RESUMEN
Granzyme B (GrB) is an immune protease implicated in the pathogenesis of several human diseases. In the current model of GrB activity, perforin determines whether the downstream actions of GrB occur intracellularly or extracellularly, producing apoptotic cytotoxicity or nonapoptotic effects, respectively. In the current study, we demonstrate the existence of a broad range of GrB-dependent signaling activities that 1) do not require perforin, 2) occur intracellularly, and 3) for which cell death is not the dominant outcome. In the absence of perforin, we show that GrB enzymatic activity still induces substoichiometric activation of caspases, which through nonlethal DNA damage response signals then leads to activity-associated phosphorylation of IFN regulatory factor-3. These findings illustrate an unexpected potential interface between GrB and innate immunity separate from the traditional role of GrB in perforin-dependent GrB-mediated apoptosis that could have mechanistic implications for human disease.
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Fibroblastos/fisiología , Granzimas/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Apoptosis , Supervivencia Celular , Células Cultivadas , Granzimas/genética , Células HEK293 , Humanos , Factor 3 Regulador del Interferón/genética , Mutación/genética , Perforina/metabolismo , Fosforilación , Proteolisis , Transducción de SeñalRESUMEN
OBJECTIVES: Long Interspersed Element 1 (LINE-1) is an endogenous retroelement that constitutes a significant portion of the human genome and has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The LINE-1 RNA chaperone protein ORF1p was recently identified as an SLE autoantigen. Here we analyse ORF1p for qualities underlying SLE autoantigen status, compared anti-ORF1p antibodies to markers of SLE disease activity, and performed screening for antibodies against LINE-1 reverse transcriptase ORF2p. METHODS: ORF1p was examined in epithelial cell lines treated with cytotoxic lymphocyte granules and UV irradiation. Anti-ORF1p and anti-ORF2p antibodies were assayed by ELISA and analysed in two SLE cohorts. RESULTS: We found that ORF1p localises to cytoplasmic RNA-containing blebs in apoptotic cells, and is a substrate of the cytotoxic protease granzyme B (GrB). Anti-ORF1p antibodies were present in 4.2% of healthy controls, compared to 15.8% (p=0.0157) and 15.5% (p=0.036) of subjects in the two SLE cohorts. Anti-ORF1p antibodies were not associated with SLE disease activity nor peripheral blood markers of interferon (IFN) activation. Anti-ORF1p titres demonstrated stability over serial time points. Anti-ORF1p antibodies were not associated with anti-DNA, anti-RNP, or other SLE autoantibodies. There was no difference in anti-ORF2p ELISA results in controls versus SLE patients. CONCLUSIONS: LINE-1 ORF1p is a component of apoptotic blebs and a substrate for GrB. Anti-ORF1p antibodies are enriched in SLE subjects but are not associated with dynamic markers of disease activity. These data support a potential role for LINE-1 dysregulation in SLE pathogenesis.
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Autoanticuerpos , Lupus Eritematoso Sistémico , Humanos , Anticuerpos Antinucleares , Autoantígenos , Granzimas/metabolismo , Interferones/genética , Retroelementos , ARN , ADN Polimerasa Dirigida por ARN/genética , ADN Polimerasa Dirigida por ARN/metabolismoRESUMEN
Inflammasomes are supramolecular signaling platforms integral to innate immune defense against invading pathogens. The NOD-like receptor (NLR) family apoptosis inhibitory protein (NAIP)·NLR family caspase-recruiting domain (CARD) domain-containing 4 (NLRC4) inflammasome recognizes intracellular bacteria and induces the polymerization of the caspase-1 protease, which in turn executes maturation of interleukin-1ß (IL-1ß) and pyroptosis. Several high-resolution structures of the fully assembled NAIP·NLRC4 complex are available, but these structures do not resolve the architecture of the CARD filament in atomic detail. Here, we present the cryo-EM structure of the filament assembled by the CARD of human NLRC4 (NLRC4CARD) at 3.4 Å resolution. The structure revealed that the helical architecture of the NLRC4CARD filament is essentially identical to that of the downstream filament assembled by the CARD of caspase-1 (casp1CARD), but deviates from the split washer-like assembly of the NAIP·NLRC4 oligomer. Our results suggest that architectural complementarity is a major driver for the recognition between upstream and downstream CARD assemblies in inflammasomes. Furthermore, a Monte Carlo simulation of the NLRC4CARD filament assembly rationalized why an (un)decameric NLRC4 oligomer is optimal for assembling the helical base of the NLRC4CARD filament. Together, our results explain how symmetric and asymmetric supramolecular assemblies enable high-fidelity signaling in inflammasomes.
