RESUMO
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.
Assuntos
Glucocorticoides/administração & dosagem , Hepatite Autoimune/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Imunossupressores/administração & dosagem , Autoanticorpos/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Indução de Remissão/métodosRESUMO
Pediatric opsoclonus-myoclonussyndrome (OMS) is a rare autoimmune disorder of which 50% are associated with neuroblastoma (NB). We investigated whether surface-binding autoantibodies in OMS can enhance natural killer (NK) cell-mediated cytotoxicity in these patients. OMS immunoglobulin G (IgG) bound to NB cell lines and NK cell-mediated cytotoxicity to NB cells was enhanced after preincubation with OMS-IgG, but not IgG from NB without OMS or healthy controls. Activation of NK cells by surface-binding autoantibodies may be an additional mechanism of antitumor immunity in children with NB and OMS.
Assuntos
Apoptose , Autoanticorpos/imunologia , Imunoglobulina G/efeitos adversos , Células Matadoras Naturais/patologia , Neuroblastoma/patologia , Síndrome de Opsoclonia-Mioclonia/patologia , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Pré-Escolar , Feminino , Seguimentos , Humanos , Imunoglobulina G/imunologia , Lactente , Células Matadoras Naturais/imunologia , Masculino , Neuroblastoma/sangue , Neuroblastoma/complicações , Neuroblastoma/imunologia , Síndrome de Opsoclonia-Mioclonia/sangue , Síndrome de Opsoclonia-Mioclonia/complicações , Síndrome de Opsoclonia-Mioclonia/imunologia , PrognósticoRESUMO
Expert opinion suggests the presence ANA and thyroid antibodies may be helpful to diagnosis autoimmune encephalitis (AE). This study investigates the sensitivity of these serum markers in a cohort of 26 patients with AE. TPO-Ab, TG-Ab and ANA (titer ≥1:320) were present in 45%, 35% and 32% of patients tested, respectively. The prevalence of TPO-Ab (11.3%), TG-Ab (10.4%) and ANA ≥1:320 (3.3%) has been previously reported in disease-free populations. Although these antibodies represent non-specific markers of autoimmunity, this study demonstrated that TPO-Ab, TG-Ab and ANA were significantly elevated in AE compared to disease-free populations (p < .001, p = .003, p < .001, respectively).
Assuntos
Autoanticorpos/sangue , Autoantígenos/sangue , Proteínas de Ciclo Celular/sangue , Encefalite/sangue , Encefalite/diagnóstico por imagem , Doença de Hashimoto/sangue , Doença de Hashimoto/diagnóstico por imagem , Iodeto Peroxidase/sangue , Proteínas de Ligação ao Ferro/sangue , Tireoglobulina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/efeitos dos fármacos , Biomarcadores/sangue , Estudos de Coortes , Eletroencefalografia/métodos , Encefalite/fisiopatologia , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Doença de Hashimoto/fisiopatologia , Humanos , Masculino , Metilprednisolona/farmacologia , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
The advent of immune checkpoint inhibitors such as anti-PD-1 antibodies had a striking impact on the treatment for advanced malignant melanoma. However, less than half of the patients benefited from those antibodies, and biomarkers that could sensitively differentiate responders from non-responders are urgently needed. Herein, we explored such biomarkers by retrospectively analyzing clinical data from patients with advanced malignant melanoma treated with nivolumab and pembrolizumab. We found that anti-PD-1 antibody was especially effective for those with metastasis only to soft tissues. Although no significant difference was found in the baseline value of relative neutrophil count (RNC), relative lymphocyte count (RLC), neutrophil to lymphocyte ratio (NLR), and relative eosinophil count (REC) between responders and non-responders, responders after anti-PD-1 therapy revealed the increase of lymphocytes and eosinophils and the decrease of neutrophils within the first 6 weeks of the treatment. We also calculated the change of RNC and RLC 3 weeks and 6 weeks after the initiation of the therapy and designated as NΔ3-LΔ3 and NΔ6-LΔ6 respectively. NΔ3-LΔ3 was significantly decreased in responders, which suggest that the neutrophil decrease and lymphocyte increase after as early as 3 weeks of anti-PD-1 therapy might be a useful clinical indicator. In addition, the difference of NΔ6-LΔ6 between responders and non-responders was even more robust. These data suggest that change of RNC, RLC, and REC together with the combination of NΔ3-LΔ3 and NΔ6-LΔ6 might be a useful tool for early and sensitive biomarkers for anti-PD-1 therapy.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptor de Morte Celular Programada 1/sangue , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Resultado do Tratamento , Melanoma Maligno CutâneoRESUMO
The recent approval of Immunologic checkpoint inhibitors as an effective therapeutic strategy against cancer came at the cost of toxicities mediated by an excessive activation of immune system against health tissues, including among others musculoskeletal and sicca complaints.The latter occur in the context of an entity reminiscent of Sjogren's syndrome, with distinct characteristics such as abrupt onset, male predominance, lower prevalence of autoantibodies and response to steroids.
Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Ipilimumab/efeitos adversos , Nivolumabe/efeitos adversos , Síndrome de Sjogren/induzido quimicamente , Idoso , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/uso terapêutico , Masculino , Neoplasias/tratamento farmacológico , Nivolumabe/uso terapêutico , Síndrome de Sjogren/imunologiaRESUMO
Immune checkpoint inhibitors have transformed the treatment of advanced malignancy, while increasing the risk of immune-related adverse events. A 56-year-old woman who had received nivolumab for stage 4 renal cell carcinoma subsequently developed altered behaviour, memory deficits and worsening of previously stable epilepsy. MR scan of the brain showed bilateral FLAIR (fluid-attenuated inversion recovery) hyperintensity of the mesial temporal lobes, and there were anti-Ma2 antibodies in both serum and cerebrospinal fluid. She was treated with corticosteroids but developed further clinical relapses requiring immunoglobulin and rituximab. The immune-related adverse events relating to immune checkpoint inhibitors are an emerging challenge for the neurologist. Some cases are refractory and require serial immunosuppression.
Assuntos
Antígenos de Neoplasias/metabolismo , Autoanticorpos/metabolismo , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Doença de Hashimoto/tratamento farmacológico , Doença de Hashimoto/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Autoanticorpos/efeitos dos fármacos , Encefalite/diagnóstico por imagem , Feminino , Doença de Hashimoto/diagnóstico por imagem , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: SLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell-targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation. METHODS: Autoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation. RESULTS: Reductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ. CONCLUSION: This study demonstrated the impact of different B cell-targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos/farmacologia , Imunidade Humoral/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo Antígeno-Anticorpo/efeitos dos fármacos , Complexo Antígeno-Anticorpo/imunologia , Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Proteínas do Sistema Complemento/imunologia , Quimioterapia Combinada , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Rituximab/farmacologia , Rituximab/uso terapêuticoRESUMO
BACKGROUND: Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia that is characterized by hyperinsulinemia, hypoglycemia, and a high autoantibody titer. About 50% of patients with IAS have taken a medication containing sulfhydryl (-SH) groups. We present a case of IAS that developed after taking clopidogrel, a drug with an active metabolite that contains an SH-group. CASE REPORT: IAS was suspected in a 63-year-old Chinese man because of high concentrations of insulin and C-peptide during hypoglycemic episodes, and positivity for anti-insulin autoantibody (IAA). During his first episode of hypoglycemia, no trigger medication was identified and prednisone therapy was effective. However, imaging examination revealed a colonic carcinoma and the patient was discharged to undergo surgery. He had no episodes of hypoglycemia for 10 weeks after discontinuation of the prednisone, but then hypoglycemia recurred. A review of his medication revealed that he had taken a 10-day course of clopidogrel just before the recurrence. Therefore, a specialized multidisciplinary team consisting of endocrinologists, dieticians, and clinical pharmacists took charge of his management. Prednisone therapy was restarted and tapered off over 16 weeks. The patient also consumed small, frequent, low-carbohydrate meals and was instructed to avoid trigger medications. No further episodes of hypoglycemia were detected. His insulin and C-peptide concentrations and his anti-IAA index normalized during the follow-up period. CONCLUSION: SH-group-containing drugs might induce or exacerbate hypoglycemia in patients with a history of IAS. Furthermore, patients with IAS can benefit from multidisciplinary team management. We suggest herein an evaluation process for patients suspected of IAS.
