RESUMO
Myasthenia gravis is an antibody-mediated autoimmune neurological disorder characterized by impaired neuromuscular junction transmission, resulting in muscle weakness. Recently, the involvement of Human Endogenous Retroviruses (HERVs) in the pathophysiology of different immune-mediated and neurodegenerative diseases, such as multiple sclerosis, has been demonstrated. We aimed to investigate potential immune system involvement related to humoral responses targeting specific epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis. Myasthenia gravis patients were recruited in the Neurology Unit, while healthy controls were selected from the Blood Transfusion Center, both affiliated with AOU Sassari. Highly immunogenic antigens of HERV-K and HERV-W envelope proteins were identified using the Immune Epitope Database (IEDB) online tool. These epitopes were utilized in enzyme-linked immunosorbent assays (ELISA) to detect autoantibodies in serum directed against these sequences. The study involved 39 Healthy Donors and 47 MG patients, further categorized into subgroups based on the presence of autoantibodies: MG-AchR Ab+ (n = 17), MG-MuSK Ab+ (n = 7), double seronegative patients (MG-DSN, n = 18), MG-LRP4 Ab + (n = 4), and one patient with no antibodies data (n = 1). Our findings revealed high levels of autoantibodies in myasthenia gravis patients directed against the HERV-K-env-su(19-37), HERV-K-env-su(109-126), HERV-K-env-su(164-186), HERV-W-env(93-108), HERV-W-env(129-14), and HERV-W-env(248-262) epitopes. Notably, these results remained highly significant even when patients were subdivided into MG-AchR Ab+ and MG-DSN subgroups. Correlation analysis further revealed significant positive associations between the antibody levels against HERV-K and HERV-W families in patients, suggesting a synergistic action of the two HERVs in the pathology context since this correlation is absent in the control group. This study marks the first identification of a specific humoral response directed against defined epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis patients. These findings lay the foundation for future investigations aimed at elucidating the molecular mechanisms driving this immune response. The detection of these autoantibodies suggests the potential for novel biomarkers, especially within the MG-DSN patient subgroup, addressing the need for new biomarkers in this population.
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Retrovirus Endógenos , Miastenia Gravis , Humanos , Epitopos , Formação de Anticorpos , Autoanticorpos , BiomarcadoresRESUMO
Natalizumab is effective against multiple sclerosis (MS), but is associated with progressive multifocal leukoencephalopathy (PML), fatal disease caused by the JCV polyomavirus. The SF2/ASF (splicing factor2/alternative splicing factor) inhibits JCV in glial cells. We wondered about SF2/ASF modulation in the blood of natalizumab-treated patients and if this could influence JCV reactivation. Therefore, we performed a longitudinal study of MS patients under natalizumab, in comparison to patients under fingolimod and to healthy blood donors. Blood samples were collected at time intervals. The expression of SF2/ASF and the presence and expression of JCV in PBMC were analyzed. A bell-shaped regulation of SF2/ASF was observed in patients treated with natalizumab, increased in the first year of therapy, and reduced in the second one, while slightly changed, if any, in patients under fingolimod. Notably, SF2/ASF was up-regulated, during the first year, only in JCV DNA-positive patients, or with high anti-JCV antibody response; the expression of the JCV T-Ag protein in circulating B cells was inversely related to SF2/ASF protein expression. The SF2/ASF reduction, parallel to JCV activation, during the second year of therapy with natalizumab, but not with fingolimod, may help explain the increased risk of PML after the second year of treatment with natalizumab, but not with fingolimod. We propose that SF2/ASF has a protective role against JCV reactivation in MS patients. This study suggests new markers of disease behavior and, possibly, help in re-evaluations of therapy protocols.
