Meng Test 2 + Dolecki (tolerance/RA)

___ (Neonatal Fc Receptor) plays a crucial role in the recycling and circulation of antibodies in the bloodstream.

FcRn

FCRN is a receptor that ___ to IgG antibodies, protecting them from degradation and facilitating their recycling back into the bloodstream.

binds

FcRn binds to IgG antibodies at __ pH of less than 6.5, and then releases the antibodies at __ pH

low, neutral

FcRn recycling step 1:

IgGs enter into ____ via fluid phase endocytosis

endosomes

FcRn recycling step 2:

endosomes are ____ by ATPase H+ pump

acidified

FcRn recycling step 3:

the acidified environment of the endosome will induce ___ to bind to the IgGs

FcRn

FcRn recycling step 4:

FcRn bound IgGs are protected from __ __

lysosomal degradation

FcRn recycling step 5+6:

bound IgGs are recycled back to __ __ and released back to __

plasma membrane, circulation

the IgG recycling mediated by FcRn creates a ___ of IgG in blood endothelium, thereby extending their __-__ in circulation

reservoir, half-lives

the IgG recycling is why IgG based therapies can be dosed every __ weeks or longer

2

the FcRn will bind to the Fc domains at pH 5-6.5 and the interactions depend on the CH2/CH3 __ __ and __

amino acids, carbohydrates

Fc ___ are carbohydrate chains attached to the Fc region of antibodies (specifically to the CH2 domain of IgG)

glycans

Fc glycans are important for ___ integrity and conformation of antibody

structural

Fc glycans are important for the antibodies ___ for Fc receptors

affinity

___ is addition of sugar molecules

glycosylation

glycosylation of IgG plays a role in monoclonal antibody (___) therapeutics

mAb

recombinant mAbs are artificially produced ____ that are major therapeutic platforms

antibodies

the production of mAbs occurs in ___ cells (hosts) and is process dependent

living

mAbs are secreted by ___ cells (coming from humans, mice, etc)

mammalian

the composition of the IgG carbohydrates (the glycosylation pattern) depends on the type of __ ___

host cell

what enzyme is responsible for glycosylation of IgG?

answer: oligosaccharyltransferase (_____)

OST

the glycosylation of IgG occurs specifically at the _____ 297 residue within the ___ domain of the antibody

Asn, Ch2

the type of sugar attached to IgG on Asn 297 within the CH2 domain is called a ___-___

N-glycan

the Biologics price competition and innovation act (BPCIA) is a part of the affordable care act and created a regulatory pathway for ___ in US

biosimilars

API in biosimilars has degree of uncertainty due to ___ differences in manufacturers

glycosylation

where do B cells develop?

red bone marrow

genetic ___ occurs for B cells in the red bone marrow

recombination

B cells after developed are transferred where?

lymph node

in lymph node, genetic ___ happens to B cells (tiny changes (mutations) occur in genes that code for antibodies after the B cells encounter an antigen--These mutations make the antibodies better at recognizing and binding to the antigen)

hypermutation

inside the bone marrow- antibodies are encoded by different germ-line genetic loci. this diversity is born out of just __ different building blocks/chains

7

in IgG the building blocks for heavy chain are __, __, __, __

VH, CH1, CH2, CH3

in IgG the building blocks for light chain are

-______

-CL (____)

-CL (___)

VL, kappa, lambda

each chain is made up of different segments, which recombine to produce enormous amount of different ____ of possible antibodies

configurations

the light chain (LC) of an antibody undergoes V (___) and J(____) segment recombination

variable, joining

the light chain (LC) of an antibody undergoes V (___), J(____), and D(_____) segment recombination

variable, joining, diversity

since antibodies have both a heavy chain and a light chain, ____ of these chains makes even more diversity

recombination

TCRs (T cell receptors) also undergo gene __ to recognize a wide variety of antigens presented by MHC molecules

recombination

TCRs are composed of diverse __ and __ chains

alpha, beta

inside the lymph nodes, B cells undergo a maturation process composed of what 3 steps?

somatic hypermutation, affinity maturation, isotope class switch

there is a ___ region in the ___ of the heavy chain and light chain of the B cell receptors that form the part of the antibody that directly binds to the antigen.

hypervariable, FaB

hypervariable regions--also known as complementarity-determining regions, or __

CDRs

mutations in the hyper variable regions create BCRs with increased ___ for antigen

affinity

during antigen-driven B cell expansion, these BCRs with mutated hyper variable regions are preferentially ____ to produce higher affinity antibodies

stimulated

B cells learn to improve the __ of antibodies produced during course of the infection

quality

the selected B cell to fight an infection will clone itself, but these clones are not perfect and are subject to high mutation rates, called ___ __

somatic hypermutation

the new B cells that arise from somatic hypermutation also have the opportunity to bind to pathogens, and if they have a high __ for the pathogen, they will in turn be activated and cloned

affinity

affinity maturation: the higher the affinity of a B cell for pathogens present, the more likely it is that B cell will __

survive

the variation in BCRs is provided by __ ___ and the selection is provided by ___ for pathogens

somatic hypermutation, competition

the hc (heavy chain) variable region of the antibody has additional diversity in 3 CDRs (hyper variable regions), which are __, __, and __

CDR1, CDR2, CDR3

these CDRs within the heavy chain (CDR1, CDR2, CDR3) form the ___ ___ that the antigen recognizes

binding pocket

what is the most variable region on the heavy chain?

