Narcolepsy type 1: what have we learned from immunology?

Abstract Narcolepsy type 1 is hypothesized to be an autoimmune disease targeting the hypocretin/orexin neurons in the hypothalamus. Ample genetic and epidemiological evidence points in the direction of a pathogenesis involving the immune system, but this is not considered proof of autoimmunity. In fact, it remains a matter of debate how to prove that a given disease is indeed an autoimmune disease. In this review, a set of commonly used criteria for autoimmunity is described and applied to narcolepsy type 1. In favor of the autoimmune hypothesis are data showing that in narcolepsy type 1 a specific adaptive immune response is directed to hypocretin/orexin neurons. Autoreactive T cells and autoantibodies have been detected in blood samples from patients, but it remains to be seen if these T cells or antibodies are in fact present in the hypothalamus. It is also unclear if the autoreactive T cells and/or autoantibodies can transfer the disease to healthy individuals or animals or if immunization with the proposed autoantigens can induce the disease in animal models. Most importantly, it is still controversial whether suppression of the autoimmune response can prevent disease progression. In conclusion, narcolepsy type 1 does still not fully meet the criteria for being classified as a genuine autoimmune disease, but more and more results are pointing in that direction.

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Probiotics and Prebiotics for the Amelioration of Type 1 Diabetes: Present and Future Perspectives

Microorganisms ◽

10.3390/microorganisms7030067 ◽

2019 ◽

Vol 7 (3) ◽

pp. 67 ◽

Cited By ~ 21

Author(s):

Sidharth Mishra ◽

Shaohua Wang ◽

Ravinder Nagpal ◽

Brandi Miller ◽

Ria Singh ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Immune System ◽

Gut Microbiota ◽

Adaptive Immune Response ◽

Early Years ◽

Autoimmune Response ◽

Β Cells ◽

Environmental Interactions

Type 1-diabetes (T1D) is an autoimmune disease characterized by immune-mediated destruction of pancreatic beta (β)-cells. Genetic and environmental interactions play an important role in immune system malfunction by priming an aggressive adaptive immune response against β-cells. The microbes inhabiting the human intestine closely interact with the enteric mucosal immune system. Gut microbiota colonization and immune system maturation occur in parallel during early years of life; hence, perturbations in the gut microbiota can impair the functions of immune cells and vice-versa. Abnormal gut microbiota perturbations (dysbiosis) are often detected in T1D subjects, particularly those diagnosed as multiple-autoantibody-positive as a result of an aggressive and adverse immunoresponse. The pathogenesis of T1D involves activation of self-reactive T-cells, resulting in the destruction of β-cells by CD8+ T-lymphocytes. It is also becoming clear that gut microbes interact closely with T-cells. The amelioration of gut dysbiosis using specific probiotics and prebiotics has been found to be associated with decline in the autoimmune response (with diminished inflammation) and gut integrity (through increased expression of tight-junction proteins in the intestinal epithelium). This review discusses the potential interactions between gut microbiota and immune mechanisms that are involved in the progression of T1D and contemplates the potential effects and prospects of gut microbiota modulators, including probiotic and prebiotic interventions, in the amelioration of T1D pathology, in both human and animal models.

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OR.9. Detection of Islet-specific Autoreactive T Cells by a Novel Robust and High Throughput Screening Strategy in Stored Blood Samples of Type 1 Diabetic Patients

Clinical Immunology ◽

10.1016/j.clim.2009.03.016 ◽

2009 ◽

Vol 131 ◽

pp. S8

Author(s):

Joana Abreu ◽

Jurjen Velthuis ◽

Wendy Unger ◽

Kees Franken ◽

Ton Schumacher ◽

...

Keyword(s):

T Cells ◽

High Throughput ◽

High Throughput Screening ◽

Screening Strategy ◽

Diabetic Patients ◽

Autoreactive T Cells ◽

Blood Samples ◽

Type 1 Diabetic Patients ◽

Stored Blood

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Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000516 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000516

Author(s):

Erika J Lampert ◽

Ashley Cimino-Mathews ◽

Joo Sang Lee ◽

Jayakumar Nair ◽

Min-Jung Lee ◽

...