Assuntos
Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Doenças Autoimunes/sangue , Doenças Autoimunes/induzido quimicamente , Clopidogrel/efeitos adversos , Anticorpos Anti-Insulina/sangue , Doenças Autoimunes/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversosRESUMO
While immune checkpoint inhibitors (ICIs) have contributed to the development of therapeutic treatments for previously incurable advanced malignancies, they may induce immune-related adverse events (irAEs) in many organs including the CNS [1]. Because immune checkpoint molecules are predominantly expressed on T cells, irAEs are largely not B cell-mediated. Here, we report a patient who was treated with pembrolizumab (a PD-1 monoclonal antibody) for lung adenocarcinoma with brain metastasis, and who developed anti-aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that PD-1 immune checkpoint blockage might induce a B cell-mediated immune response in CNS resulting in this complication, which was further supported by the observation of a transient increase in plasmablasts in their CSF.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Aquaporina 4/efeitos dos fármacos , Neuromielite Óptica/tratamento farmacológico , Aquaporina 4/imunologia , Autoanticorpos/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neuromielite Óptica/complicações , Neuromielite Óptica/diagnósticoRESUMO
Myasthenia Gravis (MG) - an autoimmune neuromuscular disease - is known by the production of autoantibodies against components of the neuromuscular junction mainly to the acetylcholine receptor, which cause the destruction and compromises the synaptic transmission. This disease is characterized by fluctuating and fatigable muscle weakness, becoming more intensive with activity, but with an improvement under resting. There are many therapeutic strategies used to alleviate MG symptoms, either by improving the transmission of the nerve impulse or by ameliorating autoimmune reactions with e.g. steroids, immunosuppressant drugs, or monoclonal antibodies (rituximab and eculizumab). Many breakthroughs in the discovery of new therapeutic targets have been reported, but MG remains to be a chronic disease where the symptoms are kept in the majority of patients. In this review, we discuss the different therapeutic strategies that have been used over the years to alleviate MG symptoms, as well as innovative therapeutic approaches currently under study.
Assuntos
Autoanticorpos/sangue , Inativadores do Complemento/uso terapêutico , Imunossupressores/uso terapêutico , Miastenia Gravis/sangue , Miastenia Gravis/tratamento farmacológico , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/imunologia , Inativadores do Complemento/farmacologia , Humanos , Imunossupressores/farmacologia , Miastenia Gravis/imunologia , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/imunologia , Junção Neuromuscular/metabolismo , Receptores Colinérgicos/imunologia , Receptores Colinérgicos/metabolismo , Literatura de Revisão como AssuntoRESUMO
Rheumatoid arthritis (RA) immunopathology starts many years before clinical disease manifests. An early event is the breakdown in B-cell tolerance and the emergence of autoantibodies. Some years later, the autoantibody response matures, with epitope spreading and isotype switching suggesting more focused T-cell involvement. Circulating proinflammatory cytokines and chemokines appear concurrently, marking a phase of preclinical inflammation. Eventually individuals develop musculoskeletal symptoms and fatigue, heralding the imminent onset of synovitis. The prevention of RA can be aligned to these disease stages, which may simplistically be viewed as breach of tolerance, maturation of autoimmunity, and subclinical inflammation. At each stage, an "ethical" balance must be struck between the potential for benefit versus harm, in large part determined by the likelihood of progression to RA. In particular, tolerogenic interventions should be favored during asymptomatic disease, providing long-lasting, possibly lifelong, benefit from a short-term intervention. During the breach-of-tolerance phase, tolerogenic interventions might involve the administration of autoantigenic peptides in an attempt to shut down autoreactive B cells. The peptides may be "naked," encapsulated in nanoparticles or loaded into autologous tolerogenic dendritic cells. It may also be possible to interfere with antigen generation and presentation, such as via peptidyl arginine deiminase inhibition. Attempts to interfere with B cells via depletion, differentiation, or intracellular signaling are also logical at this stage, if deemed sufficiently well tolerated. These interventions remain relevant during maturation of autoimmunity, but targeted T-cell interventions also become relevant, such as co-stimulation blockade and, potentially, interventions that target intracellular signaling pathways within T cells. Targeting of interleukin 23 during this phase may interfere with maturation of the autoantibody response by modulating autoantibody glycosylation, as well as by inhibiting T-helper 17 differentiation. During the phase of subclinical inflammation, targeting cytokines and chemokines could conceivably prevent progression to RA. Furthermore, tolerance induction is opposed by systemic inflammation and, during this phase, it may be necessary to consider therapeutic combinations of tolerogenic and antiinflammatory interventions.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Autoanticorpos/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Peptídeos/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/prevenção & controle , Citocinas/imunologia , Progressão da Doença , Humanos , Tolerância Imunológica , Inflamação/imunologia , Terapia de Alvo MolecularRESUMO
