Search

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D. Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case's onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood. Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation. The ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored. [ABSTRACT FROM AUTHOR]

It is widely accepted that the main common pathogenetic pathway in multiple sclerosis (MS) involves an immune-mediated cascade initiated in the peripheral immune system and targeting CNS myelin. Logically, therefore, therapeutic approaches to the disease include modalities aiming at downregulation of the various immune elements that are involved in this immunological cascade. Since the introduction of interferons in 1993, more specific immunoactive drugs have been introduced, but still most of them can, at best, effectively modulate only the early relapsing phases of MS. The more progressed phases of the disease are not efficiently amendable by the existing immunomodulatory drugs. Moreover, localized and compartmentized inflammation in the CNS, which seems to be mostly responsible for the chronic axonal damage and resulting progression of disability, is less affected by the current drugs. A more radical approach to suppress all the inflammation in MS, including that into the CNS, could theoretically be achieved with high-dose immunosuppression using strong cytotoxic medications and resetting of the immune system by hematopoietic stem cell transplantation (HSCT). HSCT, both allogeneic and autologous, has been tried as a novel therapeutic approach in various autoimmune diseases. During the last 15 years several (mostly open) clinical studies evaluated the effect of HSTC on MS patients; the published papers showed that a high proportion of the HSCT-treated MS patients were stabilized, or even improved after the transplantation and have generally indicated a beneficial effect on disease progression. In this review, the rationale of HSCT and the summary of the results of the existing clinical trials are presented. Despite the fact that it is difficult to collectively summarize the results of all the trials, due to lack of uniformity in the conditioning and treatment protocols and of completed controlled studies, these clinical studies have provided a strong 'proof of concept' for HSCT in MS and have significantly contributed to our understanding of the advantages and disadvantages of each approach and HSCT protocol. [ABSTRACT FROM AUTHOR]

Systemic autoimmunity is characterized by widespread inflammation, autoantibody production and immune complex deposition. The regulatory mechanisms for the systemic autoimmunity are not fully understood. A paper by Li et al. revealed that Egr2 and Egr3, transcription factors required for T-cell anergy, are the regulators for systemic autoimmune disease. They showed evidence that Egr2 and Egr3 control cytokine productions and cell proliferation via SOCS and Batf regulation. [ABSTRACT FROM AUTHOR]

Context: The alkaloids of Narcissus tazetta L. var. Chinensis Roem (Amaryllidaceae) have antitumor and antiviral activities. However, the immunopharmacological effects of one of its constituents, pseudolycorine chloride (PLY), have not been reported yet. Objective: We evaluated the effect of PLY on myeloid-derived suppressor cells (MDSCs) expansion and differentiation into monocyte-like MDSCs (M-MDSCs) and examined whether PLY alleviates Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Materials and methods: In vitro, MDSCs were treated with PLY (0.67, 2 and 6 μM) or solcitinib (10 μM, positive control) for 48 or 96 h, and their proliferation, expansion, and differentiation into M-MDSCs were examined by flow cytometry. Myelin oligodendrocyte glycoprotein (MOG35-55) was used to induce EAE in female C57BL/6 mice, and the mice were treated with 40 mg/kg/d PLY or 1 mg/kg/d FK-506 (tacrolimus, positive control) for 21 days. Inflammatory infiltration, spinal cord demyelination, and MDSCs and Th17 cells infiltration into the spinal cord were examined using haematoxylin and eosin staining, Luxol fast blue staining, and immunofluorescence, respectively. Results: In vitro, PLY (IC50/24 h = 6.18 μM) significantly inhibited IL-6 and GM-CSF-induced MDSCs proliferation, expansion and differentiation into M-MDSCs at all concentrations used. However, these concentrations did not show cytotoxicity. In mice, PLY (40 mg/kg) treatment alleviated EAE and inhibited inflammatory infiltration, demyelination, and MDSCs and Th17 cells infiltration into the spinal cord. Discussion and conclusions: PLY may be an excellent candidate for the treatment of MS and other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Miller Fisher syndrome (MFS) is a rare variant of Guillain–Barré syndrome that is characterised by ataxia, ophthalmoplegia, and areflexia. Its relation with other autoimmune diseases is scarcely found in the literature, and in those few cases, treatment has been especially difficult. We report a case of a 28-year-old woman who presented with ophthalmoplegia and ptosis, later developing facial palsy and hyporeflexia. She had positive GD1a, GT1a, GQ1b antibodies confirming MFS. She also had positive antinuclear and lupus anticoagulant antibodies confirming antiphospholipid syndrome. She had a mild clinical course. MFS can present with multiple autoimmunity; it is unclear if there is cross-reactivity due to myelin damage. [ABSTRACT FROM AUTHOR]