Keyword(s):

Ovarian Cancer ◽

Immune Response ◽

T Cells ◽

Immune Responses ◽

Adaptive Immune Response ◽

Cell Cycle Checkpoint ◽

High Grade ◽

Blood Samples ◽

Adaptive Immune ◽

Cycle Checkpoint

BackgroundPreclinical data suggest cell cycle checkpoint blockade may induce an immunostimulatory tumor microenvironment. However, it remains elusive whether immunomodulation occurs in the clinical setting. To test this, we used blood and fresh tissue samples collected at baseline and post therapy from a phase II trial of the cell cycle checkpoint 1 inhibitor (CHK1i) prexasertib in recurrent ovarian cancer.MethodsPaired blood samples and fresh core biopsies, taken before treatment was started at baseline (cycle 1 day 1 (C1D1)) and post second dose on day 15 of cycle 1 (C1D15), were collected. To evaluate changes in the immune responses after treatment, multiparametric flow cytometry for DNA damage markers and immune cell subsets was performed on paired blood samples. RNA sequencing (RNAseq) of paired core biopsies was also analyzed. Archival tissue immune microenvironment was evaluated with immunohistochemistry. All correlative study statistical analyses used two-sided significance with a cut-off of p=0.05.ResultsFlow cytometric analysis showed significantly increased γ-H2AX staining after CHK1i treatment, accompanied by increased monocyte populations, suggestive of an activated innate immune response (median 31.6% vs 45.6%, p=0.005). Increased expressions of immunocompetence marker HLA-DR (Human Leukocyte Antigen DR antigen) on monocytes and of TBK1, a marker of STING (stimulator of interferon genes) pathway activation, in biopsies were associated with improved progression-free survival (PFS) (9.25 vs 3.5 months, p=0.019; 9 vs 3 months, p=0.003, respectively). Computational analysis of RNAseq data indicated increased infiltration of tumor niches by naïve B-cells and resting memory T-cells, suggestive of a possibly activated adaptive immune response, and greater T-reg infiltration after treatment correlated with worse PFS (9.25 vs 3.5 months, p=0.007). An immunosuppressive adaptive immune response, perhaps compensatory, was also observed on flow cytometry, including lymphodepletion of total peripheral CD4+ and CD8+T cells after CHK1i and an increase in the proportion of T-regs among these T-cells. Additionally, there was a trend of improved PFS with greater tumor-infiltrating lymphocytes (TILs) in archival tissues (13.7 months >30% TILs vs 5.5 months ≤30% TILs, p=0.05).ConclusionOur study demonstrates that a favorable clinical response in high-grade serous ovarian carcinoma patients treated with CHK1i is possibly associated with enhanced innate and adaptive immunity, requiring further mechanistic studies. It is supportive of current efforts for a clinical development strategy for therapeutic combinations with immunotherapy in ovarian cancer.

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Apoptosis and proliferation ofperipheral blood T-cells as alternative processes in pathogenesis of diabetes mellitus type 1

Medical alphabet ◽

10.33667/2078-5631-2019-1-4(379)-16-20 ◽

2019 ◽

Vol 1 (4) ◽

pp. 16-20 ◽

Cited By ~ 1

Author(s):

A. V. Lugovaya ◽

N. M. Kalinina ◽

V. Ph. Mitreikin ◽

Yu. P. Kovaltchuk ◽

A. V. Artyomova ◽

...

