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1.
Nat Immunol ; 24(6): 955-965, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37106039

RESUMEN

The B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (Bm) cell subsets, including CD21+ resting, CD21-CD27+ activated and CD21-CD27- Bm cells. The interrelatedness between these Bm cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific Bm cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21- Bm cells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specific immunization. At months 6 and 12 post-infection, CD21+ resting Bm cells were the major Bm cell subset in the circulation and were also detected in peripheral lymphoid organs, where they carried tissue residency markers. Tracking of individual B cell clones by B cell receptor sequencing revealed that previously fated Bm cell clones could redifferentiate upon antigen rechallenge into other Bm cell subsets, including CD21-CD27- Bm cells, demonstrating that single Bm cell clones can adopt functionally different trajectories.


Asunto(s)
Subgrupos de Linfocitos B , COVID-19 , Humanos , SARS-CoV-2 , Células B de Memoria , Linfocitos B
2.
Nat Immunol ; 24(4): 604-611, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36879067

RESUMEN

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Autoanticuerpos , Síndrome Post Agudo de COVID-19 , Quimiocinas
3.
Cell ; 175(1): 85-100.e23, 2018 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-30173916

RESUMEN

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as "autoproliferation" of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.


Asunto(s)
Linfocitos B/patología , Subtipos Serológicos HLA-DR/inmunología , Esclerosis Múltiple/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/fisiopatología , Linfocitos B/metabolismo , Encéfalo/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/fisiología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Subtipos Serológicos HLA-DR/genética , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/fisiopatología , Receptores de Antígenos de Linfocitos T , Células TH1/fisiología
4.
Nat Immunol ; 25(4): 587-589, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38589620
6.
Nat Immunol ; 19(8): 809-820, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29967452

RESUMEN

Regulatory factor X 7 (Rfx7) is an uncharacterized transcription factor belonging to a family involved in ciliogenesis and immunity. Here, we found that deletion of Rfx7 leads to a decrease in natural killer (NK) cell maintenance and immunity in vivo. Genomic approaches showed that Rfx7 coordinated a transcriptional network controlling cell metabolism. Rfx7-/- NK lymphocytes presented increased size, granularity, proliferation, and energetic state, whereas genetic reduction of mTOR activity mitigated those defects. Notably, Rfx7-deficient NK lymphocytes were rescued by interleukin 15 through engagement of the Janus kinase (Jak) pathway, thus revealing the importance of this signaling for maintenance of such spontaneously activated NK cells. Rfx7 therefore emerges as a novel transcriptional regulator of NK cell homeostasis and metabolic quiescence.


Asunto(s)
Interleucina-15/metabolismo , Células Asesinas Naturales/metabolismo , Factor Regulador X1/metabolismo , Animales , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Quimera , Metabolismo Energético , Redes Reguladoras de Genes , Inmunidad Celular/genética , Inmunidad Innata/genética , Quinasas Janus/metabolismo , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor Regulador X1/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo
7.
Nature ; 602(7895): 148-155, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34875673

RESUMEN

Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen1,2. Since the outbreak of the ongoing COVID-19 pandemic, a key question has focused on which SARS-CoV-2-specific T cells stimulated during acute infection give rise to long-lived memory T cells3. Here, using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor sequencing, we longitudinally characterized individual SARS-CoV-2-specific CD8+ T cells of patients with COVID-19 from acute infection to 1 year into recovery and found a distinct signature identifying long-lived memory CD8+ T cells. SARS-CoV-2-specific memory CD8+ T cells persisting 1 year after acute infection express CD45RA, IL-7 receptor-α and T cell factor 1, but they maintain low expression of CCR7, thus resembling CD45RA+ effector memory T cells. Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, we reveal that an interferon signature marks clones that give rise to long-lived cells, whereas prolonged proliferation and mechanistic target of rapamycin signalling are associated with clonal disappearance from the blood. Collectively, we describe a transcriptional signature that marks long-lived, circulating human memory CD8+ T cells following an acute viral infection.