PURPOSE: The anti-CCR4 mAb, mogamulizumab, offers therapeutic benefit to patients with adult T-cell leukemia-lymphoma (ATL), but skin-related adverse events (AE) such as erythema multiforme occur frequently. The purpose of this study was to determine the mechanisms by which mogamulizumab causes skin-related AEs in patients with ATL. EXPERIMENTAL DESIGN: We investigated whether autoantibodies were present in patients' sera using flow cytometry to determine binding to keratinocytes and melanocytes (n = 17), and immunofluorescence analysis of tissue sections. We analyzed the IgM heavy chain repertoire in peripheral blood mononuclear cells before and after mogamulizumab or other chemotherapy by next-generation sequencing (NGS; n = 16). RESULTS: Autoantibodies recognizing human keratinocytes or melanocytes were found in the sera of 6 of 8 patients suffering from mogamulizumab-induced erythema multiforme. In one patient, complement-dependent cytotoxicity (CDC) mediated by autoantibodies against keratinocytes or melanocytes was proportionally related to the severity of the erythema multiforme. The presence of autoantibodies in the epidermis was confirmed in all biopsy specimens of mogamulizumab-induced erythema multiforme (n = 12). Furthermore, colocalization of autoantibodies and C1q, suggesting the activation of CDC, was observed in 67% (8/12). In contrast, no autoantibody or C1q was found in ATL tumor skin lesions (n = 13). Consistent with these findings, NGS demonstrated that IgM germline genes had newly emerged and expanded, resulting in IgM repertoire skewing at the time of erythema multiforme. CONCLUSIONS: Mogamulizumab elicits autoantibodies playing an important role in skin-related AEs, possibly associated with regulatory T-cell depletion. This is the first report demonstrating the presence of skin-directed autoantibodies after mogamulizumab treatment.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Autoanticorpos/imunologia , Citotoxicidade Imunológica/imunologia , Queratinócitos/imunologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/imunologia , Dermatopatias/imunologia , Adulto , Antineoplásicos/efeitos adversos , Autoanticorpos/efeitos dos fármacos , Proteínas do Sistema Complemento/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Leucemia-Linfoma de Células T do Adulto/patologia , Depleção Linfocítica , Receptores CCR4/antagonistas & inibidores , Receptores CCR4/metabolismo , Dermatopatias/induzido quimicamente , Dermatopatias/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
SUBJECT: The aim of this study was to investigate whether vitamin D plays a protective role in podocyte injury induced by autoantibodies purified from the serum of patients with lupus nephritis (LN) via reducing aberrant autophagy. METHODS: Autophagic activities of renal tissues of patients with LN were evaluated under transmission electronic microscope (TEM). Immunoglobulin G (IgG) from patients with LN was purified to induce human podocyte injury, and the role of vitamin D in injury was observed. Podocytes were observed under TEM, autophagic activity was evaluated by western blot analysis and quantitative real-time polymerase chain reaction, and mRFP-GFP-LC3B adenovirus was infected into human podocytes in vitro. RESULTS: Significantly higher autophagic levels were observed in patients with LN (P <0.05), and apparently greater autophagic levels in podocytes were shown (P <0.05). Among different classifications of LN, class V (n = 5), III + V (n = 5), and IV + V (n = 5) gained higher autophagic levels than class III (n = 5) and IV (n = 5). Induced autophagy, which was evident by increased LC3B-II and Beclin 1 level, caused consumption of p62, more autophagosomes observed under TEM, and more LC3B dots observed under confocal microscope in the IgG group, along with decreased nephrin expression, which suggests podocyte injury. Reduction of autophagy as well as alleviated podocyte injury was observed in the IgG+ vitamin D group. CONCLUSION: This study demonstrates that vitamin D plays a protective role in podocyte injury induced by autoantibodies from patients with LN and appears to be a novel therapy target in LN.
Assuntos
Autoanticorpos/sangue , Autofagia/fisiologia , Nefrite Lúpica/sangue , Podócitos/metabolismo , Vitamina D/farmacologia , Adolescente , Adulto , Autoanticorpos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Transformada , Criança , Feminino , Humanos , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Podócitos/efeitos dos fármacos , Podócitos/ultraestrutura , Adulto JovemRESUMO
Antibodies against glutamic acid decarboxylase (GAD) are reported in association with numerous neurological conditions including temporal lobe epilepsy and limbic encephalitis. We report a case of Anti-GAD-Antibody associated encephalitis presenting with epilepsia partialis continua (EPC) progressing to a fulminant encephalopathy preferentially affecting the frontal lobes associated with coma and refractory status epilepticus. The abnormalities identified on MRI included marked bilateral frontal lobe involvement which has not been reported in other auto-immune encephalitides and may be specific for Anti-GAD-Antibody associated encephalitis. Similar to the majority of cases of Anti-GAD associated neurological disturbance no underlying malignancy was identified. Treatment with high dose corticosteriods, IVIG and plasmapheresis had minimal response, but escalation of treatment with rituximab and cyclophosphamide was associated with clinical improvement, reducing antibody titers and resolution of MRI changes.
