Exam 2: Immunoglobulins Flashcards by Vanessa Weisshaupt

How are immunoglobins (antibodies) made?

By B lymphocytes of the adaptive immune system

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Why are immunoglobins considered the magic bullets for treating human disease?

They recognize and bind to ligands with high affinity + high degree of specificity

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What is the structure of an immunoglobin?

A heterotetramer comprised of 2 identical light chains and 2 identical heavy chains, held together by non-covalent + disulfide bonds

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What are the two regions of an immunoglobulin?

A constant sequence (which differs with every immunoglobulin) and and a variable sequence

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What is the function of variable sequences and where can they be found?

Function: to form antigen-binding sites
Location: amino-terminal

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Why are immunoglobulins considered to be bivalent?

There are 2 antigen-binding sites

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Where are the antigen-binding sites located?

On the tips of the two upper domains of the Y-shaped immunoglobulin

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What is the base of the Y-shaped structure made up of?

Constant regions of heavy chains

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Do immunoglobulins exhibit quaternary structure?

No, quaternary structure is defined as non-covalent assembly of two or more polypeptide chains, and immunoglobulins are covalently bonded via disulfide bonds

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Define epitope

Specific part of an antigen recognized by an immunoglobulin

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Paratope

Specific part of the immunoglobulin that binds epitopes

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How do antigens bind to immunoglobulins?

Via complementary surfaces (lock and key)

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What is a hypervariable region?

A region of extreme amino acid sequence variation in the variable region of the immunoglobulin

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How many hypervariable regions are there in an immunoglobulin?

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What do the hypervariable regions go on to form?

Binding regions for the epitopes

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Hypervariable regions are also commonly referred to as:

Complementary determining regions

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How can immunoglobulins recognize and bind to an array of different molecules?

The sequence variation within the complementary determining region

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What are B lymphocytes?

White blood cells derived from hematopoietic stem cells found in the bone marrow

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Are immunoglobulins the same across all B cells?

No, immunoglobulins expressed for one particular B cell differ from the ones synthesized in other B cells due to the unique amino acids within the variable domain

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What happens when an antigen binds to a B cell receptor?

B cell is activated, stimulating proliferation and differentiation into effector (plasma) cells, which begin producing antiibodies

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Do antigens bind to immunoglobulins via variable or constant region?

Variable. Constant region anchors the immunoglobulin to the plasma membrane

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List the 5 main immunoglobulins:

IgA, IgD, IgE, IgG, IgM

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What is the path immunoglobulins take to reach the cell surface?

Endoplasmic reticulum –> golgi –> cell surface

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How are proteins trafficked through the cell?

They’re packaged in lipid vesicles

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What does a protein need in order to enter secretory pathways?

A signal sequence at its amino terminus

What happens if the protein signal sequence is cleaved?

The protein will be localized to the lumen of the ER and packaged in lipid vesicles for transit through the secretory pathway to the cell surface

What are stop transfer sequences?

Hydrophobic stretches of amino acids that stop polypeptide chains from being translocated across the ER membrane

Which two immunoglobins (located on the cell surface) contain targeting information in addition to the signal sequence?

IgM and IgD

Are heavy/light chains synthesized dependently or independently?

Independently, and each contains a signal peptide directing it to the ER

How are hetero-tetrameric structures formed?

In the ER, light chains assemble with heavy chains

Which two immunoglobulins are found embedded in the plasma membranes of the B cells in which they are made?

IgM and IgD; they fuse with the plasma membrane and remain bound via the stop-transfer sequence which serves as a membrane anchoring domain

Which immunoglobulin is the first class to be expressed on immature B cells in the bone marrow?

IgM

When B cells transit from the bone marrow into the peripheral blood they begin to express which immunoglobulin?

IgD

Which subclass of B cells can also synthesize secreted from of IgM?

B1 lymphocytes

Which lymphocyte can produce natural IgM antibodies?

Are natural IgM antibodies spontaneously produced?

Yes, they do not require prior immunization

When first synthesized where are IgM antibodies directed against?

