Complement System Disorders and Related Diseases

Complement system
and related diseases
8th February 2019
Thansinee Saetae, MD.
Pediatric Allergy and Immunology Unit
King ChulalongkornMemorial Hospital

Outline
• Introduction
• Complement cascade
• Biologic functions of complement
• Receptors and biologic functions
• Regulation of complement activation
• Disorder associated with complement deficiency
• Laboratory assessment of complement
• Management

Introduction
• 1880s-1890s
• The complement system was
1st described.
• A system capable of inducing
lysis of bacteria and red cells.
• 1919
• Nobel prize was awarded to
the Belgian microbiologist
Bordet for his description of
the complement system.
Sullivan KE and Grumach AS. Middleton’s Allergy: Principles and Practice 8th edition

Complement system
• Consist of
• Group of 14 proteins in complement cascade
• More than 10 regulatory proteins
• At least 7 complement receptors
• Nearly 5% of all serum proteins, can increase to 7%
in inflammatory states
• Serum complement produce by
• Hepatocyte: major portion
• Myeloid cell: C1q, properdin, C7
• Adipocyte: factor D à called adipsin
Sullivan KE and Grumach AS. Middleton’s Allergy 8th edition

• The protein-protein interactions of the
complement system
• enzymatic cleavage steps
• Deposit C3 and cleave complement proteins into
smaller fragments with biologic activity.
Complement system

The three activation arms of the complement system
Cleavage C3

Biological functions
• Relate to innate immunity
• Opsonization
• Initiation of an inflammatory response
• Direct lysis of gram negative bacteria
• Relate to adaptive immunity
• B cell activation
• T cell priming
• Complement regulatory protein
• Endothelial cell homeostasis
• Clearance of apoptotic debris

The pathway of complement activation
The classical pathway
• activated by certain isotypes of antibodies bound to
antigens
The alternative pathway
• activated on microbial cell surfaces in the absence of
antibody
The lectin pathway
• activated by a plasma lectin that binds to mannose
residues on microbes
The classical pathway is a major mechanism of adaptive
humoral immunity
The alternative and lectin pathways are effector
mechanisms of innate immunity
Abbas, et al. Cellular and Molecular Immunology, 9th edition

The pathway of complement activation

C1 activation
Globular heads of C1q contact regions for Ig
• Cμ3 domain of IgM
• Cγ2 domain of IgG
Single molecule of IgM
Multiple molecule of IgG
IgM >IgG1> IgG3 >IgG2

The classical pathway

The early inflammatory response
Complement
• Ab.& C3b
• Opsonins to enhance
phagocytosis
Anaphylatoxin
• C3a, C4a, C5a
• ↑ Blood flow
• ↑ Extravasation of
antibodies and
complement into the tissue
• C5a
• Neutrophils recruitment

The alternative pathway

• Binding of microbial polysaccharides to circulating lectins,
such as plasma mannose-binding lectin (MBL), or to ficolins
• Lectins are collagen-like proteins that structurally resemble C1q
The lectin pathway

• Stalk and globular head
• MBL-associated serine
proteases (MASPs)
• MASP1, MASP2, MASP3
• MASP proteins are
• Structurally homologous
to the C1r and C1s
proteases
• Similar function: MASP2
the cleavage of C4 and C2
The lectin pathway

• MBL avidly binds to oligosaccharides that present
on bacteria, yeast, and parasites surface.
• Mannose
• N-acetyl-glucosamine
• Fucose
• Glucose
• Subsequent events in lectin pathway are identical
to the classical pathway.
The lectin pathway

The membrane attack complex
Late steps of complement activation

• Nucleated cells are resistant to lysis for two reasons
• Metabolically active: can repair membrane damage
• Eukaryotic cells: coated with complement regulatory
proteins → inhibit completion of the lytic process
• Most gram negative bacteria
• susceptible to complement-mediated lysis
• Most gram-positive bacteria
• cannot be penetrated
• Most enveloped viruses
• susceptible to complement-mediated lysis

• Clear immune complexes (IC)
• block these Fc-Fc interactions of IgG molecule à dissolution
of the immune complexes.
• Immune complexes with attached C3b are bound to CR1 on
erythrocytes, and the complexes are cleared by phagocytes
in the liver
• Facilitates B cells activation and humoral immune
response
• covalent attachment of C3b and C3d to Ag
• B lymphocytes bind C3d through CR2, enhancing antigen
induced signaling in B cells
• Opsonized antigens are also bound by follicular dendritic
cells in the germinal centers of lymphoid organs.
• FDC display Ag to B cells à selection of high-affinity B cells
Other functions of complement system

