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Immunoglobulins (antibodies) Flashcards

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1
Q

What are the three major theories of antibody specificity?

A

The selective (side chain) theory, the instructional theory, and the two gene theory.

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2
Q

What is the selective (side chain) theory of antibody specificity?

A

Proposed by Paul Ehrlich, this theory claimed that antibody-producing cells expressed multiple “side chains” of various antigen specificities. Engagement of one of these “side chains” with antigen results in the production and secretion of more side chains with identical antigen specificity.

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3
Q

What was one fundamental flaw of the side chain theory proposed by Paul Ehrlich?

A

There are over 10^8 immunoglobulin specificities, to encode that many side chains, the immunoglobulin locus would need to be 35x bigger than the entire human genome.

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4
Q

What was the instructional theory of antibody specificity?

A

Antigens themselves had a role in generating immunoglobulin specificity. The antigen would serve as a template around which the immunoglobulin molecules was folded and mutated, taking a shape complementary to that of the antigen. This would require fewer genes, as a single molecule could assume many specificities.

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5
Q

What was one fundamental flaw of the instructional theory proposed in the 1930s/40s?

A

Antibodies have specificity prior to antigen exposure. Only a small number of B-cells in the body can recognize any given antigen.

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6
Q

What is the two gene theory of antibody specificity?

A

Two genes encode the immunoglobulin molecule, one for the variable region and one for the constant region. Many copies of the variable gene (accounts for diversity), but only a few constant genes (one for each isotype). The few constant genes could be combined with any variable genes to generate diversity.

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7
Q

How was the two gene theory of antibody specificity confirmed?

A

Analysis of Igk genes from myeloma (cancer of B cells) and embryonic cells revealed that the DNA of myeloma cells was rearranged as compared to the germline DNA of the embryonic cells.

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8
Q

What modifications to the two gene theory were made upon observation of the variable and constant regions?

A

The gene coding the variable region was made up of multiple gene segments.

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9
Q

How many and what gene segments code for the variable region of the light chain?

A

2, the variable and joining gene segments.

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10
Q

How many and what gene segments code for the variable region of the heavy chain?

A

3, the variable, joining, and diversity gene segments.

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11
Q

What are the hypervariable loops of immunoglobulins?

A

Regions of the immunoglobulins in direct contact with antigens that are frequently mutated to generate genetic diversity.

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12
Q

What are the two main methods by which antibodies generate diversity?

A

Combinatorial mechanisms that randomly select variable, diversity, and joining gene segments. Junctional diversity.

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13
Q

What is junctional diversity?

A

Variation in the V(D)J joints.

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14
Q

What are the three principle mechanisms that generate junctional diversity?

A

Junctional flexibility, p-nucleotide addition, and n-nucleotide addition.

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15
Q

What is junctional flexibility?

A

The imprecise joining of the V(D)J gene segments. Through endonuclease activity, several nucleotides may be deleted from the cut ends of the gene segments being joined, resulting in shortened V, D, or J regions.

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16
Q

What are nonproductive coding joints?

A

Joints that do not function as a result of frameshift mutations interfering with the reading frame.

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17
Q

What is p-nucleotide addition?

A

Due to imprecise cutting of the hairpin loops formed at the end of cut gene segments, resolution of the hairpin will result in relocation of nucleotides from one strand to the other in a reverse sequence if cleavage does not occur exactly where the segment was originally cut. This results in palindromic sequences (hence p-nucleotide addition) once complementary nucleotides are filled in.

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18
Q

What is terminal deoxynucleotidyl transferase (TdT)?

A

TdT is an enzyme that randomly adds nucleotides to single stranded ends of DNA.

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19
Q

What is n-nucleotide addition?

A

A process where up to 15 non-templated nucleotides are randomly added to the end of gene segments.

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20
Q

Is n-nucleotide addition more common in H chain rearrangement or L chain rearrangement?

A

H chain rearrangement, a feature of VDJ joints.

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21
Q

What initiates rearrangement of immunoglobulin gene segments?

A

RAG complex - Recombination activating gene 1 and 2 (RAG-1 and RAG-2)

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22
Q

How does the RAG complex initiate immunoglobulin rearrangement?

A

After recognizing the boarders of gene segments, the RAG complex facilitates cleavage of DNA.