Assuntos
Autoanticorpos/sangue , Encefalite/sangue , Glutamato Descarboxilase/sangue , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Estado Epiléptico/sangue , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/imunologia , Diagnóstico Diferencial , Encefalite/tratamento farmacológico , Encefalite/imunologia , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Imunossupressores/farmacologia , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/imunologia , Adulto JovemRESUMO
The discovery of novel autoantigen systems related to idiopathic inflammatory myopathies (collectively referred to as myositis) in adults and children has had major implications for the diagnosis and management of this group of diseases across a wide range of medical specialties. Traditionally, autoantibodies found in patients with myositis are described as being myositis-specific autoantibodies (MSAs) or myositis-associated autoantibodies (MAAs), depending on their prevalence in other, related conditions. However, certain MSAs are more closely associated with extramuscular manifestations, such as skin and lung disease, than with myositis itself. It is very rare for more than one MSA to coexist in the same individual, underpinning the potential to use MSAs to precisely define genetic and disease endotypes. Each MSA is associated with a distinctive pattern of disease or phenotype, which has implications for diagnosis and a more personalized approach to therapy. Knowledge of the function and localization of the autoantigenic targets for MSAs has provided key insights into the potential immunopathogenic mechanisms of myositis. In particular, evidence suggests that the alteration of expression of a myositis-related autoantigen by certain environmental influences or oncogenesis could be a pivotal event linking autoantibody generation to the development of disease.
Assuntos
Autoanticorpos/metabolismo , Miosite/imunologia , Adulto , Autoanticorpos/efeitos dos fármacos , Autoantígenos/imunologia , Criança , Humanos , Miosite/tratamento farmacológico , Fenótipo , Medicina de PrecisãoAssuntos
Citoproteção/efeitos dos fármacos , Diabetes Mellitus Tipo 1/imunologia , Estrogênios/farmacologia , Imunomodulação/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/fisiologia , Ilhotas Pancreáticas/imunologia , Masculino , Caracteres SexuaisRESUMO
Gluten consumption has previously been implicated in the development of schizophrenia while an immunological link between gluten and schizophrenia was established by the detection of circulating antibodies against gliadin, a major component of wheat gluten. Several studies have reported an increase in circulating antibodies against native gliadin molecules that are unlikely to survive degradation in the digestive system. In this study, therefore, we measured plasma immunoglobulin G (IgG) and IgA antibodies against indigestible gliadin-derived peptide antigens using an in-house enzyme-linked immunosorbent assay (ELISA) among 169 patients with schizophrenia and 236 control subjects. We also examined the plasma levels of IgG and IgA antibodies against the mixture of native gliadins using commercially available ELISA kits. The results showed that patients with schizophrenia had the increased levels of plasma IgG against the γ-gliadin-derived fragment, namely AAQ6C, but decreased levels of plasma IgG against the α- and γ3-gliadin-derived antigens, as compared with control subjects. This study also demonstrated a uniform decrease in plasma IgA antibodies against gliadin-derived antigens. There was no significant difference in the levels of plasma antibodies against native gliadins between the patient group and the control group. Of eight gliadin-derived antigens tested, four showed a sensitivity of >20% against the specificity of ⩾95% for detection of their corresponding antibodies in plasma. These four tests may thus have a potential to serve as biomarkers for the identification of schizophrenia subgroups that may need an alternative therapy or precision treatment. Further investigation with clinical trials should be carried out to explore this possibility.
