Lecture 17 - Effector Mechanisms of Humoral Immunity Flashcards
What are the effector functions of Abs?
- neutralize these agents
- Opsonize them for phragocytosis
- Sensitize them for Ab-dependent cellular cytotoxicity
- Activate the complement system
Abs are produced by plasma cells where?
in primary (bone marrow) and secondary (LNs) lymphoid organs
Abs that mediate protective immunity may be derived from what cells?
short or long lived Ab-producing plasma cells
Abs perform effector functions in various tissues distant from what?
their production sites
Many of the effector functions of Abs are mediated by what?
heavy chain constant region (Fc) of Ig molecules
Different Ig heavy chain isotypes serve distinct effector functions
Ab effector functions are triggered only after what?
After Ag binding
Describe vaccine-induced humoral immunity against polio?
Oral attenuated poliovirus/ nuetralization of virus by mucosal IgA Ab
Describe vaccine-induced humoral immunity against tetanus, diphteria?
Toxoids/ neutralization of toxin by systemic IgG Ab
Describe vaccine-induced humoral immunity against Hep A or B?
Recombinant viral envelope proteins/ neutralization of virus by mucosal IgA or systemic IgG Ab
Describe vaccine-induced humoral immunity against pneumococcal pneumonia, haemophilus?
Conjugate vaccines composed of bacterial capsular polysaccharide attached to a carrier protein/ opsonization and phagocytosis mediated by IgM and IgG Abs, directly or secondary to complement activation
Abs against microbes and microbial toxins block what?
The binding of these microbes and toxins to cellular receptors
How do influenza viruses and gram-negative bacteria attack host cells?
Influenza viruses use their envelope hemagglutinin to infect respiratory epithelial cells
Gram-negative bacteria use pili to attach to and infect a variety of host cells
Abs that bind to microbial structures interefere with the ability of the microbes to do what?
interact with cellular receptors by means of steric hindrance and may thus prevent infection
What blocks the spread of microbes from an infected cell to an adjacent uninfected cell?
Antibodies
What inhibits the pathologic effects of toxins?
Antibodies that block the binding of toxins to cells
What antibodies coat microbes and promote their phagocytosis by binding to Fc receptors on phagocytes?
IgG
What are the types of Fc receptors?
- FcγRI - high affinity - phagocytosis, cell activation
- FcγRII - low - phago, cell act, feedback inhibition
- FcγRIII - low - Ab-dependent cell-mediated cytotoxicity
- FceRI - high - cell act
Binding of Fc receptors (FCγRI) on phagocytes to multivalent ab-coated particles leads to what?
phagocytosis and the activation of phagocytes
WHat are the most efficient opsonins for promoting phagocytosis via high affinity FcγRI (CD64)?
IgG1 and IgG3
Signals from what receptors activate the phagocytes to destroy these opsonized microbes?
Fc receptor
Ab of certain IgG subclasses bind to infected host cells and the Fc regions of the bound Ab are recognized by what receptor on NK cells?
FcγRIII
NK cells activated by ADCC kill what cells?
Ab-coated cells
ADCC = antibody-dependent cell-mediated cytotoxicity
What cells function together to mediate the killing and expulsion of some helminthic parasites?
IgE, eosinophils, and mast cells
Worms are too large to be engulfed by phagocytes and they are relatively resistant to what?
The microbicidal products of neutrophils and Mo
What can worms be killed by?
A toxic cationic protein, known as the major basic protein, present in the granules of eosinophils
What can cause the degranulation of eosinophils, releasing the basic protein and other eosinophil granule contents that kill the parasites?
IgE that coat helminths can bind to FCeRI on eosinophils causing these events to happen
What consists of serum and cell surface proteins that interact with one another and with other molecules of the immune system in a highly regulated manner to generate products that function to eliminate microbes?
The complement system
What is one of the major effector mechanisms of humoral immunity and is also an important effector mechanism of innate immunity ?
Complement system
What is the complement system activated by?
microbes and by Abs that are attached to microbes and other antigens
Activation of complement involves the seqential proteolysis of what molecules to generate enzyme complexes with proteolytic activity?
proteins
The products of complement activation become covalently attached to what?
microbes, Abs bound to microbes, and to other Ags, and to apoptotic bodies
What is complement activation inhibited by?
reg proteins that are present on normal host cells and absent from microbes
What are the three pathways of complement activation?
classical, alternative and lectin
The complement activation depends on the generation of what two proteolytic complexes?
The C3 convertase, which cleaves C3 into two proteolytic fragments called C3a and C3b
C5 convertase, which cleave C5 into C5a and C5b
What is the alternative pathway activated by?
