Ch. 4. Antigen Recognition in the Adaptive Immune System.

Question 1

Immune repertoire

Answer 1

The entire collection of distinct lymphocyte clones.

Question 2

Complementarity-determining region (CDR)

Answer 2

Short segments of Ig and TCR proteins that contain most of the sequence differences between antibodies or TCRs expressed by different clones of B cells and T cells that make contact with antigen; also called hypervariable regions.

Three CDRs are present in the variable domain of each antigen receptor polypeptide chain, and six CDRs are present in an intact Ig or TCR molecule.

These hypervariable segments assume loop struction that together form a surface complementary to the three-dimensional structure of bound antigen.

Question 3

B cell receptor (BCR)

Answer 3

The cell surface antigen receptor on B lymphocytes, which is a membrane-bound immunoglobulin molecule.

Question 4

B cell receptor (BCR) complex

Answer 4

A multiprotein complex expressed on the surface of B lymphocytes that recognizes antigen and transduces activating signals into the cell.

The BCR complex includes membrane Ig, which is responsible for binding antigen, and Ig(alpha) and Ig(beta) proteins, which initiate signaling events.

Question 5

T cell receptor (TCR)

Answer 5

The clonally distributed antigen receptor on T lymphocytes. The most common form of TCR is composed of a heterodimer of two disulfide-linked transmembrane polypeptide chains, designated alpha and beta, each containing one N-terminal Ig-like variable (V) domain, one Ig-like constant (C) domain, a hydrophobic transmembrane region, and a short cytoplasmic region.

The (alpha)(beta) TCR is expressed on CD4+ and CD8+ T cells and recognizes complexes of foreign peptides bound to self MHC molecules on the surface of APCs. (Another less common type of TCR, composed of gamma and delta chains, is found on a small subset of T cells and recognizes different forms of antigen).

Question 6

T cell receptor (TCR) complex

Answer 6

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Question 7

Immunoglobulin (Ig)

Answer 7

Synonymous with antibody.

Question 8

Antibody

Answer 8

A type of glycoprotein molecule, also called immunoglobulin (Ig), produced by B lymphocytes that binds antigens, often with a high degree of specificity and affinity.

The basic structural unit of an antibody is composed of two identical heavy chains and two identical light chains. The N-terminal variable regions of the heavy and light chains from the antigen-binding sites, whereas the C-terminal constant regions of the heavy chains functionally interact with other molecules in the immune system.

Every individual has millions of different antibodies, each with a unique antigen-binding site. Secreted antibodies perform various effector functions, including neutralizing antigens, activating complement, and promoting leukocyte-dependent destruction of microbes.

Question 9

Fab (fragment, antigen-binding) region

Answer 9

A part of an antibody, first produced by proteolysis of IgG, that includes one complete light chain paired with one heavy chain fragment containing the variable domain and only the first constant domain.

Fab fragments, which an be generated from all antibodies, retain the ability to monovalently bind an antigen but cannot interact with IgG Fc receptors on cells or with complement.

Therefore Fab preparations are used in research and therapeutic applications when antigen binding is desired without activation of effector functions. (The Fab’ fragment retains the hinge region of the heavy chain.)

Question 10

Fc (fragment, crystalline) region

Answer 10

A region of an antibody molecule that can isolated by proteolysis of IgG that contains only the disulfide-linked carboxyl-terminal regions of the two heavy chains.

The Fc region of Ig molecules mediates effector functions by binding to cell surface receptors or the C1q complement protein. (Fc fragments are so named because they tend to crystallize out of solution.)

Question 11

Hinge region

Answer 11

The region of Ig heavy chains between the first two constant domains that can assume multiple conformations, thereby imparting flexibility in the orientation of the two antigen-binding sites.

Because of the hinge region, an antibody molecule can simultaneously bind two epitopes that are separated by some distance from one another.

Question 12

Constant (C) region

Answer 12

The portion of Ig or TCR polypeptide chains that does not vary in sequence among different clones and is not involved in antigen binding.

Question 13

What are the five types of Ig heavy chains?

Answer 13

Mu, delta, gamma, epsilon, and alpha.

Question 14

Isotype (class)

Answer 14

One of five types of antibodies, determined by which of five different forms of heavy chain is present.

Antibody isotypes include IgM, IgD, IgG, IgA, and IgE, and each isotype performs a different set of effector functoins.

Additional variations characterize distince subtypes of IgG and IgA.

Question 15

Heavy-chain isotype (class) switching

Answer 15

The process by which a B lymphocyte changes the isotype, or class, of the antibodies that it produces, from IgM to IgG, IgE, or IgA, without changing the antigen specificity of the antibody.

Heavy-chain isotype switching is stimulated by cytokines and CD40 ligand expressed by helpher T cells and involves recombination of B cell VDJ segments with downstream heavy-chain gene segments.

