Page 705 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 50 Mechanisms of Autoimmunity 679

KEY CONCEPTS Impaired Clearance and Tolerance Induction by
Mechanisms Underlying Susceptibility Apoptotic Cells: Susceptibility Defect in
to Autoimmunity Systemic Autoimmunity
• Incomplete induction of tolerance in the thymus to peripherally Although little is known in humans about the thymic pathways
expressed autoantigens (autoimmune regulator [AIRE] deficiency of tolerance induction to ubiquitously expressed autoantigens,
causing autoimmune polyendocrinopathy with candidiasis and ecto- there is accumulating evidence to suggest that in the periphery,
dermal dysplasia [APECED]) apoptotic cells play an important role in providing a source of
• Impaired clearance and tolerance induction by apoptotic cells (e.g., autoantigens against which the organism becomes tolerant.
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deficiency of C1q, C4, milk fat globule–epidermal growth factor (EGF) Apoptotic cells are generally very efficiently cleared by phagocytic
8 [MFG-E8], Mer)
• Defective production of regulatory T cells (FOXP3 deficiency causing cells; these events are normally associated with the production
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immune dysfunction/polyendocrinopathy/enteropathy/X-linked [IPEX] of antiinflammatory cytokines and result in tolerance induction.
syndrome) Interestingly, early components of the classical complement
• Altered immune signaling thresholds (e.g., cytotoxic T lymphocyte pathway (e.g., C1q and C4) and cross-reactive protein (CRP)
antigen-4 [CTLA-4] polymorphisms, protein tyrosine phosphatase, are required for efficient apoptotic cell clearance, with production
non–receptor type 22 [PTPN22] polymorphisms) of interleukin-10 (IL-10) and transforming growth factor-β
(TGF-β). Therefore it is of particular note that homozygous C1q
deficiency is associated with a striking susceptibility to SLE in
humans, and this suggests that rapid, efficient, tolerance-inducing
clearance of apoptotic cells may play a role similar to AIRE
rare disease in which patients develop multiple autoimmune expression in the thymus in preventing subsequent emergence
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diseases, often beginning in childhood. Although candidiasis of autoimmunity to ubiquitously expressed autoantigens.
and ectodermal dystrophy (including involvement of enamel Additional support for this model comes from recent studies of
and nails, as well as keratopathy) are features of the disease, milk fat globule–epidermal growth factor (EGF) 8 (MFG-E8),
the syndrome is characterized by striking autoimmunity a glycoprotein secreted from macrophages that is required for
directed against multiple different target tissues. Autoimmune the efficient attachment and clearance of apoptotic cells by
processes include autoimmune hypoparathyroidism, Addison macrophages and immature dendritic cells (DCs). MFG-E8 is
disease, autoimmune gastritis with pernicious anemia, type I also expressed in tingible-body macrophages in the germinal
DM, thyroid disease, autoimmune hepatitis, celiac disease, and centers of secondary lymphoid tissues. Interestingly, many
gonadal failure. Numerous autoantigens have been defined as unengulfed apoptotic cells are present in the germinal centers
targets of autoimmunity in APS-1 and include enzymes specifically of the spleen in MFG-E8–deficient mice, which develop a striking
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expressed in various endocrine tissues (e.g., steroid 21-hydroxylase, lupus-like phenotype (reviewed in Rai and Wakeland ). Together,
specific for adrenal cortex; steroid 17α-hydroxylase, found in the data strongly suggest that efficient, antiinflammatory clearance
adrenal cortex and gonads; GAD65, found in pancreatic islets; of apoptotic cells plays a central role in tolerance induction and
and thyroid peroxidase). The genetic basis of APS-1 was mapped prevention of autoimmunity.
to a gene on chromosome 21q22.3, subsequently termed AIRE
(for autoimmune regulator). AIRE expression is highest in the Defective Production of Regulatory T Cells
thymus, where it is expressed in medullary thymic epithelial Although there are pathways that (i) regulate autoantigen expres-
cells. Several predicted structural features of the AIRE protein sion at sites of tolerance induction and (ii) guide autoantigens
and its localization in nuclear dots suggested that the protein toward tolerance-inducing outcomes, these pathways alone are
might be a transcriptional regulator, and significant evidence clearly insufficient to prevent the emergence of autoimmune
for this proposal was obtained in vitro. Several AIRE-deficient disease. This fact is highlighted by the emergence of autoimmunity
mouse models were subsequently generated, which allowed for when regulatory T-cell (Treg) differentiation is abnormal in
the definition of important pathogenic pathways in APS-1 that humans with IPEX syndrome, the human equivalent of the scurfy
may be broadly relevant to the mechanisms of autoimmunity mouse. IPEX is a rare, X-linked recessive disorder characterized
in general. Thus mice deficient in AIRE developed various by type I DM, thyroiditis, atopic dermatitis, and inflammatory
autoimmune phenotypes, resembling those found in human bowel disease (IBD) and is caused by mutations in the FOXP3
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APS-1. These included multiorgan lymphocytic infiltration gene. FOXP3 is a member of the forkhead family of transcription
+
and autoantibodies, as well as autoimmune eye disease. In an factors and is essential for the development of CD4 Tregs, which
elegant series of experiments, Anderson et al. demonstrated that have been shown to regulate the activation and differentiation
AIRE regulates expression in thymic epithelial cells of various of effector T cells at many different levels (Chapter 18).
peripheral autoantigens normally expressed exclusively in endo- Preliminary investigations into the role of Tregs in human
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crine target tissues. Thus AIRE appears to regulate the ectopic autoimmune diseases have produced mixed results, but these
expression in the thymus of tissue-restricted autoantigens and cells likely play important roles in regulating disease onset and
to provide an antigen source against which to establish central amplitude. As additional cell subsets and details about function
tolerance. 8 emerge, this area will be clarified significantly.
These data demonstrate that expression of peripheral autoan-
tigens in the thymus constitutes a major barrier to the subsequent Signaling Thresholds and Susceptibility
development of autoimmunity against these peripheral sites. to Autoimmunity
Although it is possible that similar principles apply to ubiquitously Several modulators of T-cell signaling have been defined as impor-
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expressed autoantigens targeted in systemic autoimmune diseases, tant susceptibility determinants in autoimmunity. For example,
there are currently few data directly addressing this issue. cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphisms