Myasthenia gravis associated with concurrent inflammatory myopathy is a rare but well-described syndrome, most often seen in patients with thymoma. We present a case of biopsy-proven granulomatous ...myositis associated with positive acetylcholine receptor binding, blocking, and modulating and antistriated antibodies, without clear clinical symptoms of myasthenia gravis and in the absence of thymoma. In addition, we include rarely reported neuromuscular ultrasound findings of granulomatous myositis in a patient without sarcoidosis. Inflammatory myopathy may precede development of myasthenia gravis in myasthenia gravis associated with concurrent inflammatory myopathy, and it is important to remain vigilant for symptoms suggestive of myasthenia gravis, especially in the presence of positive myasthenia-associated antibodies.
Objective
Toll‐like receptor 7 (TLR‐7), TLR‐8, and interferon (IFN)–induced genes are expressed in patients with idiopathic inflammatory myositis. This study was undertaken to investigate whether ...their activation influences the natural history of the disease.
Methods
Experimental autoimmune myositis was induced in mice by injection of the amino‐terminal portion of the murine histidyl–transfer RNA synthetase (HisRS). Disease was compared in the presence or the absence of the TLR‐7/8 agonist R‐848 in wild‐type mice and in mice that fail to express the IFNα/β receptor (IFNα/βR‐null mice).
Results
Experimental autoimmune myositis induced by a single intramuscular immunization with HisRS spontaneously abated after 7–8 weeks. In contrast, levels of anti‐HisRS autoantibodies, endomysial/perimysial leukocyte infiltration, and myofiber regeneration persisted at the end of the follow‐up period (22 weeks after immunization) in mice immunized with HisRS in the presence of R‐848. Myofiber major histocompatibility complex (MHC) class I molecules were detectable only in mice immunized with both HisRS and R‐848. MHC up‐regulation occurred early and in muscles that were not directly injected with HisRS. Muscle MHC expression paralleled with leukocyte infiltration. MHC class I molecules were selectively up‐regulated in myotubes challenged with R‐848 in vitro. Type I IFN was necessary for the prolonged autoantibody response and for the spreading of the autoimmune response, as demonstrated using IFNα/βR‐null mice. Muscle infiltration was maintained in the injected muscle up to the end of the follow‐up period.
Conclusion
TLR‐7/8 activation is necessary to induce and maintain a systemic autoimmune response targeting the skeletal muscle. This experimental autoimmune myositis model reproduces many characteristics of human idiopathic inflammatory myopathies and may represent a tool for preclinical studies.
The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung ...abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.
Of the idiopathic inflammatory myopathies, the anti-aminoacyl tRNA synthetase syndrome has the greatest association with interstitial lung disease (ILD). We reviewed 13 open surgical lung biopsies, ...four autopsies, and three native lungs resected at transplantation, for pulmonary ILD associated with the presence of anti-histidyl tRNA synthetase (anti-Jo-1) autoantibodies. Fifty percent (N=10) of patients presented with an acute decompensation of pulmonary function manifested as diffuse alveolar damage, although in five patients (25%) this marked diminution in function was superimposed on an underlying chronic interstitial pneumonia (usual interstitial pneumonia (three); nonspecific interstitial pneumonia(two)). Seven (35%) patients had usual interstitial pneumonia and two (10%) had nonspecific interstitial pneumonia exclusively, whereas one patient presented with an organizing pneumonia (5%). This study is the first to highlight the high biopsy incidence of diffuse alveolar damage in this patient population both de novo and superimposed on underlying chronic ILD, and also shows that usual interstitial pneumonia remains a significant pattern of interstitial injury in this autoimmune group. On the basis of coexisting patterns of lung injury, this study also suggests that nonspecific interstitial pneumonia in connective tissue disorders may progress over time to a usual interstitial pneumonia pattern of fibrosis, an observation that could be better assessed with future inclusion of autopsy and transplanted native lungs in study groups.
Background
Biomarkers have been proposed as tools to aid in the identification and prognostication of interstitial lung disease (ILD) in rheumatoid arthritis (RA). We performed a systematic review of ...studies evaluating peripheral blood biomarkers and their association with RA‐ILD and its prognosis.
Methods
Medline, Embase, the Cochrane Library, and Scopus were queried for relevant studies, with the final search update on July 12, 2021. We included studies evaluating peripheral blood biomarkers for the identification and/or prognostication of RA‐ILD, extracting the performance of individual biomarkers for identifying RA‐ILD, and predicting prognosis. Modified versions of the Quality Assessment of Diagnostic Accuracy Studies 2 and the Quality in Prognosis Studies tools were used for quality assessment.
Results
Seventy studies met eligibility criteria. Study and patient characteristics, analytical methods, strength and consistency of associations, and study quality were heterogeneous. A total of 92 biomarkers were positively associated and 12 were negatively associated with RA‐ILD among patients with RA in one or more report. Only a small number of biomarkers were evaluated in multiple cohorts using adjusted analyses. Biomarkers most strongly associated with RA‐ILD overlapped with those identified for idiopathic pulmonary fibrosis. Few prognostic biomarkers of RA‐ILD were identified.
Conclusion
Several peripheral blood biomarkers are associated with the presence of RA‐ILD, but few have been assessed in multivariable models, have been externally validated, have discriminated RA‐ILD from other lung disease, or have prognosticated the disease course. High‐quality studies investigating and validating peripheral biomarkers in RA‐ILD are needed before they can be employed in clinical care.
