Complement System Flashcards
C3a and C5a complements have biological activities as chemoattractants for other immune cells: C3a is for _____ and _____; and C5a is for _____ and _____
C3a:
- mast cells
- basophils
C5:
- macrophages
- neutrophils
The complement system functions for each mechanism, except
control of infection
Which antibody are commonly involved in the classical pathway?
immunoglobulins
IgM and IgG
Which of the following complement proteins initiates the MAC?
C5b
The complement system is part of which immune response (IR)?
natural IR
The alternative pathway is also known as?
C3 convertase pathway
Which of these complements from the pore prior to establishment of MAC?
C8 and C9
Which complement system is activated by antigen-antibody complex?
Classical Pathway
These complements proteins are part of the activation of classical pathway
3cs
C1q
C2
C4
Which of the following describes the terminal complement pathway?
Membrane Attack Complex (MAC) for microbial lysis
The alternative pathway functions to
Amplify the C3B and further activation leads to formation of C5 convertase of the alternative pathway
Activation of C1 by antibody-binding is correctly called
complement fixation
The alternative pathway remains active due to the presence of _______ needed for C3 initiation complex
C3(H20)
The alternative pathway commences upon the cleavage and production of which complement protein?
C3b
Which two of the following complement proteins comprise C3 convertase of classical pathway?
C2a
C4b
These complement proteins comprise C5-convertase complex of the classical pathway
3cs
C2a
C3b
C4b
The alternative pathway is activated by which factors
Lipopolysaccharides and other LPS present on the surface of invading pathogen
The complement proteins in the serum are generated by means of which enzymes that are part of their respective pathways?
protease
Which protein of the Ab is involved in complement activation?
Fc region
The classical pathway cascades upon the attachment to Ab of which complement molecule?
C1q
essential proteins because it complements the antibacterial activity of some of the antibodies
Complements
Complements are given numerical names as
C1 to C9, which are 20 including subunits
The concentration of complements is
3-4 G/L in the blood.
True or False
Complement makes 10% of the serum proteins.
True
This is a function of…
Activation of _____ leads to inflammation and localize the antigen or cause lysis.
Complement system
This is a function of…
Once _____ is activated, its components participate in virtually every aspect of the inflammatory response.
Complement system
This is a function of…
There is an antimicrobial activity.
Complement system
This is a function of…
Serum sickness-like immune reaction.
Complement system
This is a function of…
Autoimmune diseases.
Complement system
This is a function of…
These are not increased by infection or other antigens.
Complement system
This is a function of…
But IL-1 and γ-interferon increase the synthesis.
Complement system
Site of Action
cs
cell surface or other biological membranes.
- There are ultrastructural changes in the cell membrane.
- There are changes in the electrical charges of the cell membrane.
- There is swelling of the membrane.
- Ultimately there are circular holes 8-12 nm in diameter.
Changes by Activation of Complement
- The complement may be synthesized in the intestinal epithelium, macrophagic cells, and spleen.
- C1 is a calcium dependant complex and consists of C1q, C1r, and C1s, this is synthesized in the epithelium of the gastrointestinal and urogenital epithelium
Site of Formation
Complement and its Site of Synthesis
Synthesized in Epithelial cells and fibroblasts.
C1
Complement and its Site of Synthesis
The liver is the major site of formation.
6cs
C3
C4
C6
C7
C8
C9
Complement and its Site of Synthesis
Synthesized by macrophagic cells.
C1
C2
C3
C4
C5
factors
Complement and its Site of Synthesis
Synthesized by macrophagic cells.
Factor B
Factor D
Factor H
Factor P
Starts forming complement by the second month of pregnancy.
Fetus
- Recognition of antigen and antibody.
- Enzymatic chain reaction.
- Formation of membrane attacking complex which leads to cellular destruction
Complement activation
- Complements are present in an inactive form in blood circulation, once activated they give chain reaction like blood coagulation factors.
- Larger molecule labeled as “b”. It leads to further activation of the chain reaction.
- A smaller molecule labeled as “a” it promotes inflammation and produces pharmacological action.
- Further proteolysis gives inactive component labeled as “iC3 b”.
- Complement is catabolized in the body 1-3% per hour.
After Activation Complement is cleaved into
it leads to further activation of the chain reaction.
larger molecule
it promotes inflammation and produces pharmacological action
smaller molecule
Two Complement pathways
Classical pathway
Alternative pathway
Immunological stimuli:
Ag & Ab complex, tissue injury, or aggregated IgG.
Non-immunological stimuli:
CRP, DNA, Trypsin, E. Coli, Salmonella, viruses, endotoxin, and urate crystals.