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Proteínas Adaptadoras de Señalización CARD/química , Proteínas de Unión al Calcio/química , Modelos Moleculares , Complejos Multiproteicos/química , Proteína Inhibidora de la Apoptosis Neuronal/química , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteínas de Unión al Calcio/metabolismo , Microscopía por Crioelectrón , Humanos , Complejos Multiproteicos/metabolismo , Complejos Multiproteicos/ultraestructura , Proteína Inhibidora de la Apoptosis Neuronal/metabolismo , Estructura Cuaternaria de ProteínaRESUMEN
PURPOSE OF REVIEW: The ANCA-associated vasculitides are a group of small vessel vasculitides characterized by autoantibodies recognizing the neutrophil cytoplasmic antigens PR3 and MPO. We examine the current clinical and molecular immunology understanding of ANCA-associated vasculitides and discuss the current needs in our understanding of the pathogenic mechanisms of these rare diseases. RECENT FINDINGS: The majority of efforts to understand the pathogenesis of these diseases have focused on dissecting neutrophil biology because the neutrophil is the primary expressor of ANCA autoantigens. However, a number of important genetic, clinical, and cellular biology observations suggest that attempts to understand the pathogenesis of ANCA vasculitides should move away from emphasis on the role of the neutrophil and instead re-focus on the potential role of other immune cell mediators. Whether or not neutrophils are the key determinant of ANCA-associated vasculitis pathogenesis should be revisited in detail. A neutrophil-centric view of the pathogenesis of these diseases cannot fully account for important genetic, clinical, and cellular biology observations that implicate important and under-appreciated roles for monocytes and T cells. Refocusing on these findings will likely lead to new discovery of novel therapeutic targets and the identification of clinically useful biomarkers for disease activity.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/biosíntesis , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Medicina Basada en la Evidencia/métodos , Humanos , Tolerancia Inmunológica/inmunología , Neutrófilos/inmunologíaAsunto(s)
COVID-19 , SARS-CoV-2 , Vacunas contra la COVID-19 , Humanos , Inmunidad Celular , Rituximab , VacunaciónRESUMEN
The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors. A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia. Using a positional cloning strategy, we identified a gene, six-transmembrane epithelial antigen of the prostate 3 (Steap3), responsible for the iron deficiency anemia in the mouse mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake. Steap3 shares homology with F(420)H(2):NADP(+) oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.
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Anemia Ferropénica/metabolismo , Antígenos de Neoplasias/metabolismo , Eritrocitos/enzimología , FMN Reductasa/metabolismo , Hierro/metabolismo , Transferrina/metabolismo , Secuencia de Aminoácidos , Animales , Antígenos de Neoplasias/genética , Western Blotting , Células Cultivadas , Endosomas , FMN Reductasa/genética , Femenino , Marcación de Gen , Riñón/metabolismo , Masculino , Ratones , Ratones Mutantes , Datos de Secuencia Molecular , Oxidorreductasas , Retroviridae/genética , Homología de Secuencia de Aminoácido , Fracciones SubcelularesRESUMEN
Interferon (IFN) is a key component of the innate immune response. For reasons that remain incompletely understood, the IFN system is upregulated in several rheumatic diseases, particularly those that feature autoantibody production, such as SLE, Sjögren's syndrome, myositis and systemic sclerosis. Interestingly, many of the autoantigens targeted in these diseases are components of the IFN system, representing IFN-stimulated genes (ISGs), pattern recognition receptors (PRRs), and modulators of the IFN response. In this review, we describe features of these IFN-linked proteins that may underlie their status as autoantigens. Note is also made of anti-IFN autoantibodies that have been described in immunodeficiency states.