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Interações Hospedeiro-Patógeno , Fatores Imunológicos/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Fatores de Processamento de Serina-Arginina/genética , Adulto , Anticorpos Antivirais/sangue , Relação Dose-Resposta a Droga , Feminino , Cloridrato de Fingolimode/uso terapêutico , Regulação da Expressão Gênica , Humanos , Vírus JC/efeitos dos fármacos , Vírus JC/genética , Vírus JC/crescimento & desenvolvimento , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/virologia , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neuroglia/virologia , Fatores de Processamento de Serina-Arginina/imunologia , Transdução de Sinais , Ativação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Several viruses were reported as co-factors triggering the pathogenesis of multiple sclerosis (MS), including the endogenous retroviruses of the HERV-W family, that were also proposed as biomarkers of disease progression and therapy outcome. OBJECTIVE: The objective of this article is to clarify whether in MS patients treatment with natalizumab has effects on MSRV/syncytin-1/HERV-W expression and the possible relationship with disease outcome. METHODS: Peripheral blood mononuclear cells were collected from 22 patients with relapsing-remitting disease, at entry and after three, six and 12 months of treatment with natalizumab. The cell subpopulations and the expression of MSRVenv/syncytin-1/HERV-Wenv were analyzed by flow cytometry and by discriminatory env-specific RT-PCR assays. RESULTS: By flow cytometry the relative amounts of T, NK and monocyte subpopulations were shown to remain fairly constant. A relative increase of B lymphocytes was observed at three to six months (p = 0.033). The MSRVenv and syncitin-1 transcripts were reduced at six to 12 months of therapy (p = 0.0001). Accordingly, at month 12, the plasma-membrane levels of the HERV-Wenv protein were reduced (p = 0.0001). B cells, NK and monocytes but not T cells expressed the HERV-Wenv protein. None of the patients relapsed during therapy. CONCLUSION: Effective therapy with natalizumab downregulates MSRV/syncytin-1/HERV-W expression.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Retrovirus Endógenos/efeitos dos fármacos , Produtos do Gene env/análise , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/virologia , Proteínas da Gravidez/análise , Adulto , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Natalizumab , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
BACKGROUND: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family 'W' (HERV-W), induces dysimmunity and inflammation. OBJECTIVE: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS. METHODS: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals. RESULTS: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing-remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS -<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements. CONCLUSION: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.
Assuntos
Encéfalo/virologia , Retrovirus Endógenos , Esclerose Múltipla/virologia , Proteínas do Envelope Viral/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Reação em Cadeia da Polimerase em Tempo Real , Proteínas do Envelope Viral/análiseRESUMO
The human endogenous retrovirus-K (HERV-K) and TAR DNA-binding protein 43 (TDP-43) have been associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). Given these findings, we investigated the humoral response against HERV-K envelope surface (env-su) glycoprotein antigens and TDP-43 in the plasma of ALS patients and healthy controls (HCs). The measured levels of Abs against the different epitopes' fragments were significantly elevated in ALS patients, both in long-survivor (LS) and newly diagnosed (ND) patients, compared to HCs. We observed a positive correlation between HERV-K and TDP-43 antibodies (Abs) levels, which seemed to strengthen with disease progression, that was not found in HCs. The TDP-43 and HERV-K epitopes identified in this study are highly immunogenic and recognized by the humoral response of ALS patients. Increased circulating levels of Abs directed against specific HERV-K- and TDP-43-derived epitopes could serve as possible biomarkers.
Assuntos
Esclerose Lateral Amiotrófica/virologia , Proteínas de Ligação a DNA/imunologia , Retrovirus Endógenos/imunologia , Proteínas do Envelope Viral/imunologia , Idoso , Epitopos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Human endogenous retrovirus (HERV)-K env-su glycoprotein has been documented in amyotrophic lateral sclerosis (ALS), where HERV-K env-su 19-37 antibody levels significantly correlated with clinical measures of disease severity. Herein, we investigated further the humoral and cell-mediated immune response against specific antigenic peptides derived from HERV-K in ALS. HERV-K env glycoprotein expression on peripheral blood mononuclear cells (PBMCs) membrane and cytokines and chemokines after stimulation with HERV-K env 19-37 and HERV-K env 109-126 were quantified in patients and healthy controls (HCs). HERV-K env glycoprotein was more expressed in B cells and NK cells of ALS patients compared to HCs, whereas HERV-K env transcripts were similar in ALS and HCs. In ALS patients, specific stimulation with HERV-K env 109-126 peptide showed a higher expression of IL-6 by CD19/B cells. Both peptides, however, were able to induce a great production of IFN-γ by stimulation CD19/B cells, and yielded a higher expression of MIP-1α and a lower expression of MCP-1. HERV-K env 19-37 peptide induced a great production of TNF-α in CD8/T cells. In conclusion, we observed the ability of HERV-K to modulate the immune system, generating mediators mainly involved in proinflammatory response.
