The Genetic Landscape of Systemic Rheumatic Diseases: A Comprehensive Multigene-Panel Study Identifying Key Gene Polymorphisms.

Systemic rheumatic diseases, including conditions such as rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus, represent a complex array of autoimmune disorders characterized by chronic inflammation and diverse clinical manifestations. This study focuses on unraveling the genetic underpinnings of these diseases by examining polymorphisms in key genes related to their pathology. Utilizing a comprehensive genetic analysis, we have documented the involvement of these genetic variations in the pathogenesis of rheumatic diseases. Our study has identified several key polymorphisms with notable implications in rheumatic diseases. Polymorphism at chr11_112020916 within the IL-18 gene was prevalent across various conditions with a potential protective effect. Concurrently, the same IL18R1 gene polymorphism located at chr2_103010912, coding for the IL-18 receptor, was observed in most rheumatic conditions, reinforcing its potential protective role. Additionally, a further polymorphism in IL18R1 at chr2_103013408 seems to have a protective influence against the rheumatic diseases under investigation. In the context of emerging genes involved in rheumatic diseases, like PARK2, a significant polymorphism at chr6_161990516 was consistently identified across different conditions, exhibiting protective characteristics in these pathological contexts. The findings underscore the complexity of the genetic landscape in rheumatic autoimmune disorders and pave the way for a deeper understanding of their etiology and the possible development of more targeted and effective therapeutic strategies.

The glymphatic system as a potential biomarker and therapeutic target in secondary progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a refractory immune-mediated inflammatory disease of the central nervous system, and some cases of the major subtype, relapsing-remitting (RR), transition to secondary progressive (SP). However, the detailed pathogenesis, biomarkers, and effective treatment strategies for secondary progressive multiple sclerosis have not been established. The glymphatic system, which is responsible for waste clearance in the brain, is an intriguing avenue for investigation and is primarily studied through diffusion tensor image analysis along the perivascular space (DTI-ALPS). This study aimed to compare DTI-ALPS indices between patients with RRMS and SPMS to uncover potential differences in their pathologies and evaluate the utility of the glymphatic system as a possible biomarker. METHODS: A cohort of 26 patients with MS (13 RRMS and 13 SPMS) who met specific criteria were enrolled in this prospective study. Magnetic resonance imaging (MRI), including diffusion MRI, 3D T1-weighted imaging, and relaxation time quantification, was conducted. The ALPS index, a measure of glymphatic function, was calculated using diffusion-weighted imaging data. Demographic variables, MRI metrics, and ALPS indices were compared between patients with RRMS and those with SPMS. RESULTS: The ALPS index was significantly lower in the SPMS group. Patients with SPMS exhibited longer disease duration and higher Expanded Disability Status Scale (EDSS) scores than those with RRMS. Despite these differences, the correlations between the EDSS score, disease duration, and ALPS index were minimal, suggesting that the impact of these clinical variables on ALPS index variations was negligible. DISCUSSION: Our study revealed the potential microstructural and functional differences between RRMS and SPMS related to glymphatic system impairment. Although disease severity and duration vary among subtypes, their influence on ALPS index differences appears to be limited. This highlights the stronger association between SP conversion and changes in the ALPS index. These findings align with those of previous research, indicating the involvement of the glymphatic system in the progression of MS. CONCLUSION: Although the causality remains uncertain, our study suggests that a reduced ALPS index, reflecting glymphatic system dysfunction, may contribute to MS progression, particularly in SPMS. This suggests the potential of the ALPS index as a diagnostic biomarker for SPMS and underscores the potential of the glymphatic system as a therapeutic target to mitigate MS progression. Future studies with larger cohorts and pathological validation are necessary to confirm these findings. This study provides new insights into the pathogenesis of SPMS and the potential for innovative therapeutic strategies.

Correlation between antibodies against the pathogenic pHERV-W envelope protein and the inflammatory phase of multiple sclerosis.

The role of retroviral envelope proteins belonging to the Human Endogenous Retroviral family 'W' (HERV-W), specifically syncytin-1 and pathogenic HERV-W (pHERV-W), as potential risk factors in multiple sclerosis (MS) has been established. This study aimed to investigate the humoral response to syncytin-1 and pHERV-W-derived peptides in a group of relapsing remitting MS patients categorized as having acute or stable disease. Furthermore, an inhibition assay was conducted to assess the extent of cross-reactivity between the two epitopes. The findings revealed that MS patients in the acute phase exhibited a higher specific antibody response to the pHERV-W env epitope compared to syncytin-1. This suggests a potential pathogenic role for pHERV-W env during the inflammatory stages of central nervous system involvement, and these antibody responses could serve as useful biomarkers for monitoring the progression of the disease.

