Page 706 - Clinical Immunology_ Principles and Practice ( PDFDrive )

680 ParT Six Systemic Immune Diseases

are associated with increased risk of a variety of autoimmune
diseases, including type I DM, Graves disease, and RA. Similarly, Dominance and Crypticity
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a functional polymorphism in protein tyrosine phosphatase, Studies by Sercarz et al. have stressed that although antigens
non–receptor type 22 (PTPN22), has been identified as a major contain numerous potential determinants that could be presented
risk factor for several human autoimmune diseases, including SLE, on major histocompatibility complex (MHC) class II molecules
RA, and type I DM. Although the exact mechanisms underlying during antigen processing, not all determinants in a particular
susceptibility to autoimmunity remain unclear, in both cases, the molecule are equally likely to be efficiently presented. Those
polymorphisms appear to regulate the balance of stimulatory determinants that are most efficiently presented are termed
and inhibitory signaling in effector and Tregs, favoring effector “dominant”; those that are not loaded onto MHC class II to a
T-cell activation. significant degree are termed “cryptic.” For self antigens, it is
Recent genetic studies have also suggested a potential role for likely that a constant set of dominant determinants are generated
innate immune sensors in autoimmunity, focusing attention on during antigen processing under most circumstances, with similar
the critical balance between activation of the immune response outcomes in the thymus and the periphery. Antigens processed
to mitigate infectious damage and limiting the magnitude of by the “standard” pathway are, therefore, fully tolerized, with
the response to avoid immunopathology. Gain-of-function (GOF) the T-cell repertoire purged of reactivity to the dominant self.
variants of IFIH1 (encoding melanoma differentiation-associated However, the balance of dominant and cryptic epitopes presented
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protein 5 [MDA5]) are associated with susceptibility to SLE. during antigen processing is influenced significantly by changes
This RNA helicase is essential for the detection of cytoplasmic of protein structure, which occur during various relevant physi-
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viral RNA and activation of type I interferon (IFN) secretion ological states (Chapter 6). Several potential mechanisms that
by infected cells. The increased susceptibility to SLE with increased may alter antigen processing to reveal potentially cryptic epitopes
function of this antiviral pathway suggests that excessive IFN are summarized below.
signaling may facilitate the development of autoimmunity. Key
immune signaling pathways that protect the host from deleterious High-Affinity Binding of Antigen to Ligands or Antibodies
infectious and malignant challenges but potentially also enhance Several studies have demonstrated that antigen processing can
damage of self tissues in the process may, therefore, be important be dramatically altered when the antigen binds with high affinity
susceptibility factors in autoimmune diseases. to a ligand or antibody. The study by Simitsek and colleagues
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Thus there are many barriers to the development of autoim- (reviewed in Lanzavecchia ) demonstrated that presentation of
munity, including effective tolerance induction in the thymus T-cell determinants in tetanus toxin can be either enhanced or
and the periphery, tightly regulated immune signaling, and suppressed as a direct consequence of antibody modulation of
homeostatic pathways of immunoregulation to limit anti-self antigen processing in human B-lymphoblastoid cells. Remark-
responses should they occur. It is likely that the genetic susceptibil- ably, a single bound antibody can simultaneously enhance the
ity to autoimmunity in outbred humans represents an integrated presentation of one T-cell determinant by more than 10-fold
threshold involving genes that regulate these various pathways— while strongly suppressing the presentation of a different T-cell
upon which environmental and stochastic events act to accomplish determinant. Biochemical analyses have shown that both the
disease initiation and propagation. suppressed and boosted determinants fall within an extended
domain of antigen stabilized by this antibody during proteolysis.
PHASE 2: INITIATION Thus ligand-induced changes in processing can destroy dominant
determinants or reveal cryptic self determinants. Similar observa-
Initiation of an adaptive immune response requires presentation tions have also been made with numerous other antigen–antibody
to T cells of suprathreshold concentrations of molecules with partners. 15
structure not previously tolerized by the host. One of the more
persuasive models proposed to explain the persistence of poten- Tissue-Specific Protease Expression
tially autoreactive T cells within the repertoire of the host is that The study by Watts and associates (reviewed in Darrah and
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of immunodominance of T-cell epitopes. This model provides Rosen ) showed that a principal human leukocyte antigen–D
major insights into the pathogenesis of autoimmunity. 11,14 related type 2 (HLA-DR2)–restricted epitope in myelin basic
protein amino acids 85–99 (MBP85–99) contains a processing
site for asparagine endopeptidase (AEP), with cleavage by AEP
abolishing the epitope. AEP activity is, therefore, a critical factor
KEY CONCEPTS in presentation of this epitope. In human antigen-presenting
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Potential Mechanisms That Can Alter Antigen cells (APCs), presentation of MBP85–99 is inversely proportional
Processing to Reveal Potentially Cryptic Epitopes to the amount of cellular AEP activity, and inhibition of AEP
greatly enhances presentation of the MBP85–99 epitope. Interest-
• Modification of autoantigen processing through high-affinity binding ingly, both MBP and AEP are expressed in the thymus, AEP at
to ligands or antibodies abundant levels. These data suggest that this major epitope in
• Distinct proteolytic machinery in the thymus and periphery—or dif-
ferential modification of proteolytic activity neurological autoimmunity may not be presented under normal
• Modification of autoantigen structure that modifies its processing by circumstances in the thymus as a result of destruction by AEP,
endogenous antigen-presenting cell (APC) machinery, generally through therefore raising the potential for later presentation in the
posttranslational modifications periphery in the setting of decreased AEP activity.
• Novel proteolytic events not present in the normal APC pathways
(e.g., novel cleavage during cell death or damage or inflammation) Posttranslational Modification of Autoantigen Structure
• Novel forms of autoantigens generated by mutation, truncation, or
splicing Autoantigens undergo a variety of posttranslational modifications,
including phosphorylation, proteolytic cleavage, ubiquitination,