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Expert Review of Proteomics Jul 2017Auto-immunity against pancreatic beta-cells leads to an absolute shortage of the hormone insulin, resulting in hyperglycemia and the onset of type 1 diabetes (T1D).... (Review)
Review
Auto-immunity against pancreatic beta-cells leads to an absolute shortage of the hormone insulin, resulting in hyperglycemia and the onset of type 1 diabetes (T1D). Proteomic approaches have been used to elucidate the mechanisms of beta-cell dysfunction and death. Areas covered: In the present review, we discuss discoveries in the beta-cell proteome that have contributed to better insights in the role of the beta-cell in T1D. Techniques, such as 2D-DIGE and MALDI imaging, together with new approaches for sample preparation, including laser capture microdissection and immunopeptidomics, have resulted in novel mechanistic insights in the pathogenesis of T1D. We describe how proteomic studies in beta-cell lines as well as isolated islets from animal models and humans have discovered intracellular signaling pathways leading to beta-cell destruction, the generation of neo-antigens through post-translational modifications of beta-cell antigens as well as better biomarkers of disease progression. Expert commentary: Proteomics has contributed to the discovery of beta-cell neo-autoantigen generation through post-translational modifications, hybrid insulin peptide formation and the generation of defective ribosomal gene products. These concepts are revolutionizing our insights in the pathogenesis of T1D, acknowledging a central role for the beta-cell in its own destruction.
Topics: Animals; Autoantigens; Diabetes Mellitus, Type 1; Humans; Insulin-Secreting Cells; Proteome; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 28649880
DOI: 10.1080/14789450.2017.1345633 -
RNA Biology Feb 2021The RNA-binding protein LARP1 has generated interest in recent years for its role in the mTOR signalling cascade and its regulation of terminal oligopyrimidine (TOP)... (Review)
Review
The RNA-binding protein LARP1 has generated interest in recent years for its role in the mTOR signalling cascade and its regulation of terminal oligopyrimidine (TOP) mRNA translation. Paradoxically, some scientists have shown that LARP1 represses TOP translation while others that LARP1 activates it. Here, we present opinions from four leading scientists in the field to discuss these and other contradictory findings.
Topics: Animals; Autoantigens; Binding Sites; Carrier Proteins; Gene Expression Regulation; Humans; Multigene Family; Protein Binding; Protein Interaction Domains and Motifs; RNA; RNA Cleavage; RNA-Binding Proteins; Ribonucleoproteins; Signal Transduction; Substrate Specificity; SS-B Antigen
PubMed: 32233986
DOI: 10.1080/15476286.2020.1733787 -
Advanced Drug Delivery Reviews 2020Antigen-specific immunotherapies (ASIT) present compelling potential for introducing precision to the treatment of autoimmune diseases where nonspecific, global... (Review)
Review
Antigen-specific immunotherapies (ASIT) present compelling potential for introducing precision to the treatment of autoimmune diseases where nonspecific, global immunosuppression is currently the only treatment option. Central to ASIT design is the delivery of autoantigen, which parallels allergy desensitization approaches. Clinical success in tolerizing allergen-specific responses spans longer than a century, but autoimmune ASITs have yet to see an FDA-approved breakthrough. Allergens and autoantigens differ substantially in physicochemical properties, and these discrepancies influence the nature of their interactions with the immune system. Approved allergen-specific immunotherapies are typically administered as water soluble, neutrally charged protein fractions from 10 to 70 kDa. Conversely, autoantigens are native proteins that exhibit wide-ranging sizes, solubilities, and charges that render them susceptible to immunogenicity. To translate the success of allergen hyposensitization to ASIT, delivery strategies may be necessary to effectively format autoantigens, guide biodistribution, and engage appropriate immune mechanisms.
Topics: Allergens; Autoantigens; Autoimmune Diseases; Biological Transport; Desensitization, Immunologic; Drug Administration Routes; Drug Delivery Systems; Humans; Immunotherapy
PubMed: 32325104
DOI: 10.1016/j.addr.2020.04.005 -
Neurological Sciences : Official... Jun 2022Paraneoplastic neurological syndromes (PNSs) are group of disorders affecting one or multiple parts of the neuroaxis associated with underlying tumors. An antibody or... (Review)
Review
Paraneoplastic neurological syndromes (PNSs) are group of disorders affecting one or multiple parts of the neuroaxis associated with underlying tumors. An antibody or autoantigen-specific cell-mediated immune response against neural antigen expressed in the tumor is the potential etiology for these rare but refractory disorders. In recent years, wide variety of neurological presentations and autoantibodies has been associated with paraneoplastic autoimmunity, leading to formulation of an updated expert consensus PNS diagnostic criteria. Recognition of these phenotypes and use of serological biomarkers may aid neurologists in early diagnosis of PNS cases encountered in the inpatient or outpatient practice. In this review article, we provide an overview of various clinical, radiological, and immunopathological characteristics of PNS. Furthermore, we discuss the updated PNS criteria and increasing recognition of neurological presentations resembling the PNS among patients receiving immune checkpoint inhibitors.