Asunto(s)
Antígenos Virales/inmunología , Biomarcadores/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19/inmunología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , SARS-CoV-2/inmunología , Enfermedad Aguda , COVID-19/virología , Proliferación Celular , Células Clonales/citología , Células Clonales/inmunología , Humanos , Interferones/inmunología , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Estudios Longitudinales , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CCR7/metabolismo , Factor 1 de Transcripción de Linfocitos T/metabolismo , Factores de Tiempo , Transcriptoma
8.
Immunity ; 45(1): 172-84, 2016 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-27438770

RESUMEN

Neutrophils are the first immune cells recruited to sites of inflammation and infection. However, patients with allergic disorders such as atopic dermatitis show a paucity of skin neutrophils and are prone to bacterial skin infections, suggesting that allergic inflammation curtails neutrophil responses. Here we have shown that the type 2 cell signature cytokine interleukin-4 (IL-4) hampers neutrophil expansion and migration by antagonizing granulocyte colony-stimulating factor (G-CSF) and chemokine receptor-mediated signals. Cutaneous bacterial infection in mice was exacerbated by IL-4 signaling and improved with IL-4 inhibition, each outcome inversely correlating with neutrophil migration to skin. Likewise, systemic bacterial infection was worsened by heightened IL-4 activity, with IL-4 restricting G-CSF-induced neutrophil expansion and migration to tissues by affecting CXCR2-CXCR4 chemokine signaling in neutrophils. These effects were dependent on IL-4 acting through type 2 IL-4 receptors on neutrophils. Thus, targeting IL-4 might be beneficial in neutropenic conditions with increased susceptibility to bacterial infections.


Asunto(s)
Inflamación/inmunología , Listeria monocytogenes/fisiología , Listeriosis/inmunología , Neutrófilos/inmunología , Receptores de Superficie Celular/metabolismo , Infecciones Estreptocócicas/inmunología , Streptococcus pyogenes/fisiología , Animales , Carga Bacteriana , Movimiento Celular , Proliferación Celular , Células Cultivadas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Superficie Celular/genética , Transducción de Señal , Células Th2/inmunología
9.
Immunity ; 44(1): 59-72, 2016 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-26789922

RESUMEN

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways.


Asunto(s)
Quimiotaxis/inmunología , Inflamación/inmunología , Leucocitos Mononucleares/inmunología , Receptores CCR7/inmunología , Transducción de Señal/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Transferencia Resonante de Energía de Fluorescencia , Células HEK293 , Humanos , Inmunoprecipitación , Inflamación/metabolismo , Leucocitos Mononucleares/metabolismo , Microscopía Fluorescente , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CCR7/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transfección
10.
Allergy ; 78(4): 1073-1087, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36334079

RESUMEN

BACKGROUND: Insight into the pathomechanism of atopic diseases demonstrated a pivotal role of the cytokines interleukin-4 (IL-4) and IL-13, which has spurred the development of tailored therapeutics targeting their common IL-4 receptor (IL-4R). However, several aspects of the IL-4R system remain ill-defined in humans. METHODS: We used multicolor spectral flow cytometry to characterize IL-4R subunit expression in 28 human immune cell subsets on protein and mRNA levels and assessed their subcellular distribution by applying a specifically adapted protocol that avoided influence of fixation and permeabilization on fluorochrome and antibody performance. In patients, we investigated possible changes in IL-4Rα distribution before and during treatment with dupilumab, a monoclonal antibody-targeting IL-4Rα. RESULTS: Whereas all immune cell subsets investigated expressed IL-4Rα and common γ chain protein and mRNA, expression of IL-13Rα1 was restricted to myeloid and B cells. Interestingly, some cells contained considerably more intracellular IL-4R protein than on their surface. Naive B cells were found to carry the highest levels of IL-4Rα distributed evenly between surface and intracellular space, whereas IL-4Rα was found predominantly in intracellular pools in neutrophils. In patients with atopic diseases treated with dupilumab, we observed that engagement of IL-4Rα by dupilumab resulted in internalization of the antibody and decreased total IL-4Rα expression. Notably, even after months of treatment not all intracellular IL-4Rα molecules were occupied by dupilumab, indicating the presence of a "dormant" intracellular IL-4Rα pool that could be mobilized upon certain extrinsic or intrinsic cues. CONCLUSION: Collectively, our findings suggest that distinct human immune cell subsets contain surface and intracellular IL-4R pools, which are differently affected by targeted biologic treatment.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Receptores de Interleucina-4 , Humanos , Receptores de Interleucina-4/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos B/metabolismo , ARN Mensajero/análisis
11.
Allergy ; 77(12): 3567-3583, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36067034