In the conventional paradigm of humoral immunity, B cells recognize their cognate antigen target in its native form. However, it is well known that relatively unstable peptides bearing only partial ...structural resemblance to the native protein can trigger antibodies recognizing higher-order structures found in the native protein. On the basis of sound thermodynamic principles, this work reveals that stability of immunogenic proteinlike motifs is a critical parameter rationalizing the diverse humoral immune responses induced by different linear peptide epitopes. In this paradigm, peptides with a minimal amount of stability (DeltaG(x)<0 kcal/mol) around a proteinlike motif (x) are capable of inducing antibodies with similar affinity for both peptide and native protein, more weakly stable peptides (DeltaG(x)>0 kcal/mol) trigger antibodies recognizing full protein but not peptide, and unstable peptides (DeltaG(x)>8 kcal/mol) fail to generate antibodies against either peptide or protein. Immunization experiments involving peptides derived from the autoantigen histidyl-tRNA synthetase verify that selected peptides with varying relative stabilities predicted by molecular dynamics simulations induce antibody responses consistent with this theory. Collectively, these studies provide insight pertinent to the structural basis of immunogenicity and, at the same time, validate this form of thermodynamic and molecular modeling as an approach to probe the development/evolution of humoral immune responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Post-translational protein modifications such as citrullination have been linked to the breach of immune tolerance and clinical autoimmunity. Previous studies from our laboratory support this ...concept, demonstrating that autoantibodies targeting citrullinated isoforms of heat shock protein 90 (HSP90) are associated with rheumatoid arthritis complicated by interstitial lung disease. To further explore the relationship between citrullination and structural determinants of HSP90 immunogenicity, we employed a combination of ELISA-based epitope profiling, computational modeling, and mass-spectrometric sequencing of peptidylarginine deiminase (PAD)-modified protein. Remarkably, ELISAs involving selected citrullinated HSP90β/α peptides identified a key epitope corresponding to an internal Arg residue (R502 HSP90β/R510 HSP90α) that is normally buried within the crystal structure of native/unmodified HSP90. In vitro time/dose-response experiments reveal an ordered pattern of PAD-mediated deimination events culminating in citrullination of R502/R510. Conventional as well as scaled molecular dynamics simulations further demonstrate that citrullination of selected Arg residues leads to progressive disruption of HSP90 tertiary structure, promoting exposure of R502/R510 to PAD modification and subsequent autoantibody binding. Consistent with this process, ELISAs incorporating variably deiminated HSP90 as substrate Ag indicate a direct relationship between the degree of citrullination and the level of ex vivo Ab recognition. Overall, these data support a novel structural paradigm whereby citrullination-induced shifts in protein structure generate cryptic epitopes capable of bypassing B cell tolerance in the appropriate genetic context.
Pulmonary complications of inflammatory myopathy Miller, Shelly A; Glassberg, Marilyn K; Ascherman, Dana P
Rheumatic diseases clinics of North America,
05/2015, Letnik:
41, Številka:
2
Journal Article
Recenzirano
Pulmonary complications cause significant morbidity and mortality in the idiopathic inflammatory myopathies. Advances in biomarker discovery have facilitated clinical phenotyping, allowing ...investigators to better define at-risk patient subsets and to potentially gauge disease activity. This serologic characterization has complemented more traditional assessment tools. Pharmacologic management continues to rely on the use of corticosteroids, often in combination with additional immunosuppressive agents. The rarity of myositis-associated interstitial lung disease and lack of controlled trials have limited analyses of treatment efficacy, mandating the development of standardized outcome measures and improvement of data sharing between disciplines.
Abstract Proteomics technologies are often used for the identification of protein targets of the immune system. Here, we discuss the immunoproteomics technologies used for the discovery of ...autoantigens in autoimmune diseases where immune system dysregulation plays a central role in disease onset and progression. These autoantigens and associated autoantibodies can be used as potential biomarkers for disease diagnostics, prognostics and predicting/monitoring drug responsiveness (theranostics). Here, we compare a variety of methods such as mass spectrometry (MS)-based serological proteome analysis (SERPA), antibody mediated identification of antigens (AMIDA), circulating immune complexome (CIC) analysis, surface enhanced laser desorption/ionization-time of flight (SELDI-TOF), nucleic acid based serological analysis of antigens by recombinant cDNA expression cloning (SEREX), phage immunoprecipitation sequencing (PhIP-seq) and array-based immunoscreening (proteomic microarrays), luciferase immunoprecipitation systems (LIPS), nucleic acid programmable protein array (NAPPA) methods. We also review the relevance of immunoproteomic data generated in the last 10 years, with a focus on the aforementioned MS based methods.
The idiopathic inflammatory myopathies (IIMs) represent a heterogeneous group of disorders characterized by mononuclear cell infiltration of muscle and varying degrees of muscle dysfunction. To ...better understand the pathogenesis of these diseases, investigators have devised a number of infectious, genetic, and antigen-induced animal models that replicate different aspects of muscle involvement. Although the underlying heterogeneity of disorders encompassed by IIM precludes development of a single unifying model, several recently developed experimental systems have provided tremendous insight regarding the contributions of both immune- and non–immune-mediated disease pathways in various subsets of IIM. In turn, by elucidating the pathogenic roles of such disparate factors as endoplasmic reticulum stress and innate immune signaling, these models have established the foundation for more novel, targeted therapeutic intervention.
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