As COVID-19 is a new emerging disease, the hematological/immunological changes that develop in the infected patients remain unknown. This study aims to systematically review the hematologic autoimmune complications in these patients. Data from three online databases including Medline (via PubMed), Scopus and Web of Science were searched on 19 December 2020, and after excluding duplicate, irrelevant and inappropriate records, eligible documents were identified. Afterwards, information such as patients' history, presentations, paraclinical data, treatment course and outcome were extracted from the records. A total of 58 documents were considered to be eligible for data extraction which described 94 patients with COVID-19 who developed hematologic autoimmune disorder in their course of infection. Of these patients with COVID-19, the most common hematologic autoimmune disorder was immune thrombocytopenic purpura (55 cases) followed by autoimmune hemolytic anemia (22 cases). Other hematologic autoimmune disorders include antiphospholipid syndrome, thrombotic thrombocytopenic purpura, Evans syndrome and autoimmune neutropenia. The current study would help us to always consider an autoimmune etiology for cases with abnormal hematologic finding which further lead to an appropriate treatment of the patients, especially when the symptoms present in about 1–2 weeks after the first manifestation of the infection symptoms. Maybe, at least in this pandemic, it should be recommended to evaluate patients with unexpected and unexplained decrease in their hemoglobulin or platelet count for COVID-19. Another challenging issue is the treatment options. Given the multiorgan involvement and multifaceted nature of the infection, an individualized approach should be taken for each patient. [ABSTRACT FROM AUTHOR]

The article reviews developments in the research of regulatory Treg (T) cells in the treatment of autoimmunity. A research paper in the issue on attempts to improve the isolation of Treg cells through the addition of CD8-depletion techniques to those currently being practiced is mentioned. The author describes the possible benefits that can arise from Treg cell transfers and the clinical trials that should be performed to evaluate them.

Introduction:Despite recent advances in pharmacological management, multiple sclerosis (MS), an autoimmune disease of the central nervous system, remains a leading cause of disability. In relapsing-remitting (RR)MS, neurologists most commonly utilize immunomodulatory or immunosuppressive agents to benefit their patients. With the introduction of humanized monoclonal antibodies (mAbs) ablation of distinct immune populations has become possible. Depletion of B cells by anti-CD20 mAbs has repeatedly proven to be a very rapid and effective means to diminish disease activity in RRMS. Areas covered:We discuss the biological rationale, development, and recent clinical study results of the second generation anti-CD20 mAb ocrelizumab. Expert commentary:The topline results of two phase-III randomized clinical trials demonstrate superiority of ocrelizumab over interferon beta in RRMS patients with regards to clinical and paraclinical outcome parameters. The short term adverse events profile appears favorable. However, long-term effects of repeated B cell depletion are currently unknown. [ABSTRACT FROM PUBLISHER]

Opsoclonus-myoclonus syndrome (OMS) is a rare and primarily immune-mediated disease in children and adults. The main symptoms include opsoclonus, myoclonus and ataxia. In children, the symptoms also include irritability, and, over a long-term course, learning and behavioural disturbances. OMS can be idiopathic, parainfectious or occur as a paraneoplastic (tumour-associated) syndrome. Paraneoplastic OMS in children is almost exclusively associated with neuroblastoma, whereas in adults, small cell lung cancer and breast cancer are the main underlying tumours. An autoimmune pathophysiology is suspected because childhood OMS patients have functionally active autoantibodies, proinflammatory changes in the cytokine network and immunotherapy responses. Children appear to respond regularly to immunosuppressive treatment. However, although the neurological symptoms show a good response, most children continue to show neuropsychological disturbances. [ABSTRACT FROM PUBLISHER]

Autoimmune-related retinopathy and optic neuropathy is characterized by visual loss in the presence of antibodies against retina or optic nerve antigens in the absence of neoplasia. We report a case with progressive central visual loss accompanied by latent autoimmune diabetes in an adult. Visual fields, multimodal imaging and electrophysiological testing showed characteristic changes without evidence of neoplasia on positron emission tomography. Immunologic testing revealed abnormal reactivity against a 20 kDa optic nerve antigen and 40 kDa and 62 kDa retina antigens along with antibodies against anti-glutamic acid decarboxylase, a constellation which we believe to be unique. [ABSTRACT FROM PUBLISHER]

During gestation, maternal cells traffic to the fetus leading to the natural phenomenon of microchimerism. Although their persistence in offspring has been associated with several autoimmune disorders, the precise role of maternal cells in these disorders remains unclear. We aimed to evaluate whether alloreactive maternal T cells could directly trigger a graft-vs.-host like reaction or indirectly influence the development of the offspring's regulatory T cells (Treg) favoring autoimmunity. In a specific breeding strategy, we recently reported that maternal allogeneic T cells changed fetal Treg development and their quantities in mesenteric lymph nodes, leading to early signs of inflammation in the gut later in life. Although maternal microchimeric T cells were found in newborn tissues, we could not detect any cells in the gut from adult offspring where the inflammation occurred. Thus, strongly alloreactive maternal microchimeric T cells may indirectly drive the offspring to gut inflammation. We believe these results suggest a new mechanism for predisposition to auto-immunity. [ABSTRACT FROM AUTHOR]

