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Programmed death-ligand 1 interacts with fungal ribosomal Rpl20b in phagosomes and induces interleukin-10 secretion.
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Antígeno B7-H1 , Inflamación , Micosis , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Inflamación/inmunología , Humanos , Micosis/inmunología , Micosis/microbiología , Animales , Ratones , Proteínas Ribosómicas/inmunologíaRESUMEN
OBJECTIVES: Hypocomplementaemia is common in patients with IgG4-related disease (IgG4-RD). We aimed to determine the IgG4-RD features associated with hypocomplementaemia and investigate mechanisms of complement activation in this disease. METHODS: We performed a single-centre cross-sectional study of 279 patients who fulfilled the IgG4-RD classification criteria, using unadjusted and multivariable-adjusted logistic regression to identify factors associated with hypocomplementaemia. RESULTS: Hypocomplementaemia was observed in 90 (32%) patients. In the unadjusted model, the number of organs involved (OR 1.42, 95% CI 1.23 to 1.63) and involvement of the lymph nodes (OR 3.87, 95% CI 2.19 to 6.86), lungs (OR 3.81, 95% CI 2.10 to 6.89), pancreas (OR 1.66, 95% CI 1.001 to 2.76), liver (OR 2.73, 95% CI 1.17 to 6.36) and kidneys (OR 2.48, 95% CI 1.47 to 4.18) were each associated with hypocomplementaemia. After adjusting for age, sex and number of organs involved, only lymph node (OR 2.59, 95% CI 1.36 to 4.91) and lung (OR 2.56, 95% CI 1.35 to 4.89) involvement remained associated with hypocomplementaemia while the association with renal involvement was attenuated (OR 1.6, 95% CI 0.92 to 2.98). Fibrotic disease manifestations (OR 0.43, 95% CI 0.21 to 0.87) and lacrimal gland involvement (OR 0.53, 95% CI 0.28 to 0.999) were inversely associated with hypocomplementaemia in the adjusted analysis. Hypocomplementaemia was associated with higher concentrations of all IgG subclasses and IgE (all p<0.05). After adjusting for serum IgG1 and IgG3, only IgG1 but not IgG4 remained strongly associated with hypocomplementaemia. CONCLUSIONS: Hypocomplementaemia in IgG4-RD is not unique to patients with renal involvement and may reflect the extent of disease. IgG1 independently correlates with hypocomplementaemia in IgG4-RD, but IgG4 does not. Complement activation is likely involved in IgG4-RD pathophysiology.
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BACKGROUND: IgG4-related disease is a multiorgan fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterise differences in IgG4-related disease manifestations between male and female patients in a large single-centre cohort. METHODS: In this retrospective, single-centre cohort study, patients were recruited from the Massachusetts General Hospital Rheumatology Clinic (Boston, MA, USA) and classified according to the American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria. Only patients satisfying the ACR-EULAR classification criteria were included in the study. Data on age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B-cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-related disease Responder Index score of more than 0. Laboratory values were analysed for patients who were untreated at baseline and had active IgG4-related disease. The main outcomes were assessed in all participants with available data. FINDINGS: Of the 564 participants enrolled in the Massachusetts General Hospital Rheumatology Clinic IgG4-related disease Registry, 328 fulfilled ACR-EULAR classification criteria and were included between January, 2008, and May, 2023. There was a strong male predominance (male:female ratio 2·2:1) with 226 (69%) males and 102 (31%) females, which contrasted markedly with our general rheumatology clinic population (0·4:1; p<0·001). The male predominance increased with each decade of life starting at age 40 years. On average, male patients were 5·5 years older at diagnosis than female patients (63·7 years vs 58·2 years; p=0·0031). We observed male patients to have higher ACR-EULAR classification criteria scores at baseline with a median score of 35·0 (IQR 28·0-46·0), compared with 29·5 (25·0-39·0) for females (p=0·0010). The proportion of male patients with pancreatic and renal involvement was almost double the proportion observed in female patients (50% of the male patients had pancreatic involvement, compared with about 26% of the female patients; p<0·0001). Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly between male an female sexes, favouring higher values in males. We found that male patients with IgG4-related disease were more likely to have active B-cell responses in the blood as defined by plasmablast expansions. INTERPRETATION: IgG4-related disease is unusual among autoimmune diseases in that it is more likely to affect males than females and to present with a striking sex-dependent organ distribution and degree of B-cell response. These findings highlight important variation between IgG4-related disease and other conditions generally believed to have an autoimmune basis. Most autoimmune diseases, by contrast to IgG4-related disease, demonstrate pronounced predilections for affecting females more frequently than males. Hypotheses surrounding the cause and pathophysiology of this condition need to consider this unusual sex distribution among patients with IgG4-related disease. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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Enfermedad Relacionada con Inmunoglobulina G4 , Fenotipo , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/clasificación , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/sangre , Factores Sexuales , Anciano , Adulto , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunologíaRESUMEN
Xist-containing ribonucleoproteins drive autoimmunity in women.