Receptors and biologic functions

Receptors and biologics functions

• G-protein couple receptor
• express on hepatocytes, lung endothelium,
vascular smooth muscle, astrocyte and T cell
• C3a receptor recognized C3a, C4a
• Affinity C3a >>> C4a (100 fold)
• On cell surface of mast cell, basophil, eosinophil,
neutrophil, endothelial cell and smooth muscle cells
• C5a receptor recognized C5a
• Most powerfulchemotactic factor for neutrophil
• Potent chemotactic agent for monocytes/macrophages
Anaphylatoxin Receptors

Regulation of complement activation

C1 inhibitor

Factor I, MCP (CD46) à cleave C3b, C4b
Factor H, C4 binding protein à cleave C3b
The same process is involved in the proteolysis of C4

Factor H

CD55, DAF: Decay Accelerating Factor

Regulation formation of MAC
CD59, S protein, C8 binding protein

Regulation of Classical Pathway

Regulation of Alternative Pathway
Sullivan KE and Grumach AS.
Middleton’s Allergy 8th edition

Regulation of Lectin Activation Pathway

Disorders associated with
complement deficiency

All complement deficiencies à Autosomal recessive inhertied
Except
• Properdindeficiency à X-linked recessive
• C1 inhibitor deficiency à Autosomal dominant

Wen, Atkinson, and Giclas Allergy Clin Immunol 2004;113:585-93

• Most of the inherited complement disorders
typically are associated with a CH50 or AH50 of
near zero
• Early classical pathway components
• Function: apoptotic cell clearance, to activate C3, and to
produce anaphylatoxicactivity
• Deficiencies: autoimmunity, risk of infection,
accelerated atherosclerosis
• Terminal components
• Function: lysis of gram-negative bacteria
• Deficiencies: increased risk of Neisserial disease
Disorder associated with

• Classical pathway complement deficiency
• Alternative pathway complement deficiency
• Lectin activation pathway complement
deficiency
• Terminal pathway complement deficiency
• Complement regulatory protein deficiency
Disorder associated with

Macedo ACL and Isaac L. Front. Immunol. 2016;7:55

C1q deficiency
• Severe and early-onset SLE
• Strongest known genetic risk factor for
lupus
• The manifestations
• Similar to non-complement deficient SLE
• More severe, more often cutaneous
and CNS symptoms
• Anti-dsDNA antibodies
• Less steroid responsive
• Increased rate of infection related to
compromised opsonization
• Mild decrease in B cell co-stimulation
Lintner KE et al.Front. Immunol. 2016;7:36

• Extremely rare
• Frequently combined
• A mutation in one often leads
to diminished levels of both
• Glomerulonephritis and lupus
have been found.
C1r, C1s deficiency

• Partial C4 deficiencies are extremely
common 1-2% of general population
• Up to 15% of SLE pt have complete
C4a deficiency
• Complete deficiency of C4b 1-2%
general population and up to 50% in
pt with invasive bacteria disease
• 50% of the C4-deficient individuals
have SLE- severe, early onset
• Infection-significant
• Mechanism: impair opsonization and
B cell response to Ag
C4 deficiency

• Frequency 1/10,000 in Caucasians
• Asymptomatic
• SLE 50% of C2 deficient pt develop lupus
• Early adulthood onset
• Anti-Ro antibodies are extremely common
• Anti-dsDNA antibodies are infrequent
• Less common: cerebritis, nephritis, arthritis
• 2/3 of C2 deficient pt have invasive bacterial
disease
• Most common organisms
• S. pneumoniae, H. influenzae
• Systemic infections : meningitis, pneumonia,
epiglottitis, and peritonitis, osteomyelitis
• Most common cause of death: Sepsis
• Accelerated atherosclerosis
C2 deficiency

• Rarest of the four early component deficiencies
• Most severe phenotype
• 1/3 of cases develop Membranoproliferative
glomerulonephritis instead of SLE
• Predisposition to infection
• Neutrophil dysfunction à abscesses
• Compromise in B cell co-stimulation à sinopulmonary infection
• Opsonizationdefect à sepsis, meningitis
• Vasculitic rash may appear during infection
• Serum sickness à lack of immune complex solubilization
C3 deficiency

• Neisserialinfections are the most common manifestation
• Systemic streptococcal infections have also been seen
• Other complement levels are typically normal
Factor D deficiency
• A single case has been reported : meningococcemia
• Absent AH50
Factor B deficiency
• X-linked complement deficiency
• Deficiency à activation of alternative pathway impair
• 1⁄2 have one or more episodes of meningococcal disease
• High fatality rate
Properdin deficiency

