Elisa Caggiu

Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson's disease, a triggering role in the disease?

Environmental factors are implicated in the development of Parkinsons disease (PD). We have investigated on the role of molecular mimicry between HSV1 and α-synuclein that could foster the progression of PD. The antibody response against homologous peptides in PD patients and healthy controls was evaluated, showing that these antibodies are highly prevalent among PD patients to healthy controls. The competitive assay demonstrated cross-reactivity between HSV1 and human α-synuclein peptides. The results may suggest the hypothesis of the involvement of HSV1 in stimulating the immune cells against the neurons of the substantia nigra as a consequence of the cross reactivity.

Natalizumab Therapy Modulates miR-155, miR-26a and Proinflammatory Cytokine Expression in MS Patients

MicroRNAs fine-tune the regulation of Th1/Th17 lymphocyte subsets in multiple sclerosis. We investigated the expression of miRNAs (previously associated with mycobacterial and viral infections) in MS patients and healthy donors (HD) following 6 months natalizumab therapy. In addition, Th1/Th17 cytokines and the presence of anti-EBNA1/VCA IgG in MS patients with different pattern of miRNA expression have been evaluated. MiR-155, miR-26a, miR-132, miR-146a and Th1/Th17 cytokines expression was detected by RT-real time PCR; moreover anti-EBNA1 and VCA IgG titres were measured by ELISA. We observed an up-regulation of miR-155 (p value = 0.009) and miR-132 (p value = 0.04) in MS patients compared to HD. In MS patients, IL-17a (p = 0.037), IFN γ (p = 0.012) and TNFα (p = 0.015) but not IL-6 were over-expressed compared to HD. Two different miRNAs patterns associated to the expression of different cytokines were observed in the MS cohort. Moreover, a down-regulation of miR-155 and miR-26a was seen in MS patients during and after natalizumab therapy. MS patients that over-expressed miR-155 showed a higher EBNA1 IgG titer than MS patients with high levels of miR-26a. In conclusions the expression of particular miRNAs modulates the pro-inflammatory cytokine expression and the humoral response against EBV and this expression is natalizumab regulated.

Type 1 Diabetes at-risk children highly recognize Mycobacterium avium subspecies paratuberculosis epitopes homologous to human Znt8 and Proinsulin

Mycobacterium avium subspecies paratuberculosis (MAP) has been previously associated to T1D as a putative environmental agent triggering or accelerating the disease in Sardinian and Italian populations. Our aim was to investigate the role of MAP in T1D development by evaluating levels of antibodies directed against MAP epitopes and their human homologs corresponding to ZnT8 and proinsulin (PI) in 54 T1D at-risk children from mainland Italy and 42 healthy controls (HCs). A higher prevalence was detected for MAP/ZnT8 pairs (62,96% T1D vs. 7,14% HCs; p < 0.0001) compared to MAP/PI epitopes (22,22% T1D vs. 9,52% HCs) and decreasing trends were observed upon time-point analyses for most peptides. Similarly, classical ZnT8 Abs and GADA decreased in a time-dependent manner, whereas IAA titers increased by 12%. Responses in 0–9 year-old children were stronger than in 10–18 age group (75% vs. 69,1%; p < 0.04). Younger age, female sex and concomitant autoimmune disorders contributed to a stronger seroreactivity suggesting a possible implication of MAP in multiple autoimmune syndrome. Cross-reactivity of the homologous epitopes was reflected by a high correlation coefficient (r2 > 0.8) and a pairwise overlap of positivity (>83% for MAP/ZnT8).

Identification of a HERV-K env surface peptide highly recognized in RA patients: A cross-sectional case-control study

Endogenous retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV‐K viruses have been reported recently to be involved in the pathogenesis of rheumatoid arthritis (RA). In this study we have explored the role of humoral immune response against HERV‐K as a potential pathogenetic mechanism in RA. Four different peptides from the extracellular portion of the env protein of HERV‐K (env‐su19–37, env‐su109–126, env‐su164–186, env‐su209–226) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect enzyme‐linked immunosorbent assay (ELISA) was then carried out to quantify antibodies against those peptides on blood samples of 70 consecutive RA patients and 71 healthy controls (HC). Differences between the two groups were analysed using the Mann–Whitney test. Potential correlations between RA laboratory, clinical descriptors and immunoglobulin (Ig)G levels were explored by bivariate regression analysis. Serum autoantibodies against one of four tested peptides of HERV‐K (env‐su19–37) were significantly higher in RA than in HC (19 versus 3%, P = 0·0025). Subgroup analysis showed no association between anti‐HERV‐K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. Serum from RA patients in our series reacted significantly against HERV‐K env‐su19–37 peptide in comparison to the general population suggesting a role for the HERV‐K‐ related, secondary antigenic‐driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of this HERV‐K surface peptide as a potential therapeutic target.