Question 16

Epitope (determinant)

Answer 16

The specific part of a macromolecular antigen to which an antibody or T cell receptor binds. In the case of a protein antigen recognized by a T cell, an epitope is the peptide portion that binds to an MHC molecule fo recognition by the TCR.

Can be a linear or conformational epitope.

Question 17

Affinity

Answer 17

The strength of the binding between a single binding site of a molecule (e.g., an antibody) and a ligand (e.g., an antigen).

The affinity of of a molecule X for a ligand Y is represented by the dissociation constant (Kd), which is the concentration of Y that is required to occupy the combining sites of half the X molecules present in a solution.

A smaller Kd indicates a stronger or higher affinity interaction, and a lower concentration of ligand is needed to occupy the sites.

Question 18

Affinity maturation

Answer 18

The process that leads to increased affinity of antibodies for a particular antigen as a T cell-dependent antibody response progresses.

Affinity maturation takes place in germinal centers of lymphoid tissues and is the result of somatic mutation of immunoglobulin genes, followed by selective survival of the B cells producing the highest affinity antibodies.

Question 19

Avidity

Answer 19

The overall strength of interaction between two molecules, such as an antibody and antigen. Avidity depends on both the affinity and the valency of interactions.

Therefore, the avidity of a pentameric IgM antibody, with 10 antigen-binding sites, for a multivalent antigen is much greater than the affinity of a single antibody combining site specific for the same antigen.

Avidity can be used to describe the strength of cell-cell interactions, which are mediated by many binding interactions between cell surface molecules.

Question 20

Cross-reactivity

Answer 20

Cross-reactivity measures the extent to which different antigens appear similar to the immune system. The molecular determinants of specificity and cross-reactivity define the nature of antigenic variation and the selective processes that shape the distribution of variants in populations.

Question 21

Monoclonal antibody

Answer 21

An antibody that is specific for one antigen and is produced by a B cell hybridoma (a cell line derived by the fusion of a single normal B cell and an immortal B cell tumor line).

Monoclonal antibodies are widely used in research, clinical diagnosis, and therapy.

Question 22

Hybridomas

Answer 22

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Question 23

Positive selection

Answer 23

The process by which developing T cells in the thymus (thymocytes) whose TCRs bind to self MHC molecules are rescued from programmed cell death, whereas thymocytes whose receptors do not recognize self MHC molecules die by default.

Positive selection ensures that mature T cells are self MHC restricted and that CD8+ T cells are specific for complexes of peptides with class I MHC molecules and CD4+ T cells for complexes of peptides with class II MHC molecules.

Question 24

Negative selection

Answer 24

The process by which developing lymphocytes that express self-reactive antigen receptors are eliminated, thereby contributing to the maintenance of self tolerance.

Negative selection of developing T lymphocytes (thymocytes) is best understood and involves high-avidity binding of a thymocyte to self MHC molecules with bound peptides on thymic APCs, leading to apoptotic death of the thymocyte.

Question 25

V(D)J recombinase

Answer 25

The complex of RAG1 and RAG2 proteins that catalyze lymphocyte antigen receptor gene recombination.

Question 26

Combinatorial diversity

Answer 26

The diversity of Ig and TCR specificities generated by the use of many different combinations of different variable, diversity, and joining segments during somatic recombination of DNA in the Ig and TCR loci in developing B and T cells.

Combinatorial diversity is one mechanisms, which works together with junctional diversity, for the generation of large numbers of different antigen receptor genes from a limited number of DNA gene segments.

Question 27

Junctional diversity

Answer 27

The diversity in antibody and TCR repertoires that is created by the random addition or removal of nucleotide sequences at junctions between V, D, and J segments.

Question 28

N nucelotides

Answer 28

The name given to nucleotides randomly added to the junctions between V, D, and J gene segments in Ig or TCR genes during lymphocyte development.

The addition of up to twenty of these nucleotides, which is mediated by the enzyme terminal deoxyribonucleotidyl transferase, contributes to the diversity of the antibody and TCR repertoires.

Question 29

Pro-B cell

Answer 29

A developing B cell in the bone marrow that is the earliest cel committed to the B lymphocyte lineage.

Pro-B cells do not produce Ig, but they can be distinguished from other immature cells by the expression of B lineage-restricted surface molecules, such as CD19 and CD10.

Question 30

Pre-B cell

Answer 30

A developing B cell present only in hematopoietic tissues that is at a maturational stage characterized by expression of cytoplasmic Ig mu heavy chains and surrogate light chains, but not Ig light chains.

Pre-B cell receptors composed of mu chains and surrogate light chains deliver signals that stimulate further maturation of the pre-B cell into an immature B cell.

Question 31

Pre-B cell receptor

Answer 31

A receptor expressed on developing B lymphocytes at the pre-B cell stage that is composed of Ig mu heavy chains and invariant surrogate light chains.

