Neuromyelitis optica spectrum disorder (NMOSD) attacks require an urgent probabilistic anti-inflammatory therapeutic strategy. As inadequately treated attacks result in disability, there is a need to ...identify the optimal attack-treatment regimen. Our study aimed to identify predictors of outcome after a first attack in patients with an NMOSD presentation and propose the best treatment strategy.
We performed a retrospective cohort study on the French national NMOSD registry (NOMADMUS), a nested cohort of the French multiple sclerosis observatory (OFSEP) recruiting patients with NMOSD presentations in France. We studied the first attack for any independent locations of clinical core characteristic of NMOSD, in treatment-naïve patients. The primary outcome was the evolution of the Expanded Disability Status Scale (EDSS) score at 6 months, stratified in two ways to account for recovery (return to baseline EDSS score) and treatment response (classified as "good" if the EDSS score decreased by ≥ 1 point after a nadir EDSS score ≤ 3, or by ≥ 2 points after a nadir EDSS score > 3). We used ordinal logistic regression to infer statistical associations with the outcome.
We included 211 attacks among 183 patients (104 with anti-AQP4 antibodies, 60 with anti-MOG antibodies, and 19 double seronegative). Attack treatment regimens comprised corticosteroids (n = 196), plasma exchanges (PE; n = 72) and intravenous immunoglobulins (n = 6). Complete recovery was reached in 40 attacks (19%) at 6 months. The treatment response was "good" in 134 attacks (63.5%). There was no improvement in EDSS score in 50 attacks (23.7%). MOG-antibody seropositivity and short delays to PE were significantly and independently associated with better recovery and treatment response.
We identified two prognostic factors: serostatus (with better outcomes among MOG-Ab-positive patients) and the delay to PE. We, therefore, argue for a more aggressive anti-inflammatory management of the first attacks suggesting an NMOSD presentation, with the early combination of PE with corticosteroids.
Many studies have investigated pregnancy in women with multiple sclerosis (MS). However, no study has measured prenatal healthcare utilization in women with MS or adherence to follow-up ...recommendations to improve antenatal care quality. A better knowledge of the quality of antenatal care in women with MS would help identify and better support women with insufficient follow-up. Our objective was to measure the level of compliance to prenatal care recommendations in women with MS using data from the French National Health Insurance Database.
This retrospective cohort study included all pregnant women with MS who gave live birth in France between 2010 and 2015. Using the French National Health Insurance Database, follow-up visits with gynecologists, midwives, and general practitioners (GPs) were identified, as well as ultrasound exams and laboratory tests. Based on the Adequacy of Prenatal Care Use and Content and Timing of care in Pregnancy indices, a new tool adapted to the French recommendations was developed to measure and classify the antenatal care trajectory (adequate or inadequate). Explicative factors were identified using multivariate logistic regression models. A random effect was included because women may have had more than one pregnancy during the study period.
In total, 4,804 women with MS (
= 5,448 pregnancies ending in live births) were included. When considering only visits with gynecologists/midwives, 2,277 pregnancies (41.8%) were considered adequate. When adding visits with GP, their number increased to 3,646 (66.9%). Multivariate models showed that multiple pregnancy and higher medical density were associated with better adherence to follow-up recommendations. Conversely, adherence was lower in 25-29-year-old and >40-year-old women, in women with very low income, and agricultural and self-employed workers. No visits, ultrasound exams, and laboratory tests were recorded in 87 pregnancies (1.6%). In 50% of pregnancies, women had at least one visit with a neurologist during the pregnancy, and women restarted disease-modifying therapy (DMT) within 6 months after delivery in 45.9% of pregnancies.
Many women consulted their GP during pregnancy. This could be linked to a low density of gynecologists but may also reflect the preferences of women. Our findings can help adapt recommendations and healthcare providers' practices according to the women's profiles.
In a recent Science issue, Bousbaine et al. (2022) identified β-N-acetylhexosaminidase, a conserved antigen expressed by commensals that drives expansion and differentiation of intestinal ...intra-epithelial cells and protects against gut inflammation.
We have recently described antitumor properties of
BL23 strain in both a mouse allograft model of human papilloma virus (HPV)-induced cancer and dimethylhydrazine-associated colorectal cancer. ...However, the mechanisms underlying these beneficial effects are still unknown. Interestingly,
cellular models show that this bacterium is able to stimulate the production of high levels of IL-2. Because this cytokine has well-known antitumor properties, we decided to explore its role in the anti-cancer effects of BL23 using the HPV-induced cancer model. We found a negative correlation between IL-2 and tumor size confirming the necessity of IL-2 to protect from tumor development. Then, we blocked IL-2 synthesis using neutralizing monoclonal antibodies in mice that were challenged with lethal levels of tumor cells; this led to a significant reduction in the protective abilities of BL23. Next, we used a genetically modified strain of
to deliver exogenous IL-2 to the system, and in doing so, we were able to partially mimic the antitumor properties of BL23. Additionally, we showed the systemic role of T-cells in tumor protection through a negative correlation between tumor size and T-cells subpopulations and an increasement of BL23-specific local Foxp3 levels in tumor-bearing mice. Finally, we observed a negative correlation between tumor size and NK+ cells, but local recruitment of NK cells and cytotoxic activity appeared specific to BL23 treatment. Taken together, our data suggest that IL-2 signaling pathway plays an important role in the anti-tumoral effects of probiotic strain
BL23. These results encourage further investigation in the use of probiotic strains for potential therapeutic applications to clinical practice, in particular for the treatment of colorectal cancer. Furthermore, our approach could be extended and applied to other potential beneficial microorganisms, such as gut microbiota, in order to better understand the crosstalk between microbes and the host.