RESUMO
Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapies targeting its receptor have been developed; however, a resolution of the disease and side effects are still an issue of concern. The involvement of other factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) and envelope protein derived from human endogenous retrovirus type W (HERV-Wenv), in MS pathogenesis has been recently suggested. Here, we investigated the levels of antibodies (Abs) directed against IL-2 and HERV-Wenv in 108 MS patients, 34 patients affected by neuromyelitis optica spectrum disorder (NMOSD), and 137 healthy controls (HCs). Our results show increased levels of Abs specific to IL-2 and HERV-Wenv-su antigens in MS vs. HCs (p < 0.0001 for IL-2, p = 0.0004 for HERV-Wenv) and significantly decreased levels in NMOSD vs. MS. The assessment of different 12-month-long therapies on Abs against IL-2, HERV-Wenv, and MAP lipoarabinomannan (LAM) demonstrated the strongest effect on anti-LAM Abs (p = 0.018), a slight reduction of anti-IL-2 Abs, and small variations for anti-HERV-Wenv Abs. These results highlight the conclusion that the impact of therapy is more correlated with selected epitopes than with the therapeutic agent. Screening for anti-IL-2 and anti-HERV-Wenv Abs has a potential as additional future practice to distinguish between symptomatically similar MS and NMOSD.
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A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson's disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Retículo Endoplasmático/metabolismo , Agregados Proteicos , Proteínas de Transporte Vesicular/metabolismo , Idoso , Biomarcadores/metabolismo , Feminino , Fibroblastos/metabolismo , Fluorescência , Células HeLa , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/patologia , Proteínas de Transporte Vesicular/genéticaRESUMO
Increased expression of the retroviruses of HERV-W family has been linked to multiple sclerosis (MS) pathophysiology; nothing is known at the moment about MOG-IgG associated disorders. We compared antibody response against HERV-W peptides among patients with MOG-IgG associated disorders, multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD). A total of 102 serum samples were retrospectively analyzed. Antibody reactivity against HERV-W env peptides was similar in MOG-IgG associated disorders and MS, but different from AQP4-IgG positive NMOSD. Our findings expand the diagnostic role of HERV-W antibodies to the spectrum of demyelinating disorders associated with MOG-IgG.
Assuntos
Autoanticorpos/sangue , Produtos do Gene env/imunologia , Imunoglobulina G/sangue , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/imunologia , Proteínas da Gravidez/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Improved knowledge of different biomarkers is crucial for early diagnosis of rheumatic diseases and to provide important insights for clinical management. In this study, we evaluated the seroreactivity of patients with different connective tissue diseases (CTDs) (rheumatoid arthritis, RA; systemic lupus erythematosus, SLE; systemic sclerosis, SSc; and Sjogren's syndrome, SSj) to interferon regulatory factor 5 (IRF5) peptide and homologs derived from Epstein-Barr virus (EBV) and Mycobacterium avium subsp. paratuberculosis (MAP). Antigen-induced arthritis (AIA) experiments have been performed in control and IRF5 conditional knockout mice to reinforce the hypothesis that antibodies generated against the three homologous peptides are cross-reactive. METHODS: Reactivity against wild-type (wt) and citrullinated (cit) IRF5 (IRF5424-434), MAP (MAP_402718-32) and EBV (BOLF1305-320) peptides were tested by indirect ELISA in sera from 100 RA patients, 54 patients with other CTDs (14 SLE, 28 SSc and 12 SSj) and 100 healthy subjects (HCs). Antibody responses to the same wt peptides have been tested in AIA mouse sera after immunization with complete Freud's adjuvant (CFA) and methylated bovine serum albumin (mBSA) to induce arthritis in the knee joint. RESULTS: BOLF1, MAP_4027 and IRF5 peptides triggered different antibody responses in CTD diseases with a stronger reactivity in RA (p=0.0001). Similar trends were observed in AIA mice with significantly higher reactivity after 7 days from induction of arthritis. We also found statistically significant differences in antibody responses between SSc and HCs for BOLF1 (p=0.003), MAP_4027 (p=0.0076) and IRF5 (p=0.0042). Peripheral reactivity to cit peptides was lower compared to their wt counterparts, except for cit-MAP_402718-32, which induced stronger responses in RA than wt-MAP_402718-32 (46% vs. 26%, p=0.0170). Conclusion(s): Our results show differential antibody responses to BOLF1, MAP_4027 and IRF5 peptides among CTDs, highlighting their potential as diagnostic biomarkers in these diseases. Experiments performed in IRF5 conditional knockout mice support the hypothesis of cross-reactivity between the investigated homologous antigens.