The classical pathway may be activated by:
Immunological stimuli:
aggregated IgA, sometimes IgG.
Non- immunological stimuli:
lipopolysaccharides (endotoxin), Trypsin & trypsin-like enzyme, cobra venom. Parasite & teichoic acid of gram-positive bacteria.
Alternative Pathway may be activated by:
- Lysis of Bacteria, viruses, and cells.
- Mediate acute inflammation.
- This leads to the release of histamine.
- It helps in opsonization and phagocytosis.
- It has a regulatory role and it regulates acute inflammation in the immune response
Activation of Complement leads to:
Vasodilatation at the site of inflammation.
Increase adherence of phagocytic cells to blood vessels endothelium.
It directs movements of phagocytic cells to the area of inflammation.
Ultimately clears of the infection.
Various Complement-Proteins lead to:
Physiologic action
Cellular action
The outcome of Complement Activation:
Vasodilatation at the site of inflammation.
types of action
Physiologic action
Increased vascular permeability.
types of action
Physiologic action
Increase adherence of phagocytic cells to blood vessels endothelium.
Hemolysis in the case of RBCs.
Cytolysis.
types of action
Cellular action
Recruitment of acute inflammatory cells.
types of action
Cellular action
It directs movements of phagocytic cells to the area of inflammation.
types of action
Cellular action
Produce inflammatory mediators.
types of action
Cellular action
type of action
Opsonization of the pathogens
types of action
Cellular action
Ultimately clears of the infection.
Ultimately killing of pathogens.
Opsonization of the pathogens of Cellular Action
Various cell types express surface membrane glycoproteins that react with one or more of the fragments of C3 produced during complement activation and degradation.
Complement Receptors
important in increasing phagocytosis and an important factor present on the RBCs.
Complement receptor 1 (CR1)
CD molecule:
CD5
Specificity for the receptor:
C3b
Distribution on the cells: RBCs
Polys
Monocytes
B-lymphocytes
Dendritic cells
Glomerular visceral epithelial cell
Main functions
Promote Phagocytosis
Immune complex transport
Immune adhesion
Secondary Epstein Barr virus receptor
CR1 (Complement receptor 1)
cr?
CD molecule:
CD21
Specificity for the receptor:
C3d
Distribution on the cells: B-lymphocytes
Main functions:
B-cell coactivator
CD23 receptor
Epstein Barr virus receptor
CR2 (Complete receptor 2)
CD molecule:
CD11b and CD18
Specificity for the receptor:
iC3b
Distribution on the cells: Monocytes
Polys
NK cells
Main functions:
Polys adherence
Phagocytosis of iC3b bound particles
CR3 (Macrophage-1-antigen)
In the classic pathway antigen and antibody complex is recognized by the complement _______ and it starts a chain reaction by stimulating C1s and C1r which will stimulate C4 and C2. Then there is the stimulation of C3 C5 C6, 7, and ultimately C9.
C1q
The activation of complement is not in sequence from C1 to C9, but this is
C1, C4, C2, C3, C5, C6, C7, C8 and C9
the recognition unite and it recognizes the Ag-Ab complex and then activates C1r
C1q
molecule has a stable binding to the cell membrane (efficiency is <10%)
C4b
Clusters of C3b are activated and bound near the C4bC2b complex
C3b
acts as a C5 convertase and cleaves C5 into C5a and C5b.
C4b C2b C3b
fixation and is the beginning of the membrane attack complex.
C5b
is highly lipophilic and binds to the membrane where it acts high-affinity receptors for C8.
three cs
C5b
C6
C7
has three chains α, β, and γ where γ-chains insert into the membrane.
C8
polymerizes C9 forming tubule the MAC (membrane attacking complex), which gives rise to hole formation in the cell-membrane Like drill machine.
four cs
C5b
C6
C7
C8
directly binds to the immunoglobulin molecule.
C1q
do not bind the immunoglobulin but leads to the subsequent activation of C3.
2 cs
1r
1s
C1r and C1s
only attaches to subclasses of IgG and IgM
C1q
single molecule is able to fic C1 but IgG needs two molecules.
IgM
is functionally multivalent for to attach to the complement fixation sites of immunoglobulin.
C1q
are similar in structure, where ____ forms dimers and ____ binds to ____.
C1r and C1s
both bind to C1q in the presence of Ca++.
C1q
the only substrate for C1r.
C1s
cleaves C1S (C1S–).
C1r-
C1s also cleaves
C2 to C2a and C2b
The control mechanism for the activity of C1s is a _______, which will control the C1s for un-controlled activation of C4 and C2.