RESUMEN

Neutrophil granulocytes, or neutrophils, are the most abundant circulating leukocytes in humans and indispensable for antimicrobial immunity, as exemplified in patients with inborn and acquired defects of neutrophils. Neutrophils were long regarded as the foot soldiers of the immune system, solely destined to execute a set of effector functions against invading pathogens before undergoing apoptosis, the latter of which was ascribed to their short life span. This simplistic understanding of neutrophils has now been revised on the basis of insights gained from the use of mouse models and single-cell high-throughput techniques, revealing tissue- and context-specific roles of neutrophils in guiding immune responses. These studies also demonstrated that neutrophil responses were controlled by sophisticated feedback mechanisms, including directed chemotaxis of neutrophils to tissue-draining lymph nodes resulting in modulation of antimicrobial immunity and inflammation. Moreover, findings in mice and humans showed that neutrophil responses adapted to different deterministic cytokine signals, which controlled their migration and effector function as well as, notably, their biologic clock by affecting the kinetics of their aging. These mechanistic insights have important implications for health and disease in humans, particularly, in allergic diseases, such as atopic dermatitis and allergic asthma bronchiale, as well as in autoinflammatory and autoimmune diseases. Hence, our improved understanding of neutrophils sheds light on novel therapeutic avenues, focusing on molecularly defined biologic agents.


Asunto(s)
Antiinfecciosos , Enfermedades Autoinmunes , Hipersensibilidad , Humanos , Ratones , Animales , Neutrófilos , Autoinmunidad , Hipersensibilidad/patología , Inflamación
12.
Allergy ; 77(4): 1274-1284, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34467524

RESUMEN

BACKGROUND: Systemic sclerosis (SSc) is a multiorgan autoimmune disease characterized by inflammation, vascular modification, and progressive fibrosis of the skin and several visceral organs. Innate and adaptive immune cells, including myeloid, B and T cells, are believed to be central to the pathogenesis of SSc. However, the role and functional state of neutrophil granulocytes (neutrophils) are ill-defined in SSc. METHODS: We performed a prospective study of neutrophils freshly isolated from SSc patients and healthy donors (HD) by measuring in these neutrophils (i) functional cell surface markers, including CD16, CD62L, CD66b, CD66c, CXCR1, CXCR2, and CXCR4; (ii) cytokine-activated intracellular signal transducer and activator of transcription (STAT) pathways, such as phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6; (iii) production of neutrophil extracellular traps (NET) and intracellular myeloperoxidase (MPO); and (iv) phagocytosis of bacteria by the neutrophils. RESULTS: Neutrophils of SSc patients expressed lower CD16 and CD62L and higher pSTAT3 and pSTAT6 compared to HD. Moreover, neutrophils of SSc patients lacked CXCR1 and CXCR2, the receptors responding to the potent neutrophil chemoattractant CXCL8. Neutrophils of SSc patients were also deficient in MPO levels, NET formation, and phagocytosis of bacteria. CONCLUSIONS: Neutrophils of patients with SSc display several functional defects affecting cell migration, NET formation, and phagocytosis of bacteria.


