Wiley: Clinical & Experimental Immunology: Table of Contents

Decoding the proregenerative competence of regulatory T cells through complex tissue regeneration in zebrafish

Samudra Gupta, Satadal Adhikary, Subhra Prakash Hui — Tue, 02 Nov 2021 03:35:20 -0700

In mammals, T_reg _s modulate inflammation and lead to tissue repair through inhibition of neutrophil and inflammatory macrophage, and exerting immunosupressive role by releasing anti-inflammatory cytokines. In addition to immunosuppressive role, zT_reg _s secerete proregenerative factors in injury niche for successful tissue regeneration. zT_reg _s display unique organ-specific proregenerative factor secretion ability to induce tissue resident progenitor cell proliferation during regeneration.

Abstract

Regulatory T cells (T_regs) are specific subtype of T cells that play a central role in sustaining self-antigen tolerance and restricting inflammatory tissue damage. More recently, additional direct functions of T_regs in mammalian tissue repair have emerged, but the regenerative potential of T_regs in non-mammalian vertebrates has not been explored despite the latter possessing a highly developed adaptive immune system. Why complex organs such as the caudal fin, heart, brain, spinal cord and retina regenerate in certain non-mammalian vertebrates, but not in mammals, is an interesting but unresolved question in the field of regenerative biology. Inflammation has traditionally been thought to be an impediment to regeneration due to the formation of scars. Regenerative decline in higher organisms has been speculated to be the evolutionary advent of adaptive immunity. Recent studies, however, have shown that the innate inflammatory response in non-mammalian organisms is required for organ regeneration. It has also been found that highly advanced adaptive immunity is no longer incompatible with regeneration and for that, T_regs are important. Zebrafish regulatory T cells (zT_regs) migrate rapidly to the injury site in damaged organs, where they facilitate the proliferation of regeneration precursor cells by generating tissue-specific regenerative factors by a process distinct from the canonical anti-inflammatory pathway. We review both reparative and proregenerative roles of T_regs in mammals and zebrafish, respectively, and also give an overview of the forkhead box protein 3 (FoxP3) -dependent immunosuppressive function of T_regs in zebrafish, which makes it a useful model organism for future T_reg biology and research.

Cytotoxic T lymphocyte antigen‐4 regulates development of xenogenic graft versus host disease in mice via modulation of host immune responses induced by changes in human T cell engraftment and gene expression

Tue, 02 Nov 2021 03:35:20 -0700

We examined the role of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) in a mouse model of xenogenic GvHD (xeno-GvHD) using CTLA-4 Ig and anti-CTLA-4 antibody. We show that CTLA-4 signaling plays a key role in regulating autoimmune responses in GvHD.

Abstract

Graft versus host disease (GvHD) is a major clinical problem with a significant unmet medical need. We examined the role of cytotoxic T lymphocyte antigen-4 (CTLA-4) in a xenogenic GvHD (xeno-GvHD) model induced by injection of human peripheral mononuclear cells (hPBMC) into irradiated non-obese diabetic (NOD) SCID gamma (NSG) mice. Targeting the CTLA-4 pathway by treatment with CTLA-4 immunoglobulin (Ig) prevented xeno-GvHD, while anti-CTLA-4 antibody treatment exacerbated the lethality and morbidity associated with GvHD. Xeno-GvHD is associated with infiltration of hPBMCs into the lungs, spleen, stomach, liver and colon and an increase in human proinflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-5. Infiltration of donor cells and increases in cytokines were attenuated by treatment with CTLA-4 Ig, but remained either unaffected or enhanced by anti-CTLA-4 antibody. Further, splenic human T cell phenotyping showed that CTLA-4 Ig treatment prevented the engraftment of human CD45⁺ cells, while anti-CTLA-4 antibody enhanced donor T cell expansion, particularly CD4⁺ (CD45RO⁺) subsets, including T box transcription factor TBX21 (Tbet)⁺ CXCR3⁺ and CD25⁺ forkhead box protein 3 (FoxP3) cells. Comprehensive analysis of transcriptional profiling of human cells isolated from mouse spleen identified a set of 417 differentially expressed genes (DEGs) by CTLA-4 Ig treatment and 13 DEGs by anti-CTLA-4 antibody treatment. The CTLA-4 Ig regulated DEGs mapped to down-regulated apoptosis, inflammasome, T helper type 17 (Th17) and regulatory T cell (T_reg) pathways and enhanced Toll-like receptor (TLR) receptor signaling, TNF family signaling, complement system and epigenetic and transcriptional regulation, whereas anti-CTLA-4 antibody produced minimal to no impact on these gene pathways. Our results show an important role of co-inhibitory CTLA-4 signaling in xeno-GvHD and suggest the therapeutic utility of other immune checkpoint co-inhibitory pathways in the treatment of immune-mediated diseases driven by hyperactive T cells.

