Page 132 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 7 B-Cell Development and Differentiation 115

clear that CD5 was not a definitive marker for B-1 cells in humans, controls the fate of the GC B cell, it is essential for affinity
considerable effort was expended searching for this elusive subset. maturation of the immune response.
NAbs are present in human serum, but definition of the human
B-1 subset remains controversial. Currently B cells that are CD2 B-CELL FUNCTIONS IN ADDITION TO
+
+
−
+
0 CD27 CD43 CD70 appear to be the best candidates. 4 ANTIBODY PRODUCTION
GERMINAL CENTERS Mature B cells are not homogeneous. Functionally and devel-
opmentally distinct subsets exist. In the spleen, follicular B cells
T cell–dependent activation of follicular B cells can induce the have a key role in the adaptive immune response, whereas MZ
formation of a GC, which is the microenvironment where affinity B cells are major players at the interface between the immediate
maturation of the humoral immune response takes place. The innate immune response and the delayed adaptive response. 29
interplay of hypermutation followed by antigen selection is the B cells play an important function in the activation of T cells.
basis of affinity maturation. In the germinal center, B cells that Similar to DCs (Chapter 6), B cells can internalize antigen, process
express antibodies of high affinity are selected to develop into it, and the present antigen peptides to the T-cell receptor (TCR).
memory and long-living plasma cells. 26 In cancer, B cells can secrete tumor-associated autoantibodies
GCs develop only after T cell–dependent activation of B cells. and inflammatory cytokines and alter patterns of antigen presenta-
Their full function is dependent on the interaction between CD40 tion to T cells. Thus they can modulate T-cell and innate immune
expressed on B cells and CD40L (CD154) expressed on activated responses to the tumor. Through antigen–antibody complexes,
T cells. Patients with LOF mutations in CD40L have high serum B cells have the potential to influence immune cells that express
levels of IgM and suffer from recurrent infections (hyper-IgM Fc receptors, which include granulocytes and NK cells. In
syndrome, Chapter 34). 27 autoimmune diseases and also in response to inflammation, B
In a primary immune response, it takes about a week for the cells can have an immune suppressive function. Regulatory B
complex GC structure to develop. In the spleen, a few days after cells (Bregs) appear to exert their activity via the release of
activation of antigen-specific B cells and T cells, small clusters suppressive cytokines, such as IL-10, IL-35, and tumor growth
of proliferating B cells are observed at the border of the T-cell factor-β (TGF-β). 30
zone and the primary B-cell follicle. The rapidly expanding B-cell
clone seems to push the naïve B cells toward the edge of the
primary follicle. The naïve B cells form a mantle zone around MOLECULAR MECHANISM OF
the newly developing GCs, and the primary follicle changes into SOMATIC HYPERMUTATION AND
a secondary follicle. Subsequently, the network of FDCs becomes CLASS-SWITCH RECOMBINATION
filled with proliferating, antigen-activated B cells. An influx of
antigen-activated Tfh cells is also observed. Tfh cells express the Ig SHM and CSR are essential mechanisms for the generation
chemokine receptor CXCR5, which enable them to enter the of a high-affinity, adaptive humoral immune response. They
B-cell follicle. During the GC reaction, expression of the che- allow the generation of effector plasma cells secreting high-affinity
mokine CXCL13 by FDCs attracts both antigen-activated B and IgG, IgA, and IgE antibodies.
Tfh cells. 19
In the second week after immunization, the GC matures into Somatic Hypermutation
a classic structure that contains a dark zone and a light zone. At Hypermutation occurs only during a narrow window in B-cell
this stage of GC development, proliferation is restricted to the development. The mechanism is induced during B-cell prolifera-
dark zone. Amidst the network of FDCs, the B cells differentiate tion within the microenvironment of the GC. With a high rate
-3
into plasma cells and memory cells. In a fully developed GC, of about 10 /base pair/generation, single nucleotide exchanges
dividing cells are termed centroblasts, whereas differentiating are introduced in a stepwise manner into the rearranged V-region
cells within the FDC network are termed centrocytes. and its 3’ and 5’ flanking sequences. Mutations are randomly
In the dark zone, proliferating B cells activate a mechanism introduced, although there is a preference for transitions (cytidine
28
of SHM (Chapter 4). This is a highly specific process that is → thymidine or adenosine → guanine) over transversions.
targeted toward the gene segments that encode the antigen- Analysis of the pattern of somatic mutations has revealed that
binding domain of the antibody molecule. Hypermutation the sequence of the complementarity-determining regions (CDRs;
introduces single nucleotide changes into the rearranged variable Chapter 4), the loops that form the antigen-binding site, have
genes of the Ig molecules. Thus within the dark zone, a clone been selected to form mutation hot spots.
of variants expressing antigen receptors with various affinities Effective hypermutation requires the V-gene promoter and
for the antigen is generated from a single B-cell progenitor. By transcription-enhancer sequences. Indeed, the position of the
chance, a few of these mutations result in a receptor with higher V-gene promoter defines the start of the hypermutation domain,
affinity for antigen. B cells expressing such receptors are favored which spans about 2000 nucleotides. Any heterologous sequence
for activation and proliferation, particularly late in an immune that is introduced into the V gene segment locus will become a
response when availability of antigen is limiting. target of the hypermutation machinery. Thus SHM can sometimes
FDCs present antigen to B cells, but only those with high- play a role in lymphomas and leukemias, where oncogenes have
affinity receptors are able to internalize the antigen via their been linked to Ig promoters and enhancers.
BCR. Processing of the internalized antigen and presentation of
peptides to Tfh cells are prerequisites for B-cell differentiation Class-Switch Recombination
19
into memory and plasma cells. Thus only the few B cells with Upon transition from the immature to the mature state and
high-affinity receptors get adequate help. IL-21 provided by the leaving bone marrow, the B cell starts to express IgD as well as
Tfh cells is crucial in this differentiation phase, and since it IgM. Both IgM and IgD antibodies use the same V H DJ H -exon and