complements and complement deficiency

Complement and Complement deficiency

19-7-2013Suparat 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 Activator1. 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

C3 convertase = C4b2a

C5 convertase = C4b2a3b

Alternative pathways

internal thioester groups

C3 tickover

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 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 deficiency

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

Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th edL. Skattum et al. Molecular Immunology 48 (2011) 1643–1655

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

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 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 : diagnosisshould 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)

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

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

assesspatients 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 angioedemapatients 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

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