The Complement System Flashcards by Deleted Deleted

System of plasma proteins which completes the process initiated by the interaction of antigen and antibody combination-lysis

complement system

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Series of more than ________ that interact to enhance host defense reactions

more than 25 serum proteins

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Most are _________ that are converted to active enzymes in a precise order

inactive enzyme precursors

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It constitutes ________, heat labile that are present in normal human serum and all tissue fluids except urine and CSF

5% of normal serum protein

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The key mediator in all pathways

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Sequential activation of complement components occurs via one of the three pathways

Classical Pathway
Alternative Pathway
Lectin Pathway

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Initiated by formation of antigen-antibody complex

Classical pathway

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Initiated by foreign cell surface; antibody independent ; part of innate immunity

Alternative pathway

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Initiated by host proteins binding microbial surface

Lectin pathway

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CASCADE ACTIVATION
Complement proteins are often designated by an
uppercase letter C and are inactive until they are split into products

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CASCADE ACTIVATION
When the products are split they become active. The
active products are usually designated with a lower
case a or b

C1a and C1b

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All classes of immunoglobulin do not fix complement
only ______, ______, ______, and ______ fix in the respective order

IgM, IgG3, IgG1 and IgG2

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These Ig do not fix complement

IgG4, IgA, IgD and IgE

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Complement does not bind to ______ and ______

antigen and antibody

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Activated by antibodies bound to antigen

classical pathway

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Activated on microbial cell surfaces in the absence of antibody

alternative pathway

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Activated by plasma lectin that binds to mannose residues on microbes

lectin pathway

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4 important functions of complement system

lysis
opsonization
activation of inflammatory response
clearance of immune complexes

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Overview of the complement pathways indicating
components required for _______, _______, _______. ______, and _______

recognition, enzymatically active components and complexes, major opsonic, inflammatory, and membranolytic products

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4 components of alternative pathway

C3, factor B, factor D, properdin

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Triggering substances may be pathogens or nonpathogens:
○ Bacterial cell wall components
○ Fungi
○ Viruses
○ Parasites
○ Immune complexes
○ RBCs
○ Polymers

alternative pathway

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activation of alternative pathway

proteolysis of C3

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Binding site for factor B covalently tethered to surface of microbial or host cell

C3b

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Bound factor B cleaved by ________

factor D (serine protease)

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C3 convertase

C3bBb

Properdin bind to and stabilize _________

C3bBb complex

C5 convertase

C3bBb3b

A protein that binds to CHO

lectin

It binds to mannose on many bacterial cells

mannose-binding lectin pathway (MBL)

It produced by liver in acute phase inflammatory reactions

MBL

Once MBL binds to target cell, 2 serine proteases _______ and _______ bind

MASP-1, MASP-2

acts like C1

MBL pathway

an acute phase protein, binds to mannose residues

MBL

When MBL complex binds to a pathogen surface, MASP-2 is activated to cleave _____ and _____

C4 and C2

Importance in innate host defense mechanism in early childhood

MBL pathway

activation of MBL pathway

D-mannose, GIcNAc (microbial polysaccharides)

Binding to circulating lectins, [e.g., Mannose-binding lectin (MBL), or to _________ recognizing lectins (ficolins) collectin family and structurally resemble C1q

N-acetylglucosamine

MASP-1 cleaves to _____

MASP-2 cleaves to _____ and _____

C4 and C2

C3 convertase

MASP-1

C5 convertase

C4b2b3b

regulation of the complement cascade short half life of:

C3b, C3bBb, C5b

It inhibits the C1s activity

C1 inhibitor

Glycophosphatidylinositol-linked membrane protein

DAF

On endothelial cells and erythrocytes

DAF

If deficiency, causes Paroxysmal Nocturnal Hemoglobinuria (PNH)

DAF

Unusual feature, acquired mutation in defective gene, in hematopoietic stem cells

DAF

Plasma serine protease degrade cell-associated C3b

factor 1

Active only in presence of regulatory proteins

factor 1

MCP, factor H, C4BP, and CR1 serve as cofactors

factor 1

Cause dissociation of C3b (and C4b)-containing complexes

factor 1

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

factor 1

regulators of the C3 and C5 convertase

DAF factor 1

regulators of formation of the MAC

CD59 S protein HRF or CD59 factor H

Membrane protein inhibit formation of the MAC

CD59

Glycophosphatidylinositol-linked protein expressed on many cell types

CD59

Incorporate into assembling MACs after the membrane insertion of C5b-8, thereby inhibiting the subsequent addition of C9 molecules

