Handout 13: Effector Mechanisms of Humoral Immunity Flashcards
What are the four main effector functions of Abs?
- neutralize microbes and their toxins
- opsonize them for phagocytosis of microbes (macrophage)
- sensitize them for Ab dependent cellular cytotoxicity (Ab dependent cytotoxicity)–(NK cell)
- activate the complement system which can result in 3 outcomes: phagocytosis of microbes opsonized with complement fragments (C3b), Inflammation, lysis of microbes
These various effector functions may be mediated by different Ab isotypes
What cell produces Abs and where are they produced?
Abs are produced by plasma cells in primary bone marrow and secondary lymphoid organs
Abs that mediate protective immunity can be derived from two different types of plasma cells. What are they?
short-lived and long-lived Ab-producing plasma cells
Are Abs limited to functions to areas around where they are produced or can they work in distant areas as well?
They perform effector functions in various tissues distant from their production
Many of the effector functions of Abs are mediated by what specific portion of the Ig molecule? Do all types of this part of the Ig have the same effector function?
Many effector functions are mediated by the heavy chain constant region (Fc) of Ig molecule. No, different Ig heavy isotypes serve distinct effector functions.
What must first occur for Ab effector functions to be triggered?
Ag must bind
What are the major differences between short-lived and long-lived plasma cells?
short-lived plasma cells:
generated during T-independent responses
may be generated early during T-dependent responses in extrafollicular B cell foci
are generally found in secondary lymphoid organs in peripheral non-lymphoid tissues
long-lived plasma cells:
generated in T-dependent germinal center responses to protein Ag
Are generated by signals from the BCR and IL-21 via a stage of their precursors called plasmablasts
Plasmablasts generated in germinal centers enter the circulation and home to the ____ where they differentiate into ___ ___ ___ ___
bone marrow
long-lived plasma cells
Typically 2 to 3 weeks after immunization, what becomes a major site of Ab production?
bone marrow
Is Ag always needed to secrete Abs or can it be secreted after the Ag is not present?
Plasma cells can continue to secrete Abs for months or even years after the Ag is no longer present. These Abs can provide immediate protection if the Ag is encountered later
How much of Abs in the blood is produced by long-lived plasma cells? What type of Ags are long-lived plasma- cells specific for?
50%
Long-lived plasma cells are specific for Ags that were encountered in the past
Where are memory cells generated? What kind of Ags do memory cells respond to? Can they survive without continuing Ag stimulation?
Memory cells are generated mainly in germinal centers for T-dependent protein Ags
Yes, Memory cells acquire the ability to survive without continuing Ag stimulation.
What kind of Ag receptors (high affinity or low affinity) do memory cells express? What kind of Ig molecules do they express?
Memory cells express Ag receptors of high affinity (mutated) and Ig of switched isotype
Which anti-apoptotic protein do memory B cells express?
They express high levels of the anti-apoptotic protein Bcl-2
Are Ab production the highest/fastest during the first exposure or second exposure to Ag? Why?
Abs production is accelerated after secondary exposure to Ag because memory cells are activated in germinal centers during secondary exposure
Do all memory cells remain in the lymphoid organ?
No, they may remain in the lymphoid organ where they were generated but they can also exit germinal centers and recirculate between the blood and lymphoid organs
How Vaccine-induced humoral immunity works:
Name of infectious disease: Polio
Type of vaccine
Mechanism of protective immunity
Type of vaccine: Oral attenuated poliovirus
Mechanism of protective immunity: Neutralization of virus by mucosal IgA Ab
How Vaccine-induced humoral immunity works:
Name of infectious disease: Tetanus, diptheria
Type of vaccine
Mechanism of protective immunity
Type of vaccine: Toxoids
Mechanism of protective immunity: Neutralization of toxin by systemic IgG Ab
How Vaccine-induced humoral immunity works:
Name of infectious disease: Hepatitis A or B
Type of vaccine
Mechanism of protective immunity
Type of vaccine: Recombinant viral envelope proteins
Mechanism of protective immunity: Neutralization of virus by mucosal IgA or systemic IgG Ab
How Vaccine-induced humoral immunity works:
Name of infectious disease: Pneumococcal pneumonia, Haemophilus
Type of vaccine
Mechanism of protective immunity
Type of vaccine: conjugate vaccines composed of bacterial capsular polysaccharide attached to a carrier protein
Mechanism of protective immunity: Opsonization and phagocytosis mediated by IgM and IgG Abs, directly or secondary to complement activation
How do Abs neutralize microbes?
