Overview of Humoral Response and Antibody Structure and Function

AD

role of B cells in ___ is to produce IgE, suppress skin inflammation by controlling tfh cell maturation via Bregs

Cancer

role of B cells in ____ is secretion of pro tumorigenic factors, t ell suppression via cytokine secretion, generation of circulating immune complexes, production of anti tumor antibodies, antigen presentation

Allergic asthma

role of b ells in ____ is production of IgE and impaired Il10 production by bregs

AR

role of B cells in ___ is production of IgE in nasal mucosa, expansion of IgE repertoire, t cell activation and production of IL6 by CD38+ B cells

Food allergy

role of B cells in ____ is production of __ antigen specific IgE

Transplantation

role of B cells in ___ is induction of treg cells through multiple mediators

Autoimmune diseases

role of B cells in ____ is production of autoantibodies, cytokine production, antigen presentation to autoreactive t cells

Infections

role of b cells in ____ is production of virus neutralizing antibodies

B cell activation

recognition of BCR’s cognate antigen in the BCR results in…

Igalpha and IgB

BCR complex is made of cell surface immunoglobulin and invariant proteins __ and ___ (aka CD79a and CD79b)

CD79a and CD79b

the BCR igalpha and igb are also known as…

IgM

membrane bound, has short cytoplasmic tails that are too small to transduce signals in the BCR (which is why the Iga and Igb have cytoplasmic tails with ITAM motifs)

ITAM

the iga and igb invariant proteins that make up the BCR have ___ motifs that enables them to signal when the B cell receptor binds antigen

Immunoglobulins

undergo VDJ rearrangement (like t cells), giving them the ability to see a nearly infinite number of possible antigens

Light, heavy

igs are made up of 2 identical ___ and ___ chains

2

how many antigen binding sites are on a Ig molecule.

Disulfide bonds

hold separate protein chains of Ig molecules together

Hinge

each heavy chain of an Ig has a ___ region that allows the Ig to be flexible

Heavy

which Ig chain has the hinge region

Complementary determining regions

both the heavy and light chain of igs have 3 hypervariable regions called… that are protruding loops that create an antigen binding surface ; the amino acid composition of each are diversified due to gene rearrangement

3

the CDR is made up of ___ hypervariable regions

Papain and pepsin

the two enzymes that were vital in understanding the ig structure prior to xray crystallography

Papain

cleaves the top of ig hinge regions (above disulfide bond), leaving a portion that was fragment crystallizable (fc) and 2 separated variable fragments with antigen binding (Fab) activity

Pepsin

cleaves the bottom of each ig hinge region (below disulfide bond), leaving the Fc portion and 2 variable fragments with antigen binding activity joined together (called Fab’2)

Clonal expansion

activated b cells undergo rapid proliferation called…

Antibody producing

plasma cells are ____ b cells

Plasma cells

antibody producing b cells aka …

Memory b cells

don’t make antibody, instead are primed to more rapidly respond to cognate antigen in the future.

Increased affinity

____ maturation, somatic mutations in variable region leads to ____ of antigen recognition, no change to effector functions

Effector

change from membrane to secreted antibody form does not change antigen recognition but does change b cell receptor function to ____ function

Isotype switching

each ____ serves a different set of effector functions, but results in no change to antigen recognition

Soluble

antibodies are ____ that are a different version of the same rearranged Ig that composed the BCR (has same variable region, no transmembrane region and may include changes to heavy chain

Short lived plasma cells

plasma cells can be ____ and die off as part of clonal contraction

Long lived plasma cells

plasma cells can be and take up residency in the bone marrow

Memory b cell

previously activated b cells that never became plasma cells, but rather persist for long periods of time, and can reinitiate clonal expansion after a second antigen exposure

Zone of antigen excess

leads to small complexes of antigen, antibody associations

Zone of equivalence

leads to large complexes of antigen antibody associations

Zone of antibody excess

leads to small complexes of antigen, antibody associations

Effector functions of antibodies

neutralize microbes and toxins, opsonize microbes for phagocytosis, sensitize infected cells for antibody dependent cellular cytotoxicity, activate the complement system

Neutralization

antibody _ ; abs prevent binding of microbes to host cells and thereby infection, abs inhibit spread of microbes from infected cell to an adjacent uninfected cell, abs block the binding of toxins to cells and thus inhibit the pathologic effects of the toxins

Antibody mediated opsonization and phagocytosis

abs _ microbes via IgG and leads to the ____ of the microbes and killing via the ingestion of microbes

Antibody dependent cell mediated toxicity

infected cells or tumor cells often express antigens on their surface, Abs specific for these antigens, can coat the surface of infected cells or tumors, abs cells are then marked as targets for adcc

Classical complement pathway

initiated by the binding of C1q to antibody on a pathogen surface

Staple

pentameric IgM molecules bind to antigens on bacterial surface and adopt the ___ form.

Planar

form of IgM molecules before they bind to bacterial surface

IgG or IgM

bind to bacterial surface and then is bound by C1q which activates the classical complement pathway

C1q

binds to either one IgM or 2 IgG molecules on the surface of bacterial surface which activates the classical complement pathway

C3 convertase

binding of C1q to antibody results in the activation of _

Antibody class switching

also known as isotype switching, process that changes portions of constant regions in the Ig heavy chain, maintains the VDJ recombination, occurs after B cell activation, main classes are IgD, IgM, IgG1, IgG2, IgG3, IgA, IgE

IgM

effector function of antibody isotypes is complement activation

IgG subclasses IgG1 and IgG3

effector function of antibody isotypes is opsonization and phagocytosis, complement activation, neonatal immunity (placental transfer)

IgE, IgG4

effector function of antibody isotypes is immunity against helminths and mast cell degranulation (immediate hypersensitivity)

IgA

effector function of antibody isotypes is mucosal immunity (transport of IgA through epithelia)

Pentamer

IgM multimerization state

Dimer

IgA multimerization state

Monomer

IgG, IgE, IgD multimerization state

IgM

secreted ___ is found primarily in the blood and some inflamed tissue, secreted in pentameric form (bound by disulfide bond), excels in agglutination and fixing C1q (activation of complement pathway)

IgG isotypes

found throughout the body and have wide spread distribution compared to other isotypes, very stable (long half-life), can engage in several different effector pathways, have different hinge regions and different affinities for different Fc receptors

IgA

is the major class of Ab that mediates protection at mucosal surfaces, found in monomeric form in blood BUT dimeric form in mucosal secretions, main effector function is neutralization

IgE

unique Ab isotype because it will bind Fc (FCeR) before binding antigen, defend against multicellular parasites, found in skin and connective tissue

Mast cells, eosinophils and basophils

FCeR is expressed mainly by…

Fc receptors

are cell surface glycoproteins with affinity for the Fc portion of an antibody, can elicit activating or inhibitory signaling in the fc expressing cell depending on ITAM or ITIM presence given the specific type of Fc receptor

Blood

IgM is found mainly in ___

IgG

found in blood, tissues, extracellular fluid and is the only isotype that can cross the placenta and interact with neonatal Fc receptor

IgA

found in mucosal tissues, lumen of gut, in secretions (saliva, tears, breast milk)

IgE

found associated with mast cells just beneath epithelial surfaces (respiratory tract, GI tract, skin)

Rituximan

other B cell depleting Abs are approved for Lupus, MS, RA etc treatment