Assuntos
Formação de Anticorpos/imunologia , Gliadina/imunologia , Glutens/imunologia , Peptídeos/imunologia , Esquizofrenia/imunologia , Adulto , Formação de Anticorpos/efeitos dos fármacos , Antígenos , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/imunologia , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Glutens/efeitos adversos , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatologiaRESUMO
Objective The treatment of refractory lupus nephritis (LN) remains challenging for clinicians because these patients either do not respond to conventional therapy or relapse during the maintenance treatment period. The aim of this study was to investigate the efficacy and safety of bortezomib combined with glucocorticoids in refractory lupus patients. Methodology Five refractory LN patients aged 21 to 43 years (four females and one male) with biopsy-proven diagnosis (four with type IV and one with type V+IV) were recruited. These patients received bortezomib therapy for four cycles (1.3 mg per square meter of body surface area as an intravenous bolus on days 1, 4, 8, and 11 of 21-day cycles) and glucocorticoids (methylprednisolone 0.5 g/d intravenously for three days, followed by prednisone 0.6 mg/kg/d orally for four weeks, with gradual tapering to 10 mg/d). Proteinuria, serum albumin and creatinine, and immunological parameters were assessed, and adverse effects were also evaluated. Results After two to four bortezomib treatment cycles, four patients achieved partial remission with decreases in SLE disease activity index scores from the range of 12-16 to that of 4-8. The patients also exhibited a decline in proteinuria and an elevation of albumin level after treatment. SCr level was decreased in three of five patients with elevated SCr at baseline. The anti-autoantibodies and complements were also improved. Adverse events were of grades 1-2 and included transient thrombocytopenia, gastrointestinal symptoms and acroesthesia. During a 6- to 24-month follow-up period, three patients achieved complete remission, and one had partial remission. However, one patient received renal replacement therapy. Conclusion Bortezomib combined with glucocorticoids reduces proteinuria, improves renal function and decreases anti-autoantibodies, with good tolerance and mild adverse events, thus representing an alternative therapy for refractory LN and warranting further study.
Assuntos
Bortezomib/farmacologia , Quimioterapia Combinada/métodos , Nefrite Lúpica/tratamento farmacológico , Metilprednisolona/farmacologia , Prednisona/farmacologia , Administração Intravenosa , Adulto , Antineoplásicos/uso terapêutico , Autoanticorpos/efeitos dos fármacos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/patologia , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Prednisona/administração & dosagem , Proteinúria/tratamento farmacológico , Indução de RemissãoRESUMO
In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17ß-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.
Assuntos
Artrite Experimental/diagnóstico por imagem , Artrite Reumatoide/diagnóstico por imagem , Autoanticorpos/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/diagnóstico por imagem , Citocinas/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Indóis/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Doenças Ósseas Metabólicas/imunologia , Citocinas/imunologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Imunoglobulina G/efeitos dos fármacos , Imunoglobulina G/imunologia , Interleucina-6/imunologia , Camundongos , Ovariectomia , Radiografia , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate treatment with MEDI-551, a humanized anti-human CD19 monoclonal antibody, in a model of autoimmunity involving mice transgenic (Tg) for Sle1 and human CD19 (hCD19). METHODS: Sle1.hCD19-Tg mice were given either a single intravenous dose of MEDI-551 or repeated doses of MEDI-551 biweekly for up to 12 weeks. The numbers of B cells in the blood, spleen, and bone marrow were determined by flow cytometry assay. In the spleen and bone marrow, the number of IgM- and IgG-specific antibody-secreting cells (ASCs) and the number of ASCs specific for anti-double-stranded DNA (anti-dsDNA) were determined by enzyme-linked immunospot assay. Serum autoantibody and total immunoglobulin levels were determined by enzyme-linked immunosorbent assay, and levels of inflammatory proteins were tested using a multianalyte profiling platform. RESULTS: MEDI-551 treatment of Sle1.hCD19-Tg mice resulted in effective and sustained B cell depletion throughout the duration of the experiment. The frequency of IgM and IgG ASCs in the spleen was reduced by ≥90%, whereas in the bone marrow, the total ASC frequency was not changed. Levels of autoantibodies specific for dsDNA as well as antihistone and antinuclear antibodies were each reduced by 40-80%, but total serum immunoglobulin levels were largely unchanged at the end of 12 weeks of treatment. CONCLUSION: These findings highlight the ability of MEDI-551 to deplete B cells and ASCs in autoimmune Sle1.hCD19-Tg mice. MEDI-551 treatment resulted in a robust reduction of autoantibodies but had minimal effect on total serum immunoglobulins. Thus, the novel ability of MEDI-551 to remove a broad range of B cells as well as to lower most disease-driving autoantibodies in an autoimmune disease mouse model warrants continued research. Several clinical studies to explore the safety and activity of MEDI-551 in autoantibody-associated autoimmune diseases are ongoing.