Innate Immunity Part II Flashcards
The activation of the complement system may be inititated by 3 different ativation pathways. What are these pathways?
Classical
Alternative
Lectin
What is the early step 1 of complement activation?
The formation of C3 convertase complex, which trigger inflammation and opsonize microbes.
What is the early step 2 of the complement activation?
The formation of C5 convertase complexes that produce C5a and C5b.
This perpetuates inflammation and initiattes the late steps.
What are the late steps of complement activation?
The formation of membrane attack complexes which form holes in microbial membranes.
Complement activation involves a proteolytic cascade. What is involved in this cascade?
An inactive precursor enzyme (zymogen) is altered to become an active protras that cleaves the next complement protein in the cascade.
What do enzymatic cascades result in?
Tremendous amplification of the amount of proteolytic products that are generated.
What is the function of the by-products of the complement activation?
They perform various effector functions of the complement system.
With what other pathways does the complement system work in cooperatin with?
Blood coagulation pathways
Kinin-kallikrein system (regulates vascular permeability).
What is the result of recognition of microbes by any of the three complement pathways?
It results in sequential recruitment and assembly of additional complement proteins into protease complexes.
What is the function of C3 convertase?
It cleaves C3 to make C3a and C3b fragments.
What is the function of C3a?
It stimulates inflammation by acting as a chemoattractant for neutrophils.
What is the function of the C3b fragment?
It becomes covalently attached to the microbial surface and serves as an opsonin to promote phagocytosis of the microbes.
What is a secondary function of C3 convertase?
It binds a C3b fragment to form a protease complex called C5 convertase.
What is the function of C5 convertase?
It cleaves C5 producing C5a and C5b fragments.
What is the function of C5a?
It is a potent chemoattractant that induces changes in the permeability of blood vessels.
What is the function of C5b?
It is attached to a bacterial membrane that initiates the formation of a complex of C6 - 9 complement proteins called the membrane attack complex.
What complement proteins comprise the membrane attack complex (MAC)?
C6-9
What do multiple MACs cause?
Bacterial leak and lysis
What does the classical complement activation pathway require?
IgM or IgG and C1
C3 and C5 convertases are used.
What occurs during the lectin activation pathway?
MBP binds to bacteria and MASPs are activated.
C3 and C5 convertases are used.
What occurs during the alternative activation pathway?
C3 undergoes spontanous hydrolysis.
Factors B and D are needed.
C3 and C5 convertases are used.
What is factor B?
A serine protease and the active enzyme of C3 and C5 convertases.
What is factor D?
A plamsa serine protease that cleaves factor B when it is bound to C3b.
What is prperdin?
A protein that stabilizes the C3 convertase on microbial surfaces.
What is C1?
It initiates the classical pathway. Fragments of it lead to C4 and C2 activation.
What is C4?
It covalently binds to the surface of a microbe or cell where the antibody is bound and complement is activated.
what is C2?
A serine protease functioning as an active enzyme of C3 and C5 convertase.
What is mannose-binding lectin (MBL)?
It initiates the lectin pathway; it also activates C4 and C2, as in the classical pathway.
How is the alternative pathway capable of autoactivation?
Due to tickover at C3.
It occurs spontaneously and generates C3a and C3b.
What does C3b bind to in the alteranative pathway? What are the results?
C3b binds to factor B.
Factor B is cleaved into Ba and Bb by factor D.
In the alternative pathway, what does Bb associate with?
C3b and C3 convertase, which then cleave additional C3 molecules generating C3b.
In the alternative pathway, what protein stabilizes protein:protein interactions?
Properdin
The alternative pathway can also be initiated as an amplification loop. When does this occur?
When fixed C3b that is generated by classical or lectin pathways binds factor B.
The classical pathway is ___.
The classical pathway is Ab-mediated.
What is the first step in the classical pathway?
A plasma protein called C1q recognizes and binds to Ag-Ab complexes.
In the classical pathway, once C1q binds to the Fc portion of Abs, what occurs?
Two associated serine proteases, called C1r and C1s, become active.
In the classical ptahway. C1r and C1s become active after C1q binds to the Fc portion of Abs. What do C1r and C1s do?
Initiate a proteolytic cascade involving other complement proteins C2 and C4.
What is the lectin pathway triggered by?
A plasma protein called mannose-binding lectin (MBL)
What does mannose-binding lectin (MBL) recognize?
Terminal mannose residues on microbial glycoproteins and glycolipids.
Abter mannose-binding lectin (MBL) binds to microbes in the lectin pathway, what are activated?
Two zymogens called MASP1 and MASP2.
In the lectin pathway, MASP1 and 2 have simular functions to what other prtoeins?
C1r and C1s.
They initiate downstream proteolytic steps identical to the classical plathway.
What is mannose-binding lectin?
A soluble PRR that binds carbohydrates with terminal mannose and enhances phagocytosis of microbes.
What are low MBL levels associated with?
Increased susceptibility to a variety of infections.
MBL is a member of the collectins family of trimeric proteins. What are these more specifically?
Proteins with a lectin head with are soluble effector molecules in the innate immune system.