Abs against microbes and microbial toxins block the binding of microbes and toxins to cellular receptors
Without Ab: Infection of tissue cell by microbe–>Infected epithelial barrier cells (Infected tissue cell)
with Ab: Ab blocks the binding of microbe and infection of cell
How do microbes like influenza viruses and Gram negative bacteria infect cells?
Influenza viruses use their envelope hemagglutinin to infect respiratory epithelial cells, and Gram negative bacteria use pili to attach to and infect a variety of host cells
What specifically do Abs that bind to microbial structures do to interfere with the ability of the microbes to interact with cellular receptors?
Abs create steric hinderance to prevent infection
What do Abs do when microbes from an infected cell is about to infect an adjacent uninfected cell?
Infected tissue cells can release their microbe from dead cell and spread the infection to uninfected adjacent cell. Abs can block the infection of adjacent cell.
How do Abs neutralize toxins?
Abs block the binding of toxins to cells and thus inhibit the pathologic effects of the toxins
Without Ab, the toxin creates a pathologic effect by binding to the cell surface receptor for the toxin. Abs blocks the binding of toxin to cellular receptor
In Ab-mediated opsonization and phagocytosis, Abs of which immunoglobulin isotype coats/opsonizes microbes and promotes their phagocytosis? How do they do this?
Abs of the IgG isotype osponize microbes and promote their phagocytosis. They do this by finding to Fc receptors on phagocytes
Type of Fc receptor: Fc-gamma-RI (CD64)
Affinity for Ig:
Cell distribution:
Function:
Affinity for Ig: High; IgG1 and IgG3
Cell distribution: macrophages, neutrophils, eiosinophils
Function: Phagocytosis and cell activation
Type of Fc receptor: Fc-gamma-RII (CD32)
Affinity for Ig:
Cell distribution:
Function:
Affinity for Ig: Low
Cell distribution: Macrophages, neutrophils, DCs, B cells and NK cells
Function: Phagocytosis and cell activation; feedback inhibition
Type of Fc receptor: Fc-gamma-RIII (CD16)
Affinity for Ig:
Cell distribution:
Function:
Affinity for Ig: Low
Cell distribution: NK cells
Function: Ab-dependent cell-mediated cytotoxicity
Type of Fc receptor: Fc-epsilon-RI
Affinity for Ig:
Cell distribution:
Function:
Affinity for Ig: High
Cell distribution: Mast cells, basophils, eosinophils
Function: Cell activation (degranulation)
Sequence of events in Ab-mediated phagocytosis
Opsonization of microbe by IgG–>Binding of opsonized microbes to phagocyte Fc receptors (Fc-gamma-RI)–>Fc receptor signals activate phagocytosis–>phagocytosis of microbe–>killing of ingested microbe
What is the first step in Ab-mediated phagocytosis that leads to activation of phagocytes?
Binding of Fc receptors on phagocytes to multivalent ab-coated particles leads to phagocytosis and activation of phagocytes
What specific subtypes of Ig are the most efficient opsonins for promoting phagocytosis? What Fc receptor does this Ig use?
IgG1 and IgG3. They uses high affinity Fc-gamma-I (CD64) receptor
In Ab-mediated phagocytosis, signals from what activate the phagocytes to destroy microbes?
Signals from the Fc receptor activate the phagocytes and destroy microbes
Inhibitory Signaling by Fc-gamma-RIIB receptor summary
A. BCR singaling leads to PIP3 formation which binds other signaling molecules, leading to activation–>B cell activation
B. Fc receptor-associated phosphatase, SHIP (SH2 containing inositol phosphatase) converts PIP3 to PIP2 in B cell-receptor complex, blocking downstream signaling–>B cell receptor signaling, no activation
In inhibitory signaling, what two things does the Ag-Ab complex simultaneously bind to?
binds to membrane Ig (through Ag) and the Fc-gamma-RIIB receptor through the Fc portion of the Ab
What is the consequence of the Ag-Ab complex simultaneously binding to the membrane Ig (through Ag) and the Fc-gamma-RIIB receptor (through Fc portion of Ab)?