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Autoinmunidad , Ribonucleoproteínas , Humanos , FemeninoRESUMEN
Background: Patients with predominantly antibody deficiency (PAD) have lower anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody levels after initial 2-dose SARS-CoV-2 vaccination than healthy controls do; however, the anti-spike antibody responses and neutralization function in patients with PAD following subsequent immunizations remain understudied. Objective: We sought to characterize anti-spike antibody responses in adults with PAD over the course of 5 SARS-CoV-2 vaccine doses and identify diagnostic and immunophenotypic risk factors for low antibody response. Methods: We evaluated anti-spike antibody levels in 117 adult patients with PAD and 192 adult healthy controls following a maximum of 5 SARS-CoV-2 immunizations. We assessed neutralization of the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant and analyzed infection outcomes. Results: The patients with PAD had significantly lower mean anti-spike antibody levels after 3 SARS-CoV-2 vaccine doses than the healthy controls did (1,439.1 vs 21,890.4 U/mL [P < .0001]). Adults with secondary PAD, severe primary PAD, and high-risk immunophenotypes had lower mean anti-spike antibody levels following vaccine doses 2, 3, and/or 4 but not following vaccine dose 5. Compared with patients with mild and moderate PAD, patients with severe PAD had a higher rate of increase in anti-spike antibody levels over 5 immunizations. A strong positive correlation was observed between anti-spike antibody levels and neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Most infections were managed on an outpatient basis. Conclusions: In all of the patients with PAD, anti-spike antibody levels increased with successive SARS-CoV-2 immunizations and were correlated with neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Secondary PAD, severe primary PAD, and high-risk immunophenotypes were correlated with lower mean anti-spike antibody levels following vaccine doses 2 through 4. Patients with severe PAD had the highest rate of increase in anti-spike antibody levels over 5 immunizations. These data suggest a clinical benefit to sequential SARS-CoV-2 immunizations, particularly among high-risk patients with PAD.
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Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs function as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs.
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Vía de Señalización Hippo , Esclerodermia Sistémica , Humanos , Fibrosis , Esclerodermia Sistémica/patología , Miofibroblastos/metabolismo , Células Endoteliales/metabolismo , Piel/patología , Fibroblastos/metabolismoRESUMEN
We have attempted here to provide an up-to-date review of the collaboration between helper T cells and B cells in response to protein and glycoprotein antigens. This collaboration is essential as it not only protects from many pathogens but also contributes to a litany of autoimmune and immune-mediated diseases.
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Enfermedades Autoinmunes , Autoinmunidad , Humanos , Linfocitos T Colaboradores-Inductores , Antígenos , Linfocitos BRESUMEN
BACKGROUND: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. OBJECTIVE: We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. METHODS: We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3+ T or CD19+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T-cell and CD19+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. RESULTS: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-ß but did not express immune checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ cytotoxic T cells colocalized with MKI67+ B cells in the extrafollicular area from affected tissue sites. CONCLUSIONS: The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGF-ß in the pathogenesis of inflammatory fibrotic disorders.
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Enfermedades del Sistema Inmune , Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Anfirregulina/genética , Linfocitos T CD8-positivos , Granzimas , Receptores de Antígenos de Linfocitos B , Receptores de Antígenos de Linfocitos T , Linfocitos T Citotóxicos , Factor de Crecimiento Transformador betaRESUMEN
Insulin-specific B cells called BND2 B cells accumulate in the peripheral blood of patients with very early onset type 1 diabetes.
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Linfocitos B , Anergia Clonal , HumanosRESUMEN
In this issue of JEM, the work of Joachim et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20231028) on knockin mice with a specific tail mutation in LAT provides valuable insights about cytotoxic CD4+ T cells and human inflammatory diseases.