Pulmonary surfactant proteins SP-A and SP-D are members of what protein family? What is their major function?
Collectins family.
Their major function is to maintain the ability of the lungs to expand and as mediators of innate immune response.
They also act as opsonins.
They can also inhibit bacterial growth and activate macrophages.
SP-A and SP-D bind to various microorganisms and act as opsonins. What do opsonins do?
They facilitate phagocytosis. SP-A and SP-D facilitate phagocytosis by alveolar macrophages.
What are C1, MBL and FIcolin?
Three homologous hexameric proteins that can all initiate complement activation.
What is the function of C1q?
It binds to the Fc regions of IgM and activates the serine protease activity of C1r and C1s.
Where does MBL bind?
It binds to mannose on the surface of microbes and activates MASP1 and MASP2 associated with mannose-binding lectin.
Where does ficolin bind?
It binds to N-acetylglucosamine on the surface of microbes and activates MASP1 and MASP2 associated with ficolin.
What are ficolins?
They are humoral molecules (PRRs) of the innate immune systems which recognize N-acetylglucosamine on pathogens, apoptotic and necrotic cells.
What is a similarity between ficolins and MBL?
Ficolins bind several species of bacteria, oposninzing them and activating complement in a manner similar to that of MBL.
What are two functions of ficolins?
They are involved in an opsonin-dependent phagocytosis, which limits the infection and orchestrates the subsequent adaptive immune response.
They also initiate the lectin pathway of complement activation through MASPs.
How does MAC form?
C5b binds C6 and C7 and C5b67 complex binds to the membrane via C7.
C8 binds to C5b67 complex and inserts into the cell membrane.
Up to 16 molecules bind C9 and polymerize to form a pore.
Why is complement not activated on the surface of mammalian cells?
Because they express regulatory proteins that inhibit, disassemble or cleave the convertases.
What is the system of intracellular killing?
Microbes are ingested by different membrane receptors of phagocytes.
Microbes are internalized into phagosomes
Phagosomes fuse with lysosomes to form phagolysosomes
The microbes are killed by reactive oxygen and nitrogen species and proteolytic enzymes.
What are macrophages activated by?
Microbial products, such as LPS and by NK cell derived IFN-gamma.
What does macrophage activation lead to?
The activation of transcription factors
The transcription of various genes
The synthesis of proteins.
Macrophages are activated by stimuli from T lymphocytes. What are two examples of these lymphocytes?
CD49
IFN-gamma
What is an alternative use of macrophages?
They may be alternatively activated by other signal to mpromote tissue repair and fibrosis.
What are the functions of TNF and IL-1?
They act on leukocytes and endothelium to induce acute inflammation.
They also induce the expression of IL-6 from leukocytes and other cell types.
What is the function of TNF, IL-1 and IL-6?
They mediate protective systemic effects of inflammation, including induction of fever, acute-phase protein synthesis by the liver, and increased production of leukocytes by the bone marrow.
What are the functions of systemic TNF?
It can cause pathologic abnormalities that lead to septic shock, including:
Decreased cardiac function
Thrombosis and capillary leak
Metabolic abnormalities due to insulin resistance.
What are two proteins from the pentraxin family?
C-reactive protein (CRP) and serum amyloid P (SAP)
What do plasma proteins from the pentraxin family do?
They recognize microbial structures and participate in innate immunity.
When do plasma concentrations of CRP and SAP significantly increase?
During infections and in response to other inflammatory stimuli.
Why are there increased levels of CAP and SAP during inflammation?
They are a result of increased synthesis by the liver, which is induced by the cytokines IL-6 and IL-1 (produced by phagocytes).
What do CRP and SAP recognize?
Phosphorylcholine and phosphatidylethanolamine, which are found on bacteria and apoptotic cells.
How do CRP and SAP activate the complement?
They bind to C1q and initiate the classical pathway.
What are type I interferons (IFN-alpha and IFN-beta) produced by?
Virus-infected cells.
What is the production of IFN-alpha and IFN-beta triggered by?
It is triggered in response to intracellular TLR signaling and other sensors of viral RNA.
Where do IFN-alpha and IFN-beta bind?
To receptors on neighboring uninfected cells.
This activates the JAK-STAT signaling pathways.
It also induces expression of genes whose products intefere with viral replication.
IFN-alpha and IFN-beta bind to receptors on neighboring uninfected cells. What else do they bind to?
Receptors on infected cells. This induces the expression of genes whose products enhance the cell’s susceptibility to CTL-mediated killing.
Why is pathogen recognition through PRRs important?
It is an important bridge between innate and adpative immunity.
It also causes activation and maturation of antigen-presenting cells (APCs).
Ags that are processed by APCs are presented to what type of cells?
Naive T cells.
Secreted cytokines assist in the development and maturation of what type of cells?
T cells
Ag recognition by B cells provides signal 1 for the activation of what?
Lymphocytes
What provides a second signal to linking adaptive and innate responses in B cells?
Molecuels induced by innate immune responses to microbe provide signal 2.
What is the complement system?
Several plasma proteins that work together to opsonize microbes, to promote the recruitment of phagocytes to the site of infection and to directly kill the microbs.