C3b binding to various activating surfaces
What is the classical pathway activated by?
C1 binding to Ag-Ab complexes
What is the lectin pathway activated by?
binding of a plasma lectin to microbes
What steps of all three pathways are the same?
The late steps
The proteolytic cleavage of what chain of C3 converts it into a metastable form (alternative)?
alpha
Once C3 is in a metastable form, what are exposed and susceptible to nucleophilic attack by oxygen atoms or nitrogen atom? (alternative)
Thioester bonds
The exposed thioester bonds of C3b results in the formation of what? (alternative)
covalent bonds with proteins or carboydrates on the cell surfaces
What is structually homologous to C3 and has an identical thioester group?
C4
Spontaneous hydrolysis of plasma C3 leads to the formation of what? (alternative)
fluid-phase C3 convertase and the generation of C3b
If C3b is deposited on the surfaces of microbes, it binds what to form the alternative pathway C3 convertase?
Factor B
The C3 convertase cleaves C3 to produce more C3b, which binds to what? (alternative)
The microbial surface and participates in the formation of a C5 convertase
The C5 convertase cleaves C5 to genearte C5b, this is the initiating event in what steps of complement activation? (alternative)
Late steps
What are the functions of C3b?
Binds to the surface, opsonin, and a component of C3 and C5 convertases
What are the functions of C3a?
Stimulates inflammation
What are the functions of Bb?
A serine protease and the active enzyme of the C3 and C5 convertase
What is the function of factor D?
Plasma serine protease cleaves factor B when it is bound to C3b
What is the function of properdin?
Stabilizes C3 convertases (C3bBb) on microbial surfaces
What is the classical pathway initiated by?
binding of the C1 to IgG or IgM molecules that are bound to Ag
What is C1 composed of? (classical)
C1q, C1r, and C1s subunits
What does each subunit of C1 do?
C1q binds to Ab, while C1r and C1s are proteases
C1q consists of how many subunits?
six identical subunits arranged as radial arms
What are the contact regions for immunoglobulins on C1?
The globular heads at the end of each C1q arm, designated H
Cr1 and C1s form a tetramer composed of what?
two C1r and two C1s molecules
The ends of C1r and C1s contain what domains?
the catalytic domains of these proteins
What must C1 bind to, in order to initiate the complement cascade?
To two or more Fc portions
After IgM binds to surface-bound Ags, it undergoes what changes in the classical pathway?
A shape change that permits C1 binding and activation
Will soluable IgG molecules activate C1?
No because each IgG has only one Fc region, but after binding to cell surface Ags, adjacent IgG Fc portions can bind and activate C1
The classical pathway is initated by the binding of C1 to what molecules?
antigen-complexed antibody molecules
Activated C1s cleaves what next protein in the cascade?
C4, to generate C4b
What does C4b contain that forms covalent bonding with microbe to which the Ab is bound? (classical)
thioester bond
What does the thioester bond ensure?
classical
That the classical pathway activation proceeds on a microbial surface
What is cleaved by a nearby C1s molecule to generate a fragment of unknown importance and another fragment that remains physically associated with C4b?
C2 is cleaved into C2b and C2a (associated with C4b)
The resulting C4b2a complex is the classical pathway _________.
C3 convertase
Cleavage of C3 results in the removal of the small C3a fragment, and C3b can form covalent bonds with what? (classical)
Cell surfaces
Once C3b is deposited, it can bind what to generate more C3 convertase by the alternative pathway? (classical)
Factor B
Some of the C3b molecules generated by the classical pathway C3 convertase binds to the convertase and forms what?
C4b2a3b complex
Classical pathway C5 convertase - It cleaves C5 and initiates the late steps of complement activation
The lectin pathway is triggered by the binding of microbial polysaccharides to what?
circulating lectins, such as plasma mannose-binding lectin
MBL binds to what residues on bacterial polysaccharides?
mannose
MBL associates with MBL-associated serine proteases including what MASPs?
MASP1, 2, and 3
The MASP proteins are structurally homologous to what?
C1r and C1s proteases
What cleaves C4 and C2 to activate the complement pathway in the lectin pathway?
MASP
*subsequent events in this pathway are identical to those that occur in the classical pathway
C5 convertases cleaves C5 into what fragments?
C5a that is released and C5b that remains bound to the complement proteins deposited on the cell surface
What does C5b bind?
C6 and C7
What component of the C5b, 6, 7 complex is hydrophobic and inserts into the lipid bilayer of cell membranes?
C7
C7 becomes a high-affinity receptor for what?
C8, and then the C5b,6,7,8 complex is formed
The formation of a fully active MAC is accomplished by the binding of what?
