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1.
Cells ; 10(10)2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34685704

RESUMO

Patients with prostate cancer (PCa) receiving docetaxel chemotherapy invariably develop chemoresistance. The transcription co-activator lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 and PSIP1, is upregulated in several human cancers, including PCa and promotes resistance to docetaxel and other drugs. The C-terminal region of LEDGF/p75 contains an integrase binding domain (IBD) that tethers nuclear proteins, including the HIV-1 integrase and transcription factors, to active chromatin to promote viral integration and transcription of cellular survival genes. Here, we investigated the contribution of the LEDGF/p75 IBD interactome to PCa chemoresistance. Quantitative immunoblotting revealed that LEDGF/p75 and its IBD-interacting partners are endogenously upregulated in docetaxel-resistant PCa cell lines compared to docetaxel-sensitive parental cells. Using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners JPO2, menin, MLL, IWS1, ASK1, and PogZ, as well as transcription factors c-MYC and HRP2, in docetaxel-resistant cells, and confirmed their nuclear co-localization by confocal microscopy. Depletion of LEDGF/p75 and selected interacting partners robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of docetaxel-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.


Assuntos
Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Esferoides Celulares/patologia , Especificidade de Anticorpos/imunologia , Apoptose/efeitos dos fármacos , Autoanticorpos/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Esferoides Celulares/efeitos dos fármacos
2.
Cells ; 10(10)2021 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-34685525

RESUMO

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages' supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies.


Assuntos
Autoimunidade , COVID-19/sangue , COVID-19/imunologia , Armadilhas Extracelulares/imunologia , Imunidade Humoral , Inflamação , Neutrófilos/imunologia , Anticorpos Antinucleares , Peptídeos Catiônicos Antimicrobianos/sangue , Autoanticorpos/metabolismo , Estudos Transversais , Citocinas/metabolismo , Citocinas/farmacologia , Citometria de Fluxo , Granulócitos/metabolismo , Proteína HMGB1/sangue , Voluntários Saudáveis , Humanos , Microscopia Confocal , Monócitos/citologia , Neutrófilos/citologia , SARS-CoV-2 , Ubiquitinas/farmacologia
3.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575873

RESUMO

Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjSS) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjSS mice, as evidenced by reduced Rac1 activation in SjSS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjSS mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjSS mice.


Assuntos
Regulação Enzimológica da Expressão Gênica , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , c-Mer Tirosina Quinase/genética , Proteína ADAM17/metabolismo , Animais , Anticorpos Antinucleares/química , Apoptose , Autoanticorpos/metabolismo , Autoimunidade , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Fenótipo , Saliva/metabolismo , Transdução de Sinais , Timócitos/metabolismo
4.
J Immunol ; 207(8): 2005-2014, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34544801

RESUMO

Elevated N-linked glycosylation of IgG V regions (IgG-VN-Glyc) is an emerging molecular phenotype associated with autoimmune disorders. To test the broader specificity of elevated IgG-VN-Glyc, we studied patients with distinct subtypes of myasthenia gravis (MG), a B cell-mediated autoimmune disease. Our experimental design focused on examining the B cell repertoire and total IgG. It specifically included adaptive immune receptor repertoire sequencing to quantify and characterize N-linked glycosylation sites in the circulating BCR repertoire, proteomics to examine glycosylation patterns of the total circulating IgG, and an exploration of human-derived recombinant autoantibodies, which were studied with mass spectrometry and Ag binding assays to respectively confirm occupation of glycosylation sites and determine whether they alter binding. We found that the frequency of IgG-VN-Glyc motifs was increased in the total BCR repertoire of patients with MG when compared with healthy donors. The elevated frequency was attributed to both biased V gene segment usage and somatic hypermutation. IgG-VN-Glyc could be observed in the total circulating IgG in a subset of patients with MG. Autoantigen binding, by four patient-derived MG autoantigen-specific mAbs with experimentally confirmed presence of IgG-VN-Glyc, was not altered by the glycosylation. Our findings extend prior work on patterns of Ig V region N-linked glycosylation in autoimmunity to MG subtypes.