Because of the simulatneous ligation of receptors, phosphatases associated with the cytoplasmic tail of the Fc-gamma-RIIB inhibit signaling by the BCR complex and block B cell activation
How is FcR-Mediated Ab Feedback triggered? What does it do?
triggered by secreted Ab. It blocks further Ab production as opposing the activation via CR2. It is a physiological control mechanism in humoral immune responses
When is Abs provide complement-mediated amplification and when does it provide Fc-receptor mediated inhibition?
Not clear, but one likely scenario is that:
IgM that activates complement but do not bind to to Fc-gamma-R are involved in amplification whereas increasing production of IgG leads to feedback inhibition
What did they find in studies of mice where the Fc-gamma-IIB gene was knocked out?
Uncontrolled Ab production
What autoimmune disease is a polymorphism in the Fc-gamma-RIIB gene linked to?
susceptibility to systemic lupus erythematosus
What is Ab-dependent cell-mediated cytotoxicity (ADCC)
Ab of certain IgG subclass bind to infected host cells and the Fc regions of the bound Ab are recognized by an Fc-gammaRIII on Nk cells
The NK cells are then activated and kill Ab-coated cell
What is the role of Perforin in Ab-dependent cell-mediated cytotoxicity (ADCC)?
Perforin induces uptake of granzymes into target cell endosome and release into cytosol, activating caspases
What is the function of the IgE-Fc-epsilon-RI?
kills helminths
IgE that coat helminths can bind to Fc-epsilon-RI oneosinophils and cause the degranulation of these cells, releasing the basic protein andother eosinophil granule contents that kill the parasites
Why are microbicidal products of neutrophils and macrophages not enough to get rid of worms (helminths)? What then is needed to kill the worms?
Worms are too large to be engulfed by phagocytes and they are relatively resistant to the microbicidal products of neutrophils and macrophages.
Worms can be killed by a toxic catonic protein called major basic protein which is present in granules of eosionphils
___, ___ and ___ function together to mediate the killing and expulsion of some helminthic parasites
IgE, eosinophils, mast cells
What are the basic components of the complement system and what is its function?
Complement system 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 is a major effector mechanism for both ____ and ___ immunity
humoral, innate
How is the complement system activated?
activated by microbes and by Abs that are attached to microbes and other Ags
Activation of complement involves the ___ ___ of proteins to generate enzyme complexes with proteolytic activity
sequential proteolysis
What are the products of complement activation attached/bound to?
Products of complement activation become covalently attached to microbes, to Abs bound to microbes and to other Ags, and to apoptotic bodies
How is complement activation inhibited?
Inhibited by regulatory proteins that are present on normal host cells and absent from microbes
What are the three pathways of complement activation?
classical, alternative and lectin
What are the two proteolytic complexes that complement activation depends on?
C3 convertase and C5 convertase
What does C3 convertase do?
cleaves C3 into two proteolytic fragments called C3a and C3b
What does C5 convertase do?
cleaves C5 into C5a and C5b
How is the alternative pathway activated?
by C3b binding to various activating surfaces
How is the classical pathway activated?
by C1 binding to Ag-Ab complexes
How is the lectin pathway activated?
binding of a plsma lectin to microbes
What is similar about the three complement activation pathways (classical, alternative and lectin)?
The late steps of the three pathways are all the same
Complement activated by all three pathways serve the same function
How is the alternative pathway activated?
Proteolytic cleavage of the alpha chain of C3 converts it into a metastable form
The thioester bonds are exposed and susceptible to nucleophilic attack by oxygen atoms or nitrogen atoms
The result is the formation of covalent bonds with proteins or carbohydrates on the cell surfaces
What molecule is structurally homologous to C3 and has an identical thoester group?