• Common, 2% to 7% in the general population
• Minimally to susceptibility to infections
• range from TB to sepsis
• Combination with other primary or secondary
immunodeficiency
• CVID, C2 deficiency
• Shown to be risk factor in particular for respiratory
tract infections
• Also increased risk of autoimmune disease
Mannose-Binding-Lectin deficiency

Mannose-Binding-Lectin deficiency
L. Skattum et al. Molecular Immunology. 2011;48:1643–1655

Terminal pathway complement deficiency
L. Skattum et al. Molecular Immunology. 2011;48:1643–1655
• Neisserial disease
• Meningococcal disease
• Disseminated gonococcal infections
• Rarely fatal (≠ Properdin)

C1 inhibitor deficiency
• Autosomal dominant
• mutation in SERPING1 gene located near chromosome 11
• De novo mutations (sporadic case) 25%
• Chronic consumption of C2 and C4
• mildly increase susceptibility to infection
• increased risk for development of SLE
• The most common clinical presentation is angioedema.
• The historical features
• recurrent episodes of angioedema
• involvement of the airway in the absence of anaphylaxis
• a positive family history
• antecedent trauma
Hereditary
angioedema

C1 inhibitor
deficiency
Loss of inhibitory
activity for the
intrinsic coagulation
pathway

• Type I deficiency
• the most common (85%)
• Decrease in protein levels and function
• Type II deficiency
• Normal protein level (or elevate) but dysfunctional
protein
• Type III deficiency
• not a complement deficiency
• Normal protein levels and functional activity
• associated with mutations in factor XII of the
coagulation pathway
Hereditary
angioedema

• HAE type 1, 2 should be suspected when a patient
presents with a history of recurrent angioedema
attacks.
• 1) a positive family history (although this may not be present
in up to 25% of patients)
• 2) onset of symptoms in childhood/adolescence
• 3) recurrent and painful abdominal symptoms
• 4) occurrence of upper airway edema
• 5) failure to respond to antihistamines, glucocorticoids, or
epinephrine
• 6) presence of prodromal signs or symptoms before swellings
• 7) the absence of urticaria (wheals)
• Laboratory investigations to support the diagnosis
Maurer et al. WAO Journal.2018;11:5
Hereditary
angioedema

Zuraw BL and Christiansen SC. Middleton’s Allergy 8th edition
Hereditary
angioedema

Clinical features
• Recurrent episode of non-pruritic,
non-pitting angioedema
• Sites: face, oropharynx, extremities,
abdomen, GI tract , genitalia
• Risk for a potential laryngeal attack
• Frequency: twice per week to less
than 1/yr
• Onset: 50% at age 10 years
• Worsening of symptoms around
puberty
C1 inhibitor deficiency Hereditary
angioedema
Zuraw BL and Christiansen SC. Middleton’s Allergy 8th edition
Shiber JR. N Engl J Med 2005;353:e15

Treatment Hereditary angioedema
On demand treatment
Craig T et al. WAO Journal 2012; 5:182–199

• C1-INH concentrate Berinert, Cinryze
• 1st line treatment
• Fresh frozen plasma (FFP)
• 2nd line treatment
• greater risk of blood borne disease transmission
• Attenuated androgens Danazol
• alternative to C1-INH concentrates
• Antifibrinolytic drugs Tranexamic acid
• not recommended by most experts
Short term prophylaxis
For scheduled pre-procedural prophylaxis, androgens are used
for 5 days before and 2 to 3 days post event.

Long term prophylaxis
• C1-INH concentrate Berinert, Cinryze
• 1st line treatment
• Attenuated androgens Danazol
• 2nd line treatment
• Antifibrinolytic drugs Tranexamic acid
• not recommended due to less efficacy and side effect
• Except in children à more prefer to Danazol
Long-term prophylaxis should be individualized
• activity of the disease, frequency of attacks, quality of life, availability of
health-care resources and failure to achieve adequate control by appropriate
on-demand therapy

Common trigger of HAE
Patients should be made aware of potentially relevant triggers
of symptoms to reduce precipitation of attacks.