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23
Q

Other than the RAG complex, what DNA break and repair enzymes are required for immunoglobulin rearrangement?

A

DNA ligase IV, DNA-dependent protein kinase (DNA-PK)

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24
Q

With respect to the heavy chain, is one B-cell restricted to producing one immunoglobulin isotype?

A

No, since alternative RNA splicing of the constant gene occurs at the RNA level, multiple immunoglobulin isotypes can be synthesized by one B-cell.

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25
Do the H or L chain genes rearrange first?
The H chain genes rearrange first.
26
What is a pre-B-cell receptor?
Following H chain gene rearrangement, on the B-cell surface, products are paired with a surrogate light chain. This is a pre-B-cell receptor.
27
What is Vpre-B and lambda5?
Vpre-B mimics the variable domain of the light chain and lambda5 mimics the constant domain.
28
Which two genes compose the surrogate light chain?
Vpre-B and lambda5.
29
What causes L chain genes to rearrange?
Successful rearrangement of the H chain genes.
30
How does RAG know where to cut DNA?
Gene segments are flanked by short, conserved sequences, known as recombination signal sequences.
31
What are recombination signal sequences composed of?
A conserved heptamer (7bp), a 12 or 23 bp non-conserved spacer sequence, followed by a conserved nonamer (9bp).
32
Between what recombination signal sequences does rearrangement occur?
Always between a RSS with a 12bp spacer and another with a 23bp spacer (12/23 rule).
33
What is the functional ability of the 12/23 rule?
Rearrangement always involves V(D)J gene segments.
34
What is allelic exclusion?
Successful rearrangement of one allele for each chain inhibits rearrangement of the other alleles.
35
The production of what most likely signals the stoppage of H chain rearrangement?
A Pre-B cell receptor.
36
The production of what most likely signals the stoppage of L chain rearrangement?
A B-cell receptor.
37
What is class switch recombination?
Mature B cells that possess B-cell receptors can change the isotype of the receptors through DNA splicing changes known as class switching.
38
Is class switch recombination permanent? Why or why not?
Yes, since it occurs at the DNA level, and DNA that is spliced out will be permanently lost.
39
Can class switch recombination only happen once per B-cell receptor?
No, it can happen multiple times.
40
What enzyme is required for class switching?
Activation-indeced cytidine deaminase (AID).
41
What does AID do?
It induces single-strand breaks or "nicks" in the DNA, allowing for DNA repair mechanisms to recognize and excise intervening DNA between the breaks.
42
What syndrome does a deficiency in AID result in?
Hyper-IgM syndrome
43
How many variable regions are on each heavy or light chain?
One.
44
How many constant regions are on each heavy or light chain?
One.
45
What is the role of the variable regions of antibodies?
They are antigen-specific and mediate antigen binding.
46
What is the role of the constant regions of antibodies?
They activate effector functions, which are conserved between all immunoglobulins of a given isotype.
47
How many polypeptide chains make up an antibody?
Four, two heavy chains and two light chains.
48
What type of bonding holds together the four chains that make up an antibody?
Disulfide linkages, which are single covalent bonds between two sulfur atoms.
49
How large is the average immunoglobulin in kDa?
150 kDa.
50
How large is the average light and heavy immunoglobulin chain in kDa?
25kDa and 50kDa respectively.
51
How does papain digest antibodies?
It cuts them at the hinge region, resulting in three fragments
52
What are the three fragments that result from papain digestion?
The two arms break off into fragments of antigen binding (Fab) and the trunk is known as the fragment of crystallization (Fc). This is because papain cuts the antibody on the N-terminal side of the disulfide linkages.
53
Why or why not are antibodies digested with papain able to precipitate antigens?
Since the Fragments of antigen binding only have one arm, formation of a lattice structure cannot occur, so no antigens will be precipitated.
54
What are the two fragments that result from pepsin digestion?
Pepsin cuts the antibody on the C-terminal side of the disulfide linkages, forming a F(ab')2 where the two arms remain attached as well as a pFc' fragment.
55
What domains are sites of amino acid variability?
The variable domains.
56
What are the three regions of variability in each of the V domains known as?
The three hypervariable loops
57
How do the hypervariable loops bind antigens?
Based upon complementarity.
58