C1-proteinase inhibitor
has the ability to disintegrate the membrane-bound C4b.
C3b esterase inhibitor
act as C3-convertase and cleaves C3 to C3a and C3b
2cs
C4b and C2b
two cs
will activate the C3 molecule into C3a anaphylatoxin and C3b.
C4b
C2b
forms an opsonic macromolecular coat on the target cells and makes it susceptible to immune adherence by the C3b receptor on the phagocytic cells.
three cs
C4b
C2b
C3b
Only a ___ molecule combines with C4bC2b to form the final proteolytic complex complement pathway.
C3b
binds to C6 and make a labile reactive site for C7.
C5b
It is evaluated in the serum.
It is needed in the first reaction of complement where it will lead to activation of C4 and C2.
C1q
It takes part in the activation of C3 with the help of C4.
C2 and C2a
It increases vascular permeability.
C2 and C2a
It causes contraction of smooth muscles.
C2 and C2a
Some say that functions are unknown.
C2 and C2a
It is a weak anaphylatoxin and weak mediator of Inflammation.
C4a
It is a strong anaphylatoxin.
C3a
It leads to an increase in vascular permeability and smooth muscle contraction.
not ctwo
C3a
This leads to the release of vasoactive amines.
C3a
Leads to the release of lysosomal enzyme.
It is chemotactic.
C3a
Functions just like C3a.
C5a
It increases neutrophil activity.
C5a
More potent chemotactic factor than C3a.
C5a
Activated by the C5b and attach to C7.
C6
These are C3a, C5a, and C4a.
Anaphylatoxin
these directly activate mast cells and basophils, through their receptor for C5a, and lesser extent C3a.
Anaphylatoxin
has the highest biologic activity.
C5a
acts with C5a to activate mast cells, recruit antibody, complement, phagocytes, and increase the tissue fluid in that area.
C3a
has the least anaphylactic activity.
C4
Binding to Ag-Ab complex (Recognition unit)
C1q
Activating enzymes
C1r, C1s, C2b, Bb & D
two cs
Membrane binding proteins and Opsonin
C3b & C4b
three cs
Mediate inflammation
C5a, C3a, C4a
Membrane-attacking complex
C5b6789
It is a glycoprotein and also known as C1 esterase. It destroys C1r, C1s.
C1-inhibitor
It is proteolytic enzymes, it cleaves C3b into iC3b (inactive form). It also destroys C4b.
what factor?
The factor I
Prevents binding of C5, 6, 7 to the membrane.
Vitronectin (S-protein)
prevents activation of C4.
Decay Accelerating Factor (DAF)
Prevents activation of C4.
C4 binding protein
what factor?
It binds C3b and accelerates the destructive action of factor I.
Factor H
This is a primitive defense system. In this pathway, there is a bypass of C1, 4, 2 and there is direct stimulation of C3.
ALTERNATIVE PATHWAY
This is predominantly a non-antibody initiated pathway.
ALTERNATIVE PATHWAY
activator of the alternative complement pathway
Polysaccharides complex from the surface yeast cells.
Bacterial polysaccharides and endotoxin.
Aggregated immunoglobulins IgG2, IgA, and IgE.
Zymosan.
Inulin.
considered the counterpart of the C2a of the classical pathway.
C3a
of the classical pathway resembles factor B of the alternative pathway.
C2
no role of C1, C2, and C4, but the alternative pathways have different protein which stimulates directly
C3
Factor C3b and factor B combine to form ___,___
which is then converted into C3 convertase (C3bBb)
C3b, B
a glycine richα-2-globulin believed to be physiologically inactive through the action of factor D.
factor
Factor Ba
can convert more C3 to C3b, in turn, it binds more factor B.
C3b, Bb complex
The complement (C) system is part of the immune system called the
innate immune system.
This test can be used to diagnose various diseases e.g Pneumococcal pneumonia, syphilis and etc.
With the help of this test, one can quantitate antigen or antibody.
This test was very famous for the diagnosis of syphilis.
Complement fixation test
This test may be manipulated by making dilution of serum or complement or one can have known antibody and unknown antigen or vice versa. Even the titer of antibody or concentration of complement may be estimated by serial dilution.
Complement fixation test
This test is used to find Unknown Antibody or Antigen
Complement fixation test
The basic principle is its activity which leads to hemolysis of RBC. In this test, we need:
Serum of the patients.
Complement
Indicator system which consists of antibody-coated RBC.
Known antigen.