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Environmental factors such as bacterial infections may play an important role in the development of autoimmune diseases. Mycobacterium avium subsp. paratuberculosis (MAP) is an obligate pathogen of ruminants able to use the host's cholesterol for survival into macrophages and has been associated with multiple sclerosis (MS), type 1 diabetes (T1DM) and rheumatoid arthritis (RA) through a molecular mimicry mechanism. Here, we aimed at investigating the correlation between humoral reactivity against MAP and serum lipoprotein levels in subjects at T1DM risk (rT1DM) grouped by geographical background and in patients affected by MS or RA. Our results showed significant differences in HDL, LDL/VLDL and Total Cholesterol (TC) levels between patients and healthy controls (p < 0.0001). Patients positive to anti-MAP Abs (MAP+) had lower HDL levels in comparison with Abs negative (MAP-) subjects, while opposite trends were found for LDL/VLDL concentrations (p < 0.05). TC levels varied between MAP+ and MAP- patients in all three assessed diseases. These findings suggest the implication of anti-MAP Abs in fluctuations of lipoprotein levels highlighting a possible link with cardiovascular disease. Further studies will be needed to confirm these results in larger groups.
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Parkinson's disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons of the substantia nigra pars compacta with a reduction of dopamine concentration in the striatum. The complex interaction between genetic and environmental factors seems to play a role in determining susceptibility to PD and may explain the heterogeneity observed in clinical presentations. The exact etiology is not yet clear, but different possible causes have been identified. Inflammation has been increasingly studied as part of the pathophysiology of neurodegenerative diseases, corroborating the hypothesis that the immune system may be the nexus between environmental and genetic factors, and the abnormal immune function can lead to disease. In this review we report the different aspects of inflammation and immune system in Parkinson's disease, with particular interest in the possible role played by immune dysfunctions in PD, with focus on autoimmunity and processes involving infectious agents as a trigger and alpha-synuclein protein (α-syn).
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Myasthenia gravis (MG) is an autoimmune disease leading to varying degrees of skeletal muscle weakness. It is caused by specific antibodies directed against definite components in the postsynaptic membrane at the neuromuscular junction (NMJ), such as the acetylcholine receptor (AChR) and the muscle-specific kinase (MUSK) receptor. In clinical practice, MG patients may be classified into three main subgroups based on the occurrence of serum autoantibodies directed against AChR or MUSK receptor or antibody-negative. As the MG subgroups differ in terms of clinical characteristics, disease pathogenesis, prognosis, and response to therapies, they could benefit from targeted treatment as well as the detection of other possible disease biomarkers. We performed proteomics on plasma fractions enriched in low-abundance proteins to identify potential biomarkers according to different autoimmune responses. By this approach, we evidenced a significant reduction of vitronectin in MG patients compared to healthy controls, irrespective of the autoantibodies NMJ target. The obtained results were validated by mono- and two-dimensional Western blotting analysis. Vitronectin is a multifunctional glycoprotein involved in the regulation of several pathophysiological processes, including complement-dependent immune response, coagulation, fibrinolysis, pericellular proteolysis, cell attachment, and spreading. The pathophysiological significance of the reduction of plasma vitronectin in MG patients has yet to be fully elucidated. It could be related either to a possible deposition of vitronectin at NMJ to counteract the complement-mediated muscle damage at this level or to a parallel variation of this glycoprotein in the muscle extracellular matrix with secondary induced alteration in clustering of AChRs at NMJ, as it occurs with variation in concentrations of agrin, another extracellular matrix component. The clinical value of measuring plasma vitronectin has yet to be defined. According to present findings, significantly lower plasma values of this glycoprotein might be indicative of an impaired complement-dependent immune response.