RESUMEN
Peptidylarginine deiminase IV (PAD4) post-translationally converts arginine residues in proteins to citrullines and is implicated in playing a central role in the pathogenesis of several diseases. Although PAD4 was historically thought to be a nuclear enzyme, recent evidence has revealed a more complex localization of PAD4 with evidence of additional cytosolic and cell surface localization and activity. However, the mechanisms by which PAD4, which lacks conventional secretory signal sequences, traffics to extranuclear localizations are unknown. In this study, we show that PAD4 was enriched in the organelle fraction of monocytes with evidence of citrullination of organelle proteins. We also demonstrated that PAD4 can bind to several cytosolic, nuclear and organelle proteins that may serve as binding partners for PAD4 to traffic intracellularly. Additionally, cell surface expression of PAD4 increased with monocyte differentiation into monocyte-derived dendritic cells and co-localized with several endocytic/autophagic and conventional secretory pathway markers, implicating the use of these pathways by PAD4 to traffic within the cell. Our results suggest that PAD4 is expressed in multiple subcellular localizations and may play previously unappreciated roles in physiological and pathological conditions. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.
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Monocitos , Arginina Deiminasa Proteína-Tipo 4 , Humanos , Citrulina/metabolismo , Monocitos/enzimología , ProteómicaRESUMEN
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a dramatic sex bias, affecting 9 times more women than men. Activation of Toll-like receptor 7 (TLR7) by self-RNA is a central pathogenic process leading to aberrant production of type I interferon (IFN) in SLE, but the specific RNA molecules that serve as TLR7 ligands have not been defined. By leveraging gene expression data and the known sequence specificity of TLR7, we identified the female-specific X-inactive specific transcript (XIST) long noncoding RNA as a uniquely rich source of TLR7 ligands in SLE. XIST RNA stimulated IFN-α production by plasmacytoid DCs in a TLR7-dependent manner, and deletion of XIST diminished the ability of whole cellular RNA to activate TLR7. XIST levels were elevated in blood leukocytes from women with SLE compared with controls, correlated positively with disease activity and the IFN signature, and were enriched in extracellular vesicles released from dying cells in vitro. Importantly, XIST was not IFN inducible, suggesting that XIST is a driver, rather than a consequence, of IFN in SLE. Overall, our work elucidated a role for XIST RNA as a female sex-specific danger signal underlying the sex bias in SLE.
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Interferón Tipo I , Lupus Eritematoso Sistémico , ARN Largo no Codificante , Masculino , Humanos , Femenino , ARN Largo no Codificante/genética , Receptor Toll-Like 7 , Interferón Tipo I/genética , Expresión Génica , LigandosRESUMEN
Renal biopsy is currently the gold standard for diagnosing active renal vasculitis. In this pilot study, metabolomics analysis was used to investigate the differences in metabolic profiles between paired patients' serum and urine samples collected during both the active and the remission phase of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Ten patients with AAV renal disease were included. Mean age was 61 years, with 6 patients each being male and Caucasian. Mean Birmingham Vasculitis Activity Score (BVAS) and mean glomerular filtration rate (GFR) were 17 and 28, respectively. We found that while the citric acid cycle intermediates citrate, iso-citrate and oxaloacetate had lower intensities in the active phase samples as compared to the remission phase samples. The intensities of other metabolites of carbohydrate metabolism, amino acid metabolism, and nucleotide synthesis were significantly higher in the active phase samples, indicating the upregulation of these pathways for the production of energy and other biomolecules such as proteins and nucleic acids during the active phase of AAV. This pilot study suggests that serum and urinary metabolomic profiling may be useful to monitor disease activity in renal AAV.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Anticuerpos Anticitoplasma de Neutrófilos , Glomerulonefritis/diagnóstico , Humanos , Riñón , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