Keyword(s):

Diabetes Mellitus ◽

T Cells ◽

High Risk ◽

Peripheral Blood ◽

Cellular Response ◽

Proliferative Potential ◽

Autoreactive T Cells ◽

Alternative Processes

Apoptosis, along with proliferation, is a form of lymphocyte response to activating stimuli. In the early stages of cell differentiation, the apoptotic response prevails and it results to the formation of tolerance to inductor antigen. Mature lymphocytes proliferate in response to stimulation and it means the initial stage in the development of the immune response. Since in this case apoptosis and proliferation acts as alternative processes, their ratio can serve as a measure of the effectiveness of the cellular response to activating signals. The resistance of autoreactive T-cells to apoptosis is the main key point in the development of type 1 diabetes mellitus (T1DM). Autoreactive T-cells migrates from the bloodstream to the islet tissue of the pancreas and take an active part in b cells destruction. The resistance of autoreactive effector T-cells to apoptosis may suggest their high proliferative potential. Therefore, the comparative evaluation of apoptosis and proliferation of peripheral blood lymphocytes can give a more complete picture of their functional state and thus will help to reveal the causes of ineffective peripheral blood T-ceiis apoptosis in patients with T1DM and will help to understand more deeply the pathogenesis of the disease. in this article, the features of proliferative response of peripheral blood T-cells in patients with T1DM and in individuals with high risk of developing T1DM have been studied. Apoptosis of T-cell subpopulations has been investigated. The correlation between the apoptotic markers and the intensity of spontaneous and activation- induced in vitro T-cells proliferation of was revealed. it was determined, that autoreactive peripheral blood T-cells were resistant to apoptosis and demonstrated the increased proliferative potential in patients with T1DM and in individuals with high risk of developing T1DM.

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Faculty Opinions recommendation of Adaptive immune response of Vgamma2Vdelta2+ T cells during mycobacterial infections.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005302.62311 ◽

2002 ◽

Author(s):

Leo Lefrancois

Keyword(s):

Immune Response ◽

T Cells ◽

Adaptive Immune Response ◽

Mycobacterial Infections ◽

Adaptive Immune

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Double positive CD4+CD8+ T cells are part of the adaptive immune response against Candida albicans

Human Immunology ◽

10.1016/j.humimm.2019.09.008 ◽

2019 ◽

Vol 80 (12) ◽

pp. 999-1005 ◽

Cited By ~ 3

Author(s):

Barbara Misme-Aucouturier ◽

Adel Touahri ◽

Marjorie Albassier ◽

Francine Jotereau ◽

Patrice Le Pape ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Candida Albicans ◽

Cd8 T Cells ◽

Adaptive Immune Response ◽

Double Positive ◽

Adaptive Immune

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SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself

Nature Communications ◽

10.1038/s41467-021-22210-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marta Ferreira-Gomes ◽

Andrey Kruglov ◽

Pawel Durek ◽

Frederik Heinrich ◽

Caroline Tizian ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Immune Reaction ◽

Adaptive Immune Response ◽

Gene Expression Signature ◽

Spike Protein ◽

Single Cell Level ◽

Cell Level ◽

Adaptive Immune

AbstractThe pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself.

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Increased Density of Human Immunodeficiency Virus Type 1 Coreceptors CCR5 and CXCR4 on the Surfaces of CD4+ T Cells and Monocytes of Patients with Schistosoma mansoni Infection

Infection and Immunity ◽

10.1128/iai.71.11.6668-6671.2003 ◽

2003 ◽

Vol 71 (11) ◽

pp. 6668-6671 ◽

Cited By ~ 58

Author(s):

W. Evan Secor ◽

Amil Shah ◽

Pauline M. N. Mwinzi ◽

Bryson A. Ndenga ◽

Caroline O. Watta ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Cell Surface ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Peripheral Blood ◽

Chemokine Receptors ◽

Blood Samples ◽

Immunodeficiency Virus

ABSTRACT Distribution of chemokine receptors CCR5 and CXCR4, which are also coreceptors for human immunodeficiency virus type 1 invasion of cells, was measured on the surfaces of CD4+ T cells and monocytes in peripheral blood samples from a group of Kenyan car washers. Patients with active schistosomiasis displayed higher cell surface densities of these receptors than did cured schistosomiasis patients.

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