Programmed cell death 1 ligand 1 (PD-L1) is an important regulator of T-cell responses and may consequently limit anticancer immunity. We have recently identified PD-L1-specific, cytotoxic CD8+ T cells. In the present study, we develop these findings and report that CD4+ helper T cells spontaneously recognize PD-L1. We examined the locality of a previously identified HLA-A"0201-restricted PD-L1-epitope for the presence of possible CD4+ T-cell epitopes. Thus, we identified naturally occurring PD-L1-specific CD4+ T cells among the peripheral blood lymphocytes of cancer patients and - to lesser extents - healthy donors, by means of ELISP OT assays. PD-L1-specific CD4+ T cells appeared to be TH17 cells exhibiting an effector T-cell cytokine profile. Hence, PD-L1-specific CD4+ T cells released interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-17 (IL-17) in response to a long PD-L1-derived peptide. Furthermore, we demonstrate that the specific recognition of PD-L1 by CD4+ T cells is MHC Class II-restricted. Natural T-cell responses against PD-L1 are noteworthy as they may play a prominent role in the regulation of the immune system. Thus, cytokine release from PD-L1-specific CD4+ T cells may surmount the overall immunosuppressive actions of this immune checkpoint regulator. Moreover, PD-L1-specific T cells might be useful for anticancer immunotherapy, as they may counteract common mechanisms of immune escape mediated by the PD-L1/PD-1 pathway. [ABSTRACT FROM AUTHOR]

An assessment of antitumor immunity versus autoimmunity as provoked by the specific depletion of FOXP3+ Tregs is now possible with the development of Foxp3-diphtheria toxin receptor-like transgenic mouse models. We have used the poorly immunogenic B16F10 melanoma model to characterize a very heterogeneous antitumor effect of the immune response induced by Treg depletion. Depletion and neutralization studies demonstrated the importance of host T cells and interferon γ (IFNγ) in mediating the antitumor response developing in Treg-depleted mice. Such a response correlated with increased proliferation of granzyme B- and IFNγ-producing T cells in the tumor. Furthermore, enhanced antitumor immunity modulated the expression of MHC Class I molecules by B16F10 melanoma cells in Tregdepleted mice. Since Foxp3+ Treg depletion induced a significantly heterogeneous antitumor response, for the first time we were able to assess antitumor immunity and autoimmunity across different groups of responding mice. Strikingly, the duration of the tumor-immune system interaction provoked in individual Treg-depleted mice positively correlated with their propensity to develop vitiligo. A rapid complete tumor rejection was not associated with the development of autoimmunity, however, a proportion of mice that suppressed, but did not effectively clear, B16F10 melanoma did develop vitiligo. The significant implication is that approaches that combine with Treg depletion to rapidly reject tumors may also diminish autoimmune toxicities. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a serious, debilitating disease, with life-threatening complications, and the financial burden associated with the management of this disease is enormous. Early diagnosis and intervention can improve morbidity and mortality. Unfortunately, in Africa, type 1 diabetes is poorly characterised, and there is sparse information regarding the aetiology and epidemiology of this disease. However, there is some evidence of a later age of onset in African type 1 diabetic patients, compared to European diabetics, and it is thought that the prevalence of type 1 diabetes is lower in African populations than in the Western world. [ABSTRACT FROM AUTHOR]

Current observations link vitamin D deficiency to many autoimmune diseases. There are limited data on vitamin D in Alopecia Areata, an autoimmune disease which in our experience shows seasonality in most of its remitting-relapsing forms. Our results demonstrate the presence of insufficiency of 25-hydroxyvitamin D (25OH-D) in many patients with various clinical forms, correlated with the expected increase of the values of Parathyroid hormone (PTH). This could suggest the possible clinical use of vitamin D in the management of this frustrating disease. [ABSTRACT FROM AUTHOR]

High endothelial venules (HEVs) are blood vessels especially adapted for lymphocyte trafficking which are normally found in secondary lymphoid organs such as lymph nodes (LN) and Peyer's patches. It has long been known that HEVs develop in non-lymphoid organs during chronic inflammation driven by autoimmunity, infection or allografts. More recently, HEVs have been observed in solid, vascularized tumors and their presence correlated with reduced tumor size and improved patient outcome. It is proposed that newly formed HEV promote antitumor immunity by recruiting naive lymphocytes into the tumor, thus allowing the local generation of cancerous tissue-destroying lymphocytes. Understanding how HEVs develop and function are therefore important to unravel their role in human cancers. In LN, HEVs develop during embryonic and early post-natal life and are actively maintained by the LN microenvironment. Systemic blockade of lymphotoxin-β receptor leads to HEV de-differentiation, but the LN components that induce HEV differentiation have remained elusive. Recent elegant studies using gene-targeted mice have demonstrated clearly that triggering the lymphotoxin-β receptor in endothelial cells (EC) induces the differentiation of HEV and that CD11c+dendritic cells play a crucial role in this process. It will be important to determine whether lymphotoxin-β receptor-dependent signaling in EC drives the development of HEV during tumorigenesis and which cells have HEV-inducer properties. This may reveal therapeutic approaches to promote HEV neogenesis and determine the impact of newly formed HEV on tumor immunity. [ABSTRACT FROM AUTHOR]