The origin and mechanisms of autoantigen generation in systemic lupus erythematosus (SLE) are poorly understood. Here, we identified SLE neutrophils activated in vivo by IFN as a prominent source of Ro52, also known as tripartite motif-containing protein 21 (TRIM21), a critical autoantigen historically thought to be primarily generated by keratinocytes in SLE. Different from mononuclear cells and keratinocytes, SLE neutrophils are enriched in several unique Ro52 species containing a core sequence encoded by exon 4 (Ro52Ex4) in TRIM21. Ro52Ex4 is the main target of anti-Ro52 antibodies and is found in 2 Ro52 variants (Ro52α and a potentially novel isoform termed Ro52γ) upregulated in SLE neutrophils. Further analysis of Ro52γ revealed a subset of autoantibodies against a unique C-terminal domain (Ro52γCT) generated from a frameshift due to the lack of exon 6 in Ro52γ. Antibodies to Ro52Ex4 and Ro52γCT distinguish SLE patient subsets characterized by distinct clinical, laboratory, treatment, and transcriptional profiles that are not discerned by the "classical" anti-Ro52 antibodies. These studies uncover IFN-activated neutrophils as a key source of unique immunogenic forms of Ro52 in SLE. Moreover, the finding of Ro52Ex4 and Ro52γCT as core targets of anti-Ro52 antibodies focus interest on Ro52γ as the potential isoform toward which immunological tolerance is initially lost in SLE.
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Lupus Eritematoso Sistémico , Autoanticuerpos , Autoantígenos/genética , Exones/genética , Humanos , Queratinocitos , Lupus Eritematoso Sistémico/genéticaRESUMEN
Background: Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFN-inducible innate sensors that form supramolecular assemblies along double-stranded (ds)DNA of various origins. Here, we investigate the ALR absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a pro-immune context. Methods: AIM2 autoantibodies were measured by immunoprecipitation in SLE and control subjects. Neutrophil extracellular traps were induced in control neutrophils and combined with purified ALR proteins in immunofluorescence and DNase protection assays. SLE renal tissues were examined for ALR-containing NETs by confocal microscopy. Results: AIM2 autoantibodies were detected in 41/131 (31.3%) SLE patients and 2/49 (4.1%) controls. Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16, and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We found that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Conclusions: Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE. Funding: These studies were funded by NIH R01 DE12354 (AR), P30 AR070254, R01 GM 129342 (JS), K23AR075898 (CM), K08AR077100 (BA), the Jerome L. Greene Foundation and the Rheumatology Research Foundation. Dr. Antiochos and Dr. Mecoli are Jerome L. Greene Scholars. The Hopkins Lupus Cohort is supported by NIH grant R01 AR069572. Confocal imaging performed at the Johns Hopkins Microscopy Facility was supported by NIH Grant S10 OD016374.
Systemic lupus erythematosus (SLE or lupus for short) is an autoimmune disease in which the immune system attacks healthy tissue in organs across the body. The cause is unknown, but people with the illness make antibodies that stick to proteins that are normally found inside the cell nucleus, where DNA is stored. To make these antibodies, the immune system must first 'see' these proteins and mistakenly recognise them as a threat. But how does the immune system recognise proteins that are normally hidden inside cells? During infection, a type of immune cell called a neutrophil releases DNA from its nucleus to form structures called neutrophil extracellular traps, or NETs for short. The role of these NETs is to capture and kill pathogens, but they also expose the neutrophil's DNA and the proteins attached to it to other immune cells. It is therefore possible that other immune cells interacting with NETs during infection may contribute to the development of lupus. Two proteins of interest are AIM2 and IFI16. These proteins form large, shield-like structures around strands of DNA, and previous work has shown that some people with lupus make antibodies against IFI16. Antiochos et al. wondered whether IFI16 and AIM2 might stick to NETs, exposing themselves to the immune system. Examining the blood of people with lupus revealed that one in three of them made antibodies that could stick to AIM2. Those people were also more likely to have antibodies that could stick to IFI16 and to strands of DNA. Using microscopy, Antiochos et al. also found AIM2 and IFI16 on NETs in the kidneys of some people with lupus. Further investigation showed that the presence of AIM2 and IFI16 prevents NETs from breaking down. If proteins like AIM2 and IFI16 can stop NETs from breaking down, they could allow the immune system more time to develop antibodies against them. Further investigation could reveal whether this is one of the causes of lupus. A clearer understanding of the antibodies could also boost research into diagnosis and treatment.
