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How a B cell switch from expressing BCR to Ig?
RNA splicing out transmembrane region
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Electrophoretic mobility of serum proteins can be a tool for diagnosing ___
- Myeloma serum vs normal serum
- homogeneous population of IgG molecules (narrow band) indicated myeloma
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light chain dimers in the urine of some patients with myeloma
escapes filtration b/c light molecular weight
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Antigens recognized by BCR
- proteins
- peptides
- lipids
- carbohydrates
- nucleic acids
- small molecules (metallic)
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What is at the N terminus and C terminus of an IgG?
- N terminus= variable region
- C terminus= constant region
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Where does papain and pepsin cleave in IgG?
- Papain cleaves to the N terminal of disulfide bonds, leaving 2 identical Fab and 1 Fc fragments
- Pepsin cleaves to the C terminal of disulfide bonds in the hinge, generating 1 F(ab')2 fragment and heavy chain that gets degraded to small peptides
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Function of Fab and F(ab')2 region
antigen binding
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function of Fc region
- complement fixation
- Antibody Dependent Cell-mediated Cytotoxicity (ADCC)
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ADCC
- Antibody Dependent Cell-mediated Cytotoxicity
- NK or macrophages targeted to IgG coated cells result in lysis of target
- mediated by CD16 receptor binding the Fc region of IgG
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What experiment established the existence of 2 H and 2 L chains in Ig?
reducing agent studies
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IgG is (divalent/monovalent)?
divalent
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Where are the variable and constant domains on an Ig?
can be found in both the H and the L chains
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Which domains are responsible for complement and mediating ADCC on an Ig?
CH2 and CH3 domains on the C terminus Heavy Chain
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Which chain is glycosylated/nonglycosylated: H-chain, L-chain?
- H chain is glycosylated (on CH2 domain)
- L chain is nonglycosylated
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What aa residues make up the hinge?
Proline, cysteine
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Characteristics of the IgG domain
loops of ~110 aa which show homology and have an intra-chain disulfide bond
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4 regions of interaction betweeh H-L and H-H
- VH-VL
- CH1-CL @ hinge
- CH2-CH2 of HC
- CH3-CH3 of HC
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CDR
- complementarity determining regions
- aka hypervariable portions of the variable regions in HC Ig
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2 parts of the V-region
- framework region- less variable
- hypervariable region/ CDR- most variable region
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5 Ig isotypes (secreted structure, serum structure)
- IgM in serum= (μ2L2)5J
- IgG in secretion= γ2L2
- IgA in secretions (α2L2)2JS
- IgD
- IgE
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Which 2 Ig don't have a hinge and have an extra C-terminal HC domain?
IgM and IgE
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Distribution of Ig in the body
- Blood: IgG (major), IgM
- Tissue fluids: IgG (major), IgM and IgA monomer (trace)
- Secretions: IgA dimers (major) some IgG
- Fetus: passive IgG1, 3, and 4 from mom
- Beneath epithelium: IgE on mast cells
- Brain: none b/c of BBB
- Respiratory mucosa: IgD
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Half-life of IgG
23d except IgG3 which is 7d
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Which class of IgG is responsible for complement inding? placental passage, and monocyte binding?
- complement binding: IgG3>>IgG1, IgG2 >>IgG4
- placental passage: all except IgG2
- monocyte binding: IgG1, IgG3 > IgG2 > IgG4
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During what phase of an immune response are IgGs secreted?