Asunto(s)
Trampas Extracelulares , Esclerodermia Sistémica , Humanos , Neutrófilos , Fagocitosis , Estudios Prospectivos , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología
13.
Allergy ; 77(8): 2468-2481, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35567391

RESUMEN

BACKGROUND: T-cell lymphopenia and functional impairment is a hallmark of severe acute coronavirus disease 2019 (COVID-19). How T-cell numbers and function evolve at later timepoints after clinical recovery remains poorly investigated. METHODS: We prospectively enrolled and longitudinally sampled 173 individuals with asymptomatic to critical COVID-19 and analyzed phenotypic and functional characteristics of T cells using flow cytometry, 40-parameter mass cytometry, targeted proteomics, and functional assays. RESULTS: The extensive T-cell lymphopenia observed particularly in patients with severe COVID-19 during acute infection had recovered 6 months after infection, which was accompanied by a normalization of functional T-cell responses to common viral antigens. We detected persisting CD4+ and CD8+ T-cell activation up to 12 months after infection, in patients with mild and severe COVID-19, as measured by increased HLA-DR and CD38 expression on these cells. Persistent T-cell activation after COVID-19 was independent of administration of a COVID-19 vaccine post-infection. Furthermore, we identified a subgroup of patients with severe COVID-19 that presented with persistently low CD8+ T-cell counts at follow-up and exhibited a distinct phenotype during acute infection consisting of a dysfunctional T-cell response and signs of excessive pro-inflammatory cytokine production. CONCLUSION: Our study suggests that T-cell numbers and function recover in most patients after COVID-19. However, we find evidence of persistent T-cell activation up to 12 months after infection and describe a subgroup of severe COVID-19 patients with persistently low CD8+ T-cell counts exhibiting a dysregulated immune response during acute infection.


Asunto(s)
COVID-19 , Linfopenia , Linfocitos T CD8-positivos , Vacunas contra la COVID-19 , Humanos , Linfopenia/etiología , Linfopenia/metabolismo , SARS-CoV-2
14.
Allergy ; 77(8): 2415-2430, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35364615

RESUMEN

BACKGROUND: Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19. METHODS: We performed highly sensitive indirect immunofluorescence assays to detect antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed up to 1 year after infection, eleven vaccinated individuals, and 41 unexposed controls. RESULTS: Compared with healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, the paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B-cell compartment after recovery. CONCLUSION: Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased antiviral humoral immune responses and inflammatory immune signatures.


Asunto(s)
Autoanticuerpos , COVID-19 , Anticuerpos Anticitoplasma de Neutrófilos , Anticuerpos Antinucleares , Antivirales , Humanos , Inmunidad Humoral , SARS-CoV-2
15.
Allergy ; 77(12): 3648-3662, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35869837

RESUMEN

BACKGROUND: Although avian coronavirus infectious bronchitis virus (IBV) and SARS-CoV-2 belong to different genera of the Coronaviridae family, exposure to IBV may result in the development of cross-reactive antibodies to SARS-CoV-2 due to homologous epitopes. We aimed to investigate whether antibody responses to IBV cross-react with SARS-CoV-2 in poultry farm personnel who are occupationally exposed to aerosolized IBV vaccines. METHODS: We analyzed sera from poultry farm personnel, COVID-19 patients, and pre-pandemic controls. IgG levels against the SARS-CoV-2 antigens S1, RBD, S2, and N and peptides corresponding to the SARS-CoV-2 ORF3a, N, and S proteins as well as whole virus antigens of the four major S1-genotypes 4/91, IS/1494/06, M41, and D274 of IBV were investigated by in-house ELISAs. Moreover, live-virus neutralization test (VNT) was performed. RESULTS: A subgroup of poultry farm personnel showed elevated levels of specific IgG for all tested SARS-CoV-2 antigens compared with pre-pandemic controls. Moreover, poultry farm personnel, COVID-19 patients, and pre-pandemic controls showed specific IgG antibodies against IBV strains. These antibody titers were higher in long-term vaccine implementers. We observed a strong correlation between IBV-specific IgG and SARS-CoV-2 S1-, RBD-, S2-, and N-specific IgG in poultry farm personnel compared with pre-pandemic controls and COVID-19 patients. However, no neutralization was observed for these cross-reactive antibodies from poultry farm personnel using the VNT. CONCLUSION: We report here for the first time the detection of cross-reactive IgG antibodies against SARS-CoV-2 antigens in humans exposed to IBV vaccines. These findings may be useful for further studies on the adaptive immunity against COVID-19.


