibits mutations in factor XII
• The genetic abnormality of most HAE-3 patients has not
yet been defined
• Diagnosis requires a family history of angioedema
WAO Journal 2012; 5:182–199)
52. HAE : diagnosis
should be suspected :
• history of recurrent angioedema, esp. if hives are absent
• with
(1) positive family history
(2) onset of symptoms in childhood/adolescence
(3) recurrent abdominal pain attacks
(4) occurrence of upper airway edema
(5) failure to respond to antihistamines, glucocorticoid, or
epinephrine; and
(6) presence of prodromal signs or symptoms before swellings
• Suspicion of HAE-1/2 should prompt laboratory workup
WAO Journal 2012; 5:182–199)
53. HAE
- Extremities, face, or genitalia are most often involved
- Angioedema typically progresses for 1–2 days and
resolves in another 2–3 days
- Common precipitants are illness, hormonal
fluctuations, trauma, and stress
- Infections have rarely been reported in HAE in spite of the
associated hypocomplementemia
- very low levels of C4 ,C2 : enough for CP-dependent protection against
infection
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
54. HAE : work up
• blood levels of C4, C1-INH protein, and C1- INH function
• if abnormally low repeat to confirm the diagnosis
(Evidence grade: D, strength of recommendation: strong)
• normal results may need to be checked during an attack of
angioedema
WAO Journal 2012; 5:182–199)
C4
-C4 level is useful for screening
-cannot be relied upon to confirm or exclude Dx
- repeat C4 during an attack ↑probability
- False negative measurement of C4d
55. HAE-1/2 : work up
• The C1-INH antigenic level
– low in HAE-1 and acquired C1-INH deficiency patients
– normal in HAE-2 patients
• The C1-INH functional activity
– low in HAE-1 and HAE-2 and acquired C1-INH
deficiency patients
• In rare patients Gene analysis
– SERPING1 gene : HAE-1/2
– factor XII genes : HAE-3
WAO Journal 2012; 5:182–199)
• C3 levels : normal
• CH50 is not useful
57. Treatment
• All attacks that result in debilitation/dysfunction and/ or
involve the face, the neck, or the abdomen should be
considered for on-demand treatment
• Treatment of attacks affecting the upper airways is
mandatory
• treated attack as early
• Every patient with HAE-1/2 should be considered for
home therapy and self-administration training, once the
diagnosis of C1-INH deficiency is confirmed
WAO Journal 2012; 5:182–199)
59. WAO Journal 2012; 5:182–199)
Plasma-derived C1-INH (pdC1-INH)
recombinant C1 INH
B 2 receptor antagonist
kallikrein inhibitor
60. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in complement regulatory proteins
61. CD59 DEFICIENCY AND PNH
• CD59 is expressed on most hematopoietic cells and endothelial cells
where it confers protection from intravascular complement mediated lysis
• phenotypic resemblance to PNH
– recurrent episodes of hemoglobinuria due to
intravascular hemolysis
• The diagnosis of PNH is made by flow cytometry for CD59
or CD55 (DAF)
• DAF deficiency does not have a hemolytic phenotype
– CD59 is the more important than CD55
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
62. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
Deficiencies in complement receptor
64. Evaluation
assess
patients with recurrent sepsis/systemic infection or sepsis
on the background of autoimmune disease
(or a family history of autoimmune disease)
CH50
AH50
MBL levels
Patients with a single meningococcal infection, either
meningitis or meningococcemia, probably deserve an
evaluation in non-endemic areas
CH50
AH50
patients with meningococcal disease with an unusual
serotype (serotypes X, Y, Z, W135 or 29E), on background of
a positive family Hx, or recurrent meningococcal disease
CH50
AH50
Patients with lupus CH50
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
65. Evaluation
assess
patients with Membranoproliferative glomerulonephritis
and HUS
-CH50
-AH50,
-C3 level
(factor H, I, MCP
mutation
analyses )
recurrent angioedema in the absence of allergic reactions,
patients with a family history of angioedema
patients with angioedema preceded by a reticular rash,
patients with angioedema after trauma
-C4 levels
-C1 inhibitor
antigen and
functional levels
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
66. Evaluation
• Deficiencies of all the cascade components lead to a
CH50 of 0 or near 0
– With the exception of C9 deficiency
• Low levels of CH50 or AH50 results should be repeated
due to
– mishandling of the serum is an extremely common
– C’ consumption due to active immune complex disease
– diminished hepatic production : liver disease, immaturity
of hepatic production seen in young infants
– Less common : regulatory protein defects leading to
consumption of C3 such as factor D, factor H, and factor I
deficiency
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
67. Evaluation
• abnormal CH50 or AH50 has been confirmed
serum levels of certain components (C3 and C4
primarily)
Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
68. Management
• completely dependent on the type of defect
– susceptibility to infectious agents
– course of the disease
• Treat infection, Autoimmune, associated
diseases
L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
69. Management
• Prevention
– Replacement of the missing component
• C1-INH concentrate is the only product that is licensed
and is used in a regularly fashion
• FFP
– Antibiotic prophylaxis
– Vaccination
• Encapsulated bacteria : S. pneumoniae and H.
influenzae
• meningococcal vaccine (tetravalent serogroup A, C, Y and W-135)
– Hygienic measures
L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
70. Take home message
• The complement system : essential component of innate
immunity
– opsonize microbes
– promote the recruitment of phagocytes to site of infection
– in some cases to directly kill the microbes
• One of the major effector mechanisms of humoral immunity
• Also crucial role in the preservation of the immunological
homeostasis
• 3 pathways : Classical , Alternative, Lectin
– Activator, Regulatory protein
71. Take home message
• Complement deficiencies are uncommon
• infection susceptibility and disease susceptibility depend
on which factor is missing
• consequence can vary from almost none (C9 deficiency)
to very serious infections (C3 deficiency)
– C3 deficiency : severe, recurrent, often lethal bacterial
infections
• SLE , meningococcal disease : two most common
phenotypes associated with complement deficiencies
72. Take home message
• CP deficiencies : encapsulated bacteria
• AP and terminal pathway deficiencies : Neisseria species
• Complement deficiency does in general not confer
increased susceptibility to fungal, parasitic or viral
infections
• The diagnosis of most complement deficiencies begins
with the demonstration of a markedly low CH50 or AH50
• The identification of complement deficiency states is
important to ensure optimal prevention and treatment