The Role of Immune Dysfunction in Parkinson's Disease Development.

Recent research has unveiled intriguing insights suggesting that the body's immune system may be implicated in Parkinson's disease (PD) development. Studies have observed disparities in pro-inflammatory and anti-inflammatory markers between PD patients and healthy individuals. This finding underscores the potential influence of immune system dysfunction in the genesis of this condition. A dysfunctional immune system can serve as a primary catalyst for systemic inflammation in the body, which may contribute to the emergence of various brain disorders. The identification of several genes associated with PD, as well as their connection to neuroinflammation, raises the likelihood of disease susceptibility. Moreover, advancing age and mitochondrial dysfunction can weaken the immune system, potentially implicating them in the onset of the disease, particularly among older individuals. Compromised integrity of the blood-brain barrier could facilitate the immune system's access to brain tissue. This exposure may lead to encounters with native antigens or infections, potentially triggering an autoimmune response. Furthermore, there is mounting evidence supporting the notion that gut dysbiosis might represent an initial trigger for brain inflammation, ultimately promoting neurodegeneration. In this comprehensive review, we will delve into the numerous hypotheses surrounding the role of both innate and adaptive immunity in PD.

Epstein-Barr Virus and Human Endogenous Retrovirus in Japanese Patients with Autoimmune Demyelinating Disorders.

Multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocytes glycoprotein-antibody disease (MOGAD) are distinct autoimmune demyelinating disorders characterized by varying clinical and pathological characteristics. While the precise origins of these diseases remain elusive, a combination of genetic and environmental factors, including viral elements, have been suggested as potential contributors to their development. Our goal was to assess the occurrence of antibodies against pathogenic peptides associated with Epstein-Barr virus (EBV) and the human endogenous retrovirus-W (HERV-W) in serum samples obtained from Japanese individuals diagnosed with MS, NMOSD, and MOGAD and to make comparisons with a group of healthy controls (HCs). We conducted a retrospective analysis involving 114 Japanese participants, comprising individuals with MS (34), NMOSD (20), MOGAD (20), and HCs (40). These individuals were tested using a peptide-based enzyme-linked immunosorbent assay. A marked increase in antibody response against EBV nuclear antigen 1 (EBNA1)386-405 was observed in the serum of MS and MOGAD patients, as compared to HCs. Notably, we observed a correlation between antibodies against EBNA1386-405 and HERV-W486-504 peptides in a subset of the antibody-positive MS patients. These findings emphasize the involvement of EBV in the pathogenesis of MS and potentially MOGAD, suggesting its role in the reactivation of HERV-W.

Association of HLA-A*11:01, -A*24:02, and -B*18:01 with Prostate Cancer Risk: A Case-Control Study.

The major histocompatibility complex (MHC) loci, the most polymorphic regions within the human genome, encode protein complexes responsible for antigen presentation and CD4+ and CD8+ cell activation. In prostate cancer (PCa), the second most diagnosed cancer in the male population, MHC loci undergo significant changes in their expression patterns, which affect the ability of the immune system to attack and eliminate malignant cells. The purpose of this study was to explore the genetic diversity of human leukocyte antigen (HLA)-A and HLA-B in patients with PCa and healthy controls (HCs) by performing HLA genotyping using NGS technology. The analysis highlighted statistically significant differences (p < 0.05) in the prevalence of three alleles (A*11:01, A*24:02, and B*18:01). Among the HCs analyzed, 14.89% had A*11:01, 20.21% had A*24:02, and 30.61% had B*18:01; while 5.21% of patients with PCa presented A*11:01, 9.38% presented A*24:02, 18.08% presented B*18:01. Odds ratio (OR) calculations underlined a negative association between the three alleles and the risk of PCa (OR < 1). The results presented in this study suggest a protective role of A*11:01, A*24:02, and B*18:01 in PCa.

Mycobacterium avium subsp. paratuberculosis Antigens Elicit a Strong IgG4 Response in Patients with Multiple Sclerosis and Exacerbate Experimental Autoimmune Encephalomyelitis.