What is another name for the hypervariable loops?
The complementarity determining region (CDR).
59
What is the name for the remaining regions of the V domain that are structurally conserved?
The framework regions.
60
What is the roll of the constant light and the constant heavy 1 regions?
They add flexibility to antigen binding and stabilize the H-L chain interactions that occur through the disulfide linkages.
61
What is the roll of the hinge region?
It adds flexibility to the Ig molecule and also stabilizes the H-H chain interactions through the disulfide linkages.
62
What is the roll of constant heavy region 2,3 and 4?
It is hydrophillic, allowing for complement interactions, and it may contain a transmembrane domain at the C-terminus end, acting as a surface receptor for B-cells.
63
What is an idiotype?
An antigenic determinant contained in the V region of immunoglobulins. Immunoglobulins against different antigens will have different idiotypes.
64
What is an allotype?
A subtle amino acid difference within the same C region between individuals of the same species.
65
What is an isotype?
A collection of C region antigenic determinants.
66
How many isotypes of the constant heavy chain are there?
5, IgA, IgD, IgE, IgG, IgM.
67
How many isotypes of the constant light chain are there?
Two, kappa and lambda.
68
What are the defining characteristics of IgG?
It is the most abundant Ig in serum, lymph, CSF, and peritoneal fluid. It can activate complement and functions as an opsonin by binding to Fc receptors.
69
How do the different subclasses of IgG differ in effector abilities?
They differ in their ability to activate complement. IgG3 is stronger than IgG1, which is stronger than IgG2, which is stronger than IgG4
70
What are the defining characteristics of IgM?
It is always the first Ig produced, and it accounts for 5-10% of serum immunoglobulin. The heavy chains contain four constant domains, and there is no hinge region.
71
Is IgM monomeric as a free antibody?
No, it is pentameric.
72
Is IgM monomeric as a B-cell receptor?
Yes.
73
Why is IgM good at activating complement?
Its polyvalent binding efficiently agglutinates antigens, thereby activating complement due to its high avidity.
74
What is the functional role of the J chain in IgM?
It facilitates polymerization and transport across the epithelium
75
What are the defining characteristics of IgD?
It is a very small component of serum (0.2%) that has a long hinge region that is sensitive to proteolytic cleavage. They key to IgD is that its function in the serum is unknown.
76
What is one potential function of IgD?
Since it is present with IgM on the surface of mature B-cells, it may play a function in B-cell activation.
77
What are the defining characteristics of IgA?
It is the most frequent antibody produced, predominant in secretions such as milk, saliva, tears, respiratory mucus, and GI mucus. It is only a minor component of serum (5-10%), and it exists in a monomeric and dimeric form.
78
Is serum IgA found in a monomeric or dimeric form?
A monomeric form.
79
Is secreted IgA found in a monomeric or dimeric form?
A dimeric form with a J chain that allows for polymerization.
80
How many subclasses of IgA are there and how are they chemically different?
There are two subclasses, IgA1 and IgA2. Differing by 30 amino acids, IgA1 is primarily found in serum while IgA2 is primarily found in secretions.
81
Does IgA1 have a shorter or longer hinge than IgA2?
It has a longer hinge.
82
What is one potential reason why IgA2 is more commonly found in secretions?
Given it shorter hinge, IgA2 is more protected from proteolytic cleavage during digestion, so it is able to better survive in secretions containing bacteria (such as the GI and respiratory tracts).
83
What are the chemically defining characteristics of IgE?
It contributes the least to serum Ig (1/10 IgD levels). It does not contain a hinge region, and the heavy chains are composed of four constant domains.
84
What are the defining properties of IgE?
IgE binds Fc receptors on basophils and mast cells. Crosslinking the Fc bound IgE results in degranulation, causing immediate hypersensitivity reactions (such as asthma, hives, anaphylaxis).
85
What is desensitization as an allergy treatment?
By exposing patients to small doses of an allergen, patients may become desensitized, allowing slow increases in subsequent dose exposure.
86
What are the two potential mechanisms by which desensitization acts?
1) Immune tolerance - cells that produce the recognized allergen are silenced 2) the body stops making IgE and starts making IgG.
87
What is immunotherapy?
An allergy treatment where IgE antibodies are neutralized by anti-IgE antibodies, silencing the immune response.
