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62 Cards in this Set

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What is the selected function of IgG?
IgG is the most common Ig and circulates in the bloodstream. It opsonizes targets, phagocytoses, fixes complement, signals cytotoxic cells to kill virus infected cells
What is the selected function of IgM?
Potent activator of complement. The secreted pentameric form is pentameric. When it binds Ag, it flattens out and exposes the complement-binding site and triggers the cascade.
What is the selected function of IgA?
Important in mucosal immunity
What is the selected function of IgE?
Important in parasitic diseases, allergy, asthma, and hypersensitivity reactions.
How many antigens can the IgG molecule bind to?
Antigen binds to the light chain therefore each Ig molecule can bind 2 Ag molecules.
What is the function of the Fc receptor?
The Fc gamma receptor is located in the "tail" region of the of the IgG molecule initiates the complement cascade, neutralizes toxins from bacteria, prevents entry of virus into the cell, mediates ADCC, and stimulates phagocytosis
What are the two types of Fc-gamma receptors?
Activating and Inhibiting Fc-gamma receptors.
What occurs after ligating the activating Fc-gamma receptors?
Once ligated a cascade of sterotypic changes are initiated which include phagocytosis, actin polymerization, exocytosis, reactive oxygen species production.
What do the inhibiting Fc-gamma receptors do?
The inhibiting Fc-gamma receptors (subtype IIB) are contained on all myeloid cells and they serve to damp down the immune response.
What type of Fc-gamma receptor is found on NK cells?
Only Fc-gamma-RIII, there are no inhibitory Fc-gamma receptors on NK cells.
What type of Fc-gamma receptors do macrophages, neutrophils, and mast cells have?
Fc-gamma-RI, RII, RIII.
What type of receptor class are Fc-gamma receptors like? How are they different from that class?
Fc-gamma receptors are like receptor tyrosine kinases because of their autophosphorylation capability. They however, oligomerizes instead of dimerizing and the Fc-gamma receptor only has ligand binding function, no catalytic function.
What are ITAMs ?
Immunoreceptor tyrosine-based activation motifs. This moiety has two key tyrosines spaced a certain distance apart and is recognized by other kinases.
Where are ITAMs found on the Fc-gamma receptor?
ITAMs are found in the tail of the receptor or in the ligand binding domain
Which kinases phosphorylate the ITAMs in Fc-gamma receptors?
Src kinases phosphorylate ITAMs.
Describe the function of Src kinases
Specifically they recognize a complex composed of ligand binding domains, and ITAM bearing a signal incompetent domain, and 1 or more additional tyrosines kinases
Is the Fc-gamma receptor a high affinity or low affinity receptor?
Most Fc-gamma receptors are low affinity however when the cluster due to the clustering of Ig on opsonized targets the avidity is increasead and binding occurs
What causes the Src tyrosine kinases to bind the ITAMs?
Clustering of the complexes and the Src kinases causes the tyrosine kinases to bind the ITAMs, which then phosphorylates Syk
What are the essential functions of Syk?
Syk is essential in B-cell development, phagocytosis and optimal platelet function.
What does PIP-3 kinase do?
phosphorylates PIP2 to PIP3 which activates other proteins including BTK
Give the path from an activating Fc-gamma receptor to end functions.
Fc-gammaR->Src->ITAM->Syk->PI3K->PIP2->PIP3->BTK activation and other proteins involved in: phagocytosis, B-cell development, optimal platelet function.
How does SHIP inhibit Fc-gamma receptor functions?
Binding of Fc-gammR inhibiting activates ITIM which activates SHIP forms 3,4 bisphosphate from PIP3, SHIP also interacts with Fc-gamma-IIB receptor (inhibitory Fc-gamma receptor) inhibits phagocytosis, B-cell development, etc.
What is IV Ig and what are some therapeutic uses of it?
IV Ig are pooled Igs from thousands of individuals and purified. Used in neurological variant of Guillan-Barre.
How can IV Ig be harmful?
IVIg causes platelet count to rise because Abs bind to platelets and trigger their phagocytosis. The IVIg distracts the Fc receptors and cause autoimmune thromboctopenic purpura.
What is the Arthus Reaction?
Ag-Ab complexes lead to edema and swelling in animals, degranulation of mast cels. Glomerulonephritis occurs when complexes deposit in the kidney. Found in lupus and post-streptococcal glomerulaonephritis.
What are the functions of complement?
host defense, clearance of immune complexes, disposal of apoptotic debris, and regulation of the immune response
What are the different pathways for activating complement?
Classical Pathway, Alternative Pathway, and the Lectin Pathway
Describe the classical pathway?
Ag-Ab complexes mainly composed of IgM in its pentameric form leads to complement activation. This pathway results in recruitment of inflammatory cells, opsonization, and killing/lysing.
How is the alternative pathway activated?
The pathway is activated by pathogen surfaces and is not antibody dependent
What occurs in the the Lectin pathway of complement activation?
Manin-binding lectin binds mannose residues on the surface of bacteria and fungi. Protein that recognizes mannin also activates complement.
what is the initiating protein of the classical complement pathway?
C1q is the initiating protein. It has a binding site on IgG/IgM. IgG/IgM is bound to the surface of pathogen.
C1q is and oligomer and structurally similar to collectins.