Neuroinflammation can be triggered by microbial products disrupting immune regulation. In this study, we investigated the levels of IgG1, IgG2, IgG3, and IgG4 subclasses against the heat shock protein (HSP)70533-545 peptide and lipopentapeptide (MAP_Lp5) derived from Mycobacterium avium subsp. paratuberculosis (MAP) in the blood samples of Japanese and Italian individuals with relapsing remitting multiple sclerosis (MS). Additionally, we examined the impact of this peptide on MOG-induced experimental autoimmune encephalomyelitis (EAE). A total of 130 Japanese and 130 Italian subjects were retrospectively analyzed using the indirect ELISA method. Furthermore, a group of C57BL/6J mice received immunization with the MAP_HSP70533-545 peptide two weeks prior to the active induction of MOG35-55 EAE. The results revealed a significantly robust antibody response against MAP_HSP70533-545 in serum of both Japanese and Italian MS patients compared to their respective control groups. Moreover, heightened levels of serum IgG4 antibodies specific to MAP antigens were correlated with the severity of the disease. Additionally, EAE mice that were immunized with MAP_HSP70533-545 peptide exhibited more severe disease symptoms and increased reactivity of MOG35-55-specific T-cell compared to untreated mice. These findings provide evidence suggesting a potential link between MAP and the development or exacerbation of MS, particularly in a subgroup of MS patients with elevated serum IgG4 levels.

Comparing clinical and imaging features of patients with MOG antibody-positivity and with and without oligoclonal bands.

Introduction: Myelin-oligodendrocyte glycoprotein antibody (MOG)-associated disorder (MOGAD) is a recently identified immune-mediated inflammatory disorder of the central nervous system (CNS). The significance of oligoclonal bands (OCBs) is not fully elucidated. This study investigated the clinical differences between patients with MOGAD who tested positive or negative for OCBs. Methods: The study was conducted on 23 patients with MOG-IgG-seropositivity who presented with central nervous system (CNS) symptoms. The patients were screened and divided into OCB-positive (n=10) and OCB-negative (n=13) groups, and their demographic, clinical, and magnetic resonance imaging (MRI) features were compared. Results: The results revealed that patients with OCB-positivity had a significantly higher frequency of relapse, and their IgG index was significantly higher. Discussion: OCBs were common in MOGAD met the consensus criteria. The study concluded that careful treatment decision-making is necessary in MOG antibody-positive cases with OCB-positivity.

Adjuvant Activity of Mycobacterium paratuberculosis in Enhancing the Immunogenicity of Autoantigens During Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) requires immunization by a MOG peptide emulsified in complete Freund's adjuvant (CFA) containing inactivated Mycobacterium tuberculosis. The antigenic components of the mycobacterium activate dendritic cells to stimulate T-cells to produce cytokines that promote the Th1 response via toll-like receptors. Therefore, the amount and species of mycobacteria present during the antigenic challenge are directly related to the development of EAE. This methods paper presents an alternative protocol to induce EAE in C57BL/6 mice using a modified incomplete Freund's adjuvant containing the heat-killed Mycobacterium avium subspecies paratuberculosis strain K-10. M. paratuberculosis, a member of the Mycobacterium avium complex, is the causative agent of Johne's disease in ruminants and has been identified as a risk factor for several human T-cell-mediated disorders, including multiple sclerosis. Overall, mice immunized with Mycobacterium paratuberculosis showed earlier onset and greater disease severity than mice immunized with CFA containing the strain of M. tuberculosis H37Ra at the same doses of 4 mg/mL. The antigenic determinants of Mycobacterium avium subspecies paratuberculosis (MAP) strain K-10 were able to induce a strong Th1 cellular response during the effector phase, characterized by significantly higher numbers of T-lymphocytes (CD4+ CD27+), dendritic cells (CD11c+ I-A/I-E+), and monocytes (CD11b+ CD115+) in the spleen compared to mice immunized with CFA. Furthermore, the proliferative T-cell response to the MOG peptide appeared to be highest in M. paratuberculosis-immunized mice. The use of an encephalitogen (e.g., MOG35-55) emulsified in an adjuvant containing M. paratuberculosis in the formulation may be an alternative and validated method to activate dendritic cells for priming myelin epitope-specific CD4+ T-cells during the induction phase of EAE.