Asunto(s)
Anticuerpos Antivirales , COVID-19 , Agricultores , Virus de la Bronquitis Infecciosa , Humanos , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , Inmunoglobulina G , Virus de la Bronquitis Infecciosa/inmunología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Reacciones Cruzadas , Aves de Corral , Animales
16.
J Allergy Clin Immunol ; 147(2): 545-557.e9, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33221383

RESUMEN

BACKGROUND: Whereas severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody tests are increasingly being used to estimate the prevalence of SARS-CoV-2 infection, the determinants of these antibody responses remain unclear. OBJECTIVES: Our aim was to evaluate systemic and mucosal antibody responses toward SARS-CoV-2 in mild versus severe coronavirus disease 2019 (COVID-19) cases. METHODS: Using immunoassays specific for SARS-CoV-2 spike proteins, we determined SARS-CoV-2-specific IgA and IgG in sera and mucosal fluids of 2 cohorts, including SARS-CoV-2 PCR-positive patients (n = 64) and PCR-positive and PCR-negtive health care workers (n = 109). RESULTS: SARS-CoV-2-specific serum IgA titers in patients with mild COVID-19 were often transiently positive, whereas serum IgG titers remained negative or became positive 12 to 14 days after symptom onset. Conversely, patients with severe COVID-19 showed a highly significant increase of SARS-CoV-2-specific serum IgA and IgG titers after symptom onset. Very high titers of SARS-CoV-2-specific serum IgA were correlated with severe acute respiratory distress syndrome. Interestingly, some health care workers with negative SARS-CoV-2-specific serum antibody titers showed SARS-CoV-2-specific IgA in mucosal fluids with virus-neutralizing capacity in some cases. SARS-CoV-2-specific IgA titers in nasal fluids were inversely correlated with age. CONCLUSIONS: Systemic antibody production against SARS-CoV-2 develops mainly in patients with severe COVID-19, with very high IgA titers seen in patients with severe acute respiratory distress syndrome, whereas mild disease may be associated with transient production of SARS-CoV-2-specific antibodies but may stimulate mucosal SARS-CoV-2-specific IgA secretion.


Asunto(s)
Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Membrana Mucosa/inmunología , SARS-CoV-2/inmunología , Adulto , Anciano , Anticuerpos Antivirales/sangre , COVID-19/sangre , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Saliva/inmunología , Índice de Severidad de la Enfermedad , Lágrimas/inmunología
17.
Immunol Rev ; 283(1): 176-193, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29664568

RESUMEN

Upon stimulation with their cognate antigen, naive T cells undergo proliferation and differentiation into effector cells, followed by apoptosis or survival as precursors of long-lived memory cells. These phases of a T-cell response and the ensuing maintenance of memory T cells are shaped by cytokines, most notably interleukin-2 (IL-2), IL-7, and IL-15 that share the common γ chain (γc ) cytokine receptor. Steady-state production of IL-7 and IL-15 is necessary for background proliferation and homeostatic survival of CD4+ and CD8+ memory T cells. During immune responses, augmented levels of IL-2, IL-15, IL-21, IL-12, IL-18, and type-I interferons determine the memory potential of antigen-specific effector CD8+ cells, while increased IL-2 and IL-15 cause bystander proliferation of heterologous CD4+ and CD8+ memory T cells. Limiting availability of γc cytokines, reduction in regulatory T cells or IL-10, and persistence of inflammation or cognate antigen can result in memory T cells, which fail to become cytokine-dependent long-lived cells. Conversely, increased IL-7 and IL-15 can expand memory T cells, including pathogenic tissue-resident memory T cells, as seen in lymphopenia and certain chronic-inflammatory disorders and malignancies. These abovementioned factors impact immunotherapy and vaccines directed at memory T cells in cancer and chronic infection.