Topics: Autoantibodies; Autoantigens; Humans; Neoplasms; Paraneoplastic Syndromes, Nervous System
PubMed: 35460452
DOI: 10.1007/s10072-022-06083-y -
ELife Oct 2022Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of...
Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.
Topics: Humans; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Bacteriophages; COVID-19; Homeodomain Proteins; Immunoprecipitation; Proteome
PubMed: 36300623
DOI: 10.7554/eLife.78550 -
Biochemistry. Biokhimiia Jan 2017This review considers the functions of extracellular actin - cell surface bound, associated with extracellular matrix, or freely circulating. The role of this protein in... (Review)
Review
This review considers the functions of extracellular actin - cell surface bound, associated with extracellular matrix, or freely circulating. The role of this protein in different pathological processes is analyzed: its toxic effects and involvement in autoimmune diseases as an autoantigen. The extracellular actin clearance system and its role in protection against the negative effects of actin are characterized. Levels of free-circulating actin, anti-actin immunoglobulins, and components of the actin clearance system as prognostic biomarkers for different diseases are reviewed. Experimental approaches to protection against excessive amounts of free-circulating F-actin are discussed.
Topics: Actins; Animals; Autoantibodies; Autoantigens; Autoimmune Diseases; Biomarkers; Humans; Prognosis
PubMed: 28320282
DOI: 10.1134/S0006297917010011 -
Journal of Proteome Research Jun 2023Understanding autoimmunity to endogenous proteins is crucial in diagnosing and treating autoimmune diseases. In this work, we developed a user-friendly AAgAtlas portal...
Understanding autoimmunity to endogenous proteins is crucial in diagnosing and treating autoimmune diseases. In this work, we developed a user-friendly AAgAtlas portal (http://biokb.ncpsb.org.cn/aagatlas_portal/index.php#), which can be used to search for 8045 non-redundant autoantigens (AAgs) and 47 post-translationally modified AAgs against 1073 human diseases that are prioritized by a credential score developed by multisource evidence. Using AAgAtlas, the immunogenic properties of human AAgs was systematically elucidated according to their genetic, biophysical, cytological, expression profile, and evolutionary characteristics. The results indicated that human AAgs are evolutionally conserved in protein sequence and enriched in three hydrophilic and polar amino acid residues (K, D, and E) that are located at the protein surface. AAgs are enriched in proteins that are involved in nucleic acid binding, transferase, and the cytoskeleton. Genome, transcriptome, and proteome analyses further indicated that AAb production is associated with gene variance and abnormal protein expression related to the pathological activities of different tumors. Collectively, our data outlines the hallmarks of human AAgs that facilitate the understanding of humoral autoimmunity and the identification of biomarkers of human diseases.
Topics: Humans; Autoantigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; Amino Acid Sequence
PubMed: 37183442
DOI: 10.1021/acs.jproteome.2c00799 -
Frontiers in Immunology 2024Autoimmune blistering disorders (AIBDs) are a heterogeneous group of approximately a dozen entities comprising pemphigus and pemphigoid disorders and dermatitis... (Review)
Review
Autoimmune blistering disorders (AIBDs) are a heterogeneous group of approximately a dozen entities comprising pemphigus and pemphigoid disorders and dermatitis herpetiformis. The exact diagnosis of AIBDs is critical for both prognosis and treatment and is based on the clinical appearance combined with the detection of tissue-bound and circulating autoantibodies. While blisters and erosions on the skin and/or inspectable mucosal surfaces are typical, lesions may be highly variable with erythematous, urticarial, prurigo-like, or eczematous manifestations. While direct immunofluorescence microscopy (IFM) of a perilesional biopsy is still the diagnostic gold standard, the molecular identification of the major target antigens opened novel therapeutic avenues. At present, most AIBDs can be diagnosed by the detection of autoantigen-specific serum antibodies by enzyme-linked immunosorbent assay (ELISA) or indirect IFM when the clinical picture is known. This is achieved by easily available and highly specific and sensitive assays employing recombinant immunodominant fragments of the major target antigens, i.e., desmoglein 1 (for pemphigus foliaceus), desmoglein 3 (for pemphigus vulgaris), envoplakin (for paraneoplastic pemphigus), BP180/type XVII collagen (for bullous pemphigoid, pemphigoid gestationis, and mucous membrane pemphigoid), laminin 332 (for mucous membrane pemphigoid), laminin β4 (for anti-p200 pemphigoid), type VII collagen (for epidermolysis bullosa acquisita and mucous membrane pemphigoid), and transglutaminase 3 (for dermatitis herpetiformis). Indirect IFM on tissue substrates and in-house ELISA and immunoblot tests are required to detect autoantibodies in some AIBD patients including those with linear IgA disease. Here, a straightforward modern approach to diagnosing AIBDs is presented including diagnostic criteria according to national and international guidelines supplemented by long-term in-house expertise.