Identification of a HERV‐K env surface peptide highly recognized in Rheumatoid Arthritis (RA) patients: a cross‐sectional case–control study

Endogenous retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV‐K viruses have been reported recently to be involved in the pathogenesis of rheumatoid arthritis (RA). In this study we have explored the role of humoral immune response against HERV‐K as a potential pathogenetic mechanism in RA. Four different peptides from the extracellular portion of the env protein of HERV‐K (env‐su19–37, env‐su109–126, env‐su164–186, env‐su209–226) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect enzyme‐linked immunosorbent assay (ELISA) was then carried out to quantify antibodies against those peptides on blood samples of 70 consecutive RA patients and 71 healthy controls (HC). Differences between the two groups were analysed using the Mann–Whitney test. Potential correlations between RA laboratory, clinical descriptors and immunoglobulin (Ig)G levels were explored by bivariate regression analysis. Serum autoantibodies against one of four tested peptides of HERV‐K (env‐su19–37) were significantly higher in RA than in HC (19 versus 3%, P = 0·0025). Subgroup analysis showed no association between anti‐HERV‐K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. Serum from RA patients in our series reacted significantly against HERV‐K env‐su19–37 peptide in comparison to the general population suggesting a role for the HERV‐K‐ related, secondary antigenic‐driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of this HERV‐K surface peptide as a potential therapeutic target.

Natalizumab modulates the humoral response against HERV-Wenv73–88 in a follow-up study of Multiple Sclerosis patients

Multiple Sclerosis (MS) is a heterogeneous disorder of the central nervous system (CNS) that begins as an inflammatory autoimmune disorder mediated by auto-reactive lymphocyte followed by microglial activation and chronic degeneration. The etiology of Multiple Sclerosis (MS) is unknown but several data support the hypothesis of possible infectious agents which may act as a trigger for the pathogenic cascade. Human endogenous retrovirus (HERV-W/MSRV), Epstein Barr Virus (EBV) and Mycobacterium avium ss. paratuberculosis (MAP) have been associated to Multiple Sclerosis. In this study, we evaluated the humoral response against different peptides: the human endogenous retrovirus HERV-Wenv73-88, MAP106c121-132 from MAP, EBNA1 400-413 from EBV and the homologous human peptide MBP85-98 in a cohort of MS patients treated with natalizumab. Results showed a statistically significant difference in the response against the HERV-W peptide in MS patients after two years of natalizumab treatment.

Homologous HSV1 and alpha-synuclein peptides stimulate a T cell response in Parkinson's disease

Environmental factors are implicated in the development of Parkinsons disease (PD). The aim of this study is to investigate the role of cell-mediated immunity upon a specific immune-stimulation with HSV-1 and human alpha-synuclein homologues peptides by using the intracellular cytokine method on Parkinsons patients and healthy controls. The study showed, for the first time, a specific response to TNF-α CD8, CD4 and NK cells after stimulation in PD patients. Our data show a possible role of the immune system in the pathogenesis of Parkinsons disease, and that HSV-1 infections may lead to a progression of the disease.

Is there a role for Mycobacterium avium subspecies paratuberculosis in Parkinson's disease?

In Parkinsons disease (PD) ZnT proteins play an important role. Zinc is a co-factor of numerous enzymes and stabilizes the tertiary structure of several proteins. Nothing is known about previous infections mediated by Mycobacterium avium subsp. paratuberculosis (MAP). We evaluated if a previous infection with MAP could induce the production of antibodies that cross-reacted with the Znt homologous antigenic peptides associated to Parkinson. The humoral response toward MAP3865c peptides, ZnT3 and ZnT10 was evaluated. The hypothesis of cross-reactivity needs to be confirmed; we have observed the presence of MAP in PD patients by PCR, positivity to MAP3865c peptides, therefore MAP infection but not cross-reaction with human homologous Znt proteins.

Antibody response against HERV-W env surface peptides differentiates multiple sclerosis and neuromyelitis optica spectrum disorder

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.

Serum BAFF levels, Methypredsinolone therapy, Epstein-Barr Virus and Mycobacterium avium subsp. paratuberculosis infection in Multiple Sclerosis patients.

Elevated B lymphocyte activating factor BAFF levels have been reported in multiple sclerosis (MS) patients; moreover, disease-modifying treatments (DMT) have shown to influence blood BAFF levels in MS patients, although the significance of these changes is still controversial. In addition, BAFF levels were reported increased during infectious diseases. In our study, we wanted to investigate on the serum BAFF concentrations correlated to the antibody response against Mycobacterium avium subspecies paratuberculosis (MAP), Epstein-Barr virus (EBV) and their human homologous epitopes in MS and in patients affected with other neurological diseases (OND), divided in Inflammatory Neurological Diseases (IND), Non Inflammatory Neurological Diseases (NIND) and Undetermined Neurological Diseases (UND), in comparison to healthy controls (HCs). Our results confirmed a statistically significant high BAFF levels in MS and IND patients in comparison to HCs but not NIND and UND patients. Interestingly, BAFF levels were inversely proportional to antibodies level against EBV and MAP peptides and the BAFF levels significantly decreased in MS patients after methylprednisolone therapy. These results implicate that lower circulating BAFF concentrations were present in MS patients with humoral response against MAP and EBV. In conclusion MS patients with no IgGs against EBV and MAP may support the hypothesis that elevated blood BAFF levels could be associated with a more stable disease.