Assuntos
Autoanticorpos/metabolismo , Linfócitos B/imunologia , Imunoglobulina G/metabolismo , Região Variável de Imunoglobulina/metabolismo , Miastenia Gravis/metabolismo , Adulto , Idoso , Feminino , Glicosilação , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Fenótipo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Adulto Jovem
5.
J Immunol ; 207(9): 2217-2222, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34588220

RESUMO

Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid and B cell APCs express B7 ligands (CD80 and CD86), the prevailing model holds that dendritic cell costimulation is sufficient for CD28-dependent T cell activation. In this study, we report that B cell-intrinsic CD80/CD86 deletion unexpectedly abrogates GCs in murine lupus. Interestingly, absent GCs differentially impacted serum autoantibodies. In keeping with distinct extrafollicular and GC activation pathways driving lupus autoantibodies, lack of GCs correlated with loss of RNA-associated autoantibodies but preserved anti-dsDNA and connective tissue autoantibody titers. Strikingly, even heterozygous B cell CD80/CD86 deletion was sufficient to prevent autoimmune GCs and RNA-associated autoantibodies. Together, these findings identify a key mechanism whereby B cells promote lupus pathogenesis by providing a threshold of costimulatory signals required for autoreactive T cell activation.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoanticorpos/metabolismo , Autoimunidade , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Ativação Linfocitária , Camundongos , Camundongos Knockout , Receptor Cross-Talk
6.
Handb Clin Neurol ; 181: 173-186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34238456

RESUMO

Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system that preferentially affects the optic nerve and the spinal cord. In around 80% of NMO patients, autoantibodies binding to aquaporin-4 (AQP4) are detected. AQP4-IgG unifies a spectrum of disorders (NMOSD) that include not only optic neuritis, longitudinally extensive transverse myelitis but also syndromes caused by lesion of the diencephalic region and the circumventricular organs (CVOs). The distinctive immunopathological characteristics of NMOSD lesions, occurring in regions where AQP4 is highly expressed, supports a central role for AQP4-IgG in disease pathogenesis. AQP4 expression is concentrated in CVOs and in the hypothalamus, mainly in the dorsal hypothalamic area, dorsomedial hypothalamic nucleus and suprachiasmatic nucleus. Several neuroendocrine disorders caused by inflammatory lesions involving the diencephalic region have been described in patients with NMOSD, including syndrome of inappropriate antidiuresis, sleep disorders, and other endocrinopathies caused by hypothalamic injury. Focus of this chapter is the involvement of hypothalamus and CVOs in AQP4 autoimmunity.


Assuntos
Mielite Transversa , Neuromielite Óptica , Aquaporina 4 , Autoanticorpos/metabolismo , Humanos
7.
Front Immunol ; 12: 650856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211460

RESUMO

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.


Assuntos
Autoimunidade/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Suplementos Nutricionais , Ácido Eicosapentaenoico/farmacologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Plasmócitos/efeitos dos fármacos , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Autoimunidade/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Plasmócitos/metabolismo
9.
Front Immunol ; 12: 582768, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177880

RESUMO

Background: The presence of fluid attenuated inversion recovery (FLAIR)-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated cerebral cortical encephalitis with seizures (FLAMCES) was recently reported. However, the clinical characteristics and outcome of this rare clinico-radiographic syndrome remain unclear. Methods: The present study reported two new cases. In addition, cases in the literature were systematically reviewed to investigate the clinical symptoms, magnetic resonance imaging (MRI) abnormalities, treatments and prognosis for this rare clinico-radiographic syndrome. Results: A total of 21 cases were identified during a literature review, with a mean patient age at onset of 26.8 years. The primary clinicopathological characteristics included seizures (100%), headache (71.4%), fever (52.3%) and other cortical symptoms associated with the encephalitis location (61.9%). The common seizure types were focal to bilateral tonic-clonic seizures (28.6%) and unknown-onset tonic-clonic seizures (38.1%). The cortical abnormalities on MRI FLAIR imaging were commonly located in the frontal (58.8%), parietal (70.6%) and temporal (64.7%) lobes. In addition, pleocytosis in the cerebrospinal fluid was reported in the majority of the patients (95.2%). All patients received a treatment regimen of corticosteroids and 9 patients received anti-epileptic drugs. Clinical improvement was achieved in all patients; however, one-third of the patients reported relapse following recovery from cortical encephalitis. Conclusions: FLAMCES is a rare phenotype of MOG-associated disease. Thus, the wider recognition of this rare syndrome may enable timely diagnosis and the development of suitable treatment regimens.