C4
Sequence of events for alternative pathway:
Intact C3 (inaccessible thioester group)-->Cleavage of C3alpha chain by C3 convertase-->Accessible thioester group in C3b--> In fluid phase, C3b is activated by hydrolysis OR Covalent attachment of C3b to cell surface protein or polysaccharide by thioester linkage
In the alternative pathway, how is C3b generated?
Spontaneous hydrolysis of plasma C3 leads to formation of a fluid-phase C3 convertase and the generation of C3b
Under what conditions in the alternative pathway is C3 convertase formed?
If the C3b is deposited on the surfaces of microbes, it binds Factor B and forms the alternative pathway C3 convertase
How is C5 convertase formed from C3 convertase?
C3 convertase cleaves C3 to produce more C3b, which binds to the microbial surface and participates in the formation of a C5 convertase
What does C5 convertase do? What is the function of C5b?
The C5 convertase cleaves C5 to generate C5b, the initiating event in the late steps of complement activation (formation of membrane attack complex)
What are the four proteins involved in the alternative pathway?
C3, Factor B, Factor D and Properdin
Which alternative pathway protein has the highest concentration? What is the concentration of this protien?
C3 has the highest concentration of 1000-12000 microgram/mL
What is the function of the alternative pathway protein C3?
C3b binds to the surface. functions as an opsonin and is a component of C3 and C5 convertases
C3a stimulates inflammation (anaphylatoxin)
What is the function of the alternative pathway protein Factor B?
Bb is a serine protease and the active enzyme of the C3 and C5 convertases
What is the function of the alternative pathway protein Factor D?
It is plasma serine protease that cleaves factor B when it is bound to C3b
What is the function of the alternative pathway protein Properdin?
Properdin stabalizes C3 convertases (C3bBb) on microbial surfaces
How is the classical pathway initiated?
By binding of C1 to IgG or IgM molecules that bound Ag
What classes of Abs are the most efficient activators of complement in the classical pathway?
IgG3 and IgG1 are more efficient activators of complement
What are the components/subunits that make up C1?
C1q, C1r, and C1s subunits
What is the major difference between C1q and C1r/C1s in terms of its binding?
C1q binds Ab whereas C1r and C1s are proteases
How is C1q arranged?
It consists of six identical subunits arranged as radial arms
Where do Ig contact on the C1q?
The globular heads at the end of each arm, designated H are the contact regions for Immunoglobulin
How is C1r and C1s arranged? What important part of the protein do C1r and C1s contain?
C1r and C1s form a tetramer composed of two C1r and two C1s molecules. The ends of C1r and C1s contain the catalytic domains of these proteins
Which immunoglobulins leads to complement activation? Which ones do not?
Ag-bound IgM (stable form) and Ag-bound IgG results in complement activation
Soluble IgM (planar form) and Soluble IgG (Fc portions not adjacent) do NOT lead to complement activation
What must happen with C1 for it to initiate complement?
It must bind to two or more Fc portions to initiate complement cascade
What portions are not accessible to C1?
The Fc portions of soluble pentameric IgM
How does IgM lead to C1 binding and activation?
After IgM binds to surface-bound Ags, it undergoes a shape change allowing C1 binding and activation
Why don’t soluble IgG activate C1? What needs to happen with IgG to activate C1?
Soluble IgG doesn’t activate C1 because each IgG has only one Fc region, but after binding to cell surface Ags, adjacent IgG Fc portions can bind and activate C1
Formation of C3 convertase summary:
Binding of Abs to multivalent Ag; binding of C1 to Abs
Binding of C4 to Ig Associated C1q
Cleavage of C4 by C1r2S2 enzyme; covalent attachment of C4b to antigenic surface and to Abs
Binding of C2 to C4; cleavage of C2 to form C4b2a complex (C3 convertase)
Cleavage of C3 by C3 convertase
How is the classical pathway initiated?
By the binding of C1to Ag-complexed Ab
Whad does the C1s cleave?
Activated C1s cleaves the next protein in the cascade, C4, to generate C4b
What is the function of C4b?
C4b contains an internal thioester bond that forms covalent bonding with microbe to which the Ab is bound which ensures that classical pathway activation proceeds on a microbial surface
What cleaves C2?
