Page 709 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 50 Mechanisms of Autoimmunity 683

recent studies have demonstrated that components from stressed, autoimmunity, IFN-α–inducing activity is abrogated by chlo-
injured, and dying cells may play critical roles in this regard. 6 roquine or bafilomycin, agents that interfere with endosome
Working in several models, numerous investigators have now acidification and TLR7 and TLR9 signaling. In addition, Rön-
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provided evidence that the frequent targeting of nucleoprotein nblom and colleagues (reviewed in Hall and Rosen ) demon-
autoantigens (which contain DNA or RNA) results from the ability strated that when added to material from apoptotic or necrotic
of these nucleic acid components to ligate TLRs (reviewed in cells, autoantibodies from patients with SLE and Sjögren syndrome
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Kawasaki et al. ). For example, antichromatin immune complexes with specificity for DNA or RNA autoantigens induce striking
can activate DCs and B cells through ligation of both FcγR and IFN secretion. Type I IFNs have a broad set of functions that
TLR9. B-cell activation via TLR7 ligation by RNA-containing likely contribute to the feed forward, propagation phase of
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immune complexes has also been demonstrated. In vivo studies systemic autoimmune diseases. For example, they (i) promote
have linked these in vitro findings to the development of autoim- the differentiation of monocytes into mature DCs, which drive
munity. For example, when TLR9 deficiency is bred onto MRL-lpr autoreactive T- and B-cell responses; (ii) increase target cell
mice—which are an excellent model of SLE—animals no longer sensitivity to killing pathways; (iii) upregulate cytotoxic effector
develop autoantibody responses to chromatin. Interestingly, these pathways; and (iv) upregulate expression of autoantigens, such
animals, nevertheless, manifest the SLE phenotype—in some cases, as Ro52.
more severely than the TLR9-sufficient animals. Similarly, when This general ability of autoantigens, particularly in the context
mice are rendered TLR7 deficient, the autoantibody response to of immune complexes, to stimulate secretion of IFN and other
Sm is markedly inhibited, and severity of the SLE phenotype is cytokines is likely an important principle in the initiation and
reduced. Reciprocally, overexpression of TLR7 is sufficient to propagation of autoimmunity.
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induce an SLE-like disease (reviewed in Kawasaki et al. ). These
data confirm that autoantigens frequently selected in different Enhanced Autoantigen Expression in the Target Tissue
autoimmune phenotypes likely have the dual property of being The striking association of specific autoantibody responses
able to simultaneously activate the innate and adaptive immune with distinct phenotypes suggests that autoantigen expression
systems. The source, form, and uptake of nucleic acids clearly or form in specific target tissues may play an important role in
influence adjuvant activity. For example, bacterial and viral DNA both focusing the immune response and generating tissue damage.
and oligonucleotides with CpG motifs have significant adjuvant Unfortunately, very little is currently known about such param-
activity, whereas mammalian genomic DNA, in which CpG is eters in vivo in relevant target tissues, both in normal and
usually methylated, has very poor adjuvant activity. In contrast, pathological circumstances.
human DNA present within immune complexes in SLE serum Recent studies on human autoimmune myopathies have begun
activates plasmacytoid DCs effectively in a DNA-dependent way. to provide important insights into this problem. Myositis-specific
Several potential explanations have been advanced to explain these autoantigens are expressed at very low levels in control muscle
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observations. First, FcγR-mediated uptake effectively captures but at high levels in myositis tissue, where antigen expression is
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self DNA bound by anti-DNA antibodies and directs it to the at highest levels in regenerating muscle cells. Interestingly,
correct endosomal compartment for TLR signaling. Second, histidyl tRNA synthetase (HRS) expression is also found at high
coligation of TLR9 and either B-cell receptor or FcγR alters the levels in lungs, and anti-HRS antibodies are associated with
signaling threshold of immune complexes. Last, the difference autoimmune myopathies with interstitial lung disease. Recently,
lies in the nucleic acid itself, with additional modifications of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)
DNA and RNA structure occurring in cells under different physi- was identified as an autoantigen in patients with statin-associated
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ological circumstances (e.g., cell death) and regulating nucleic autoimmune myopathy. In addition to the induction of HMGCR
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acid binding to TLRs. Recent studies have suggested that other protein expression by statin treatment of cultured cells, this group
sensors of PAMPs (e.g., nucleotide-binding oligomerization also demonstrated increased expression of this protein in
domain [NOD]–like receptors [NLRs], RIG-like receptors) may regenerating muscle fibers of anti–HMGCR-positive patients.
play similar roles to TLRs in amplifying adaptive responses to These data suggest that enhanced autoantigen expression in the
specific intracellular autoantigens (e.g., MDA5, interferon-γ– target tissue may be a feature of disease propagation and that
inducible protein 16 [IFI16]), but definitive evidence is not yet antigen expression during tissue repair may provide an ongoing
available. antigen source to sustain and amplify tissue damage.
The TLR–IFN interface has been recognized as critical in the Defining whether similar principles are operating in other
propagation phase of systemic autoimmune diseases (reviewed autoimmune diseases and elucidating the pathways of antigen
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in Hall and Rosen, and Swiecki and Colonna ). Much attention expression and modification in relevant target tissues are an
has been focused on plasmacytoid dendritic cells (pDCs), a important areas of focus in future studies and may have important
relatively rare class of immature DCs that can secrete large therapeutic potential.
amounts of type I IFNs upon TLR ligation and that express
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TLR7 and TLR9 at high levels. Recent studies in mouse models
have demonstrated the ability of pDCs to alternately promote ON THE HOriZON
wound healing or chronic inflammation, depending on the • Precise clinical and molecular phenotyping of patients at various disease
predisposing genetic background. For example, nonspecific skin stages is critical for improving diagnosis, monitoring, and treatment
injury in wild-type mice (by tape stripping) leads to pDC recruit- of autoimmune diseases.
ment, TLR7 and TLR9 recognition of nucleic acids, and transient • Understanding mechanisms of disease amplification, propagation, and
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expression of type I IFNs with subsequent wound healing. In regulation will enable the development of effective targeted
contrast, the same skin damage in a lupus-prone mouse strain therapies.
results in chronic inflammation mediated by sustained type I • Understanding the mechanisms of human autoimmunity will likely
IFN expression, which can be ameliorated with pDC depletion provide important insights into the normal functioning of the immune
system, particularly with regard to natural cancer immunity.
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or TLR7/9 inhibition. Extending these observations to human