Assuntos
Autoanticorpos/metabolismo , Córtex Cerebral/patologia , Líquido Cefalorraquidiano/imunologia , Encefalite/diagnóstico , Doenças do Complexo Imune/diagnóstico , Corticosteroides/uso terapêutico , Adulto , Anticonvulsivantes/uso terapêutico , Córtex Cerebral/imunologia , Encefalite/tratamento farmacológico , Feminino , Cefaleia , Humanos , Doenças do Complexo Imune/tratamento farmacológico , Leucocitose , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Glicoproteína Mielina-Oligodendrócito , Convulsões , Adulto Jovem
11.
J Neuromuscul Dis ; 8(5): 801-814, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34024774

RESUMO

BACKGROUND: FSHD is caused by specific genetic mutations resulting in activation of the Double Homeobox 4 gene (DUX4). DUX4 targets hundreds of downstream genes eventually leading to muscle atrophy, oxidative stress, abnormal myogenesis, and muscle inflammation. We hypothesized that DUX4-induced aberrant expression of genes triggers a sustained autoimmune response against skeletal muscle cells. OBJECTIVE: This study aimed at the identification of autoantibodies directed against muscle antigens in FSHD. Moreover, a possible relationship between serum antibody reactivity and DUX4 expression was also investigated. METHODS: FSHD sera (N = 138, 48±16 years, 48% male) and healthy control sera (N = 20, 47±14 years, 50% male) were analyzed by immunoblotting for antibodies against several skeletal muscle protein extracts: healthy muscle, FSHD muscle, healthy and FSHD myotubes, and inducible DUX4 expressing myoblasts. In addition, DUX4 expressing myoblasts were analyzed by immunofluorescence with FSHD and healthy control sera. RESULTS: The results showed that the reactivity of FSHD sera did not significantly differ from that of healthy controls, with all the tested muscle antigen extracts. Besides, the immunofluorescent staining of DUX4-expressing myoblasts was not different when incubated with either FSHD or healthy control sera. CONCLUSION: Since the methodology used did not lead to the identification of disease-specific autoantibodies in the FSHD cohort, we suggest that autoantibody-mediated pathology may not be an important disease mechanism in FSHD. Nevertheless, it is crucial to further unravel if and which role the immune system plays in FSHD pathogenesis. Other innate as well as adaptive immune players could be involved in the complex DUX4 cascade of events and could become appealing druggable targets.


Assuntos
Autoanticorpos/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular Facioescapuloumeral/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Mioblastos/metabolismo
12.
Brain Nerve ; 73(5): 475-482, 2021 May.
Artigo em Japonês | MEDLINE | ID: mdl-34006678

RESUMO

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder primarily associated with optic neuritis, myelitis or area postrema syndrome. Several lines of evidence suggest that NMOSD is a humoral immune disease mainly caused by aquaporin-4 antibody and related complement-dependent cytotoxicity against astrocytes. Therefore, NMOSD is distinct from multiple sclerosis (MS). In the diagnosis of NMOSD, it is recommended to examine by high-sensitive cell-based assay targeting against M23-AQP4 but we always have to be careful for the possibility of false negative or false positive result due to each assay. To prevent relapse of the disease, it is best to avoid disease-modifying drugs used for treatment of MS because of possible acute exacerbation of the disease activity. Usually, it is recommended to start treatment with administration of oral steroids and then gradually move to immunosuppressants. However, side effects of such treatments need to be evaluated. Currently, there are additional options for therapy with biopharmaceutical agents such as eculizumab, satralizumab, rituximab, or inebilizumab to prevent relapse of the disease. These new options can clearly exceed or surpass the usual treatments and should be considered positively in aggressive cases of NMOSD.


