Mim: Immunoglobulins

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immunoglobulins

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Ig
(antibodies)
synthesized by B-lymphocytes
primary mediators of humoral immunity
functions to identify and react DIRECTLY with foreign antigens in order to neutralize them
can be found either on surfaces of B-cells as receptors, or secreted by the B-cells in a soluble form into bodily fluids such as saliva and tears

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basic immunoglobulin structure

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2 identical heavy chains and 2 identical light chains held together by disulfide bonds

hinge region in center links the two HC regions and is rich in proline residues
-gives flexibility to the antigen binding arms

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variable and constant regions

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variable regions bind antigen
-is unique and specific for the antigens they rebinding to

constant region is the rest of the immunoglobulin molecule, and is common to all immunoglobulins

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Ig Fragments

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cleavage of an antibody with papain, which occurs in the hinge region, generates two different types of fragments- Fab and Fc

each antibody has two Fab fragments and these fragments are the 2 arms above the hinge region that have the antigen binding properties

the Fc fragment is the heavy chain segments below the hinge region, and is the part of the Ig molecule that binds to the cell surface

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light chains and variability

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two kinds (isotopes) of LC
-kappa and lambda

each antibody has either 2 identical kappa or 2 identical lambda LC
-determined by amino acid sequence of the constant region

kappa isotype is slightly more prominent in humans

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heavy chains and variability

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5 isotypes (classes) of HC based on a.a. sequence of their constant regions

determines Ig's classifications and thus its function

mu -> IgM
gamma (1-4) -> IgG
alpha (1-2) -> IgA
delta -> IgD
epsilon -> IgE

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2 main functions of immunoglobulins

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1. effector functions
-which determine how they interact with other components of the immune system

2. antigen recognition
-determined by the variable regions of the light/heavy chains at the Ig's N-terminus

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IgM

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expressed at cell surface of immature B-cells in bone marrow (first antibody made)

on naive B-cell surface, Ig exists as a mono more, but in solution it is a pentamer (held together by disulfide bonds and a J peptide)
-as a pentamer it can effectively agglutinate and surround the antigen of interest, and with 10 Ag binding sites it is effective at binding antigens with repeating subunits (epitopes)

can activate complement cascade, which leads to destruction of the bound antigen

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___ is a marker of mature B cell

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IgD

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___ is major Ig in primary (initial) immune response

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IgM

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IgG

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most abundant Ig in serum (75%)
major player in secondary immune response
longest serum half-life
4 subclasses: IgG1, IgG2, IgG3, IgG4
crosses placenta to protect fetus
can bind to Fc receptors and trigger opsonization
can activate classical pathways of complement cascade

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opsonization

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IgG (or IgM) can bind to Fc receptors on phagocytic cells (while bound to antigen at its Fab region)

Fc receptors on a phagocyte (such as a macrophage) can recognize the Fc region of the IgG (called the "opsonin")
-this causes the phagocyte to uptake the Ig and any antigen bound to it, so that it may be destroyed

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activating the complement cascade

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requires 2 adjacent Ig to bind C1

IgG and IgM can do this

IgM is better because it is a pentamer

but at sufficient IgG density, IgG (monomer) can activate this too
-IgG3 is the strongest subtype of IgG that can activate this pathway

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which Ig subtype is able to most easily cross the fetal-placental barrier?

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IgG1

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properties of IgG subclasses

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Serum Level: IgG1 is highest --> IgG4 is lowest

Half Life: ~20 days (IgG3 is only 7)

IgG1 and IgG3 are best at activating complement cascade

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IgA

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Two Subclasses: IgA1, IgA2

Primarily monomer in serum
Dimer in secretions

predominant Ig class in external secretions (saliva, tears, breast milk, mucus)

role: block major portal of entry for most pathogenic organisms, protect newborn

has highest rate of synthesis
-due to high turnover rate

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IgE

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least abundant of all Ig's in serum
primary role in allergic response and protection tom parasitic infection

Fc region of IgE can bind to mast cells, neutrophils, and basophils

shortest serum half life
lowest synthesis rate

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IgE and parasite protection

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parasites which are normally too large for phagocytes to handle are dealt with by binding to IgE, which can then bind via its Fc region to receptors on Eosinophils

this causes degranulation of the eosinophils and the release of toxic contents directly onto the par aside

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IgE and allergies

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in the allergic response, multivalent allergens can be cross-linked to IgE's linked to the surfaces of mast cells and basophils (vis Fc-FcR interactions)

this causes the degranulation of these cells, leading to the release of histamine, which binds to its receptors systemically and causes hypersensitivity reactions

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which Ig has longest half life?

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IgG

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which Ig has highest serum level? lowest?

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highest= IgG

lowest= IgE

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most prominent Ig in serum? least?

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most= IgG

least= IgE

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Ig with longest half life? shortest?

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longest= IgG

shortest= IgE

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which Ig can activate complement cascade?

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IgM (strongest bc it exists as pentameter in serum)
IgG

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Ig with highest synthesis rate?

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IgA

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generation of antibody pool

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prior to encounter with any antigen, B-lymphocytes are already secreting Ig's specific to certain antigens, even tho they haven't been exposed to them

antibody pool changes as B-lymphoytes die off and new ones form in their place

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light chain gene organization

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DNA rearranges itself so that one of 40 V segments aligns with one of 5 J-segments (many possible combinations)

this leads to formation of a functional locus

this rearrangement is permanent

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junctional diversity

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contributes to diversity of LC's

mechanism by which the splice site at the V-J junction can be varied

this gives us the characteristic hyper-variable regions within the Ig light chain

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germ line heavy chain gene organization

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multiple gene segments encode the variable region of heavy chains

there are 51 V gene segments, 27 D segments, and 6 J segments

mu is the first gene order in the C segments

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heavy chain gene rearrangement

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first, one of the D segments is randomly spliced next to one of the J segments

then a V segment along with tis corresponding signal segment is spliced to rearrange D-J

C region determines Ig Class

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somatic hypermutation

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occurs in the germinal centers of secondary lymphoid tissue

targets the rearranged gene segments that code for the variable regions in Ig (V/J in light chains, V/D/J in heavy chains)

only occurs in somatic cells (germ line cells remain unaffected)

leads to changes in the binding affinity for antigens

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affinity maturation

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occurs after encounter with an antigen in order to optimize the response to antigen

changes in heavy and light chain of variable region in B-cells to "fine-tune" B-cells to mount the most effective espouse the next time the antigen is encountered

B-cells with the highest bonding affinity are encouraged to proliferate rapidly and dominate the immune response

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Isotype/Class switch

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initially a B cell expresses IgM and can simultaneously express IgD

after encounter with antigen, class switch can occur and the B cell can express either IgG, IgA, or IgE

the antibodies that are produced carry the same antigen binding specificity as the original B Cell

this process only alters the effector functions of the antibody by changing the class of antibody produced