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Proteínas de Unión al ADN , Trampas Extracelulares , Lupus Eritematoso Sistémico , Melanoma , Proteínas Nucleares , Fosfoproteínas , Autoanticuerpos , Autoantígenos/metabolismo , Proteínas de Unión al ADN/metabolismo , Desoxirribonucleasas/metabolismo , Trampas Extracelulares/metabolismo , Humanos , Interferones/metabolismo , Melanoma/metabolismo , Neutrófilos , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismoRESUMEN
OBJECTIVE: To evaluate the safety and utility of core needle biopsy (CNB) for diagnosis of salivary gland lymphoma in Sjögren's syndrome (SS). METHODS: We analyzed data from consecutive SS patients who underwent ultrasound-guided major salivary gland CNB for lymphoma diagnosis and determined whether CNB yielded an actionable diagnosis without need for further intervention. RESULTS: CNBs were performed in 24 patients to evaluate discrete parotid (n = 6) or submandibular (n = 2) gland masses or diffuse enlargement (n = 16; 15 parotid). One patient had 3 CNBs of the same mass. Of the 26 CNBs, 24 included flow cytometry, using CNB and/or fine needle aspirate material, and 14 targeted sonographically identified focal lesions. No patient reported complications. In the 23 patients with 1 CNB, final diagnoses were marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT; n = 6), atypical lymphoid infiltration (n = 3), benign lymphoepithelial sialadenitis (n = 9), normal gland tissue (n = 4), and lymphoepithelial cyst (n = 1). In the patient with serial CNBs, the initial one without flow cytometry was benign, but the next 2 showed atypical lymphoid infiltration. Monoclonal lymphoid infiltration was detected in 12 patients: 6 with MALT lymphoma, 3 were benign, and 3 with atypical lymphoid infiltration. Of the latter 3, 1 was treated with rituximab and 2 with expectant observation. The diagnosis changed from atypical lymphoid infiltration to MALT lymphoma in 1 patient following biopsy of inguinal adenopathy 6 months post-CNB. CNB provided actionable results and avoided open excisional biopsies in all cases. CONCLUSION: CNB is safe and useful in the evaluation of suspected salivary gland lymphoma in SS.
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Biopsia Guiada por Imagen , Linfoma/patología , Glándula Parótida/patología , Neoplasias de la Parótida/patología , Síndrome de Sjögren/patología , Neoplasias de la Glándula Submandibular/patología , Glándula Submandibular/patología , Ultrasonografía Intervencional , Adolescente , Adulto , Anciano , Biopsia con Aguja Gruesa , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Adulto JovenRESUMEN
Background: The incidence of venous thromboembolism (VTE) is increased in ANCA-associated vasculitis (AAV). We assessed the frequency of VTE observed among patients with AAV evaluated at our center and identified risk factors. Methods: Patients from the Johns Hopkins Vasculitis Center cohort who were evaluated between 1998 and 2018 and had a diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were eligible for analysis. Baseline demographics and clinical and serologic data were extracted. Univariate and multivariate analyses were performed to identify factors associated with VTE in AAV. Results: A total of 162 patients with AAV were identified, 105 (65%) with GPA; 22 (14%) of these patients had a recorded VTE with a median time to VTE of 1 month. The mean (SD) age in the VTE versus non-VTE groups was 54±20 versus 55±17 years (P=0.99), 64% versus 60% female (P=0.93), 82% versus 49% PR3-ANCA positive (P=0.01), with a total mean BMI of 33.3±5.7 versus 28.3±6.1 kg/m2, (P<0.001) respectively. The median Birmingham Vasculitis Activity Score (BVAS version 3) was 19 versus 14 (P=0.02). Univariate analyses identified PR3-ANCA, rapidly progressive GN (RPGN), and hypoalbuminemia. In multivariate analysis, the significant associations with VTE included PR3-ANCA (OR, 4.77; P=0.02), hypoalbuminemia (OR, 4.84; P=0.004), and BMI (OR, 1.18; P<0.001). Conclusions: VTE is a surprisingly common complication of AAV. PR3-ANCA and hypoalbuminemia are risk factors for developing VTEs. Further studies are needed to confirm these findings. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/K360/2020_04_30_KID0000572019.mp3.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Anticuerpos Anticitoplasma de Neutrófilos , Femenino , Granulomatosis con Poliangitis/complicaciones , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mieloblastina , Peroxidasa , Factores de RiesgoRESUMEN
