exam 2 - IgG recycling, allergic reactions, autoimmunity

what does FcRn do

extends the circulation of antibodies

what pH do IgG antibodies bind to FcRn at

below 6.5

what are the 6 basic steps in FcRn recycling

1. IgG's enter endosomes through endocytosis

2. endosomes are acidified by ATPase H+ pump

3. FcRn binds to IgGs in endosome

4. FcRn bound IgGs become protected by lysosomal degredation

5. bound IgG's are recycled to the plasma membrane

6. IgGs are released back into the circulation

what does IgG recycling do to their half lives

extends half lives in circulation

how long can IgG therapies be dosed for

q2w or longer

what are the interactions between FcRn and IgGs dependent on

CH2/CH3 amino acids and carbohydrates

what are Fc glycans on IgGs important for

structural integrity and conformation, affinity for Fc receptors

what are the major platforms for IgG therapies

recombinant monoclonal antibodies

where do recombinant monoclonal antibodies have to be produced in

living mammalian cells

what is the problem of creating recombinant monoclonal antibodies

composition of IgG carbohydrates is a function of the host cells lines which can cause differences in products between manufacturers

what enzyme is used in glycostylation

oligosaccharyltransferase

where does enzymatic glycostylation occur

Asn 297 on CH2 domains

what does glycostylation add to the recombinant monoclonal antibodies

complex branched carbohydrates

where does B cell maturation occur

bone marrow

what is genetic recombination

produces pre B cells by mixing or recombination of genes in the bone marrow

where does gene hypermutation occur

lymph nodes

how many chains are antibody gene segments encoded by

7 (4 heavy, 3 light)

what are the names of the heavy chains

VH, CH1, CH2, CH3

what are the names of the light chains

VL, CL kappa, CL lambda

the recombination of ___________ creates diverse light chains

V and J

the recombination of ____________ creates diverse heavy chains

V, D and J

what regions do TCR genes have

V, D and J

what are the chains in TCR genes

alpha and beta chains - 1 of each

what are the three steps of B cell maturation following activation and clonal expansion

somatic hypermutation, affinity maturation, isotope class switch

mutations in _______________ create B cell receptors with _______ receptor affinity

hypervariable; increased

what are hyper variable regions

complementarily-determining regions within the Fab region of HC and LC

what are B cells subject to when it clones itself

somatic hypermutation

what does somatic hypermutation cause

increased mutation rates

if a B cell has a high affinity for pathogens, it will be ____________

activated and cloned, more likely to survive

what does variation account for

hypermutation

what does selection account for

competition for pathogens

what does the HC variable region contain

3 hypervariable complementarity-determining regions CDR1, CDR2 and CDR3

what Is the most variable region

CDR3

how are variable N regions created

deleting a few bases and adding random sequences

what is the difference between an adverse effect and an allergic reaction

adverse effects are predictable and allergic reactions are unpredictable

difference between non-immunological and immunological allergic reactions

non-immunological - unsure why, nonspecific, intolerance

immunological - allergy, hypersensitivity

3 categories of risk factors for an allergic reaction

drug factors, patient factors, disease factors

drug risk factors for an allergic reaction

penicillin, NSAIDs, sulfonamide, ACE inhibitors, biologics

patient risk factors for an allergic reaction

metabolism , MHC alleles

disease risk factors for an allergic reaction

alteration of metabolic pathways, variations in immunologic responses

features of drug hypersensitivity

1. no correlation with known pharmacologic actions of the drug

2. no clear relationship with drug dosage

3. severity is drug and patient specific

4. initial exposure might be asymptomatic, mild or severe

5. past severity does not predict intensity of future reactions

mediator in type 1 hypersensitivity

IgE

antigen in type 1 hypersensitivity

soluble antigen

effectors in type 1 hypersensitivity

mast cells, basophils

mediator in type II hypersensitivity

IgG

antigen in type II hypersensitivity

cell-associated antigen

effectors in type II hypersensitivity

cells that express FCgR, NK, macrophage, neutrophil

mediator in type III hypersensitivity

IgG

antigen in type III hypersensitivity

Ag-IgG complex

effectors in type III hypersensitivity

complement, leukocytes

mediator in type IV hypersensitivity

activated T cells

antigen in type IV hypersensitivity

modified T cell epitopes

effectors in type IV hypersensitivity

T-lymphocytes

what are the macromolecule drug allergens in type I, II and III reactions

monoclonal antibodies and growth factors

what is a hapten

a small molecule that creates an immune reaction when attached to a larger carrier