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Subgrupos de Linfocitos T , Cola (estructura animal) , Humanos , Animales , Ratones , Linfocitos T Citotóxicos , Mutación/genéticaRESUMEN
Although therapeutic B cell depletion dramatically resolves inflammation in many diseases in which antibodies appear not to play a central role, distinct extrafollicular pathogenic B cell subsets that accumulate in disease lesions have hitherto not been identified. The circulating immunoglobulin D (IgD)-CD27-CXCR5-CD11c+ DN2 B cell subset has been previously studied in some autoimmune diseases. A distinct IgD-CD27-CXCR5-CD11c- DN3 B cell subset accumulates in the blood both in IgG4-related disease, an autoimmune disease in which inflammation and fibrosis can be reversed by B cell depletion, and in severe COVID-19. These DN3 B cells prominently accumulate in the end organs of IgG4-related disease and in lung lesions in COVID-19, and double-negative B cells prominently cluster with CD4+ T cells in these lesions. Extrafollicular DN3 B cells may participate in tissue inflammation and fibrosis in autoimmune fibrotic diseases, as well as in COVID-19.
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Subgrupos de Linfocitos B , COVID-19 , Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Fibrosis , Inmunoglobulina D , Inflamación , Receptores CXCR5 , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patologíaRESUMEN
Cytotoxic CD4+ T cells specific for CMV cull senescent skin fibroblasts.
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Linfocitos T CD4-Positivos , Infecciones por Citomegalovirus , Femenino , HumanosRESUMEN
The continued emergence of SARS-CoV-2 variants and waning vaccine immunity are some of the factors that drive the continuing search for more effective treatment and prevention options for COVID-19. In this issue of the JCI, Changrob, et al. describe an anti-SARS-CoV-2 spike antibody, isolated from a patient, that targets a vulnerable site on the spike protein receptor binding domain when it adopts a configuration called the "up" conformation. This antibody cross-neutralized all variants studied, including recent Omicron subvariants, and was protective against multiple variants in a hamster model. These results are of interest when considering the next generation of prophylactic and therapeutic antibodies for COVID-19, but they may also shape future approaches to vaccination against SARS-CoV-2.
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COVID-19 , SARS-CoV-2 , Animales , Cricetinae , Humanos , Anticuerpos Antivirales , Vacunación , Anticuerpos NeutralizantesRESUMEN
Repeated doses of mRNA vaccines for COVID-19 result in increased proportions of anti-spike antibodies of the IgG4 subclass, which are known to neutralize well and to form mixed immune complexes with IgG1 but, in a pure form, might be less effective than IgG1 or IgG3 antibodies in facilitating opsonization by phagocytes, complement fixation, and NK cell-dependent elimination of infected cells (see related Research Article by Irrgang et al.).
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COVID-19 , Inmunoglobulina G , Humanos , Vacunas contra la COVID-19RESUMEN
BACKGROUND: Obexelimab is a bifunctional, non-cytolytic, humanised monoclonal antibody that binds CD19 and Fc gamma receptor IIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease. METHODS: We conducted an open-label, single-arm, single centre, phase 2 pilot trial at the Massachusetts General Hospital in Boston, MA, USA. Eligible patients were aged 18-80 years and had active IgG4-related disease confirmed by an IgG4-related disease responder index score of 3 or more. Patients received 5 mg/kg of obexelimab intravenously every 2 weeks for 24 weeks. Patients on glucocorticoids at baseline were expected to discontinue usage within 2 months following enrolment. The primary endpoint was the proportion of patients with a decrease of 2 or more from baseline in the IgG4-related disease responder index at day 169 (ie, primary responders). Patients who achieved a decrease of 2 or more at any visit were designated as responders. Adverse events were graded on a scale of 1-5 (ie, mild, moderate, severe, life-threatening, or death) according to the Common Terminology Criteria for Adverse Events grading scale (version 4.3). Exploratory analyses were quantification of B-cell CD19 receptor occupancy, plasmablast, total B-cell and CD4+ cytotoxic T-cell count by flow cytometry, and immunoglobulin concentrations by nephelometry. This study is registered with ClinicalTrials.gov, NCT02725476. FINDINGS: Between Feb 24, 2016, and Dec 21, 2016, we enrolled 15 patients. The median age was 63 years (IQR 52-65). Ten (67%) of 15 patients were male, five (33%) were female, and 12 (80%) were White. At baseline, 12 (80%) of 15 patients had an elevated median serum IgG4 concentration of 220 mg/dL (IQR 124-441), and the median IgG4-related disease responder index score was 12 (IQR 7-13). 12 (80%) of 15 patients achieved the primary endpoint (ie, primary responders), 14 (93%) were defined as responders. Reductions from baseline in serum B cells and plasmablasts were observed following treatment with obexelimab. However, in most patients with follow-up data, serum B cells recovered to 75% of baseline concentrations within 42 days of the final obexelimab dose. 13 (87%) of 15 patients reported adverse events, one of which (an infusion reaction) resulted in treatment discontinuation. INTERPRETATION: All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease. FUNDING: Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.