The innate immune system provides host defense against a variety of threats, including microbial infection and cellular damage. Pattern recognition receptors identify both pathogen and damage associated molecular motifs associated with these events. Nucleic acid is one such danger signal that is detected by a set of cytoplasmic sensors. Oligomerization is a key mode of activation shared by many of these sensors, who form large multimeric structures when activated. Microscopy is one of several techniques that facilitates study of these molecules, permitting visualization of oligomeric forms, and tracking of relevant signaling partners. In this chapter, we will discuss methods of generating and imaging cytoplasmic DNA sensors and inflammasome complexes by fluorescence microscopy.
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ADN/metabolismo , Inflamasomas/metabolismo , Microscopía Confocal/métodos , Animales , Técnicas Biosensibles , Humanos , Inmunidad Innata/fisiología , Microscopía Fluorescente , Receptores de Reconocimiento de Patrones/metabolismoRESUMEN
ANCA-associated vasculitis (AAV) can present in an atypical manner and obscure the clinical picture. We sought to characterize clinical characteristics and outcomes in these uncommon presentations. We conducted a retrospective study of 171 AAV patients in our vasculitis database to identify patients with atypical presentation of AAV. Patient demographics, serologies, renal indices, and treatment regimens were assessed. Of the 171 patients, eight were identified to have uncommon presentations. These patients were usually extremes of age with three being less than 30 years and four being more than 70 years. Six patients were positive for PR3 antibodies. The mean delay in diagnosis from time of symptom development was 12 months. All patients developed acute kidney injury during their clinical course. Pancreatitis was the most frequent atypical presentation (n = 3), with pulmonary pathologies (cystic lung disease and usual interstitial pneumonia) and splenic infarcts being present in two patients each. The diagnosis of AAV was established by positive ANCA serology and renal or lung biopsy evidence of vasculitis. Six patients received induction therapy with steroids and rituximab, while two received steroids and cyclophosphamide. One patient died of respiratory failure in the first month following diagnosis while the remaining patients achieved disease remission. One patient developed end-stage renal disease. Uncommon presentations of AAV afflict extremes of age with a PR3 ANCA predominance and are associated with subsequent development of AKI. This case series demonstrates that a significant delay in diagnosis can be associated with these presentations. KEY POINTS: ⢠Uncommon manifestations of AAV are seen more often with PR3 ANCA disease and respond to standard induction therapy of AAV. ⢠High index of suspicion is required to avoid delays in diagnosis.
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Lesión Renal Aguda/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Ciclofosfamida/administración & dosificación , Bases de Datos Factuales , Diagnóstico Tardío , Femenino , Granulomatosis con Poliangitis/inmunología , Humanos , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares Intersticiales/complicaciones , Masculino , Persona de Mediana Edad , Pancreatitis/complicaciones , Inducción de Remisión , Insuficiencia Respiratoria/terapia , Estudios Retrospectivos , Rituximab/administración & dosificación , Esteroides/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
The family name of the co-author of the article mentioned above was incorrectly spelled. The correct name should have been "Veena S. Katikineni"instead of "Veena Katikeneni". The original article has been corrected.