Invariant NKT (iNKT) cells differentiate in the thymus into three distinct lineages defined by their cytokine and transcription factor expression. Signaling lymphocyte activation molecule ...(SLAM)‐associated protein (SAP) is essential for early stages of iNKT cell development, but its role during terminal differentiation of iNKT1, iNKT2, or iNKT17 cells remains unclear. Taking advantage of SAP‐deficient mice expressing a Vα14‐Jα18 TCRα transgene, we found that SAP is critical not only for IL‐4 production but also for the terminal differentiation of IL‐4‐producing iNKT2 cells. Furthermore, without SAP, the IL‐17 producing subset is expanded, while IFN‐γ‐producing iNKT1 differentiation is only moderately compromised. Lack of SAP reduced the expression of the transcription factors GATA‐3 and promyelocytic leukemia zinc finger, but enhanced the levels of retinoic acid receptor‐related orphan receptor γt. In the absence of SAP, lineage commitment was actually shifted toward the emergence of iNKT17 over iNKT2 cells. Collectively, our data unveil a new critical regulatory function for SAP in thymic iNKT cell fate decisions.
SLAM‐associated protein (SAP) is required early in invariant NKT (iNKT) cell development, but its role in later stages is less clear. Here, we reported that signals from SAP are critical for iNKT2 but dispensable for iNKT17 commitment highlighting a new role for SAP on iNKT cell development.
S
is a commensal bacterium ubiquitously present on human skin. This species is considered as a key member of the healthy skin microbiota, involved in the defense against pathogens, modulating the ...immune system, and involved in wound repair. Simultaneously,
is the second cause of nosocomial infections and an overgrowth of
has been described in skin disorders such as atopic dermatitis. Diverse isolates of
co-exist on the skin. Elucidating the genetic and phenotypic specificities of these species in skin health and disease is key to better understand their role in various skin conditions. Additionally, the exact mechanisms by which commensals interact with host cells is partially understood. We hypothesized that
isolates identified from different skin origins could play distinct roles on skin differentiation and that these effects could be mediated by the aryl hydrocarbon receptor (AhR) pathway.
For this purpose, a library of 12 strains originated from healthy skin (non-hyperseborrheic (NH) and hyperseborrheic (H) skin types) and disease skin (atopic (AD) skin type) was characterized at the genomic and phenotypic levels.
Here we showed that strains from atopic lesional skin alter the epidermis structure of a 3D reconstructed skin model whereas strains from NH healthy skin do not. All strains from NH healthy skin induced AhR/OVOL1 path and produced high quantities of indole metabolites in co-culture with NHEK; especially indole-3-aldehyde (IAld) and indole-3-lactic acid (ILA); while AD strains did not induce AhR/OVOL1 path but its inhibitor STAT6 and produced the lowest levels of indoles as compared to the other strains. As a consequence, strains from AD skin altered the differentiation markers FLG and DSG1. The results presented here, on a library of 12 strains, showed that
originated from NH healthy skin and atopic skin have opposite effects on the epidermal cohesion and structure and that these differences could be linked to their capacity to produce metabolites, which in turn could activate AHR pathway. Our results on a specific library of strains provide new insights into how
may interact with the skin to promote health or disease.
Extracellular matrix (ECM) proteins secreted by blood-brain barrier (BBB) endothelial cells (ECs) are implicated in cell trafficking. We discovered that the expression of ECM epidermal growth ...factor-like protein 7 (EGFL7) is increased in the CNS vasculature of patients with multiple sclerosis (MS), and in mice with experimental autoimmune encephalomyelitis (EAE). Perivascular CD4 T lymphocytes colocalize with ECM-bound EGFL7 in MS lesions. Human and mouse activated T cells upregulate EGFL7 ligand αvβ3 integrin and can adhere to EGFL7 through integrin αvβ3. EGFL7-knockout (KO) mice show earlier onset of EAE and increased brain and spinal cord parenchymal infiltration of T lymphocytes. Importantly, EC-restricted EGFL7-KO is associated with a similar EAE worsening. Finally, treatment with recombinant EGFL7 improves EAE, reduces MCAM expression, and tightens the BBB in mouse. Our data demonstrate that EGFL7 can limit CNS immune infiltration and may represent a novel therapeutic avenue in MS.