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BACKGROUND: Multiple sclerosis (MS) is believed to be an autoimmune disease occurring in genetically predisposed individuals after an appropriate environmental exposure such as viral infections. Recent studies suggest a significant association between MS and the functional 5'-(GT)n polymorphism in the promoter region of the NRAMP1 gene. In the present study we aimed to evaluate the contribution of the allelic variation in the NRAMPI promoter to MS susceptibility and to study the role of viral infection in relation to specific NRAMP1 genotypes, in a Sardinian cohort. METHODS: Sixty MS patients and 66 healthy individuals were genotyped, and screened for the presence of Epstein-bar virus (EBV) and JC virus (JCV) sequences. RESULTS: Consistent with previous autoimmune disease studies, allele 3 at the functional 5'(GT)n promoter region repeat polymorphism, was significantly overrepresented among MS patients when compared to controls (p=0.02). The EBV and JCV sequences were detected in 8/60 (13.33%) and in 4/60 (6.66%) of MS patients respectively and in 5/66 (7.57%) and in 0/66 of controls. CONCLUSION: The allelic variation in the NRAMP1 promoter may contribute to MS susceptibility in the Sardinian population. The viral sequences were not confined to a specific NRAMP1 genotype.
Assuntos
Proteínas de Transporte de Cátions/genética , Esclerose Múltipla/genética , Polimorfismo Genético , Proteínas de Transporte de Cátions/metabolismo , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Herpesvirus Humano 4/genética , Humanos , Itália , Vírus JC/genética , Esclerose Múltipla/virologia , Regiões Promotoras GenéticasRESUMO
Parkinson's disease is a neurodegenerative disorder and its etiology is unknown, numerous studies show how different environmental factors can influence the development of disease. miRNAs are involved in several pathologies and their dysregulation contribute to different pathologies, also in neurodegenerative such as Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic lateral sclerosis. In this study, we profiled the expression of different candidate miRNAs: miR-155, miR-26a, miR-146a, and miR132, in PBMCs of L-dopa treated Parkinson patients and unaffected controls (HCs).We investigated the expression of miRNAs by RT-real time PCR, the results were subjected to statistical analysis. miRNA-155-5p was generally up-regulated in PD patients compared to HCs whereas miRNA-146a-5p was down-regulated in PD patients in comparison to HCs. It is interesting to point out that the expression of miR-155-5p was modified by levodopa treatment, in fact a down-regulation of miR-155-5p in PD patients with the highest dosage was observed. In conclusion, miRNA 155 could not only be a promising target for the anti-inflammatory therapy in PD but also a good candidate as a disease progression biomarker. The role of levodopa in modulating the levels of miRNA 155 requires further studies.
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Mycobacterium avium ssp. paratuberculosis (Map) is the etiological agent of Paratuberculosis in ruminants. Protein tyrosine phosphatase A (PtpA) and protein kinase G (PknG) are secreted proteins necessary for the survival of the pathogen within macrophages. In this study we analyzed if Map was able to grow within astrocytes and investigated on the presence of antibodies against PtpA and PknG proteins in MS and NMOSD patients by ELISA. Map was unable to proliferate in astrocytes after of 72â¯h post-infection, but we observed a high level of antibodies against both virulence factors, suggesting that these patients have been exposed/infected with Map.