Self and non-self antigens

What is the structure of a secreted IgM antibody?

Pentameric form with a joining chain

Which domain must be left out of IgM for it to be secreted from cells rather than being localized to the plasma membrane?

Stop-transfer sequence

How many subclasses of IgG are there and what differentiates them?

4; they have slightly different heavy chains

Do IgG immunoglobulins contain stop-transfer sequences?

No, they are secreted immunoglobulins and lack stop-transfer sequences

When are IgG's produced?

Once naive B cells are activated and become effector B cells (plasma cells)

Which is the most common antibody?

IgG

Which is the largest antibody?

IgM

Light and heavy chains are linked together via?

Disulfide bonds

Which digestive enzyme can cleave immunoglobulins into Fc and Fab fragments?

Papain

What is the Fab fragment useful for?

Pathogens are recognized by immunoglobulins through sequences in their variable regions which are Fab fragments (top half of the immunoglobulin in monomer form)

What is the Fc fragment useful for?

Pathogens can be targeted for destruction by macrophages and neutrophils through sequences in the constant region (Fc fragment)

Describe the personality of IgE:

"Eve gives me allergies" IgE is monomer-shaped and binds to Fc (constant region) receptors on mast cells promoting cytokine and histamine release and attracting other immune system components

Describe IgA personality:

"And" IgA is found most abundantly in bodily secretions (saliva, mucous) and are the first line of defense against inhaled/ingested pathogens

Which is the only dimer immunoglobulin?

IgA

Why are IgA unusual?

They are synthesized by mature plasma cells lying beneath epithelial cell surfaces

What happens when IgA cells are released from epithelial cells?

They are proteolytically cleaved of their IgA receptor and a portion of their receptor remains associated with the secreted IgA (secretory component)

IgA are recognized by which basolateral epithelial cells?

pIgR cells

How many structural motifs (Ig domains) do light/heavy chains contain?

Light: 2 Heavy: 4

In what element of secondary structure are the hypervariable regions (hypervariable loops) of immunoglobulins found?

Random structure

Define Ig repertoire:

Different immunoglobulin sequence variants formed by naive B cells

Define secondary Ig repertoire:

When B lymphocytes switch from IgM to IgD to IgG during activation, their affinities for antigens increase through continued amino acid sequence variation in the variable region

Which 3 segments of DNA create light chains?

Variable, joining, constant

Which 3 segments of DNA create heavy chains?

Variable, joining, diversity

How does the recombination of V, J, and D regions happen?

Via an enzyme called V(D)J recombinase

How does V(D)J recombinase work?

Randomly selects a downstream V site and links it to a J site on the light chain. Upstream V regions are excluded by transcription. Downstream J regions are removed by RNA splicing

Define clonal deletion:

A mistake made when V and J segments were joined while making a light chain which prevents a functional protein from being expressed will die in the bone marrow

When is V(D)J recombinase shut off?

When a B cell begins producing a functional immunoglobulin (heavy + light chain combined)

Why is the V(D)J recombinase shut off?

To ensure that only one single immunoglobulin in made by any individual B cell

How are autoimmune diseases caused?

When B cells escape the process of having their V(D)J recombinase shut off

What is a hyper-mutable state?

When B cells are activated by antigen and being making a unique immunoglobulin

Which cells are preferentially activated leading to their survival and enhanced proliferation?

B cell clones

What is the largest change that occurs from class switching?

Exchanging 1 heavy chain (constant region) for another and the subsequent production of secreted immunoglobulins instead or membrane-bound

Which enzyme promotes class switching?

Deaminase which is the same enzyme involved in hypermutation of the variable region

What do deamination events cause?

Double-stranded breaks in switch sequences between heavy chain constant regions

Recombination between which two regions allows class switching?

Cu and other C regions

Is recombination reversible?

No, it's irreversible because the circular DNA released by the recombinase process is degraded

Are high-affinity or low-affinity immunoglobulins the ones commonly used therapeutically?

High affinity