Altered peripheral B lymphocyte homeostasis and functions mediated by IL‐27 via activating the mammalian target of rapamycin signaling pathway in patients with rheumatoid arthritis

Tue, 02 Nov 2021 03:35:20 -0700

RA B cells showed altered peripheral B cell homeostasis and functions via activating mTOR signaling pathway. Increased levels of IL-27 in RA serum promoted immune dysfunctions of B cells through the activation of mTOR signaling pathway. IL-27 may play a vital role in the pathogenesis of RA, and will be a candidate cytokine for targeted therapy in future.

Abstract

B cell dysfunction and inflammatory cytokine over-production participate in the pathogenesis of rheumatoid arthritis (RA). Here we compared peripheral B cell homeostasis and immune functions between RA patients and healthy controls (HC) and explored vital signaling pathways involved in altered RA B cells. We found that RA patients showed significantly decreased frequencies of peripheral CD19⁺CD27⁺CD24^high regulatory B (Breg) cells but increased frequencies of CD19⁺CD27⁺CD38^high plasmablasts and CD19⁺CD138⁺ plasma cells, and higher levels of serum immunoglobulin (Ig)M and IgG. Compared to HC peripheral B cells, RA peripheral B cells had more increased proliferation and higher expression of activation markers. Importantly, our results showed that RA peripheral B cells displayed the mTOR signaling pathway to be more activated, and inhibition of mTOR could restore RA B cell homeostasis and functions. RA serum-treated B cells exhibited more increased expressions of mTOR, which could be restored with the addition of anti-interleukin (IL)-27 neutralizing antibody. Serum IL-27 levels were significantly increased in RA patients and positively correlated with disease activity, the frequencies of plasma cells and the levels of autoantibodies. In vitro, IL-27 notably promoted immune dysfunction of RA B cells, which were inhibited by anti-IL-27 neutralizing antibody. Also, the mTOR pathway was more activated in IL-27-treated RA B cells, and mTOR inhibition apparently reversed abnormalities of RA B cells mediated by IL-27. These results suggest that increased serum IL-27 levels could promote peripheral B cell dysfunction in RA patients via activating the mTOR signaling pathway. Thus, IL-27 may play a pro-pathogenic role in the development of RA, and antagonizing IL-27 could be a novel therapy strategy for RA.

Inflammatory cytokine responses in children with asymptomatic malaria infection living in rural, semi‐urban and urban areas in south‐eastern Gabon

Tue, 02 Nov 2021 03:35:20 -0700

This report investigated ten cytokines circulating levels in asymptomatic Gabonese children living in urban, semi-urban and rural areas and found significantly higher IL-10 and IL-6 levels without modifying the balance between pro- and anti-inflammatory cytokines in asymptomatic-infected compare to uninfected children. Results suggest that IL-10 may be a better indicator of asymptomatic infection as signicantly higher levels were associated with the asymptomatic form in all areas. Also the asymptomatic infected-children of rural area could be subject to a higher susceptibility to infection than the asymptomatic children of the two others areas.