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Anticorpos Antibacterianos/sangue , Proteínas de Bactérias/sangue , Esclerose Múltipla/sangue , Mycobacterium avium subsp. paratuberculosis/metabolismo , Neuromielite Óptica/sangue , Proteínas Serina-Treonina Quinases/sangue , Proteínas Tirosina Fosfatases/sangue , Adulto , Astrócitos/metabolismo , Astrócitos/microbiologia , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/microbiologia , Neuromielite Óptica/microbiologiaRESUMO
Epstein-Barr virus (EBV) is the main environmental agent associated to neuromyelitis optica spectrum disorder (NMOSD). Following to studies reporting an increased prevalence of antibodies against peptides derived from Mycobacterium avium subsp. paratuberculosis (MAP) homologous to EBV and human epitopes (MBP85-98, IRF5424-434) in multiple sclerosis (MS), we investigated whether seroreactivity to these antigens display a NMOSD-specific pattern. The sera of 34 NMOSD patients showed elevated levels of antibodies against MAP and MBP compared to healthy controls (44% vs. 5%, pâ¯<â¯0.0002 and 50% vs. 2%, pâ¯<â¯0.0001, respectively), while, unlike in MS, responsiveness to EBV was similar.
Assuntos
Anticorpos Antibacterianos/imunologia , Autoanticorpos/imunologia , Mycobacterium avium subsp. paratuberculosis/imunologia , Proteína Básica da Mielina/imunologia , Neuromielite Óptica/imunologia , Adulto , Antígenos de Bactérias/imunologia , Autoantígenos/imunologia , Epitopos/imunologia , Feminino , Humanos , Fatores Reguladores de Interferon/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Several epidemiological investigations conducted in Sardinia, insular Italy, indicate that the strong selective pressure of malaria along the centuries may have concurred to the elevated genetic MS-risk in this region. To test such hypothesis in an experimental setting, we have compared the immune response to P. falciparum (the causative agent of malaria) in Sardinian MS patients relative to their ethnic healthy controls and control MS patients of different ethnicity. To this purpose, the P. falciparum-driven peripheral mononuclear cell proliferation, the production of pro-inflammatory cytokines of the innate immunity such as TNF-alpha, IL-6 and IL-12 and the ability to inhibit the parasite growth have been tested in relation to HLA-DR alleles and TNF promoter polymorphisms known of being associated to MS. We found that P. falciparum-induced proliferation, cytokine production and parasite killing are significantly augmented in Sardinian MS patients as compared to controls (p<0.01). Additionally, a correlation is found with genes associated to Sardinian MS, namely the TNF(-376A) promoter polymorphism and the class II HLA-DRB1*0405 allele. In conclusion, we have found evidences that some genetic traits formerly selected to confer a protective responses to P. falciparum now partially contribute to the elevated MS susceptibility amongst Sardinians.
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Imunidade Inata , Malária/imunologia , Esclerose Múltipla/microbiologia , Plasmodium falciparum/imunologia , Adulto , Animais , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Feminino , Predisposição Genética para Doença , Antígenos HLA-DR , Humanos , Subunidade p40 da Interleucina-12/biossíntese , Interleucina-6/biossíntese , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Esclerose Múltipla/imunologia , Polimorfismo Genético , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Background: A specific humoral immune response against HERV-W envelope surface (env-su) glycoprotein antigens has been reported in serum of patients with multiple sclerosis (MS). However, it has not been evaluated to date in patients with neuromyelitis optica spectrum disorder (NMOSD). Objective: The objective of this paper is to investigate whether antibody (Ab) response against HERV-W env-su antigenic peptides differs between NMOSD and MS. Methods: Serum samples were collected from 36 patients with NMOSD, 36 patients with MS and 36 healthy control individuals (HCs). An indirect ELISA was set up to detect specific Abs against HERV-W env-su peptides. Results: Our data showed that two antigenic peptides, particularly HERV-Wenv93-108 and HERV-Wenv248-262, were statistically significantly present only in serum of MS compared to NMOSD and HCs. Thus, the specific humoral immune response against HERV-W env-su glycoprotein antigens found in MS is widely missing in NMOSD. Conclusion: Increased circulating serum levels of these HERV-W Abs may be suitable as additional biomarkers to better differentiate MS from NMOSD.