Asunto(s)
Citocinas/metabolismo , Susceptibilidad a Enfermedades , Inmunidad Celular , Memoria Inmunológica , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Diferenciación Celular/inmunología , Homeostasis , Humanos , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Especificidad de Órganos/inmunología , Psoriasis/genética , Psoriasis/inmunología , Psoriasis/metabolismo , Transducción de Señal
18.
Allergy ; 76(9): 2673-2683, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33368349

RESUMEN

BACKGROUND: Biologic agents (also termed biologics or biologicals) are becoming increasingly important in the treatment of immune-mediated diseases. However, the diversity of clinical trials along with the fast pace of publication makes it difficult to determine the level of evidence for the use of a biologic for a given disorder. To address this challenge, we are publishing a series of systematic reviews evaluating the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. In this article, we have assessed the safety and efficacy of belimumab, a fully human IgG1 monoclonal antibody targeting the cytokine B cell-activating factor (BAFF). OBJECTIVE: To evaluate belimumab's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics. METHODS: The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist guided the reporting of the data. We searched the PubMed database between October 4, 2016, and June 23, 2019, concentrating on immune-mediated disorders. RESULTS: The literature search identified 583 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 17 articles were finally included in a narrative synthesis. CONCLUSIONS: Belimumab is both safe and effective for the treatment of systemic lupus erythematosus. Results were further promising for the use of belimumab in patients with rheumatoid arthritis and Sjögren's syndrome. Conversely, results using belimumab in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and myasthenia gravis were rather disappointing.


Asunto(s)
Enfermedades del Sistema Inmune , Lupus Eritematoso Sistémico , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Resultado del Tratamiento
19.
Allergy ; 76(9): 2866-2881, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33884644

RESUMEN

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and shows a broad clinical presentation ranging from asymptomatic infection to fatal disease. A very prominent feature associated with severe COVID-19 is T cell lymphopenia. However, homeostatic and functional properties of T cells are ill-defined in COVID-19. METHODS: We prospectively enrolled individuals with mild and severe COVID-19 into our multicenter cohort and performed a cross-sectional analysis of phenotypic and functional characteristics of T cells using 40-parameter mass cytometry, flow cytometry, targeted proteomics, and functional assays. RESULTS: Compared with mild disease, we observed strong perturbations of peripheral T cell homeostasis and function in severe COVID-19. Individuals with severe COVID-19 showed T cell lymphopenia and redistribution of T cell populations, including loss of naïve T cells, skewing toward CD4+ T follicular helper cells and cytotoxic CD4+ T cells, and expansion of activated and exhausted T cells. Extensive T cell apoptosis was particularly evident with severe disease and T cell lymphopenia, which in turn was accompanied by impaired T cell responses to several common viral antigens. Patients with severe disease showed elevated interleukin-7 and increased T cell proliferation. Furthermore, patients sampled at late time points after symptom onset had higher T cell counts and improved antiviral T cell responses. CONCLUSION: Our study suggests that severe COVID-19 is characterized by extensive T cell dysfunction and T cell apoptosis, which is associated with signs of homeostatic T cell proliferation and T cell recovery.


Asunto(s)
COVID-19 , Estudios Transversales , Homeostasis , Humanos , Activación de Linfocitos , SARS-CoV-2
20.
Allergy ; 76(1): 90-113, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32593226

RESUMEN

Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.


Asunto(s)
Asma , Enfermedades Autoinmunes , Hipersensibilidad , Enfermedades Autoinmunes/terapia , Autoinmunidad , Humanos , Hipersensibilidad/terapia , Linfocitos T Reguladores
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