Symptom occurrence at the first ingestion suggests that food allergy may result from earlier sensitization via non-oral routes. We aimed to characterize the cellular populations recruited at various ...mucosal and immune sites after experimental sensitization though different routes. BALB/cJ mice were exposed to a major allergenic food (peanut) mixed with cholera toxin via the intra-gastric (i.g.), respiratory, cutaneous, or intra-peritoneal (i.p.) route. We assessed sensitization and elicitation of the allergic reaction and frequencies of T cells, innate lymphoid cells (ILC), and inflammatory and dendritic cells (DC) in broncho-alveolar lavages (BAL), lungs, skin, intestine, and various lymph nodes. All cellular data were analyzed through non-supervised and supervised uni/multivariate analysis. All exposure routes, except cutaneous, induced sensitization, but intestinal allergy was induced only in i.g.- and i.p.-exposed mice. Multivariate analysis of all cellular constituents did not discriminate i.g. from control mice. Conversely, respiratory-sensitized mice constituted a distinct cluster, characterized by high local inflammation and immune cells recruitment. Those mice also evidenced changes in ILC frequencies at distant site (intestine). Despite absence of sensitization, cutaneous-exposed mice evidenced comparable changes, albeit less intense. Our study highlights that the initial route of sensitization to a food allergen influences the nature of the immune responses at various mucosal sites. Interconnections of mucosal immune systems may participate in the complexity of clinical manifestations as well as in the atopic march.
Naive CD4 lymphocytes undergo a polarization process in the periphery to become induced Th17 (iTh17) cells. Using retinoic acid-related orphan receptor γt (RORγt)-gfp mice, we found that RORγt and ...the transcription factor promyelocytic leukemia zinc finger (PLZF) are valuable new markers to identify the recently described natural Th17 (nTh17) cell population. nTh17 cells are thymically committed to promptly produce large amounts of IL-17 and IL-22. In this study, we show that, in addition to responding to TCR cross-linking, nTh17 cells secrete IL-17 and IL-22 when stimulated with IL-23 plus IL-1β, either in recombinant form or in supernatants from TLR4-activated dendritic cells. This innate-like ability of RORγt(+) nTh17 cells to respond to TLR4-induced cytokines was not shared by iTh17 cells. The other distinct properties of RORγt(+) nTh17 cells are their high expression of PLZF and their absence from lamina propria; iTh17 cells are found therein. RORγt(+) nTh17 cells are present in the thymus of germ-free RORγt-gfp and IL-6(-/-) RORΓ: t-gfp mice, indicating that these cells do not require symbiotic microbiota or IL-6 for their generation. Finally, we found that PLZF(+)RORγt(+) nTh17 cells represent one of the primary IL-17-producing innate-like T cell populations in a TLR7 imiquimod model of psoriasis-like disorder, indicating their involvement in this kind of lesion. Collectively, our results reveal RORγt and PLZF as characteristic markers for identifying nTh17 cells and demonstrate one of their novel properties: the ability to respond promptly to TLR-dependent proinflammatory stimuli without TCR engagement, placing them as members of the innate-like T cell family.
Innate immunity genes have been reported to affect susceptibility to inflammatory bowel diseases (IBDs) and colitis in mice. Dectin-1, a receptor for fungal cell wall β-glucans, has been clearly ...implicated in gut microbiota modulation and modification of the susceptibility to gut inflammation. Here, we explored the role of Dectin-1 and Dectin-2 (another receptor for fungal cell wall molecules) deficiency in intestinal inflammation.
Susceptibility to dextran sodium sulfate (DSS)-induced colitis was assessed in wild-type, Dectin-1 knockout (KO), Dectin-2KO, and double Dectin-1KO and Dectin-2KO (D-1/2KO) mice. Inflammation severity, as well as bacterial and fungal microbiota compositions, was monitored.
While deletion of Dectin-1 or Dectin-2 did not have a strong effect on DSS-induced colitis, double deletion of Dectin-1 and Dectin-2 significantly protected the mice from colitis. The protection was largely mediated by the gut microbiota, as demonstrated by fecal transfer experiments. Treatment of D-1/2KO mice with opportunistic fungal pathogens or antifungal agents did not affect the protection against gut inflammation, suggesting that the fungal microbiota had no role in the protective phenotype. Amplicon-based microbiota analysis of the fecal bacterial and fungal microbiota of D-1/2KO mice confirmed the absence of changes in the mycobiota but strong modification of the bacterial microbiota. We showed that bacteria from the Lachnospiraceae family were at least partly involved in this protection and that treatment with Blautia hansenii was enough to recapitulate the protection.
Deletion of both the Dectin-1 and Dectin-2 receptors triggered a global shift in the microbial gut environment, affecting, surprisingly, mainly the bacterial population and driving protective effects in colitis. Members of the Lachnospiraceae family seem to play a central role in this protection. These findings provide new insights into the role of the Dectin receptors, which have been described to date as affecting only the fungal population, in intestinal physiopathology and in IBD. Video Abstract.
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