late primary or early secondary response
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IgG characteristics
- Protects fetus (IgG1, 3, 4)
- activates complement
- acts as an opsinizing antibody
- mediate ADCC
- neutralize toxins and viruses
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IgM characteristics
- B cell surface: μ2λ2 or μ2κ2, no hinge
- secreted: largest molecular wt Ig with 5 functional binding sites
- first Ig to appear during ontogeny and during immune response
- most effective complement activator and agglutinating antibody
- anti-AB blood type
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IgD characteristics
- B cell surface
- sensitive to proteolysis
- triggers IL1, TNF release in mast cells and basophils in respiratory mucosa
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IgE characteristics
- reaginic antibody (related to allergy)
- lowest serum concentration and shortest 1/2 life
- extra H domain which bins to mast cells and basophils
- also binds to eosinophils (protect against parasites)
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IgA characteristics
- monomer in serum/cell surface; dimer in secretion
- short half life
- major Ig in the body and in external secretions
- protects all mucosal surfaces
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Structure of secretory IgA
- 2 tail-to-tail molecules linked by J chain at the C terminus
- mucophillic secretory component
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function of secretory component of IgA
- protect IgA from proteolysis
- facilitate attachment to epithelia so antigens can be trapped in mucus and lysozyme can degrade the IgA-Ag complex
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disease related to IgA deficiency
- congenital immunodeficiency
- causes local infections (not systemic)
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Synthesis of secretory IgA
- J chain is added to the IgA dimer in the plasma cell in lamina propria or Peyer's patch and secreted
- GI epithelial cells express poly-Ig receptors that bind to Fc portion of IgA dimer
- pinocytosis and exocytosis transports the IgA dimer to lumen surface
- a piece of the poly-Ig receptor is destroyed so IgA is secreted
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Defense of mucosal surfaces
- 1' encounter with pathogen will cause an infection
- 2' response:
- IgA secreted into lumen binds pathogen to hinder its entrance
- IgE bound to mast cells defend against pathogens that enter mucosa
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How is IgG levels regulated?
- FcRn present in endothelium and hematopoietic cells
- IgG enters cells via pinocytosis, binds to FcRn in acidic pH=6 allows recycling to ECM.
- excess unbound Ab is degraded by lysosomes
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How is IgM levels regulated?
large amounts are synthesized during 1' response but rapidly cleared and degraded
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How is IgA level regulated?
- Secretory IgA remains in gut for a long time
- Secretory component (SC) protects against proteolysis
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How is IgE level regulated?
- IgE binds to FcRs on mast cells and remain there for a long time
- serum concentration is low
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How is IgD level regulated?
- Binds to receptors of mast cells and basophils
- serum concentration is very low
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3 determinants of Ig
- Isotypic: 5 different constant regions of HC determines class, LC also has 2 isotypes
- Allotypic: aa differences in constant region of HC or LC; intraspecies differences
- Idiotypic (Ids): present in the variable regions of HC or LC; anti-Id antibody serves as clonal marker for an Ig or the B cell that makes it
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Genetic mutations and diseases of Ig
- Hyper IgM (CD40, CD40L, AID): recurrent infections b/c failure to class switch
- Hyper IgE (STAT3, Tyk2): allergic type syndromes
- Hyper-IgD (Mevalonate kinase, pyrin, TNFR): periodic fevers
- Hypogammaglobulinemia (transient in infancy or btk mut): recurrent infections
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3 major type sof TCR and what they recognize
- αβ TCR: recognizes peptide/HLA
- γδ TCR: recognizes peptide/HLA
- NK TCR: recognizes glycolipid/CD1d
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how are the 2 chains of a TCR joined?
a single disulfide bond near te plasma membrane
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distribution of TCR types throughout body
- αβ TCR: throughout the body
- γδ TCR: skin, mucosa, gut
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TCR complex components
- responsible for signaling once TCR has bound to antigen
- CD3γε (part of immunoglobulin supergene family)
- CD3δε (part of immunoglobulin supergene family)
- ζζ
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constant portion of TCR
- CD3
- contains cytosol region that mediates signal transduction
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SCID symptoms and genetic mutaiton
- recurrent bacterial and viral infections
- ZAP70, CD3 (δ, ε, ζ), Rag
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DiGeorge syndrome genetic mutations
- recurrent bacterial and viral infections
- 22q11, 10p
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