Page 707 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 50 Mechanisms of Autoimmunity 681

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transglutamination, citrullination, and isoaspartyl modification. mechanism may play an important role in generating immune
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In several cases, autoantibodies recognize exclusively the modified responses to self and tumor antigens. In this study, Engelhorn
form of the antigen (e.g., RNA polymerase-II large subunit, serine/ et al. examined whether mutated self gene products are more
arginine-rich [SR] proteins, citrullinated vimentin, and other likely to initiate immunity and used a systematic approach to
RA autoantigens), indicating that the modified forms of the define some of the principles that determine this. They generated
molecules are important in driving the immune response. In complementary DNA (cDNA) libraries encoding large numbers of
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addition, Doyle and Mamula have demonstrated that post- random mutations in syngeneic TRPs. They then used an approach
translational modification of autoantigen structure may be more of DNA immunization of black mice to test the immunogenicity
broadly relevant than can be appreciated by studying autoantibody of the altered proteins encoded by the pools of mutated cDNA.
specificity alone. They showed that although mouse immunization Immunization with nonmutated proteins induced no detectable
with a murine cytochrome c peptide (amino acids 90–104) immune responses, consistent with establishment of tolerance to
resulted in no T- or B-cell response, immunization with the the full-length molecules. In contrast, the mutated cDNA pools
isoaspartyl form of this peptide resulted in strong T- and B-cell elicited both autoimmune depigmentation and the ability to reject
responses. The autoantibodies that were elicited recognized both melanoma tumors. Additional analysis showed that autoimmunity
the modified and the native forms of the antigen, but T cells resulted from mutations that altered autoantigen cell biology,
only recognized the isoaspartyl form. Similar observations have particularly degradation rates and pathways. Mutations also
also been made for several SLE autoantigens. The difficulty created new T-helper (Th) cell epitopes and induced recognition
detecting and quantifying antigen-specific T cells in various of nonmutated but previously cryptic epitopes. Interestingly,
autoimmune diseases may reflect their preferential recognition mutations themselves did not form part of CD8 epitopes that drive
of subtly modified forms of autoantigen. This is an important the anti-self and antitumor immune responses. Mutated molecules
area for future study—currently there is no systematic way to that were immunogenic were frequently truncated, leading the
generate the relevant autoantigen forms. authors to propose that inappropriately truncated self proteins
can provoke autoimmunity when present in a proinflammatory
Novel Antigen Cleavage During Cell Damage, Cell Death, environment. This study has provided an important mechanistic
or Inflammation underpinning for the proposal that accumulated mutations have
Recent studies have provided evidence that single proteolytic a role in the initiation of autoimmunity and that “autoimmunity”
events early in antigen processing can play critical roles in defin- might target the cancer mutanome.
ing the epitopes generated. For example, Watts and colleagues Recent work in the autoimmune rheumatic diseases (sclero-
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(reviewed in Darrah and Rosen ) have conclusively demonstrated derma and dermatomyositis) highlights the relationship between
that early cleavage by AEP determines subsequent proteolytic cancer and the autoimmune process. In these diseases, patients
events. Modifications of the antigen that affect this early cleav- demonstrate an increased risk of cancer compared with controls.
age dramatically change the epitopes loaded onto MHC class They also show a temporal clustering of cancer diagnosis around
II molecules. 16 the time of dermatomyositis or scleroderma onset (reviewed in
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Inflammatory microenvironments can create significant Shah ). Similarly, there is evidence for an association between
potential to load distinct epitopes because unique proteolytic SLE and cancer, particularly lymphoma, clustered within the first
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activities are present. Activated inflammatory cells constitute a 2 years of SLE diagnosis. These associations, both with timing
major source of proteases, including various cytotoxic lymphocyte of diagnosis and preferentially with specific tumor types, are
granule proteases (granzymes), as well as numerous neutrophil strongly indicative of a nonrandom clustering of autoimmune
and monocyte granule proteases. It is of interest that numerous processes and cancer, which is likely of mechanistic significance.
autoantigens targeted in systemic autoimmune diseases are The mechanistic link between scleroderma and cancer was
substrates for these inflammatory proteases and that unique confirmed in a study that tested the hypothesis that an anticancer
autoantigen fragments are generated through the activity of immune response may target a mutated autoantigen in the
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granzyme B and potentially other similar proteases. Such patient’s cancer, which spreads to the wild-type version of the
autoantigen forms are not generated during other forms of cell antigen to trigger a self-sustaining autoimmune disease (reviewed
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damage or death, and similar activity is not observed against in Shah ). In this study of patients with scleroderma and cancer,
nonautoantigens. Thus novel proteolytic cleavage of intracellular genetic changes (either mutations or loss of heterozygosity) were
autoantigens during activity of cytotoxic immune effector identified in POLR3A (encoding RNA polymerase III large
pathways may provide a source of cryptic epitopes not generated subunit) in the tumors of six of eight patients with anti-RNA
during homeostatic “tolerance-inducing” tissue turnover. Direct polymerase III antibodies, whereas no such changes were identified
evidence that inflammatory protease-mediated revelation of in eight patients who lacked these antibodies. Anti-RNA poly-
cryptic epitopes is relevant to initiation of autoimmunity in vivo merase III autoantibodies in patients with cancer demonstrated
is still needed. no specificity for the mutant form of the protein over the wild-
type version, and analyses of peripheral blood lymphocytes
Autoantigen Alteration Caused by Mutation, Truncation, identified T-cell reactivity against the mutant protein. These data
or Splicing suggest that somatic mutations arising in the context of cancer
Since the final epitopes generated and loaded onto MHC class II may prompt immune responses that mediate immunoediting
molecules can be profoundly influenced by single, early cleavage as well as damage to nontumor host tissues.
events during antigen processing, relatively minor but critically It is, therefore, likely that somatic mutations acquired with
placed changes in the primary structure of autoantigens can age and their association with malignancy are important in the
have the capacity to influence peptide selection. A study of the genesis of some forms of human autoimmunity. Additional studies
melanoma and vitiligo-associated autoantigens, tyrosinase-related to confirm this and elucidate the underlying mechanisms remain
proteins (TRPs) 1 and 2 has strikingly demonstrated that this a high priority. However, the barriers to such studies in humans