C2 is cleaved by a nearby C1s molecule to generate a soluble C2b fragment of unknown importance and a larger C2a fragment that remains physically associated with C4b. The resulting C4b2a complex is the classical pathway C3 convertase
What is the purpose of cleaving C3?
Cleavage of C3 results in the removalof the small C3a fragment, and C3bcan form covalent bonds with cell surfaces. Once C3b is deposited, it can bind Factor B and generate more C3 convertase by the alternative pathway
How is C5 convertase formed?
Some of the C3b molecules generated by the classical pathway C3 convertase bind to the convertase and form a C4b2a3b complex which functions as the classical pathway C5 convertase
What does C5 convertase do?
It cleaves C5 and initiates the late steps of complement activation
Formation of C5 convertase sequence of events:
Binding of C2 to C4; cleavage of C2 to form C4b2a complex (C3 convertase)
Cleavage of C3 by C3 convertase
Binding of C3b to antigenic surface and to C4b2a complex
Cleavage of C5; initiation of late steps of complement activation
What are the six major proteins associated with the classical pathway?
C1, C1q, C1r, C1s, C4, and C2
Which of the six proteins in the classical pathway has the highest concentration? What is the concentration of this protein?
C4 has the highest concentration of 300-600 micrograms/mL
What is the function of the classical patway protein C1?
Initiates classical pathway
What is the function of the classical patway protein C1q?
Binds to Fc portion of Ab that has bound Ag, to apoptotic cells, and to cationic surfaces
What is the function of the classical patway protein C1r?
Serine protease, cleaves C1 to make it an active protease
What is the function of the classical patway protein C1s?
Serine protease, cleaves C4 and C2
What is the function of the classical patway proteinC4?
C4b covalently binds to microbe and complement is activated
C4b binds C2 for cleavage by C1s
C4a stimulates inflammation (anaphylatoxin)
What is the function of the classical patway protein C2?
C2a is a serine protease and functions as the active enzyme of C3 and C5 convertases to cleave C3 and C5
How is the lectin pathway initiated?
triggered by the binding of microbial polysaccharides to circulating lectins, such as plasma mannose-binding lectin (MBL)
What does MBL do?
It binds to mannose residueson bacterial polysaccharides
What are the proteases that MBL associates with?
It associates with MBL-associated proteases (MASPs) including MASP1, MASP2,and MASP3
What are MASP homologous to (from a different pathway)?
It is structurally homologous to the C1r and C1s proteases and cleaves C4 and C2 to activate the complement pathway
What happens in the lectin pathway after C4 and C2 are cleaved by the MASP proteins?
The subsequent events are identical to those from classical pathway
What are the four major proteins associated with the lectin pathway?
Mannose-binding lectin
MASP-1
MASP-2
MASP-3
What is the function of Mannose binding lectin?
Agglutinin, opsonin and complement fixing
In the lectin pathway, what is the function of MASP1?
Forms complex with MASP2 and collectins or ficolins and activates MASP3
In the lectin pathway, what is the function of MASP2?
Forms complex with lectins, especially ficolin-3
In the lectin pathway, what is the function of MASP3?
Associates with collectins or ficolins and MASP1 and cleaves C4
How is the MAC formed?
C5 convertases cleave C5 into a small C5a that is released and a C5b fragment that remains bound to the complement proteins deposited on the cell surface
C5b binds C6 and C7
The C7 complement of the resulting C5b, 6, 7 complex is hydophobic, and it inserts into the lipid bilayer of cell membranes, where it becomes a high-affinity receptor for the C8 and C5b,6,7,8 complex is formed
The formation of a fully active MAC is accomplished by the binding of ____.
C9
What does C9 do?
C9 polymerizes at the site of the bound C5b-8 to form pores in plasma membranes
What are the proteins of the MAC?
C5, C6, C7, C8, C9
What is the function of the MAC protein C5?
C5b initiates assembly of the MAC
C5a stimulates inflammation
What is the function of the MAC protein C6?
Component of the MAC; binds to C5b and accpets C7
What is the function of the MAC protein C7?