A Multigene-Panel Study Identifies Single Nucleotide Polymorphisms Associated with Prostate Cancer Risk.

The immune system plays a critical role in modulating cancer development and progression. Polymorphisms in key genes involved in immune responses are known to affect susceptibility to cancer. Here, we analyzed 35 genes to evaluate the association between variants of genes involved in immune responses and prostate cancer risk. Thirty-five genes were analyzed in 47 patients with prostate cancer and 43 healthy controls using next-generation sequencing. Allelic and genotype frequencies were calculated in both cohorts, and a generalized linear mixed model was applied to test the relationship between prostate cancer risk and nucleotide substitution. Odds ratios were calculated to describe the association between each single nucleotide polymorphism (SNP) and prostate cancer risk. Significant changes in allelic and genotypic distributions were observed for IL4R, IL12RB1, IL12RB2, IL6, TMPRSS2, and ACE2. Furthermore, a generalized linear mixed model identified statistically significant associations between prostate cancer risk and SNPs in IL12RB2, IL13, IL17A, IL4R, MAPT, and TFNRS1B. Finally, a statistically significant association was observed between IL2RA and TNFRSF1B and Gleason scores, and between SLC11A1, TNFRSF1B and PSA values. We identified SNPs in inflammation and two prostate cancer-associated genes. Our results provide new insights into the immunogenetic landscape of prostate cancer and the impact that SNPs on immune genes may have on affecting the susceptibility to prostate cancer.

Bacillus Calmette-Guérin Tokyo-172 vaccine provides age-related neuroprotection in actively induced and spontaneous experimental autoimmune encephalomyelitis models.

Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system in young adults but still has no cure. Bacillus Calmette-Guérin (BCG) vaccine is reported to have non-specific anti-inflammatory effects and therapeutic benefits in autoimmune disorders including multiple sclerosis. However, the precise mechanism of action of BCG and the host immune response to it remain unclear. In this study, we aimed to investigate the efficacy of the BCG Tokyo-172 vaccine in suppressing experimental autoimmune encephalomyelitis (EAE). Groups of young and mature adult female C57BL/6J mice were BCG-vaccinated 1 month prior or 6 days after active EAE induction using myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Another group of 2D2 TCRMOG transgenic female mice was BCG-vaccinated before and after the onset of spontaneous EAE. BCG had an age-associated protective effect against active EAE only in wild-type mice vaccinated 1 month before EAE induction. Furthermore, the incidence of spontaneous EAE was significantly lower in BCG vaccinated 2D2 mice than in non-vaccinated controls. Protection against EAE was associated with reduced splenic T-cell proliferation in response to MOG35-55 peptide together with high frequency of CD8+ interleukin-10-secreting T cells in the spleen. In addition, microglia and astrocytes isolated from BCG-vaccinated mice showed polarization to anti-inflammatory M2 and A2 phenotypes, respectively. Our data provide new insights into the cell-mediated and humoral immune mechanisms underlying BCG vaccine-induced neuroprotection, potentially useful for developing better strategies for the treatment of MS.

Latent Potential of Multifunctional Selenium Nanoparticles in Neurological Diseases and Altered Gut Microbiota.

Neurological diseases remain a major concern due to the high world mortality rate and the absence of appropriate therapies to cross the blood-brain barrier (BBB). Therefore, the major focus is on the development of such strategies that not only enhance the efficacy of drugs but also increase their permeability in the BBB. Currently, nano-scale materials seem to be an appropriate approach to treating neurological diseases based on their drug-loading capacity, reduced toxicity, targeted delivery, and enhanced therapeutic effect. Selenium (Se) is an essential micronutrient and has been of remarkable interest owing to its essential role in the physiological activity of the nervous system, i.e., signal transmission, memory, coordination, and locomotor activity. A deficiency of Se leads to various neurological diseases such as Parkinson's disease, epilepsy, and Alzheimer's disease. Therefore, owing to the neuroprotective role of Se (selenium) nanoparticles (SeNPs) are of particular interest to treat neurological diseases. To date, many studies investigate the role of altered microbiota with neurological diseases; thus, the current review focused not only on the recent advancement in the field of nanotechnology, considering SeNPs to cure neurological diseases, but also on investigating the potential role of SeNPs in altered microbiota.

Age related immune modulation of experimental autoimmune encephalomyelitis in PINK1 knockout mice.

