Complements and complement deficiency

Complement and
Complement deficiency
19-7-2013
Suparat Sirivimonpan, MD.

Topic outlines
Complement
• Complement pathway activation
– Classical pathway
– Alternative pathway
– Lectin activation pathway
• Complement receptors
• Regulation of complement activation
• Functions
Complement deficiencies
• Disorders associated with complement deficiencies
• Evaluation
• Management

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

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

Complement activation
• Complement activator  proteolytic enzyme cascade
• Complement regulatory protein
• Complement receptor

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

- Alternative and lectin : effector
mechanisms of innate immunity
- Classical : major mechanism of
adaptive humoral immunity

Classic pathways

Classic pathways
C3 convertase = C4b2a
C5 convertase = C4b2a3b

Alternative
pathways

Alternative
pathways
internal thioester groups
C3 tickover

Alternative
pathways
C3 convertase =
C3bBb
C5 convertase
=C3bBb3b

Classic Lectin pathways

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
Subsequent events in this pathway are
identical to those that occur in the
classical pathway

Lectin
pathways
C3 convertase = C4b2a
C5 convertase = C4b2a3b

Pores : 100 A in diameter (10 nm)

L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655

Complement receptors

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

Regulators of Complement Activation (RCA)

MCP, CR1, DAF are produced by mammalian cells
but not by microbes

iC3b, C3d, and C3dg  recognized by receptors on phagocytes and B lymphocytes

Protein Cell 2012, 3(7): 487–496

Function
C5a > C3a > C4a :
anaphylatoxin
C3b,C4b: opsonin

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

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

Deficiencies in classical pathway components

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

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

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

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

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

Deficiencies in Alternative pathway components

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

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

Deficiencies in Lectin pathway components

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

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

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

Deficiencies in complement regulatory
proteins& complement receptor

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

Curr Allergy Asthma Rep (2012) 12:273–280
HAE type 1,2

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)

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)

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

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

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

WAO Journal 2012; 5:182–199)

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)

WAO Journal 2012; 5:182–199)
Plasma-derived C1-INH (pdC1-INH)
recombinant C1 INH
B 2 receptor antagonist
kallikrein inhibitor

Deficiencies in complement regulatory proteins

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

Deficiencies in complement receptor

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

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

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

Evaluation
• abnormal CH50 or AH50 has been confirmed 
serum levels of certain components (C3 and C4
primarily)

Management
• completely dependent on the type of defect
– susceptibility to infectious agents
– course of the disease
• Treat infection, Autoimmune, associated
diseases

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

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

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

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

Complements and complement deficiency

Complements and complement deficiency

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