Assuntos
Neuromielite Óptica , Neurite Óptica , Anticorpos Monoclonais Humanizados , Aquaporina 4 , Autoanticorpos/metabolismo , Humanos , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/tratamento farmacológico
13.
Brain Nerve ; 73(5): 595-604, 2021 May.
Artigo em Japonês | MEDLINE | ID: mdl-34006693

RESUMO

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease caused by autoantibodies against the extracellular conformational epitope of the NR1 subunit of the NMDAR (GluN1 antibodies). A series of autoantibodies directed against neuronal surface (NS) or synaptic proteins play an important role in the pathophysiological mechanisms of post-herpes simplex encephalitis (post-HSE), overlapping autoimmune encephalitis and demyelinating syndrome, epileptic seizures, psychosis, involuntary movements (orofacial and limb dyskinesias, catatonia, dystonia, chorea, myoclonus, psychogenic nonepileptic seizures, and faciobrachial dystonic seizures), postpartum psychosis, stiff-person spectrum disorder (including progressive encephalomyelitis with rigidity and myoclonus [PERM]), cerebellar ataxia, and sleep behavior disorders. These NS antibodies are identified with cell-based assays and immunohistochemistry using nonperfused paraformaldehyde-fixed rodent brain tissue. This paper presents an update on anti-NMDAR encephalitis, including the differential diagnosis of cryptogenic new-onset refractory status epilepticus (NORSE), and on the treatment strategy, including third-line therapy.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Doença de Hashimoto , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Autoanticorpos/metabolismo , Feminino , Humanos , Receptores de N-Metil-D-Aspartato , Convulsões
14.
Ann Hematol ; 100(7): 1701-1709, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33982136

RESUMO

Immune thrombocytopenia (ITP) is a disorder in which autoantibodies are responsible for destruction and decreased production of platelets. In the meantime, thrombocytopenia is frequent in patients with myelodysplastic syndromes (MDS) and immune clearance of megakaryocytes could be a reason. The aim of the present study is to evaluate and compare IgG binding to megakaryocytes in bone marrow of ITP and MDS patients to determine megakaryocytes targeting by autoantibodies in vivo as a mechanism of platelet underproduction in these disorders. The study was carried out on 20 ITP (group I) patients, 20 thrombocytopenic patients with (MDS) (group II), and 20 non-ITP patients as a control (group III) who were admitted to Minia University Hospital. Serial histological sections from bone marrow biopsies were stained for IgG. All patients in group I and 50% of group II patients showed bleeding tendency and the difference was significant (p < 0.001). No patient experienced fatigue in group I while 35% of patients in group II complained of easy fatigability, and the difference was significant (p < 0.008). High IgG antibody binding was found in ITP and MDS compared to the control group but no significant difference between ITP and MDS patients (14/20 (70%) vs. 13/20 (65%)) (p value = 0.736). Antibody binding to megakaryocytes in a proportion of MDS patients suggests that immune-mediated mechanism underlies platelet underproduction in those patients.


Assuntos
Imunoglobulina G/metabolismo , Megacariócitos/metabolismo , Trombocitopenia/imunologia , Adulto , Anemia Aplástica/complicações , Anemia Megaloblástica/complicações , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Medula Óssea/imunologia , Medula Óssea/patologia , Estudos Transversais , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Megacariócitos/imunologia , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/patologia , Trombocitopenia/etiologia , Trombocitopenia/patologia , Adulto Jovem
15.
J Neurol ; 268(11): 4163-4169, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33988764