CDR3

on either side of the __ (diversity) gene segment of the CDR3 is the __ regions (short random nucleotide additions)

D, N

The N-regions are generated by __ a few bases and adding random sequences--this is why the CDR3 is hyper-variable

deleting

somatic hypermutaion and affinity maturation are why ___ vaccinations are so helpful (bc each booster will lead to antibodies with even higher affinity)

booster

a predictable drug reaction is related to the __ actions of the drug

pharmacologic

an unpredictable reaction is either non-immunological ("intolerance") or immunological (includes hypersensitivity and ___)

allergy

risk factors for allergies:

the chemical or drug classes of penicillin, NSAIDs, sulfonamide, ACE inhibitors account for most drug ____ reactions

allergic

risk factors for allergies:

patients may have __ predisposition

genetic

genetic predisposition of patient for allergies may be from metabolism factors or ___ alleles that present drug allergen epitopes to t cells

MHC

risk factors for allergies:

___ that alter metabolic pathways or vary immunologic responses

diseases

drug ___: disease following a response by the immune system to an otherwise innocuous antigen

hypersensitivity

does drug hypersensitivity have a correlation with known pharmacological actions of the drug?

no

does drug hypersensitivity have a clear relationship with drug dosage?

no

drug hypersensitivity severity is drug and patient ___, and past severity does ___ necessarily predict intensity of future reactions

specific, not

4 types of hypersensitivity reactions

Type I, Type II, Type III, Type IV

Type 1 hypersensitivity reaction is mediated by ___

IgE

Type 1 hypersensitivity reaction is mediated by IgE and involves a __ antigen

soluble

Type 1 hypersensivity reaction effectors includes __ __ and __

mast cells, basophils

Type 2 hypersensitivity reaction is mediated by ___

Igg

Type 2 hypersensitivity reaction is mediated by IgG and involves a __-associated antigen

cell

type 2 hypersensitivity reaction effectors include __ and __

complement, leukocytes

type 3 hypersensitivity reactions are mediated by __

IgG

Type 3 hypersensitivity reactions is mediated by IgG and involves an antigen-__ __

IgG complex

type 3 hypersensitivity reaction effectors include __ and __

complement, leukocytes

type 4 hypersensitivity reactions are mediated by __ __ __

activated T cells

type 4 hypersensitivity reactions involves the antigen of modified _ __ __

T cell epitopes

type 4 hypersensitivity reactions effector is __ __

t lymphocytes

Type 1, 2, and 3 hypersensitivity rxns are all mediated by __.

antibodies

Type 1, 2, and 3 hypersensitivity rxns can be triggered by macromolecule drug allergens, such as ____ proteins (e.g., monoclonal antibodies, growth factors)

recombinant

___ proteins (clumping together of protein molecules) will further increase risk for type 1, 2, 3 hypersensitivity rxn

aggregated

___: a small molecule that elicits an immune response only when attached to a larger carrier

hapten

The hapten reacts with a protein, forming a ___ bond between the two. This process is called haptenation.

covalent

Once this covalent bond is formed in haptenation, the protein now contains multiple drug molecules attached to it, and is therefore a ___ antigen

multivalent

___ ____ of antibodies after haptenation will result in immune activation

cross linking

____: first exposure to allergen or drug.

___: re-exposure to allergen or drug

sensitization, elicitation

sensitization (first exposure)

1) small molecule drugs will react with ___ to form antigen

proteins

sensitization (first exposure)

2) B cells and helper T cells must recognize the __ antigen in this stage for the reaction occur

same

sensitization (first exposure)

3) B cells will recognize the epitope/antigen with their surface ____ receptors

4) After this recognition, the B cell will internalize and ___ the allergen

Ig, degrade

sensitization (first exposure)

5) After B cell degrades antigen, it will be presented on a MHC __ molecule to a __ T cell (ie helper T cell)

2, CD4

sensitization (first exposure)

6) the CD4 helper T cells will help B cells differentiate into __ cells, which release anti-drug ___

plasma, antibodies

elicitation (re-exposure)

1) the anti-drug antibodies already exist in body from first exposure

2) ____ B cells will capture the drug-bound proteins and immediately produce even ___ anti-drug antibodies

memory, more

elicitation (re-exposure)

3) the severity of response depends on antibody (Ab) __ and ____ B cell pool

(ie need high antibody levels and many memory B cells to elicit a strong immune response)

titer, memory

for type 1, 2, and 3 rxns, IgE and IgG bridge drug allergens with unique __ receptors on leukocytes

Fc

both IgE and IgG antibodies are ___ to the antigen/allergen that triggered them

specific

IgE and IgG antibodies are produced by activated __ cells with help by __ T cells

B, cd4

__ ___ will determine the duration of the allergic reactions mediated by IgG and IgE

half lives

both IgG and IgE will bind to the drug-protein complex through their bivalent variable regions called ___

Fab

IgG and IgE will bind to ___ __ or unique __ receptors on cells

complement proteins, Fc

Type I hypersensitivity is known as ____ hypersensitivity bc of its fast response

immediate

type 1 hypersensitivity is mediated by IgE and includes both an __ response and a __-__ response

immediate, late-phase