CD59

Present on normal host cells, where it limits MAC formation, but it is not present on microbes

CD59

Binding to soluble C5b,6,7 complexes

S protein

Prevent insertion into cell membranes near the site where the complement cascade was initiated

S protein

Bind to C8

HRF or CD59

Inhibits C9 binding

HRF or CD59

Binds to C3b

factor H

Facilitates binding of Factor I

factor H

FACTOR H Cleaves C3b to _____

inactive iC3b

FACTOR H Cleaves C4b to _____

inactive fragments

Decay Accelerating Factor

factor H

Immune and rheumatic

C1, C2, C3, C4 disorders

Recurrent infection (Neisseria)

C5, C6, C7, C8 disorders

Combined immunodeficiency states

C1q disorders

Many infections and lupus-like symptoms

C1r disorders

Systemic Lupus Erythematosus

C1s disorder

Lupus-like symptoms

C4 disorder

Increased susceptibility to infection

C2 disorder

Severe pyogenic infections

C3 disorder

Recurrent infection of GIT

C5 disorder

Disseminated gonococcal infections and recurrent Meningococcal meningitis

C6, C7, C8 disorder

Not more susceptible to disease than other individual in general populations

C9 diorder

Hereditary angioneurotic oedema

C1 inhibitors

INACTIVATOR FACTOR 1

C3b

A multi component triggered enzyme cascade, attracts phagocytic cells to the microbes which engulf them

the complement system

Complement can be activated by _____ and _____

classical and alternative pathway

(T/F) The amount of complement present in the serum cannot be increased by immunization

true

Complement participates in ________ and ________

type II and type III hypersensitivity

Several serum complement components are lowered in many autoimmune diseases such as ______ and ______

systemic lupus erythematosus and rheumatoid arthritis

(T/F) Complement mediates immunological membrane damage

true

_______ released during cascade reaction help in amplifying the inflammatory response

C fragments

It mediate immune adherence

C3 and C4

It participates in coagulation process

C3 and C6

Present with early onset SLE, anti-dsDNA less common, more severe disease, less steroid responsive

C1q deficiency

Strongest known genetic risk factor for lupus

C1q deficiency

C4a deficiency, risk factor for SLE (less severity than sufficient complement) early onset SLE, anti-dsDNA less common

C4 deficiency

C4B deficiency, with invasive bacterial disease

C4 deficiency

Most common of the inherited classical complement component deficiencies in Caucasians

C2 deficiency

most common cause of death in C2 deficiency

sepsis

Most common organisms in C2 deficiency

S. pneumoniae and H. influenzae

Rarest of the four early component deficiencies

C3 deficiency

Most severe phenotype

C3 deficiency

Membranoproliferative glomerulonephritis

C3 deficiency

Neutrophil dysfunction (abscesses), humoral deficiencies (sinopulmonary disease), and complement deficiencies (sepsis, meningitis)

C3 deficiency

Single case has been reported (meningococcemia)

factor B deficiency

Neisserial infections are the most common manifestation

factor D deficiency

X-linked complement deficiency

properdin deficiency

One of the more common complement deficiencies and occurs largely in Caucasians

properdin deficiency

One or more episodes of meningococcal disease

properdin deficiency

High fatality rate in contrast to terminal complement component deficiencies

properdin deficiency

Plasma derived MBL is now being produced by Co-operative Research Centre for Vaccine Technology (CRC-VT)

MBL DEFICIENCY THERAPY

On phase I safety, tolerability, and pharmacokinetics

MBL DEFICIENCY THERAPY

● Hereditary angioedema ● Mildly increased susceptibility to infection ● Increased risk of SLE ● Recurrent episodes of angioedema, involvement of airway in absence of anaphylaxis, abdominal episodes, a positive family history, or angioedema arising after trauma ● Type I deficiency, most common (85%) of inherited cases ● Type II deficiency normal production, but dysfunctional protein

C1 inhibitor deficiency

● Recurrent episodes of hemoglobinuria due to intravascular hemolysis ● Thrombosis occurs for unknown reasons ● Aplastic anemia ● Due to acquired somatic mutations of PIG-A or PIG-M in a clone of bone marrow progenitor cells ● These protein products are required for GPI-anchored proteins and C8-binding proteins which protect hematopoietic cells from complement mediated lysis ● DAF deficiency does not have a hemolytic phenotype ● CD59 is more important

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)