RESUMO

BACKGROUND: AP3B2 is one of the subunits of vesicle coat protein AP3 and is specifically expressed in central nervous system neurons. AP3B2 antibody has been reported in patients with autoimmune cerebellar ataxia and various extracerebellar symptoms. However, there have been few reports on its clinical features and treatment response. METHODS: We report a 47-year-old man with AP3B2 antibody who presented with insidious-onset paresthesia and gait disturbance. His serum and cerebrospinal fluid (CSF) showed reactivity with the cytoplasm of Purkinje cells and granular layer synapses comparable to the reported specific pattern of anti-AP3B2 IgG, and this was confirmed by a cell-based assay. His symptoms improved after the administration of intravenous immunoglobulin, and oral prednisone and mycophenolate mofetil. Extensive examination and long-term follow-up showed no evidence of malignancy. A literature review was included to emphasize the neurological syndrome associated with this rare autoantibody. RESULTS: Eleven cases with AP3B2 antibody, including our patient, were identified. The diversity of symptoms, including cerebellar and sensory ataxia, paresthesia, and weakness, was in line with the extensive binding of AP3B2 antibody to the spinal cord gray matter, dorsal root ganglia, cerebellar cortex, and nucleus. In the CSF, half of patients had elevated white blood cell counts, increased protein concentrations, or CSF-specific oligoclonal bands. All previous cases had subacute onsets and no improvement was noted after immunotherapy. CONCLUSION: Our case indicated that disorders associated with AP3B2 antibody can also start insidiously. Immunotherapy is warranted given the possibility of clinical improvement.


Assuntos
Ataxia Cerebelar , Doenças da Medula Espinal , Complexo 3 de Proteínas Adaptadoras , Subunidades beta do Complexo de Proteínas Adaptadoras , Autoanticorpos/metabolismo , Sistema Nervoso Central/metabolismo , Cerebelo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade
16.
Front Immunol ; 12: 649502, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968042

RESUMO

Pemphigus Vulgaris (PV) is a life-threatening autoimmune disease manifested with blisters in the skin and mucosa and caused by autoantibodies against adhesion protein desmoglein-3 (Dsg3) expressed in epithelial membrane linings of these tissues. Despite many studies, the pathogenesis of PV remains incompletely understood. Recently we have shown Dsg3 plays a role in regulating the yes-associated protein (YAP), a co-transcription factor and mechanical sensor, and constraining reactive oxygen species (ROS). This study investigated the effect of PV sera as well as the anti-Dsg3 antibody AK23 on these molecules. We detected elevated YAP steady-state protein levels in PV cells surrounding blisters and perilesional regions and in keratinocytes treated with PV sera and AK23 with concomitant transient ROS overproduction. Cells treated with hydrogen peroxide also exhibited augmented nuclear YAP accompanied by reduction of Dsg3 and α-catenin, a negative regulator of YAP. As expected, transfection of α-catenin-GFP plasmid rendered YAP export from the nucleus evoked by hydrogen peroxide. In addition, suppression of total YAP was observed in hydrogen peroxide treated cells exposed to antioxidants with enhanced cell-cell adhesion being confirmed by decreased fragmentation in the dispase assay compared to hydrogen peroxide treatment alone. On the other hand, the expression of exogenous YAP disrupted intercellular junction assembly. In contrast, YAP depletion resulted in an inverse effect with augmented expression of junction assembly proteins, including Dsg3 and α-catenin capable of abolishing the effect of AK23 on Dsg3 expression. Finally, inhibition of other kinase pathways, including p38MAPK, also demonstrated suppression of YAP induced by hydrogen peroxide. Furthermore, antioxidant treatment of keratinocytes suppressed PV sera-induced total YAP accumulation. In conclusion, this study suggests that oxidative stress coupled with YAP dysregulation attributes to PV blistering, implying antioxidants may be beneficial in the treatment of PV.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autoanticorpos/metabolismo , Estresse Oxidativo/imunologia , Pênfigo/imunologia , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Linhagem Celular , Desmogleína 3/imunologia , Desmogleína 3/metabolismo , Técnicas de Silenciamento de Genes , Voluntários Saudáveis , Humanos , Queratinócitos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Estresse Oxidativo/efeitos dos fármacos , Pênfigo/sangue , Pênfigo/tratamento farmacológico , Pênfigo/patologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , alfa Catenina/metabolismo
17.
Ren Fail ; 43(1): 651-657, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33820495

RESUMO

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Although several cases of BP in end-stage renal disease patients receiving peritoneal dialysis (PD) or hemodialysis have been reported, the incidence of BP in these patients remains unknown. We recently experienced three PD patients diagnosed with BP. The skin injury was likely to be a trigger of BP in all the three PD patients. Nifedipine and icodextrin exposures were possible factors directly or indirectly affecting the onset of BP, because they were common in the three cases. We also report that the incidence of BP in PD patients was 3/478.3 person-years in a single-center 10-year study. This case series with a literature survey describes that the skin and tissue injuries are potential triggers responsible for the onset of BP in dialysis patients and that the incidence of BP in these patients seems to be much higher than that in the general population.