what is haptenation

drug reacts with a protein to form covalent links

what happens in the sensitization process in the generation of anti-drug antibodies

drug reacts with hapten, B cells and T cells recognize same antigen, epitope on allergen is recognized by surface Ig on B cell, allergen is internalized and degraded by B cell, B cells differentiate, plasma cells release anti-drug antibodies

what happens in the elicitation process in the generation of anti-drug antibodies

there are pre-existing anti-drug antibodies and memory B cells capture drug bound proteins which causes rapid production of anti-drug antibodies

how are IgG and IgE different in binding of drug allergens

they bridge drug allergens with unique Fc receptors on leukocytes

type I hypersensitivity reactions have ______________ hypersensitivity

immediate

what response does type I reactions have

immediate and late phase

what is the severity of type I reactions

varies from mild to full blown systemic reaction

what are type I reactions characterized by

hives

where do mast cells and basophils originate

bone marrow

where are mast cells contained

mucosal tissues and skin

where are basophils contained

blood

what are mast cells and basophils activated by

IgE via FcR

what receptor do mast cells and basophils express in type I reactions

FgE receptor

what do both mast cells and basophils contain

histamine

what happens during dimerization

tyrosine phosphorylation adds P, pro inflammatory mediators are synthesized

what happens during anaphylaxis

histamine is dumped into the body at once

what is involved In the immediate phase of type I reactions

histamine, mast cells, basophils

what is involved in the late phase of type I reaction

leukotriene and cytokine infiltration

clinical presentation of type I reactions

rash, airway, GI, cardiovascular

what happens during type II reactions

cytotoxic binding of drug molecules on circulating blood cell membranes that destroys RBCs and platelets

signs and symptoms of a type II reaction occur ________ after exposure

days

how do type III reactions occur

IgG-drug aggregates form in blood, immune complexes deposit in tissues, immune complexes activate complement protiens

symptoms of type III reactions

chills, fever, rash, arthritis, nephritis

type III reactions happen __________ after exposure

24-72 hours

what is vesculitis and what type of reaction does it occur in

inflammation of vascular endothelium; 24-72 hours after exposure

what are type IV reactions mediated by

CD8 T cells

symptoms of type IV reactions

dermatitis, rash, blisters

what are the contact sensitizing agents in type IV reactions

highly reactive lipophilic molecules

symptoms of SJS and toxic epidermal necrolysis

mucocutaneous eruption, epidermal detachment and skin loss, mucosal erosions and organ damage,

SJS and TEN occurs _________ after drug administration and lasts __________

1-3 weeks; 4-8 weeks

what drugs can cause SJS and TEN

allopurinol, sulfonamides, carbamazepine

what are the two types of tolerance

central and peripheral

what is central T cell tolerance

death of immature T cells that recognize and respond to self antigens

what is peripheral T cell tolerance

mature T cells recognize self antigens in peripheral tissues

what can peripheral T cell tolerance lead to

anergy, deletion and suppression

what is anergy

inactivation that occurs to the loss of the second signal needed for full T-cell activation

what is central B cell tolerance

immature B lymphocytes interact with self antigens in bone marrow

what can central B cell tolerance lead to

receptor editing, deletion

what is peripheral B cell tolerance

mature B cells that either anergy or deletion

what is autoimmunity

loss of self tolerance and the immune responds against self antigens

what are the two factors that play a role in autoimmunity

inheritance of susceptible genes, environmental triggers

what is the most common trigger for autoimmunity

infections

environmental factors that can lead to lupus

UV light, smoking, EBV infection, femaleness

Lupus is associated with positive ________

ANAs

what parts of the body does lupus effect

all parts