Page 21 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 1 The Human Immune Response 7

foreign antigen. These molecules are Igs, TCRs, and MHC with its unique antigen receptor. The variable domain of the
molecules (see Fig. 1.1) (Chapters 4, 5). All are products of a mature receptor is created by the rearrangement of two or three
very large family of ancestrally related genes, the immunoglobulin separate gene segments. These are designated V (variable) and
superfamily, which includes many other molecules essential to J (joining), for IgL chains and TCR α and γ chains, and V, D
induction and regulation of immune responses. 15,16 Members of (diversity) and J, for IgH and TCR β and δ chains. In addition
the Ig superfamily exhibit characteristic structural features. The to rearrangement, N-nucleotide addition also contributes sub-
most notable of these is organization into homologous domains stantially to receptor diversity. N-nucleotide addition results in
of approximately 110 amino acids that are usually encoded by the insertion, at the time of rearrangement, of one or more
a single exon with an intradomain disulfide bond, characteristically nongenomic nucleotides at the junctions between V, D, and J
configured as antiparallel strands, forming two opposing β-pleated segments through the action of terminal deoxynucleotidyl
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sheets. transferase (TdT). This permits receptor diversity to extend
beyond germline constraints. Analysis of the linear sequences
Immunoglobulins and T-Cell Receptors of many Ig V regions domains has shown that they contain three
The remarkable specificity of Ig and TCR molecules for antigen sites of high sequence variability that have been designated
is achieved by a mechanism of genetic recombination that is complementarity determining regions 1–3 (CDR1–3) to indicate
unique to Ig and TCR genes (Chapter 4). The antigen-binding that they are the sites that contact antigen (see Fig. 1.1).
site of both types of molecules comprises a groove formed by DNA rearrangement involved in generating T- and B-cell
contributions from each of two constituent polypeptides. In the receptors is controlled by recombinases that are active in early
case of immunoglobulins, these are a heavy (H) chain and one thymocytes and in B precursor cells in bone marrow. The process
of two alternative types of light (L) chains, κ or λ. In the case is sequential and carefully regulated, generally leading to transla-
of TCRs, either of two alternative heterodimers can constitute tion of one receptor of unique specificity for any given T or B
the antigen-binding molecule, one comprised of α and β chains, lymphocyte. This result is achieved through a process termed
and the other of γ and δ chains. The polypeptides contributing to allelic exclusion, wherein only one member of a pair of allelic
both Igs and TCRs can be divided into an antigen-binding amino- genes potentially contributing to an Ig or TCR molecule is
terminal variable (V) domain and one or more carboxy-terminal rearranged at a time. 18
constant (i.e., nonvariable) domains. Ig constant region domains The process of allelic exclusion is not absolute, and a small
generally include specific sites responsible for the biological effector number of lymphocytes will express dual functional Ig or TCR
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functions of the antibody molecule (Chapter 15). transcripts and, in some cases, two distinct surface receptors.
But B cells exclusively rearrange Ig genes, not TCR genes, and
KeY ConCePtS vice-versa for T cells. Moreover, after producing a functional
Comparison of T-Cell and B-Cell Receptors heavy chain, B cells sequentially rearrange L chain genes, typically
for Antigen κ before λ. Thus B cells express either κ or λ chains, but not
both. Similarly, thymocytes express α and β genes or γ and δ
Similarities genes, and only rarely T cells with αδ or γβ receptors.
• Members of the immunoglobulin (Ig) superfamily There is one feature of V region construction that is essentially
• Two polypeptide chains contribute to antigen-binding site reserved to B cells. This is somatic hypermutation (SHM), a
• Each chain divided into variable and constant regions process that can continue at discrete times throughout the life
• Variable regions constructed by V(D)J rearrangements of a mature B cell at both the V H D H J H and V L J L gene exons.
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• Nongenomic N-nucleotide additions at V(D)J junctions Because these rearranged gene exons encode the binding groove
• Exhibit allelic exclusion
• Negative selection against receptors with self-antigen specificity that contains the specific points of contact with antigen, on
• Transmembrane signaling involving coreceptor molecules occasion the random process of SHM will result in cells expressing
mIg with increased affinity for the antigen they recognize. Typically,
Differences cells with increased affinity for antigen are activated preferentially,
• Ig can be secreted; T-cell receptor (TCR) is not particularly at limiting doses of antigen. Thus the average affinity
• Ig recognizes conformational antigen (Ag) determinants; TCR recognizes of antibodies produced during the course of an immune response
linear determinants tends to increase, a process termed affinity maturation.
• Ig can bind antigen in solution; TCR binds antigen when presented TCRs do not show evidence of SHM. This absence may be
by major histocompatibility complex (MHC) molecule on antigen-
presenting cell (APC) related to the focus on selection in the thymus involving corecog-
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• Somatic hypermutation of Ig genes can enhance antigen-binding nition of a self-MHC molecule and self-peptides, (Chapter 8)
affinity rather than the continuous process of antigen-driven selection
• Ig genes can undergo isotype switching in the periphery by B cells after SHM. Thymic selection results
• Inflammatory effector functions by the Ig constant domains in deletion by apoptosis of the vast majority of differentiating
• Positive selection of TCR for self-MHC recognition
thymocytes by mechanisms that place stringent boundaries
around the viability of a thymocyte with a newly expressed
TCR specificity. Once a T cell is fully mature and ready for
The most noteworthy feature of the vertebrate immune system emigration from the thymus, its TCR is essentially fixed, reducing
is the process of genetic recombination that generates a virtually the likelihood of emergent autoimmune T-cell clones in the
limitless array of specific antigen receptors from a rather limited periphery.
genomic investment. This phenomenon is accomplished by the
recombination of genomic segments that encode the variable Receptor Selection
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domains of Ig and TCR polypeptides (Chapter 4). The products The receptor expressed by a developing thymocyte must be capable
of these rearranged gene elements provide a specific B or T cell of binding with low-level affinity to some particular MHC