Factor I deficiency
First phenotype: susceptibility to infections
• Secondary deficit in C3
• The infectious similar to true C3 deficiency
• Neisserialdisease, S. pneumoniae, H. influenzae
• Serum sickness: some patients
• Lab: ↓CH50 ↓ AH50 , ↓C3 antigen levels
Second phenotype: Atypical HUS MPGN II
• vascular endothelial damage after micro-trauma
• Atypical HUS = lack of common trigger of infectious diarrhea,
toxin elaborated form E. coli are typical trigger
• Lab: C3 may depressed, Factor I level typically is normal

• Phenotypes
1. Early age of onset and recurrent HUS
2. Macular degeneration
3. Infection
• 15–30% of atypical HUS
• Inability to protect fenestrated endothelium in the
glomerulus from complement-mediated damage
• Microtrauma from high oncotic pressure à
complement activation at basement membrane
Factor H deficiency

• Macular degeneration
• leading cause of blindness
• less protection to the choroidal vessels
• gradual damage to the endothelium
• central region of retina is gradually destroyed by a process
that leaves deposits of protein termed drusen
• Susceptibility to infection
• Lab
• diminished C3, ↓CH50 and ↓AH50 , but not absent
• direct mutation analysis
• Treatment FFP may be benefit
Factor H deficiency

• Later onset of atypical HUS
• Mechanism: same as for factor H and factor I deficiencies
• MCP mutation found in 10% of all cases of atypical HUS
• This defect is intrinsic to the kidney
• Renal transplantation can be successful
• Traditional complement analysis: normal
Membrane cofactor protein (MCP, CD46) deficiency

• Chronic hemolytic anemia and recurrent stroke
• CD59
• Expressed on most hematopoietic cells, endothelial cells
• Function: Protect intravascular complement-mediated lysis, RBC
most vulnerable because not able to repair membrane damage
• Defect: phenotypic resemblance to PNH
• PNH
• Recurrent episodes of intravascular hemolysis, hemoglobinuria
• thrombosis occurs for unknown reasons
• aplastic anemia can both pre-date and post-date the PNH
• Diagnosis of PNH flow cytometry for CD59 or CD55 (DAF)
CD59 deficiency and
Paroxysmal nocturnal hemoglobinuria (PNH)

• DAF is a glycosyl phosphatidylinositol (GPI) anchored
membrane protein found on erythrocytes,
lymphocytes, granulocytes, endothelium, and
epithelium
• It inhibits the assembly of classical and alternative
pathway C3 converting enzymes.
• DAF deficiency is also termed the Inab blood group
phenotype.
• Does not have a hemolytic phenotype
• Associated with protein-losing enteropathy: CHAPLE
Decay accelerating factor (CD55) deficiency
O Zen et al. N Engl J Med 2017;377:52-61

5 distinct homozygous,
novel, loss-of- function
CD55 variants mutations

After incubation with human serum (A), and stimulation of the classical pathway by
coating the cells with mouse IgG1 (B)
• increased C3 fragment deposition on patients’ CD4+ T-cell blasts by staining for
an epitope common to C3d

Excessive Production of Inflammatory
Cytokines by CD55-Deficient T Cells
• Cd55−/− mice producing more interferon-γ and
less interleukin-10
• TNF and interferon-γinduced procoagulatory
decreases in thrombomodulin and increases in
tissue factor
• Thus instigate the severe thrombophilia
• CD55 can convey a costimulatory signal for T-cell
activation and production of IL-10, inhibitory
cytokine to intestinal inflammation

CHAPLE
• CD55 deficiency
• Hyperactivation of
complement
• Angiopathic
thrombosis
• Protein-Losing
Enteropathy

• Defect in the three β2 integrin adhesion molecules
• β2 Integrins are essential for the firm adhesion
step and diapedesis
• Lacking β2 integrins
• Neutrophils remain in the vascular space
• Unable to participate in the defense against bacteria
• Lack of pus at sites of active infection
• Pathophysiology
• ineffective opsonization
• inability to traverse the vascular endothelium to
phagocytose bacteria
CR3, CR4 deficiency

• LAD type I à No residual expression of β2 integrins
• Clinical is very serious disorder, heavy mortality
• Assorted other serious bacterial and fungal infections
• Treatment: Bone marrow transplantation
• LAD type II à defect in fucosylation of selectin
ligands
• LAD type III à activation defect of integrins
• Infection, moderate to severe bleeding tendency
secondary to impaired activation of platelet adhesion
molecules
CR3, CR4 deficiency Leukocyte adhesion defect

Laboratory assessment
of complement

Warning signs for complement deficiency
• Meningococcal meningitis > 5 years of age
• Family history or recurrent meningococcal disease
• Infection to uncommon serotypes (X, Y, Z, W135 or 29E)
• Chronic meningococcemia
• Terminal complement (C5-9) , properdin, Factor H, Factor I
deficiency
• C5-C8 deficiency à 1,000-10,000 fold increase risk infection
• 40% of C5-C9 deficiency, 6% of properdindeficiency
A.S. Grumach, M. Kirschfink. Molecular Immunology. 2014;61:110–117

