Page 716 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 51 Systemic Lupus Erythematosus 689

the tyrosine-kinase proteins Blk and Lyn and B-cell scaffold adaptive immune responses and suggesting that the effect of
protein with ankarin repeats; all are associated with intracellular IFN-α on autoimmunity is complex.
signaling pathways. ETS1 and IKZF1 encode transcription factors Multiple polymorphisms in the IL10 gene have been reported,
and are believed to play a role in B-cell differentiation and self- with conflicting results with respect to SLE susceptibility. A
tolerance. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is meta-analysis of 15 studies concluded that some IL10 polymor-
upregulated on T cells after activation and dampens inflammatory phisms do associate with SLE, but their importance is modulated
responses. It has a higher affinity than CD28 for B7.1 (CD80) by ethnic background. 19
and B7.2 (CD86), thereby competitively inhibiting engagement In the NZB/W murine model, a tumor necrosis factor (TNF)
of CD28 and blocking the costimulatory signal required for T-cell allele associated with low production is linked with disease, and
activation. CTLA-4 ligation of B7 also activates indoleamine treatment with TNF decreases autoantibody production. Con-
dioxygenase (IDO) expression, an enzyme involved in tryptophan sistent with this observation, TNF blockade for rheumatoid
metabolism, and diminishes T-cell proliferation. Finally, CTLA-4 arthritis or inflammatory bowel disease can lead to autoantibody
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is critical for activation of regulatory T cells. In CTLA-4 mice, production and infrequently to frank lupus. Several polymor-
an uncontrolled, lethal inflammatory response occurs. CTLA-4 phisms for genes encoding TNF-α and -β (lymphotoxin-α) have
alleles with decreased production of soluble CTLA-4 are impli- been associated with SLE; these associations are also influenced
cated in the pathogenesis of several autoimmune diseases, by ethnicity. 20
including Sjögren disease, ulcerative colitis, psoriasis, type 1
diabetes, and multiple sclerosis as well as SLE. 16 Genes Associated With Cell Survival
The PTPN22 gene encodes a tyrosine phosphatase that has Fas ligand (expressed on activated T cells) binding to Fas (CD95)
been suggested to downregulate T-cell and B-cell receptor (BCR) stimulates a signaling pathway resulting in apoptotic death of
activation, although the precise role of polymorphic PTPN22 I the Fas-expressing cell. Fas-induced apoptosis of activated cells
disease pathogenesis remains unresolved. A PTPN22 polymor- contributes to the elimination of autoreactive B and T lympho-
phism resulting in diminished ability to control T-cell antigen cytes. Lymphopenia in SLE has been associated with increased
receptor activation has been reported in SLE and other auto- Fas expression on lymphocytes, and Fas and Fas ligand alleles
21
immune diseases, suggesting a common mechanism of immune have been linked to disease susceptibility. Whereas lack of Fas
dysregulation. The PTPN22 risk allele has also been associated expression in mice leads to an SLE-like phenotype, lack of Fas
with reduced type I IFN production by myeloid cells after activa- expression in humans is associated with a lymphoproliferative
tion of Toll-like receptor (TLR) 7. disease that does not share autoantigen specificities and target
organs with SLE.
Genes Encoding Cytokines and Chemokines Bcl-2 family genes encode intracellular proteins that are either
IFN regulatory factor 5 gene (IRF5) encodes a critical transcription pro- or antiapoptotic. Increased expression of Bcl-2, an anti-
factor in the type I IFN pathway; the IRF5 locus has the strongest apoptotic molecule, leads to a lupus-like serology and nephritis
association with SLE outside of the MHC region. Four allelic in mice with certain genetic backgrounds. Increased intracellular
variants have been identified in multiple ethnically diverse levels of Bcl-2 have been reported in SLE, particularly in Chinese
populations. Variants of the signal transducer and activator of and Mexican populations. The combination of a Bcl-2 susceptibil-
transcription factor 4 protein (STAT4) gene have also been ity allele and interleukin-10 (IL-10) susceptibility allele confers
associated with SLE susceptibility in GWASs of Caucasian and a 40-fold increased risk of SLE, demonstrating that infelicitous
Asian populations. There are data suggesting interaction between combinations of risk alleles potentiate risk. 22
IRF5 and STAT4, and the presence of one or more risk alleles
of the two genes may confer increased susceptibility. IL-1 receptor- Genes Regulating Target Organ Damage
associated kinase 1 (IRAK1) and methyl-CPG-binding protein Only a few genes are known to regulate the vulnerability of
2 (MECP2) genes are both found on the X chromosome. IRAK1 target organs, the kidney in particular, to autoimmune attack.
regulates multiple pathways in innate and adaptive immune In mice, genes encoding kallikreins, which upregulate bradykinins,
responses, including the link between immune complexes, TLR have SLE susceptibility alleles. In human studies a risk allele for
signaling, T-cell receptor (TCR) signaling, and IFN production. ABIN1, which regulates nuclear factor (NF)-κB activation, can
Monocyte chemoattractant protein (MCP-1) is a potent chemoat- lead to greater kidney disease. Two risk alleles of APDOL1 are
tractant for monocytes, memory T cells, and natural killer T particularly common in the African American population and
cells. MCP-1 expression is upregulated in renal tubular cells, and are thought to contribute to the increased severity of renal disease
glomeruli in lupus nephritis and urine levels of MCP-1 are in this population.
increased in patients with active lupus nephritis. An MCP-1
polymorphism resulting in increased MCP-1 production has Epigenetic Contributions
17
been associated with SLE nephritis. Polymorphisms in the Epigenetic regulation plays a determining role in gene activation.
tyrosine kinase-2 (TYK2) gene are associated with increased Major epigenetic influences in SLE involve DNA methylation at
expression of type I IFNs (IFN-α, IFN-β) in SLE. IFN-α-regulated cytosine-guanine nucleotides (CpG methylation) and histone
genes are highly expressed in peripheral blood cells from SLE posttranslational modifications (lysine acetylation or methylation,
18
23
patients compared with healthy controls (the IFN signature). phosphorylation of serine or threonine, arginine methylation).
IFN-α mediates maturation of DCs and monocytes, increasing SLE susceptibility and autoantibody production is associated
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the capacity for T-cell activation, and promotes B-cell differentia- with DNA hypomethylation. Several drugs known to induce
tion and Ig class switching. However, in two murine models of a lupus-like disease (procainamide, hydralazine) also cause
lupus, decreases in type I IFNs unexpectedly led to worsening decreased DNA methylation. A landmark study of high-throughput
disease, consistent with numerous studies showing that type I analysis of DNA methylation in discordant twins demonstrated
25
IFNs have both pro- and antiinflammatory effects on innate and greater DNA hypomethylation in the affected siblings. It is not