Component of the MAC; binds to C5b, 6, and inserts lipid membranes
What is the function of the MAC protein C8?
Component of MAC: binds to C5b, 6, 7 and initates the polymerization of C9
What is the function of the MAC protein C9?
Component of the MAC; polymerizes to form membrane pores
What is the function of the CR1 complement receptor?
Phagocytosis of C3b and C4b coated particles and clearance of immune complexes from the circulation
Clearance of immune complexes
Promotes dissociation of C3 convertases by acting as cofactor for cleavage of C3b
CR1 is a high affinity receptor for ___ and ___
C3b and C4b
How do phagocytes use the CR1 receptor?
Phagocytes use the receptor to bind and internalize microbes and debris
What are the functions of the CR2 complement receptor?
Coreceptor for B cell activation
Trapping of Ags in GCs
Receptor for EBV
CR2 binds the cleavage products of ___
C3b (C3d, C3dg, and iC3b)
What do CR2 do on B cells?
enchances the responses of B cells to Ag
What do CR2 do on follicular DC?
CR2 traps iC3-coated Ag-Ab complexes in germinal centers
What do Epstein-Barr virus to B cells?
It enters B cells via CR2, infects these B cells and can remain latent in infected cells for life
What is the structure and function of CR3 (Mac-1) complement receptor?
It is an integrin that functions as a receptor for the iC3b fragment generated by proteolysis of C3b
Its also involved in the recruitment of leukocytes to sites of infection and tissue injury by binding to ICAM-1 on endothelial cells
What is the function of CR4?
Integrin that binds IC3b and its function is similar to Mac-1
Receptor: CR3, Mac-1 (CD11bCD18) Structure Ligands Cell distribution Function
Integrin
iC3b, ICAM-1
Mononuclear phagocytes, neutrophils, NK cells
Fnx: Phagocytosis, leukocyte adhesion to endothelium (via ICAM-1)
Receptor: CR4 (CD11cCD18)
Structure
Cell distribution
Function
Integrin
iC3b
Mononuclear phagocytes, neutrophils, NK cells
Phagocytosis, cell adhesion?
Why is it important for complement activation to be regulated?
To prevent complement activation on normal host cells and to limit the duration of complement activation even on microbial cells and Ag-Ab complexes
C1 inhibitor receptor regulator: What does it interact with and what is its function?
interacts with C1r, C1s
Serine protease inhibitor
found in plasma protein
Factor I receptor regulator: What does it interact with and what is its function?
interacts with C4b and C3b
cleaves C3b and C4b
found in plasma protein
Factor H receptor regulator: What does it interact with and what is its function?
interacts with C3b
Binds C3b and displaces Bb
Cofactor for factor I-mediated cleavage of C3b
found in plasma protein
Membrane cofactor protein (MCP) receptor regulator: What does it interact with and what is its function?
Interacts with C3b, C4b
Cofactor for I-mediated cleavage of C3b
Found in leukocytes, epithelial cells, endothelial cells
Decay-accelerating factor (DAF) receptor regulator: What does it interact with and what is its function?
Interacts with C4b2a, C3bBb
displaces C2a from C4b and Bb from C3b (dissociation of C3 convertases)
Found in blood cells, endothelial cells, epithelial cells
What does C1 INH do?
It displaces C1r2s2 from C1q and terminates classical activation
events: C1q binds to Ag-complexed Abs, resulting in activation of C1r2s2–>C1 INH prevents C1r2s2 from becoming proteolytically active
What does DAF do?
Decay accelerating factor (DAF) dissociates the classical C4b2a or alternative C3 convertase
events: Formation of C3 convertase–>Dissociation of C3 convertases by DAF
What two other proteins function similarly to DAF?
MCP and CR1
What is the purpose of cell-membrane bound co-factors?
In the presence of cell-membrane bound cofactors (MCP or CR1), plasma factor I proteolytically cleaves C3b attached to cell surfaces
It generates inactive form of C3b (iC3b)
events: Covalent attachment of C3b (or C4b) to cells–>MCP (and CR1-mediated cleavage of C3b, producing iC3b)
What other Factor canserve as cofactors for factor I-mediated cleavage of C3b
Factor H can also serve as cofactors for factor I-mediated cleavage of C3b
The MAC is formed on cell surfaces as an end result of complement activation. which membrane proteins result in the plasma inhibit the formation of MAC?