Assuntos
Falência Renal Crônica/terapia , Penfigoide Bolhoso/etiologia , Diálise Peritoneal/efeitos adversos , Pele/patologia , Idoso , Autoanticorpos/metabolismo , Feminino , Humanos , Icodextrina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nifedipino/efeitos adversos , Penfigoide Bolhoso/imunologia
18.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810246

RESUMO

Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens and the control of pro- or anti-inflammatory immune reactions. In autoimmunity, hyposialylation is responsible for chronic inflammation, the anarchic activation of the immune system and organ lesions. A detailed characterization of this mechanism is a key element for improving the understanding of these diseases and the development of innovative therapies. This review focuses on the impact of sialylation in autoimmunity in order to determine future treatments based on the regulation of hyposialylation.


Assuntos
Autoanticorpos/metabolismo , Doenças Autoimunes/imunologia , Processamento de Proteína Pós-Traducional , Ácidos Siálicos/metabolismo , Animais , Autoanticorpos/imunologia , Doenças Autoimunes/terapia , Humanos , Imunofenotipagem/métodos , Medicina de Precisão/métodos , Ácidos Siálicos/imunologia
19.
Molecules ; 26(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916567

RESUMO

The exact mechanisms of multiple sclerosis (MS) development are still unknown, but the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice is associated with the violation of bone marrow hematopoietic stem cells (HSCs) differentiation profiles associated with the production of harmful for human's autoantibodies hydrolyzing myelin basic protein, myelin oligodendrocyte glycoprotein (MOG35-55), and DNA. It was shown that IgGs from the sera of healthy humans and autoimmune patients oxidize many different compounds due to their H2O2-dependent peroxidase and oxidoreductase activity in the absence of H2O2. Here we first analyzed the change in the relative redox activities of IgGs antibodies from the blood of C57BL/6 mice over time at different stages of the EAE development. It was shown that the peroxidase activity of mice IgGs in the oxidation of ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) is on average 6.9-fold higher than the oxidoreductase activity. The peroxidase activity of IgGs increased during the spontaneous development of EAE during 40 days, 1.4-fold. After EAE development acceleration due to mice immunization with MOG35-55 (5.3-fold), complexes of bovine DNA with methylated bovine serum albumin (DNA-metBSA; 3.5-fold), or with histones (2.6-fold), the activity was increased much faster. The increase in peroxidase activity after mice immunization with MOG35-55 and DNA-metBSA up to 40 days of experiments was relatively gradual, while for DNA-histones complex was observed its sharp increase at the acute phase of EAE (14-20 days). All data show that IgGs' redox activities can play an important role in the protection of mice from toxic compounds and oxidative stress.


Assuntos
Anticorpos Catalíticos/metabolismo , Autoanticorpos/metabolismo , Encefalomielite Autoimune Experimental/enzimologia , Células-Tronco Hematopoéticas/imunologia , Oxirredutases/metabolismo , Peroxidases/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Imunoglobulina G/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Oxirredução , Oxirredutases/imunologia , Fragmentos de Peptídeos/administração & dosagem , Peroxidases/imunologia
20.
J Immunol ; 206(8): 1729-1739, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33789980

RESUMO

Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.


Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Encéfalo/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Macrófagos/imunologia , Transtornos do Humor/prevenção & controle , Soro/metabolismo , Triptofano/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Autoanticorpos/metabolismo , Suplementos Nutricionais , Humanos , Hibridomas , Lúpus Eritematoso Sistêmico/complicações , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transtornos do Humor/etiologia , Fosfoproteínas/imunologia , Receptores de IgG/metabolismo , Proteínas Ribossômicas/imunologia , Triptofano/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo
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