The pre-B cell receptors associates with the Ig(alpha) and Ig(beta) signal transduction proteins to form the pre-B cell receptor complex.

Pre-B cell receptors are required for stimulating the proliferation and continued maturation of the developing B cell, serving as a checkpoint that ensures productive mu heavy chain VDJ rearrangement.

It is not known whether the pre-B cell receptor binds a specific ligand.

Question 32

Surrogate light chains

Answer 32

Two non-variable proteins that associate associate with Ig mu heavy chains in pre-B cells to form the pre-B cell receptor.

The two surrogate light chain proteins include the V pre-B protein, which is homologous to the alight-chain V domain, and (lambda)5, which is covalently attached to the mu heavy chain by a disulfide bond.

Question 33

X-linked agammaglobulinemia

Answer 33

An immunodeficiency disease, also called Bruton agammaglobulinemia, characterized by a block in early B cell maturation and an absence of serum Ig.

Patients suffer from pyogenic bacterial infections.

The disease is caused by mutations or deletions in the gene encoding Btk, an enzyme involved in signal transduction in developing B cells.

Question 34

Allelic exclusion

Answer 34

The exclusive expression of only one of two inherited alleles encoding Ig heavy and light chains and TCR beta chains.

Allelic exclusion occurs when the protein product of one productively recombined antigen receptor locus on one chromosome blocks rearrangement and expression of the corresponding locus on the other chromosome. This property ensures that each lymphocyte will express a single antigen receptor and that all antigen receptors expressed by one clone of lymphocytes will have the identical specificity.

Because the TCR alpha chain locus does not show allelic exclusion, some T cells do express two different TCRs.

Question 35

Immature B lymphocyte

Answer 35

A membrane IgM+, IgD- B cell, recently derived from marrow precursors, that does not proliferate or differentiate in response to antigens but rather may undergo apoptotic death or become functionally unresponsive.

This property is important for the negative selection of B cells that are specific for self antigens present in the bone marrow.

Question 36

Receptor editing

Answer 36

A process by which some immature B cells that recognize self antigens in the bone marrow may be induced to change their Ig specificities.

Receptor editing involves reactivation of the RAG genes, additional light chain VJ recombinations, and new Ig light chain production, which allows the cell to express a different Ig receptor that is not self-reactive.

Question 37

Mature B cell

Answer 37

IgM- and IgD-expressing, functionally competent naive B cells that represent the final stage of B cell maturation in the spleen and that populate peripheral lymphoid organs.

Question 38

Pro-T cell (Double-negative thymocyte)

Answer 38

A developing T cell in the thymic cortex that is a recent arrive from the bone marrow and does not express TCRs, CD3, zeta chains, or CD4 or CD8 molecules.

Question 39

Pre-T cell

Answer 39

A developing T lymphocyte in the thymus at a maturational stage characterized by expression of the TCR beta chain but not the alpha chain or CD4 or CD8.

In pre-T cells, the TCR beta chain is found on the surface as part of the pre-T cell receptor.

Question 40

Pre-T cell receptor

Answer 40

A receptor expressed on the surface of pre-T cells that is composed of the TCR beta chain and an invariant pre-T(alpha) protein.

This receptor associates with CD3 and zeta molecules to form the pre-T cell receptor complex.

The function of this complex is similar to that of the pre-B cell receptor in B cel development, namely, the delivery of signals that stimulate further proliferation, antigen receptor gene rearrangements, and other maturational events.

It is not know whether the pre-T cell receptor binds a specific ligand.

Question 41

Pre-T(alpha)

Answer 41

An invariant transmembrane protein with a single extracellular Ig-like domain that associates with the TCR beta chain in pre-T cells to form the pre-T cell receptor.

Question 42

Double-positive thymocyte (immature T cell)

Answer 42

A subset of developing T cells in the thymus (thymocytes) that express both CD4 and CD8 and are at an intermediate developmental stage.

Double-positive thymocytes also express TCRs and are subject to selection processes, and they mature to single-positive T cells expressing only CD4 or CD8.

Question 43

Single-positive thymocyte (single-positive T cell)

Answer 43

A maturing T cell cell precursor in the thymus that expressed CD4 or CD8 molecules but not both.

Single-positive thymocytes are found mainly in the medulla and have matured from the double-positive stage, during which thymocytes express both CD4 and CD8.

Question 44

Double-negative thymocyte (pro-T cells)

Answer 44

A subset of developing T cells in the thymus (thymocytes) that express neither CD4 nor CD8.

Most double-negative thymocytes are at an early developmental stage and do not expression antigen receptors. They will later express both CD4 and CD8 during the intermediate double-positive stage before further maturation to single-positive T cels expressing either CD4 or CD8.