Membrane protein CD59 and S protein
Regulation of the MAC sequence of events:
Activation of late components of activaton–>Formation of the MAC
CD59 inhibits poly-C9 assembly–>Inhibition of MAC formation
S protein inhibits membrane insertion of C5b-C7–>Inhibition of MAC formation
What are the three major functions of complement?
- opsonization and phagocytosis–>Phagocytosis of microbe
- Stimulation of inflammatory reactions–>Recruitment and activation of leukocytes by C5a, C3a–>Destruction of microbes by leukocytes
- Complement-mediated cytolysis–>Osmotic lysis of bacteria
Microbes on which complement is activated by the alternative or classical pathway become coated with ___, ___ or ___ and are phagocytized by the binding of these proteins to specific receptors on ____ and ___
C3b, iC3b, or C4b
macrophages, neutrophils
The proteolytic complement fragments C5a, C4a and C3a induce acute inflammation by activating ____cells, _____, and _____ cells
By binding to Ag-Ab complexes, complement proteins promote the ____ of these complexes and their clearance by phagocytes
mast cells, neutrophils, endothelial cells
solubilization
The C3d protein generated from C3 binds to ___ on B cells and facilitates B cell activation and the initiation of humoral immune responses
CR2
What deficiency is the most common human complement deficiency?
C2
What autoimmune disease is C1q, C2 and C4 deficiencies associated with?
systemic lupus erythematosus; defects in complement activation lead to failure to clear circulating immune complexes; complexes may be deposited in blood vessel walls and tissues, where they produce local inflammation
Are C2 and C4 deficiencies usually associated with increased succeptibility to infections? Why or why not?
No, because the alternative pathway can compensate
What is C3 deficiency associated with?
associated with frequent serious pyogenic bacterial infections that may be fatal
What do deficiencies in properdin and Factor D result in?
increased susceptibility to infection with pyogenic bacteria
What doe deficiencies in C5, C6, C7, C8 and C9 result in?
disseminated infections by Neisseria bacteria
Complement system can cause significant tissue damage. Some of the pathologic effects associated with bacterial infections may be de to complement-mediated ___ ___ responsed toinfectious organisms
acute inflammatory
Complement activation is associated with intravascular ___ and can lead to ischemic injury to tissues
thrombosis
In an auto-Ab-mediated kidney disorder, membranous nephropathy, damage to glomelular epithelial cells can be mediated by the ___ that is generated after Ab binds to a glomerular auto-Ag.
MAC
How do microbes evade the complement system?
By recruiting host complement regulatory proteins
Many pathogens evade complement by expressing ___ ___ which can inhibit the alternative pathway of complement by recruiting Factor H, which displaces C3b from Bb. Many other pathogens have evolved proteins that facilitate the recruitment of Factor H to their cell walls
sialic acids
Other microbes like HIV incorporate multiple host regulatory proteins into their envelopes to evade complement. For instance, HIV incorporates the GPI-anchored complement regulatory proteins ___ and ___ when it buds from an infected cell
DAF and CD59
How are neonates protected from microbes?
They lack the ability to mount effective immune responses against microbes so for several months after birth, their major defense against infection is passive immunity provided by maternal Abs
Newborns are protected from infection by maternal Abs transported across the placenta into the fetal circulation. What is transcytosis?
The process by which Abs ingested in milk is transported across the gut epithelium of newborns
What Ig receptor mediates the transport of maternal IgG across the placenta and across the neonatal intestinal epithelium?
IgG-specific Fc receptor called neonatal Fc receptor (FcRn)
Which Igs are transported across the placenta and which ones are found in breast milk and are ingested by the nursing the infant?
Maternal IgG is transported across the placenta
Maternal IgA and IgG are in breast milk
Ingested IgA and IgG can ____ pathogenic organisms that attempt to colonize the infant’s gut
neutralize