Objective: Recent research has shown that Parkin, an E3 ubiquitin ligase, modulates peripheral immune cells-mediated immunity during experimental autoimmune encephalomyelitis (EAE). Because the PTEN-induced putative kinase 1 (PINK1) protein acts upstream of Parkin in a common mitochondrial quality control pathway, we hypothesized that the systemic deletion of PINK1 could also modify the clinical course of EAE, altering the peripheral and central nervous systems' immune responses. Methods: EAE was induced in female PINK1-/- mice of different age groups by immunization with myelin oligodendrocyte glycoprotein peptide. Results: Compared to young wild-type controls, PINK1-/- mice showed earlier disease onset, albeit with a slightly less severe disease, while adult PINK1-/- mice displayed early onset and more severe acute symptoms than controls, showing persistent disease during the recovery phase. In adult mice, EAE severity was associated with significant increases in frequency of dendritic cells (CD11C+, IAIE+), lymphocytes (CD8+), neutrophils (Ly6G+, CD11b+), and a dysregulated cytokine profile in spleen. Furthermore, a massive macrophage (CD68+) infiltration and microglia (TMEM119+) and astrocyte (GFAP+) activation were detected in the spinal cord of adult PINK1-/- mice. Conclusions: PINK1 plays an age-related role in modulating the peripheral inflammatory response during EAE, potentially contributing to the pathogenesis of neuroinflammatory and other associated conditions.

HERV-K Envelope Protein Induces Long-Lasting Production of Autoantibodies in T1DM Patients at Onset in Comparison to ZNT8 Autoantibodies.

Human endogenous retroviruses (HERVs) have been thought of as silent passengers within our genomes, but their reactivation has been linked with several autoimmune diseases, including type 1 diabetes (T1DM). In order to evaluate the potential role of HERVs, in addition to the recognized role of HERV-W, we focused on the debated role of the HERV-K family in T1DM. Therefore, we performed a serological evaluation of IgG antibodies against HERV-K Env epitope (HERV-K Env19−37) in comparison to an important ß-cellular autoimmunity biomarker, ZnT8, from plasma samples of Sardinian children at the onset of T1DM, different T1DM groups (1−5 and 6−12 years since diagnosis), and healthy controls (HCs), by an indirect enzyme-linked immunosorbent assay (ELISA). A significant antibody response was observed against HERV-K Env19−37 (p < 0.0001) in T1DM patients compared to HCs, and significantly higher IgG responses were detected in the group at the onset compared to the other T1DM groups and HCs. Unlike the trend of the ß-cellular autoimmunity autoantibodies, for HERV-K Env antibodies we observed positive values that persist over time up to 5 years since the onset of T1DM. Our results add new evidence about the presence of antibodies against HERV-K in T1DM, but further investigations are necessary to relate these results with the established role of HERVs, considering the contrasting results for HERV-K.

Efficacy of BCG vaccine in animal models of neurological disorders.

The Bacillus Calmette-Guerin (BCG) vaccine can modulate the immune response via antigen-specific immune response, but also it can confer nonspecific protection and therapeutic benefits in several neurological conditions through different heterologous effects of vaccination. However, the precise mechanism of action of BCG remains unclear. In this review, different mechanisms underlying BCG-mediated immunity will be explained in animal models that reflects characteristic feature of neuroinflammatory and neurodegenerative disorders such as multiple sclerosis, Alzheimer's and Parkinson's diseases. Furthermore, evidence for a beneficial effect of the BCG on neuropsychiatric disorders, will be also discussed.

HERV-W and Mycobacteriumavium subspecies paratuberculosis Are at Play in Pediatric Patients at Onset of Type 1 Diabetes.

The etiology of T1D remains unknown, although a variety of etiological agents have been proposed as potential candidates to trigger autoimmunity in susceptible individuals. Emerging evidence has indicated that endogenous human retrovirus (HERV) may play a role in the disease etiopathogenesis; although several epigenetic mechanisms keep most HERVs silenced, environmental stimuli such as infections may contribute to the transcriptional reactivation of HERV-Wand thus promote pathological conditions. Previous studies have indicated that also Mycobacterium avium subspecies paratuberculosis (MAP) could be a potential risk factor for T1D, particularly in the Sardinian population. In the present study, the humoral response against HERV-W envelope and MAP-derived peptides was analyzed to investigate their potential role in T1D etiopathogenesis, in a Sardinian population at T1D onset (n = 26), T1D (45) and an age-matched healthy population (n = 45). For the first time, a high serum-prevalence of anti-Map and anti-HERV-W Abs was observed in pediatric patients at onset of T1D compared to T1D patients and healthy controls. Our results support the hypothesis that external infections and internal reactivations are involved in the etiology of T1D, and that HERV-W activation may be induced by infectious agents such as MAP.

