Page 717 - Clinical Immunology_ Principles and Practice ( PDFDrive )

690 Part SIX Systemic Immune Diseases

surprising that genes encoding integrins, NGAL, CD40 ligand, healthy donors shows that the frequency of germinal centers
+
IFN-γ receptor, and IL-6 are among the hypomethylated genes with 9G4 cells is less than 1%, implying that negative selection
in SLE. Mechanisms for hypomethylation remain unclear; of autoreactive cells occurs at the transition of naïve to germinal
decreased efficacy of DNA methyltransferases (DNMTs) and center B cells. In contrast, tonsillar biopsies from SLE patients
overexpression of microRNAs (miRNA) that interfere with DNMT demonstrate that 15–20% of germinal centers are positive for
activity have been proposed. 26 autoreactive 9G4 B cells. This study, as well as others, suggests
Vitamin D has been shown to contribute to the regulation that checkpoints exist for entry into and exodus from the germinal
of the epigenome. Vitamin D levels are low in many lupus patients, center response and that these may be altered in SLE.
but the relationship of vitamin D levels to disease risk or disease For example, it is clear that some pathogenic autoantibodies
severity remains controversial. 27 are not derived from natural autoantibodies. Back mutation of
Inflammation itself may alter the epigenome; some studies suggest several anti-DNA antibodies to their germline-encoded precursors
that the metabolic modulator metformin can reverse some of has identified nonautoreactive precursors. The failure of censoring
the inflammation-induced alterations. Recent studies show that mechanisms in germinal centers to prevent the maturation of
metformin can reduce murine lupus, although the mechanism autoreactive cells may reflect intrinsic B-cell abnormalities or
for this therapeutic effect is not completely clear. abnormalities in costimulatory molecules, cytokines (such as B
cell–activating factor [BAFF]; see below), follicular DCs, or T-cell,
B Cells B-cell interactions.
B-Cell Selection
The process of immunoglobulin variable region gene rearrange- B-Cell Signaling
ment produces large numbers of self-reactive B cells. Most B Hyperactive B-cell responses to immunological stimulation are
cells displaying self-reactive immunoglobulin are deleted centrally implicated in the production of pathogenic antibodies. SLE B
2+
in the bone marrow and at subsequent checkpoints in the cells have increased intracellular Ca flux in response to BCR
29
periphery (Fig. 51.2), so the frequency of autoreactive cells signaling, partially due to FcγRIIb dysfunction (Ile 232 Thr). 15
decreases from ~75% in immature B cells in the bone marrow The intracellular protein tyrosine kinase Lyn has both positive
to ~20% in the mature naïve B-cell population in healthy and negative effects on BCR signaling. Decreased expression of
2+
individuals. Many of the autoreactive B cells in the naïve popula- Lyn results in increased intracellular Ca flux and B-cell hyper-
tion are normally suppressed by anergy induction. Several of activity. Correspondingly, Lyn expression is decreased in resting
these checkpoints appear deficient in SLE. The IgM cross-reactive and activated B cells in one-half to two-thirds of SLE patients,
autoantibodies made by these remaining autoreactive mature suggesting that Lyn may modulate negative regulation of BCR
naïve B cells are thought to facilitate clearance of apoptotic cells, signaling in human disease. In contrast, a Lyn mutation in mice
decreasing the development of potentially pathogenic T- and leading to increased expression results in autoantibody production
B-cell responses to self-antigens. When IgM autoreactive antibod- and severe glomerulonephritis, suggesting that balanced Lyn
ies are missing in mice, a lupus-like phenotype develops. expression is critical to tolerance pathways.
Another important peripheral checkpoint is entry into the
T-cell-dependent, long-lived memory compartment. B cells with B-Cell Rescue
the 9G4 idiotype express antibodies encoded by the VH4-34 B lymphocyte stimulator (BAFF; also known as BLyS) is a member
gene, reactive with N-acetyllactosamine (NAL) determinants of of the TNF family and participates in B-cell maturation and
glycoproteins on blood group antigens targeted by cold agglu- survival. BAFF enhances survival of B cells through engagement
tinins, gangliosides, gastrointestinal (GI) mucins, glycolipids, of several receptors–BCMA, BAFF-R, and TACI. High levels of
28
and CD45 on B lymphocytes. 9G4 B cells are reported to be this cytokine allow survival of autoreactive B cells in mice,
30
present in 5–10% of the naïve B-cell population in healthy donors resulting in a lupus-like disease (reviewed in Liu and Davidson).
as well as in the IgM memory compartment. However, 9G4 B Evidence supporting a role for BAFF in autoreactive B-cell rescue
cells are excluded from the T-cell–dependent IgG memory and and human SLE includes the elevated levels seen in lupus patients,
plasma cell populations, suggesting that these autoreactive cells associations of BAFF levels with autoantibody titers, and, in
fail to cross a developmental checkpoint after activation in normal some reports, correlations with disease activity. Recently belim-
individuals. Evaluation of tonsillar biopsies and spleens from umab, a monoclonal antibody directed against soluble BAFF,

Immature Transitional 1 B cells Bone marrow
Transitional 1 Transitional 2 B cells Spleen

Transitional 2 Mature/naïve B cells Spleen
Mature/naïve Germinal center/long-lived plasma cells Spleen/lymph nodes

Short-lived plasma cells
? Pathogenic autoantibodies
FIG 51.2 Autoreactive B-Cell Checkpoints. There are tolerance checkpoints at every stage of
B-cell activation and maturation. How many checkpoints need to be breached to achieve a
pathogenic state and clinical disease is not known.