88
Can a surface Ig (sIg) mediate intracellular signals alone?
No, sIgs have short cytoplasmic domains.
89
How are intracellular signals within B-cells mediated by immunoglobulins?
sIg associates with the Ig superfamily members Ig alpha and Ig beta. Ig alpha and Ig beta generate intracellular signals through Immunoreceptor Tyrosine-based Activation Motifs (ITAMs).
90
How does IgM and IgG activate complement?
Complement component C1q must bind to at least 2 Fc regions, this could either be through 1 IgM (since it has 5 Fc regions), or 2 IgGs that are close together. Binding of C1q induces a conformational change, activating serine protease, initiating the classical complement pathway.
91
Which immunoglobulins are able to neutralize bacteria, viral particles, and toxins, and how are the able to do so?
Due to their high affinity, IgG and IgA are able to bind to these pathogens, preventing their binding to target cells. Thus, they cannot infect host tissues. For toxins specifically most must bind cellular receptors to mediate an effect (toxin internalization), which is prevented by IgG and IgA.
92
What are the possible impacts of immunoglobulin Fc binding to cell surface receptors?
Cellular activation or inhibition, phagocytosis, induction of target killing, and granule release.
93
With which constant domain do immunoglobulins bind to cell surface receptors?
The second domain of the heavy chain.
94
What part of Fc receptors is immunoglobulin bound to?
The alpha chain of the Fc receptor (FcR)
95
How does the FcR mediate signalling?
Through its gamma chain.
96
How do the Fc receptors on macrophages activate or inhibit them?
Immunoglobulin bound to bacteria can crosslink Fc receptors on the surface of macrophages. This results in the generation of an intracellular signal which can either be stimulatory or inhibitory depending on the Fc receptor bound.
97
How does binding to Fc receptors result in phagocytosis?
Binding of Ig-covered bacterium to FcR on a macrophage can lead to phagocytosis. Here the immunoglobulins act as opsonins.
98
What is antibody-dependent cell-mediated cytotoxicity?
Pathogens coated with soluble antibodies can bind to natural killer cells via Fc(gamma)RIII can result in crosslinking of FcR, inducing targeted granule release and ultimately death of the target pathogen.
99
What is granulocyte degranluation?
Mast cells, basophils, and activated eosinophils express a high affinity IgE receptor (Fc(epsilon)RI), with which IgE stably associates in the absence of antigen binding. Thus, these cells are pre-coated in polyclonal antibodies. Crosslinking of FcR bound IgE by antigen results in degranulation.
100
Where are the germinal centers located?
Within the lymph nodes.
101
What is a primary follicle?
Resting B cells clustered around a dense network of processes of follicular dendritic cells (FDC).
102
What is a secondary follicle?
A germinal center (a transient structure where B cells activate, proliferate, differentiate, and mutate).
103
How do germinal centers form?
In this T-cell dependent process, antigens trapped by follicular dendritic cells cause B cells to proliferate, resulting in the process of affinity maturation.
104
What is affinity maturation?
The germinal center reaction produces high affinity B-cells to a specific antigen, the affinity maturation process produces higher affinity B-cells through the introduction of random nucleotide changes into the DNA of rearranged Ig variable genes.
105
What is hypermutation?
The random nucleotide changes that occur during affinity maturation.
106
What mediates hypermutation?
Hypermutation is mediated by AID and is antigen dependent.
107
What are centroblasts?
Rapidly dividing B-cells in the germinal center.
108
What are centrocytes?
The non-dividing progeny of centroblasts which have been hypermutated and are being selected for based on antigen affinity.
109
Does hypermaturation occur in centroblasts or centrocytes?
Centroblasts.
110
What type of cells form the dark zone of a germinal center?
Dividing centroblasts which are composed of little cytoplasm and many nucleii.
111
What type of cells form the light zone of a germinal center?
Centrocytes in the process of selection and maturation, containing more cytoplasm.
112
Where does hypermutation occur in centroblasts?
In the hypervariable loops of the V region genes.
113
How are centrocytes selected for survival?
Those with higher affinity receptors are selected as they will remain attached to antigens on follicular dendritic cells, while lower affinity clones will be displaced and will die via apoptosis.
114
Will centrocytes die if their sIg does not bind an antigen?
Yes.

Immunology (7 decks)

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