Abstract

Cytokines are soluble mediators of the immune response, and their evolution influences the disease outcome. Gaining knowledge on cytokines has become important, as they can constitute biomarkers allowing the diagnosis of malaria and preventing severe forms of the disease. Here, we investigated 10 cytokines and their circulating levels in asymptomatic Gabonese children with Plasmodium falciparum infection living in urban, semi-urban and rural areas. Blood samples were collected from 273 schoolchildren (153 uninfected and 120 infected) aged 6 to 192 months. Hematological parameters were determined and P. falciparum diagnosis was performed using a rapid diagnosis test, microscopy and nested polymerase chain reaction (PCR). Plasma pro- [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12p70, IL-17A and IL-22] and anti-inflammatory [IL-10, IL-4, IL-13 and transforming growth factor (TGF)-β] cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA) and compared between asymptomatic-infected and uninfected children. Results revealed that without distinction of area, IL-10 and IL-6 levels were higher in infected compared to uninfected children; however, the pro- and anti-inflammatory ratios (IL-6/IL-10 and TNF-α/IL-10) were similar. Furthermore, with area distinction significantly elevated levels of IL-10 in these asymptomatic children were always accompanied by either significantly low or high levels of a proinflammatory cytokine. Also, comparison between asymptomatic-infected children from the three areas showed significantly lower IL-17A, IL-22 and TGF-β levels in urban area compared to semi-urban and rural areas. These results suggest that asymptomatic malaria infections induce significantly high inflammatory cytokine levels without modifying the balanced between pro- and anti-inflammatory cytokines and underline the higher exposure to infections of children in rural areas.

Neutrophil‐mediated mechanisms of damage and in‐vitro protective effect of colchicine in non‐vascular Behçet’s syndrome

Tue, 02 Nov 2021 03:35:20 -0700

Neutrophil-mediated mechanisms of damage might be directly involved in non-vascular Behçet's syndrome. Neutrophil extracellular traps (NETs), more than an impaired redox status, might play a central role in the pathogenesis of mucosal, articular and intestinal BS manifestations. Colchicine might be effective to counteract neutrophils-mediated damage in Behçet's syndrome, via the inhibition of NETs release.

Abstract

Behçet’s syndrome (BS) is a systemic vasculitis with several clinical manifestations. Neutrophil hyperactivation mediates vascular BS pathogenesis, via both a massive reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) release. Here, we investigated neutrophil-mediated mechanisms of damage in non-vascular BS manifestations and explored the in-vitro effects of colchicine in counteracting these mechanisms. NETs and intracellular ROS production was assessed in blood samples from 80 BS patients (46 with active non-vascular BS, 34 with inactive disease) and 80 healthy controls. Moreover, isolated neutrophils were incubated for 1 h with an oxidating agent [2,2′-azobis (2-amidinopropane) dihydrochloride; 250 nM] and the ability of pure colchicine pretreatment (100 ng/ml) to counteract oxidation-induced damage was assessed. Patients with active non-vascular BS showed remarkably increased NET levels [21.2, interquartile range (IQR) = 18.3–25.9 mU/ml] compared to patients with inactive disease (16.8, IQR = 13.3–20.2 mU/ml) and to controls (7.1, IQR = 5.1–8.7 mU/ml, p < 0.001]. Also, intracellular ROS tended to increase in active BS, although not significantly. In active non-vascular BS, NETs correlated with neutrophil ROS production (p < 0.001) and were particularly increased in patients with active mucosal (p < 0.001), articular (p = 0.004) and gastrointestinal symptoms (p = 0.006). In isolated neutrophils, colchicine significantly reduced oxidation-induced NET production and cell apoptosis, although not via an anti-oxidant activity. Neutrophil-mediated mechanisms might be directly involved in non-vascular BS, and NETs, more than ROS, might drive the pathogenesis of mucosal, articular and intestinal manifestations. Colchicine might be effective in counteracting neutrophils-mediated damage in BS, although further studies are needed.