C9
C9 polymerizes at the site of the bound C5b-8 to form what?
pores in the plasma membranes
CR1 promotes phagocytosis of what particles?
C3b and C4b-coated particles
CR1 promotes clearance of what?
Immune complexes from the circulation
Phagocytes use what receptor to bind and internalize microbes and debris?
CR1
CR1 also transduces signals that activate what mechanisms of phagocytes?
killing
CR2 binds the cleavage products of what?
C3b (C3d, C3dg, and iC3b)
On B cells, what does CR2 enhance?
The responses of B cells to Ag
On follicular DC, CR2 does what?
traps iC3-coated Ag-Ab complexes in germinal centers
What virus enters B cells via CR2 and infects these cells and remain latent in infected cells for life?
Epstein-Barr virus
What is CR3 also called?
Mac-1
What is an integrin that functions as a receptor for the iC3b fragment generated by proteolysis of C3b?
CR3
CR3 is involved in the recruitment of of leukocytes to sites of infection and tissue injury by binding to what?
ICAM-1 on endothelial cells
What binds to iC3b and the functions of this receptor is probably similar to that of Mac-1?
CR4
Why must complement activation be regulated?
To prevent complement activation on normal host cells and to limit the duration of complement activation even on microbial cells and antigen-antibody complexes
What is C1 INH?
Sering protease inhibitor that displaces C1r2s2 from C1q and terminates classical activation
What is DAF?
Decay-accelerating factor: displaces C2a from C4b and Bb from C3b (dissociates C3 convertase)
What functions similarly to DAF?
MCP and CR1
In the presence of what cell membrane-bound cofactors does plasma factor 1 proteolytically cleave C3b attached to cell surfaces?
MCP or CR1
*Factor H can also serve as cofactors for factor I-mediated cleavage of C3b
What does plasma factor I generates?
inactive form of C3b - iC3b
What inhibits the formation of MAC?
Membrane protein CD59 and S protein in the plasma
Microbes on which complement is activated by the alternative or classical pathway become coated with what?
C3b, iC3b or C4b, and are phagocytized by the binding of these proteins to specific receptors on macrophages and neutrophils
What proteolytic complement fragments induce acute inflammation by activating mast cells, neutrophils and endothelial cells?
C4a, C4a, and C3a
What protein generated from C3 binds to CR2 on B cells and facilitates B cell activation and the initiation of humoral immune responses?
C3d
What is the most common human complement deficiency?
C2 deficiency
What deficiencies develop systemic lupus erythematosus?
C1q, C2 and C4
Defects in complement activation leads to failure to clear what?
Circulating immune complexes
Complexes may be deposited in blood vessel walls and tissues, where they produce local inflammation
What deficiencies are not usually associated with increased susceptibility to infections?
C2 and C4 - alternate pathway may compensate
What is C3 deficiency associated with ?
frequent serious pyogenic bacterial infections that may be fatal
Deficiencies in what results in increased susceptibility to infection with pyogenic bacteria?
properdin and Factor D
Deficiencies in C5-C9 may result in what?
disseminated infections by Neisseria bacteria
Complement system can cause significant ____ damage
tissue
Some of the pathologic effects associated with bacterial infections may be due to complement-mediated _____ ______ responses to infectious organizations.
Acute inflammatory
Complement activation is associated with _______ ________ and can lead to ischemic injury to tissues
Intravascular thrombosis
In an autoantibody-mediated kidney disorder, membranous nephropathy, damage to glomerular epithelial cells can be mediated by what?
The MAC that is generated after Ab binds to a glomerular auto-Ag
How can microbes evade the complement system?
By recruiting host complement regulatory proteins
Many pathogens express _____ that can inhibit the alternative pathway of complement by recruiting Factor H - which displaces C3b from Bb
Sialic acids
Many other pathogens have evolved proteins that facilitate the recruitment of what?
Factor H to their cell walls
HIV incorporates multiple host reg proteins into their envelopes. Name specifics
GPI-anchored complement reg proteins DAF and CD59 when it buds from an infected cell
Abs in ingested milk transport across what epithelium of newborns?
The gut
How do Abs transport across the gut epithelium?
Process known as transcytosis
Transport of maternal IgG across the placenta and across the neonatal intestinal epithelium is mediated by what?
An IgG-specific Fc receptor called the neonatal Fc receptor (FcRn)
Maternal IgG is transported across what?
placenta
Maternal IgA and IgG are given to an infant how?
In breast milk
Ingested IgA and IgG can neutralize pathogenic organisms that attempt to do what?
colonize in infant’s gut
