Page 22 - Clinical Immunology_ Principles and Practice ( PDFDrive )

8 Part one Principles of Immune Response

self-molecule, either class I or class II, expressed by a resident messenger RNAs (mRNAs) to include or exclude a transmembrane
thymic epithelial cell or APC. Because their receptors are generated segment that is encoded by the Ig heavy-chain genes.
by a process of semirandom joining of rearranging exon segments
coupled with N-nucleotide additions, most thymocytes fail this Immunoglobulin Class Switching
test. They are consequently deleted as not being useful to an In addition to synthesizing both membrane and secreted forms
immune system that requires T cells to recognize antigen that of Igs, B cells also undergo class switching. Antibody molecules
is bound to self-MHC molecules. Thymocytes surviving this are comprised of five major classes (isotypes). In order of
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hurdle are said to have been “positively selected” (Fig. 1.2A). abundance in serum, these are IgG, IgM, IgA, IgD, and IgE
Conversely, a small number of thymocytes bind with an unal- (Chapters 4 and 15). In humans the IgG class is further
lowably high affinity for a combination of MHC molecule plus subdivided into four subclasses and the IgA class into two
antigenic peptide expressed by a thymic APC. Because the peptides subclasses. The class of Ig is determined by the sequence of the
available for MHC binding at this site are derived almost entirely constant region of its heavy chain (C H ). The H chain constant
from self-proteins, differentiating thymocytes with such receptors region gene locus is organized with exons that encode each of
are intrinsically dangerous as potentially autoimmune. This the Ig isotypes and subclasses located downstream (3’) of the
deletion of thymocytes with high-affinity receptors for self-MHC variable (V H ) genes. Thus an antibody-producing cell with a
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plus (presumptively) self-peptide is termed “negative selection” successfully rearranged V H D H J H exon can change the class of
(Fig. 1.2B), a process that may also involve activity of regulatory antibody molecule that it synthesizes by utilization of different
T cells (Tregs). 22,23 C H genes without changing its unique antibody specificity. This
Another feature that distinguishes B cells from T cells is that process, termed class switch recombination, is regulated by
the cell surface antigen receptors of the former can be secreted cytokines and is accomplished through the action of activation-
in large quantities as antibody molecules, the effector functions induced cytidine deaminase. 24
of which are carried out in solution or at the surfaces of other There is no process comparable with class switch recombina-
cells. Secretion is accomplished by alternative splicing of Ig tion in T cells. The two types of TCRs are products of four

Positive selection Negative selection

Cortical Cortical Med. Med.
Epi Epi Epi Epi
APC APC APC APC
MHC MHC MHC MHC

TCR TCR TCR TCR

Thymocyte Thymocyte Thymocyte Thymocyte

Die or Try again Migrate to Die Emigrate
(Vα–Jα) medulla
A B
FIG 1.2 Two-Stage Selection of Thymocytes Based on Binding Characteristics of Randomly
+
+
Generated T-Cell Receptors (TCRs). (A) Positive selection. “Double-positive” (CD4 , CD8 )
thymocytes with TCRs capable of low avidity binding to some specific self-MHC molecule (either
class I or class II) expressed by thymic cortical epithelial cells are positively selected. This process
may involve sequential attempts at α gene rearrangement in order to express an αβ TCR of
appropriate self-MHC specificity. If binding is to a class I molecule, the positively selected thymocyte
becomes CD8 single-positive, and if to a class II molecule, a CD4 single-positive. Thymocytes
that are unsuccessful in achieving a receptor with avidity for either a class I or a class II self-MHC
molecule die by apoptosis. The solid diamond represents a self-peptide derived from hydrolysis
of an autologous protein present in the thymic microenvironment or synthesized within the
+
+
thymic epithelium itself. (B) Negative selection. “Single-positive” (CD4 or CD8 ) thymocytes,
positively selected in the thymic cortex, that display TCRs with high avidity for the combination
of self-MHC plus some self (autologous) peptide present in the thymus are negatively selected
(i.e., die) as potentially “autoimmune.” Those few thymocytes that have survived both positive
and negative selection emigrate to the periphery as mature T cells.