• Other recurrent bacterial infections
• C3 deficiency, Factor H, Factor I deficiency (C3
consumption)
• Encapsulated pyogenic bacteria: S.pneumoniae, H.influenzae
• Defect in CR3, CR4 à LAD
• MBL deficiency
• Autoimmune disorders
• Early complement deficiency
• Early onset SLE, prominent cutaneous manifestation
• less renal, pulmonary or pericardial involvement
• Pediatric-onset severe SLE with negative result on ANA,
anti-dsDNA

• Angioedema without urticaria
• C1 inhibitor deficiency
• Recurrent angioedema in the absence of allergic reactions
• Family history of angioedema
• Angioedema is preceded by a reticular rash
• Angioedema after trauma
• Membranoprolifertaive glomerulonephritis
• Atypical HUS, pregnancy-associated HUS, Severe
preclampsia
• Factor H, Factor I, Factor B, C3, MCP deficiency
• Age-related macular degeneration

CH50
• Adding dilutions of patient serum to sensitized
sheep red cells à leads to lysis.
• The assay result reports the dilution of serum
capable of lysing 50% of the sheep cells.
• Deficiencies of all the cascade components lead to
a CH50 of 0 or near 0, except C9 deficiency
• Low levels of CH50 or AH50, assays should be
repeated
Mishandling of the serum is an extremely common à
leading to diminished complement levels.

Causes of low but not absent CH50
• Complement consumption
• active immune complex disease
• Diminished hepatic production
• liver disease, immaturity of hepatic production
• Regulatory protein defects
• factor H, factor I, and factor D deficiency
• C9 deficiency
CH50

• Screening test for complement abnormalities in the
alternative pathway
• Similar assay to CH50 but rabbit red cells are used
in AH50
• Factors D, B, and Properdin, as well as regulatory factors
H and I
• Patients with disseminated infections with pyogenic
bacteria in the presence of a normal CH50
AH50

Abnormal CH50 or AH 50
• Define the serum levels of certain components
• Nephelometry (C1q, C3, and C4 primarily)
• ELISAs available for certain other components
• Add-back hemolytic assay
• identification of a component that is absent or markedly
diminished
• Screening with hemolytic assays is not adequate for
C9, properdin, MBL, MASP-2, or ficolin deficiencies.
• The specific diagnosis à the management path can
be defined.

Bonilla FA et al. J Allergy Clin Immunol 2015;136(5):1186-205

Management of complement deficiency
• Early classical component deficiencies
• Features: SLE and infection
• Treat infection, autoimmune
• Give vaccines to raise titers of antibodies to encapsulated
organisms to high levels → S. pneumoniae and H. influenzae
• Lifelong antibiotic prophylaxis
• Management of cardiac risk factors
• Terminal complement component deficiencies
• Increased risk of neisserialdisease
• Meningococcal disease: most common
• Disseminated gonococcal infections: significant frequency
• Vaccination every 3 years with the meningococcal vaccine

• C3 deficiencies
• Loss of opsonization, loss of B cell costimulation, and
loss of immune complex solubilization
• Intravenous immune globulin (IVIG)
• Compensate for the compromised B cell function
• Prophylactic antibiotics
• Membranoproliferativeglomerulonephritis
• No specific intervention
• Renal transplantation, in end-stage renal disease
Management of Complement Deficiency

• Factor D and properdin deficiencies
• Manifestations related to secondary consumption of C3
• Neisserial disease, S. pneumoniae, H. influenzae
infection
• Vaccination to achieve high titers of antibody
• Prophylactic antibiotics
• Factor H, I, MCP deficiencies
• Neisserial disease à the same strategies with terminal
complement component deficiency
• Renal disease and atypical HUS
• Factor H : FFP
• MCP: renal transplantation
Management of Complement Deficiency

Indicate Contraindicate
Middleton 8th • All routine vaccines
• Pneumococcal, Meningococcal
None
JACI 2016/2018 • All inactivated vaccines are safe and effective
• Consider encapsulated bacteria (PCV/PPSV,
Hib, MCV)
None
Redbook 2015 • All inactivated and live-virus vaccines are safe
and probably are effective
• PPSV23 at 2 years or older
• MCV4 vaccine are recommended in addition to
standard vaccines
None
IDSA 2013 • All routine vaccines
• PCV and PPSV
• 4-dose series of MCV4 and Hib, reactivate with
MCV4 every 5 years
None
Vaccine in Complement Deficiency

ATB prophylaxis in Complement Deficiency
Bonilla FA et al. J Allergy Clin Immunol 2015;136(5):1186-205
Kuruvilla and De La Morena. J Allergy Clin Immunol Pract 2013;1:573-82

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