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Antineoplásicos , Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Femenino , Masculino , Persona de Mediana Edad , Proyectos Piloto , Anticuerpos Monoclonales , Linfocitos B , Células Plasmáticas , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19RESUMEN
Multisystem inflammatory syndrome in children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory illness characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigenemia, cytokine storm, and immune dysregulation. In severe COVID-19, neutrophil activation is central to hyperinflammatory complications, yet the role of neutrophils in MIS-C is undefined. Here, we collect blood from 152 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 78 pediatric controls. We find that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism that is distinct from the neutrophil interferon-stimulated gene (ISG) response we observe in pediatric COVID-19. Moreover, we observe extensive spontaneous neutrophil extracellular trap (NET) formation in MIS-C, and we identify neutrophil activation and degranulation signatures. Mechanistically, we determine that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Our findings suggest that hyperinflammatory presentation during MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia, driven by uncontrolled neutrophil activation and NET release in the vasculature.
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COVID-19 , Neutrófilos , Humanos , Niño , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/diagnósticoRESUMEN
A conditional knockout system permitting deletion of ILC2 cells reveals non-redundant roles in eosinophil recruitment and helminth clearance.
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Inmunidad Innata , Linfocitos , Eosinófilos , CinéticaRESUMEN
Sjögren's syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren's syndrome were undertaken, including the quantitation of the frequency of selected cell-cell interactions in the disease milieu. Quantitative analyses of CD4+ T cell subsets and of CD8+ T cells in the labial salivary glands from untreated patients with primary Sjögren's syndrome revealed that activated CD8+ cytotoxic T cells (CD8+CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8+ T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren's syndrome is primarily driven by CD8+CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells.
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Síndrome de Sjögren , Linfocitos T CD8-positivos , Humanos , Glándulas Salivales/metabolismo , Glándulas Salivales Menores/patología , Síndrome de Sjögren/patología , Linfocitos T Citotóxicos/patologíaRESUMEN
Microbial adhesion and contamination on shared surfaces can lead to life-threatening infections with serious impacts on public health, economy, and clinical practices. The traditional use of chemical disinfectants for sanitization of surfaces, however, comes with its share of health risks, such as hazardous effects on the eyes, skin, and respiratory tract, carcinogenicity, as well as environmental toxicity. To address this, we have developed a nonleaching quaternary small molecule (QSM)-based sprayable coating which can be fabricated on a wide range of surfaces such as nylon, polyethylene, surgical mask, paper, acrylate, and rubber in a one-step, photocuring technique. This contact-active coating killed pathogenic bacteria and fungi including drug-resistant strains of Staphylococcus aureus and Candida albicans within 15-30 min of contact. QSM coatings withstood multiple washes, highlighting their durability. Interestingly, the coated surfaces exhibited rapid killing of pathogens, leading to the prevention of their transmission upon contact. The coating showed membrane disruption of bacterial cells in fluorescence and electron microscopic investigations. Along with bacteria and fungi, QSM-coated surfaces also showed the complete killing of high loads of influenza (H1N1) and SARS-CoV-2 viruses within 30 min of exposure. To our knowledge, this is the first report of a coating for multipurpose materials applied in high-touch public places, hospital equipment, and clinical consumables, rapidly killing drug-resistant bacteria, fungi, influenza virus, and SARS-CoV-2.
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Antiinfecciosos , COVID-19 , Desinfectantes , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Acrilatos/farmacología , Antibacterianos/química , Antiinfecciosos/farmacología , Bacterias , COVID-19/prevención & control , Desinfectantes/farmacología , Hongos , Humanos , Nylons/farmacología , Polietilenos/farmacología , Goma , SARS-CoV-2RESUMEN
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.