Topics: Humans; Autoantibodies; Autoimmune Diseases; Autoantigens; Skin Diseases, Vesiculobullous; Enzyme-Linked Immunosorbent Assay
PubMed: 38903493
DOI: 10.3389/fimmu.2024.1363032 -
Journal of Autoimmunity Jan 2023Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with...
OBJECTIVES
Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM.
METHODS
Plasma samples from 217 patients with IIM according to 2017 EULAR/ACR criteria, including 50 patients with ASSD, 165 without, and two with unknown ASSD status were identified retrospectively, as well as age and gender-matched sera from 156 population controls, and 219 disease controls. Patients with previously documented ASSD had to test positive for at least one of the five most common anti-aaRS autoantibodies (anti-Jo1, -PL7, -PL12, -EJ, and -OJ) and present with one or more of the following clinical manifestations: interstitial lung disease, myositis, arthritis, Raynaud's phenomenon, fever, or mechanic's hands. Demographics, laboratory, and clinical data of the IIM cohort (ASSD and non-ASSD) were compared. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 117 recombinant protein variants, representing 33 myositis-related proteins, including all nineteen cytoplasmic aaRS. Prospectively collected clinical data for the IIM cohort were retrieved and compared between groups within the IIM cohort and correlated with the results of the autoantibody screening. Principal component analysis was used to analyze clinical manifestations between ASSD, non-ASSD groups, and individuals with novel anti-aaRS autoantibodies.
RESULTS
We identified reactivity towards 16 aaRS in 72 of the 217 IIM patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four previously seronegative patients for myositis-specific autoantibodies and eight with previously detected myositis-specific autoantibodies. IIM individuals with novel anti-aaRS autoantibodies (n = 12) all had signs of myositis, and they had either muscle weakness and/or muscle enzyme elevation, 2/12 had mechanic's hands, 3/12 had interstitial lung disease, and 2/12 had arthritis. The individuals with novel anti-aaRS and a pathological muscle biopsy all presented widespread up-regulation of major histocompatibility complex class I. The reactivities against novel aaRS could be confirmed in ELISA and western blot. Using the multiplex bead array assay, we could confirm previously known reactivities to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n = 45)) and identified patients positive for anti-Zo, -KS, and -HA (n = 10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was also detected in controls.
CONCLUSION
Our results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.
Topics: Humans; Amino Acyl-tRNA Synthetases; Retrospective Studies; Autoantigens; Myositis; Autoantibodies; Lung Diseases, Interstitial; Arthritis; Syndrome
PubMed: 36470210
DOI: 10.1016/j.jaut.2022.102951 -
Advanced Drug Delivery Reviews Jan 2019Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting 3 million individuals in the U.S. The pathogenesis of T1DM is driven by immune-mediated destruction of... (Review)
Review
Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting 3 million individuals in the U.S. The pathogenesis of T1DM is driven by immune-mediated destruction of pancreatic β cells, the source of glucose regulator insulin. While T1DM can be successfully managed with insulin replacement therapy, approaches that can modify the underlying immuno-pathology of β cell destruction has been long sought after. Immunotherapy can attenuate T cell responses against β cell antigens. Given the detailed cellular and molecular definitions of T1DM immune responses, rational immunomodulation can be and have been developed in mouse models, and in some instances, tested in humans. The possibility of identifying individuals who are predisposed to T1DM through genotyping lend to the possibility of preventive vaccines. While much has been accomplished in delineating the mechanisms of immunotherapies, some of which are being tested in humans, long-term preservation of β cells and insulin independency has not been achieved. In this regard, the drug delivery field has much to offer in maximizing the benefits of immune modulators by optimizing spatiotemporal presentation of antigens and costimulatory signals. In this review, we attempt to capture the current state of T1DM immunotherapy by highlighting representative studies.
Topics: Animals; Autoantigens; Biocompatible Materials; Diabetes Mellitus, Type 1; Humans; Immunotherapy
PubMed: 30528629
DOI: 10.1016/j.addr.2018.12.003