Elevated mycobacterium avium subsp. paratuberculosis (MAP) antibody titer in Japanese multiple sclerosis.

To investigate whether antibody production against mycobacterium avium subsp. paratuberculosis (MAP) is related to clinical characteristics of multiple sclerosis (MS) and human leukocyte antigen (HLA) alleles, IgG antibody against three MAP peptides and two human peptides homologous to MAP were measured in sera from 103 MS patients and 50 healthy controls (HCs). MS patients had higher IgG levels against MAP2694295-303 (MAP2694-IgG) than HCs, while the other antibodies were comparable. Multivariate analysis demonstrated that higher MAP2694-IgG titers were associated with higher EDSS scores, but not with HLA alleles or dairy product consumption. Immune response against MAP may worsen MS disability.

Potential of PINK1 and PARKIN Proteins as Biomarkers for Active Multiple Sclerosis: A Japanese Cohort Study.

Background: Mitochondrial dysfunction has been suggested to play an important role in all stages of multiple sclerosis (MS). Objective: To determine the expression of two mitophagy-related proteins, PTEN-induced kinase 1 (PINK1) and PARKIN, in a cohort of Japanese patients with different neuroinflammatory disorders. Methods: Protein concentrations were measured using commercial ELISA in paired cerebrospinal fluid (CSF) and serum samples from patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), and from age- and sex-matched controls. Results: CSF and serum concentrations of PINK1 were higher in patients with MS than in patients with NMOSD (p = 0.004 and p < 0.001, respectively), MOGAD (p = 0.008 and p = 0.011, respectively), and controls (p = 0.021 and p = 0.002, respectively). CSF and concentrations of PARKIN were elevated in patients with MS in comparison with those in controls (p = 0.016 and p = 0.05, respectively). Conclusions: Our study highlighted the importance of mitophagy in MS and suggested the potential application of PINK1 and PARKIN as biomarkers to predict disease activity.

PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE).

Neuroinflammation plays an important role in the pathogenesis of several neurodegenerative disorders. To elucidate the effects of the mitophagy-related gene Parkin on neuroinflammation, we used a mouse model of experimental autoimmune encephalomyelitis (EAE). Female Parkin-/- and female wild type control mice were immunized with myelin oligodendrocyte glycoprotein to develop active EAE. Compared to the wild type controls, the Parkin-/- mice showed an earlier onset and greater severity of EAE with a greatly increased number of CD8αß+TCRαß+ T cells in the spleen and brain as well as a stronger T-cell proliferative response and an altered cytokine secretion in splenocytes. Furthermore, the Parkin-/- mice showed massive recruitment of monocytes/macrophages and activated microglia in the spinal cord during the acute phase of the disease. They also showed accumulation of microglia co-expressing M1 and M2 markers in the brain and a strong over-expression of A1 reactive astrocytes in the spinal cord. Furthermore, the Parkin-/- mice that developed persistent disease exhibited reduced glial cell numbers and abnormalities in mitochondrial morphology. Our study sheds light on the role of PARKIN protein in modulating peripheral immune cells-mediated immunity during EAE, highlighting its importance in neuroinflammation, and thus elucidating its potential in the development of novel neuroprotective therapies.

A mucosal immune response induced by oral administration of heat-killed Mycobacterium avium subsp. paratuberculosis exacerbates EAE.

Findings in humans and animals have demonstrated a potential role for Mycobacterium avium subsp. paratuberculosis (MAP) antigenic components in encephalitogenic T cell activation. Here we reported that oral administration of MAP activates the mucosal immunity and exacerbates active experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice, modulating the immune cell traffic from secondary lymphoid organs to central nervous system. The detection of antigenic mycobacterial components by intestinal antigen-presenting cells may modulate the immune system and the subsequent inflammatory status through various signaling mechanisms, including the synthesis of pro-inflammatory cytokines involved in EAE pathogenesis.