Following binding of C1q to IgG/IgM what happens in the classical complement pathway?
C1q associates with and cleaves C4 and C2 to C3 convertase. C4 cleaved to C4a and C4b, C2 cleaved to C2a and C2b. C4a falls off and C2b falls off giving C4bC2a which is C3 convertase
What does C3 convertase do?
Acts on C3 to give C3a and C3b.
How do the stuctures and functions of C3a and C3b differ?
C3a is a small soluble protein that has a high affinity for specific G-protein coupled receptors. It is a potent chemoattractant causing inflammation.
C3b has a thioester group exposed which covalently associates with lysine residues or other nueclophilic groups on bacteria to serve as an opsonin.
In addition to serving as an opsonin for bacteria what function does C3b have?
It covalently modifies C3 convertase. Converts it to C5 convertase.
C5a is a potent _________. It is created from ________ by the action of _____, which is formed by
_______.
chemoattractant for inflammation
C5
C5 convertase
C3b action on C3 convertase.
How is the alternative pathway of complement activation initiated?
Direct deposition of C3 on pathogen surfaces.
What is the common step in all three complement pathways?
C3 convertase step that produces C3a and C3b
How do you get to the common complement step in the alternative pathway?
Cleavage of C3 by B component of complement which is similar to C3 convertase
What do Lectins bind?
Lectins bind carbohydrates
What is a collectin?
Lectin with collagen-like domains.
What is MBP and how does it relate to the complement cascade?
Mannose Binding Protein. It is very similar to C1q in structure. It binds to mannose on the bacterial cell walls in addition to serine proteases. The proteases cleave C4 and C2 creating C3 convertase. This is done without the use of antibodies.
In addition to the 3 major pathways what are some other ways to activate complement proteins?
CRP (C-reactive protein) is an acute phase protein produced by the liver that binds to bacterial cell wall lipopolysaccharide. C1q can bind to CRP and activate complement.
What are the by products of the cleavages of C2, C4, and C5 that occur in complement activation?
C3a, C4a, and C5a are all byproducts that end up binding to GPCRs on the surfaces of many cells. They cause chemotaxis, leakage, and inflammation. Especially important in allergic reactions.
C5b induces formation of MAC complex
How does the MAC complex form and what does it do?
C5b associates ith the terminal complexes of complement C5-C9. It forms a hole in the membrane of bacetria.
What infections are individuals with defiecency in terminal components of complement prone to?
Gonorrhea and meningitis due to the lake in formation of MAC commplex which lyses bacteria
Why does't complement deposit on our cels like auto-antibodies?
There are a series of proteins, complement regulatory proteins, that humans have that prevent complement self-activation. These proteins can be membrane bound or soluble. DAF (decay accelerating factor) is an example.
DAF
Delayed Accelerating Factor. displaces Bb from C3b which blocks C3convertase in early stages and inactivates complement
What are the complement receptors of interest?
C5aR - causes inflammation and chemotaxis
CR3- leukocyte integrin stimulating phagocytosis, widely expressed
CR1- clearance of immune complexes, found on surface of RBCs
CR2- part of immune regulation. B-cells and FDC, EBV receptor
LAD
leukocyte adhesion disease - a congenital absence of B2 subunit of integrins. If you have LAD you get recurrent bacterial infections, no surface expression of LFA1, CR3, CR4, impaired phagocytosis and diapedesis.
What component of complement is useful in disposal of apoptotic cells?
C1q. A deficiency in C1q causes increased deposition in kidney and possible stimulation of autoantibody production
How does complement help regulate the immune process?
C3d complement deposition on antigen that is bount to BCR. CR2 on the B-cell can bind C3d. ITAM activation leads to activation of PI3K which activates the B-cell.
How are complement defeciencies related to autoimmunity?
Absence of CR2 leads to autoimmunity because amplification afforded by CR2 during tolerance induction (negative selection). Complement deficiency can also lead to impairment of apoptotic clearance causing a potent source of auto-antigen.
Hereditary Angionuerotic Edema
Deficiency in protein C1INH which causes an inhibition of C1q pathway. Generates bradykinin. Patients are predisposed to edema of upper airway and face.
Paroxysomal Nocturnal Hemoglobinuria (PNH)
defect in enzymes that synthesize GPI-linked proteins (DAF and CD59 on RBCs). Lysing of RBCs during night. RBCs and platelets cannot repair damage caused by unregulated complement deposition. Patients suffer hemolysis and thrombosis
Deficiency : C1q, C1r, C1s, C2, C4
Disease: _________________
increased incidence of autoimmune disease
Deficiency : Properdin, Factor D, C6, C7, C8, C9
Disease: _________________
leads to increased incidence of Neisseria infection due to lack of MAC
Deficiency : CR3
Disease: _________________
deficiencies in leukocyte integrins
Deficiency : C1INH
Disease: _________________
Hereditary Angioedema
Deficiency : DAF, CD59
Disease: _________________
PNH (Paroxysomal Nocturnal Hemoglobinuria)
How do you measure complement?
CH50 which is the 50% point when you mix RBC and antibodies vs RBCs and Serum. Make serial dilutions. The more dilutions you have the more complement
If a patient has a low CH50 what might that indicate?
That the person has an autoimmune disease.