Page 718 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 51 Systemic Lupus Erythematosus 691

has been shown to increase the percentage of ANA-positive B IFN-α in SLE pathogenesis is now well described; the primary
cells that are anergic in SLE patients. cells responsible for IFN-α production are pDC. TLR7 or TLR9
Interactions between CD40 (B cell) and CD40 ligand (CD40L, activation with RNA and DNA, respectively, induces immature
T cell) are essential for B-cell proliferation, differentiation of DC to differentiate to immunocompetent, IFN-α-producing DC
memory cells into plasma cells, and germinal center formation. that have wide-reaching effects on T cells, B cells, neutrophils, and
Immature autoreactive B cells can be rescued from antigen- monocytes. Of note, type I IFN increases plasmablast differentiation
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induced apoptosis by engagement of CD40 or by IL-4. SLE T favoring short-lived plasma cells over germinal center matured
and B cells have upregulated CD40L, providing a critical molecule long-lived plasma cells. Plasmacytoid dendritic cells (pDC) have
to mediate B-cell rescue. The combination of IL-17 and BAFF been demonstrated in skin and renal lesions, and upregulation of
facilitates B-lymphocyte proliferation and maturation. This the “IFN signature” is observed in many, but not all, SLE patients
combination can serve as an alternative stimulatory signal for and has been associated with disease activity. A number of sus-
B-cell activation and can replace CD40/CD40L interactions. ceptibility genes identified through GWASs are associated with
Therefore in a permissible and proinflammatory cytokine milieu, IFN pathways in SLE including IRF5, IRF7, and STAT4.
B-cell activation and autoantibody production may occur in the
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absence of cognate T-cell help. These studies are consistent T Cells
with the increased numbers of plasmablasts present in blood of T cells are critical in the abrogation of self-tolerance by providing
lupus patients with active diseases and with the increased numbers help to autoreactive B cells and facilitating the production of
of class-switched CD27-negative B cells in blood of lupus patients. somatically mutated, high-affinity, pathogenic autoantibodies.
Lupus patients can exhibit T-cell phenotypes consisting of
B-Cell Pathogenicity Unrelated to Antibody Production increased numbers of CD3 CD4 CD8 T cells, increased Th17
+
−
−
An essential role for B cells in SLE that is independent of antibody cells, T-follicular helper (Tfh) cells, and decreased numbers or
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production is demonstrated by the T-cell activation, kidney function of T regulatory cells (Tregs). Additionally, lupus T
inflammation, and increased mortality in MRL/lpr lupus-prone cells display increased expression of activation markers and
mice that lack the ability to secrete antibody and the absence of abnormal TCR signaling responses. A substitution of TCR ζ-chain
such cells in mice that lack B cells. B cells are efficient antigen- by the γ-chain of the Fc receptor results in increased intracellular
2+
presenting cells; B cells with self-reactive specificity that have influx of Ca after TCR stimulation and a concomitant decrease
escaped tolerance are likely to present self-antigen to autoreactive in IL-2 production, disfavoring the induction of Tregs.
T cells. This may explain, in part, the beneficial effects of treatment Self-tolerance is maintained in part by the suppressive actions
with rituximab, a B-cell–depleting drug, in SLE as autoantibody of Treg. “Natural” Tregs arise de novo in the thymus, whereas
levels remain unaffected. “induced” Tregs evolve from naïve T cells exposed to IL-2 and
transforming growth factor (TGF)-β in the periphery. These
Neutrophils cells are characterized by high surface expression of the IL-2
An important link exists between neutrophils and autoimmunity. receptor α-chain, CD25, and high levels of FOXP3 intracellularly.
Neutrophil extracellular traps (NETS) are chromatin filaments Tregs act together with tolerogenic DC to maintain a steady state
released from neutrophils to trap microbes. In addition to of immature DC. In contrast, effector T cells can secrete IFN-γ
microbial peptides, NETS also contain neutrophil peptides, and IL-17 that promote immature DC differentiation to immu-
including neutrophil-encoded antimicrobial peptide LL37 nogenic DC capable of secreting IL-1, IL-6, IL-12, and TNF-α
(cathelicidin). Circulating DNA-containing immune complexes and can activate autoreactive T cells, thereby establishing a
from lupus patients have been shown to contain peptide LL37. feedback loop with impaired Tregs and activation of autoreactive
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These combined DNA/LL37 immune complexes are potent TLR9 T cells. Studies demonstrate alterations in Tregs in patients
stimulants, resulting in production of IFN-α by plasmacytoid with SLE. Some have demonstrated reduced numbers and altered
+
+
+
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DC (pDC). Moreover, anti-RNP antibodies also induce “NETosis” function of peripheral CD4 CD25 FOXP3 cells in patients with
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in a process that is dependent on TLR7 and FcγRIIa signaling. active disease, whereas others fail to identify a defect. 39
Thus it is possible that autoantibodies accelerate NET formation
and increase formation of DNA/LL37 immune complexes and HORMONAL INFLUENCES
pDC production of IFN-α. These studies confirm earlier work
that described a “granulocyte signature” with significant upregula- The most compelling evidence for the role of sex hormones in
tion of granulocyte-specific transcripts within peripheral blood SLE is the observation that lupus preferentially affects women
mononuclear cells in pediatric SLE patients. 35 of childbearing age. The female-to-male ratio is 2 : 1 before
menarche, 8–9 : 1 in the fourth decade, and 2 : 1 after menopause.
Dendritic Cells Numerous case reports and studies of disease flares correlating
DCs recognize pathogens through membrane pattern recognition with pregnancy, menstruation, and use of oral contraceptives
receptors (PRRs) and are a critical component of the immune containing high doses of estrogen suggest a role for estrogen in
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system connecting innate and adaptive immune responses. They disease activity. A significant correlation between plasma levels
can be tolerogenic or highly inflammatory due to their high of estradiol and clinical disease activity and increased
expression of costimulatory molecules. DCs function normally α-hydroxylation of estrogen in SLE yielding the more active
40
as surveillance cells, phagocytizing cellular debris and determining metabolite 16α-hydroxyestrone are also reported. No significant
whether there is cause for alarm. PRRs on DCs bind pathogen- differences in levels of sex hormones (including estrogen, tes-
associated molecular patterns (PAMPs) and damage-associated tosterone, prolactin) are noted in male SLE patients, suggesting
molecular patterns (DAMPs) that are present in sterile inflam- that the development of SLE in females may be more closely
mation. After internalization of the PAMPs or DAMPs, endosomal related to sex hormones than in men. Randomized controlled
TLRs are activated by nucleic acids and other ligands. Enhanced studies of estrogen in SLE suggest that the use of exogenous