Complement fixation test
Diseases caused by the complement deficiency
C1s
SLE
Angioedema
Diseases caused by the complement deficiency
C1r
Glomerulonephritis
Chronic infection
SLE
Dermatomyositis
Vasculitis
Necrotizing skin lesion
Arthritis
Diseases caused by the complement deficiency
C1q
SLE
Decreased secondary to agammaglobulinemia
C2
Diseases caused by the complement deficiency
C2
Recurrent pyogenic infection
SLE
Membranoproliferative glomerulonephritis
Discoid lupus erythematosus
Dermatitis herpetiformis
Dermatomyositis
Synovitis
Purpura
Hodgkin’s disease
Chronic lymphocytic leukemia
Polymyositis
C3
Diseases caused by the complement deficiency
C3
Recurrent pyogenic infection
SLE
Arthritis
Skin rash
Diseases caused by the complement deficiency
C3b inactivator
Recurrent pyogenic infection
Urticaria
Diseases caused by the complement deficiency
C4
SLE
Vasculitis
Dermatomyositis like syndrome
Diseases caused by the complement deficiency
C5
Recurrent infection (Neisserai)
SLE
Diseases caused by the complement deficiency
C6
Gonorrheal infection
Meningococcal infection
SLE
Scleroderma
Vasculitis
Raynaud’s phenomenon
Diseases caused by the complement deficiency
C7
Raynaud’s disease
Renal disease
Neisseria infection
SLE
Vasculitis
Scleroderma
Diseases caused by the complement deficiency
C8
Glomerulonephritis
SLE
Neisseria infection
Xeroderma pigmentosa
Decreased Level Of Complement (Deficiency Of Complements):
Autoimmune diseases
Infectious diseases
Deficiency of controlling proteins
what kind of disease?
SLE.
Rheumatoid arthritis.
Systemic vasculitis.
Essential mixed cryoglobulinemia.
Autoimmune diseases
what kind of disease?
Arterioventricular shunts with infection.
Subacute bacterial endocarditis.
Gram-negative sepsis.
Pneumococcal sepsis.
Viral hepatitis B leading to viremia.
Viremia in measles.
Malarial parasite infestation.
Infectious diseases
These are quite uncommon primary immune deficiency <2%.
The factor H deficiency.
The factor I deficiency.
Hereditary angioedema (C1 inhibitor deficiency).
Deficiency of controlling proteins
Inflammatory process.
Trauma.
Myocardial infarction.
In acute illnesses where complement raised as acute-phase proteins.
Raised Level Of Complement:
Diseases associated with complement deficiency
C1s deficiency
C4 deficiency
SLE
Diseases associated with complement deficiency
C1q deficiency
SLE, Nephritis & hypogammaglobulinemia
Diseases associated with complement deficiency
Renal diseases, SLE, recurrent infection, and Rheumatoid arthritis
C1r deficiency
Diseases associated with complement deficiency
Recurrent infections (pyogenic)
C3 deficiency
Diseases associated with complement deficiency
Recurrent infections + Gonococcal infections and SLE
C5 deficiency
Diseases associated with complement deficiency
Recurrent infections + Meningococcal infection
C6 deficiency
Diseases associated with complement deficiency\
Recurrent infections + Glomerulonephritis
C7 deficiency
Diseases associated with complement deficiency
Recurrent infections + Gonococcal & Meningococcal infections
C8 deficiency
Binds to pathogen surface.
Binds factor B for cleavage by D.
C3b
It is a C3 convertase.
C3bBb
It is a C5 convertase.
C3b2Bb
It is a small fragment and function is unknown
Ba
It is an active enzyme and C3 convertase.
Bb
factor
Plasma serine protease cleaves factor B when it is bound To C3b to Ba and Bb.
Factor D
are certain substances, which enhance and give positive regulation of the alternative pathways:
Factor P (Properdin).
Cobra Venom Factor (CoVF):- This complexes with Bb (CoVFBb) which acts as C3/C5 convertase. It is resistant to factor H & I.
Positive Regulators for Alternative Pathways
Inhibitors of Alternative Pathways
Factor H which binds to C3b.
It present on Mast cells and Basophils
not c3
C1q
Present on Mast cells and Basophils.
Receptors identified on Neutrophil, Monocytes, B, and Null cells.
C3a and C5a Receptors
Receptors identified on Neutrophil, Monocytes, B, and Null cells.
C3b
Present on phagocytic cells, lymphocytes, and RBC.
C4b
Virus neutralization.
C1 and C4
Immune adherence, phagocytosis & take part in Arthus reaction.
C3b
Anaphylatoxin
C3a, C5a
Chemotaxis
4 cs
C3a, C5a, and C6 C7
Lysis
-to-
C5 to C9
Cytotoxic action
C8 and C9
