Page 85 - Clinical Immunology_ Principles and Practice ( PDFDrive )

70 Part one Principles of Immune Response

Ag C3d share the ability to negatively regulate signaling by activating
receptors.
The ability of passively administered soluble antibody to inhibit
CD21 humoral responses has long been appreciated and was initially
IgM thought to occur by soluble antibody effectively masking all
available antigen epitopes. The molecular mechanism accounting
CD19 for this suppression is now known to be mediated by the binding
Ig-α of IgG to FcRγIIB and the subsequent recruitment of cytosolic
Ig-β CD81 phosphatases to the FcRγIIB ITIM upon tyrosine phosphorylation.
Thus the inhibitory effect of IgG on BCR-mediated B cell activa-
tion is explained by the interaction of the FcγRIIB ITIM, and
specifically associated phosphatases, with the BCR (Fig. 4.13).
PTK Coligation of the BCR and FcRγIIB by antigen–IgG complexes
results in the tyrosine phosphorylation of the FcRγIIB ITIM,
Syk P13-K presumably by the BCR-associated tyrosine kinases. Phosphory-
+ lated FcRγIIB ITIMs then recruit two different SH2-containing
+ phosphatases, SHIP and SHP-1, which function to remove
Lyn phosphate groups from inositol lipids or tyrosines, respectively.
Fyn Vav
Although both phosphatases can negatively regulate BCR-
FIG 4.12 Proposed Mechanisms for the Augmentation of mediated signaling events, SHIP appears to be the most relevant
B-Cell Receptor (BCR) Signaling by the CD21/19 Coreceptor. phosphatase in FcRγIIB inhibition of BCR signaling (see Fig.
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Coligation of the BCR and CD21–CD19 complex by C3d–antigen 4.13). Thus once the majority of antigen exists in immune
complex allows a CD79-associated Src-family tyrosine kinase complexes together with antigen-specific IgG, attenuation of an
to phosphorylate tyrosine residues within the CD19 cytoplasmic ongoing immune response occurs by the juxtaposition of FcRγIIB
domain. Subsequently, tyrosine-phosphorylated CD19 effectively with the BCR.
recruits key SH2-containing signaling molecules to the BCR
complex, allowing the initial BCR-mediated signal to quickly CD22
disseminate along different intracellular signaling pathways. CD22 is a 135-kDa to 140-kDa transmembrane glycoprotein that
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is restricted in its expression to the B lineage. CD22 expression
is limited to the cytoplasm of progenitor and pre-B cells in early
B-cell development. Expression on the surface of the B cell occurs
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response. Antigen bearing either two or three copies of C3d concomitant with the appearance of surface, or membrane, IgD.
was respectively 1000 and 10 000 times more immunogenic than Upon B-cell activation, CD22 expression is initially transiently
antigen alone. Thus the CD21–CD19 coreceptor complex provides upregulated and subsequently downmodulated upon terminal
a link between the innate and adaptive immune responses. In differentiation to Ig-secreting plasma cells. Although the onset
vivo, CD19-deficient mice appear to have more severely affected of CD22 expression follows a similar pattern during murine B
T-dependent immune responses compared with CD21-deficient lymphopoiesis, it is not restricted to the cytoplasm in early B
animals, suggesting alternative roles for CD19 in regulating BCR lymphopoiesis but rather is expressed on the surface from the
signals beyond the CD21–CD19 coreceptor complex. progenitor stage onward. The basis or function of CD22 intracel-
lular retention in human B cell development is not understood.
Coreceptors That Negatively Regulate BCR Signaling CD22 maps to chromosome 19q13.1 and encodes alternatively
FcγRIIB spliced forms of CD22, CD22α, and CD22β, of which the latter
Among the several receptors for the Fc portion of Ig expressed is the predominant species expressed by B cells. The CD22β
by B cells, the Fc receptor for IgG, FcγRIIB (a member of the isoform contains seven extracellular IgSF domains, of which all
CD32 cluster), has an important role in negatively regulating but one are of the C type. The single exception is the N-terminal
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BCR-mediated signal transduction. FcγRIIB is a 40 kDa domain, which is of the V type. CD22α lacks the IgSF third and
single-chain molecule that is encoded by single gene located fourth domains, although the significance of this minority
on chromosome 1q23-24. Alternative splicing of different alternatively spliced product remains unclear. The CD22 murine
cytoplasmic exons permits expression of three isoforms. The homologue has only been found as a full-length CD22β isoform.
extracellular domain of FcγRIIB is composed of two C-type IgSF The extracellular domain of CD22 is homologous to the carci-
domains that can bind with low affinity to IgG. All three FcγRIIB noembryonic antigen subfamily of adhesion molecules, which
isoforms share a common cytoplasmic region that is important includes the myelin-associated glycoprotein (MAG) and CD33.
for negatively regulating activation signals delivered by associated CD22 also functions as an adhesion molecule belonging to the
surface receptors. The region within the cytoplasmic domain of Siglec subfamily of the IgSF, whose members function as mam-
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FCγRIIB responsible for the inhibitory activity of this Fc receptor malian sialic acid–binding Ig-like lectins. The two N-terminal
toward the BCR has been identified as a sequence that contains a IgSF domains have been shown to mediate adhesion to both B
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tyrosine residue critical for its activity. Analogous to the ITAM, and T lymphocytes via the binding of structures carrying α2,6
which provides an activation signal, this inhibitory sequence has sialic acids.
been referred to as an immunoreceptor tyrosine-based inhibitory In addition to acting as an adhesion molecule, CD22 is
motif (ITIM). The ITIM is carried by the canonical sequence of also capable of modulating BCR signaling (see Fig. 4.13).
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I/L/VxYxxI/V/L (where x is any amino acid). ITIMs are found A fraction of CD22 associates with the BCR, and CD22 is
in a number of other transmembrane structures, all of which rapidly tyrosine-phosphorylated upon mIgM engagement.