Progressive B cell depletion in human MALT1 deficiency

Tue, 02 Nov 2021 03:35:20 -0700

The pathogenic model for lymphocyte-specific functions of MALT1-deficiency including the CARD11/BCL-10/MALT1 (CBM) complex signal pathway.The patients with complete MALT1-deficiency show aberrant differentiation and depletion of B cells after ligation of BCR and CpG induced-TLR9 stimulation. The hematopoietic cell transplantation successfully reconstituted the differentiation of mature B cells and T cell-dependent phenotypes.

Abstract

Mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1)-deficiency is a rare combined immunodeficiency characterized by recurrent infections, dermatitis and enteropathy. We herein investigate the immunological profiles of our patient and previously reported children with MALT1-deficiency. A mutation analysis was performed by targeted panel sequencing for primary immunodeficiency. Lymphocyte subset, activation and B cell differentiation were analyzed by flow cytometry and t-distributed stochastic neighbor embedding. Pneumocystis pneumonia developed in a 6-month-old Japanese infant with atopic dermatitis, enteritis and growth restriction. This infant showed agammaglobulinemia without lymphopenia. At 8 years of age, the genetic diagnosis of MALT1-deficiency was confirmed on a novel homozygous mutation of c.1102G>T, p.E368X. T cell stimulation tests showed impairments in the production of interleukin-2, phosphorylation of nuclear factor kappa B (NF-κB) p65 and differentiation of B cells. In combination with the literature data, we found that the number of circulatory B cells, but not T cells, were inversely correlated with the age of patients. The hematopoietic cell transplantation (HCT) successfully reconstituted the differentiation of mature B cells and T cells. These data conceptualize that patients with complete MALT1-deficiency show aberrant differentiation and depletion of B cells. The early diagnosis and HCT lead to a cure of the disease phenotype associated with the loss-of-function mutations in human CARD11.

Intravenous immunoglobulin and the current risk of moderate and severe anaphylactic events, a cohort study

Carlos Martinez, Christopher Wallenhorst, Sheryl van Nunen — Tue, 02 Nov 2021 03:35:20 -0700

This observational cohort study of 24,919 patients with a total of 175,535 administrations of intravenous immunoglobulin (IvIg) in a hospital setting shows a substantial reduction in the risk of moderate and severe anaphylaxis over a decade and establishes that anaphylaxis is rare overall. The risk of anaphylaxis has progressively reduced from 14.9/10,000 in 2009-2010 to 4.4/10,000 IvIg administrations in 2017-2018. Strong independent predictors of anaphylaxis were age under 18 and first dose of IvIg, and neither the IvIg dose nor the indication for its use was associated with the risk of anaphylaxis.

Abstract

This large cohort study from the US Premier Healthcare Database evaluated the risk and predictors of anaphylaxis in association with intravenous immunoglobulin (IvIg) therapy in the inpatient and outpatient setting. Data were collected retrospectively (January 2009–December 2018) from 24 919 patients administered IgPro10 IvIg, median age 54 years. Immunoglobulins of interest were IgPro10 and other IvIg given before or after IgPro10. Moderate and severe anaphylaxis was identified from same-day parenteral epinephrine and IvIg use and reviews of patient record summaries. Predictors for first anaphylactic reactions associated with IvIg administration were derived from adjusted incidence rate ratios (IRR) using Poisson regression. Moderate anaphylaxis in IvIg use was rare and severe anaphylaxis very rare based on a total of 124 moderate and four non-fatal severe first anaphylactic events, incidence rate of 7.11 and 0.23/10 000 IvIg administrations, respectively. Age under 18 years was an independent predictor of moderate or severe anaphylactic events [adjusted incidence rate ratio = 2.94, 0.95 confidence interval = 1.91–4.52] compared with those aged 18 years and older. First IvIg administration was a strong predictor of anaphylaxis. The IRR in those with a subsequent IvIg administration in the preceding 42 days decreased to 0.27 (0.17–0.42) and in those effectively IvIg-naive (no IvIg for > 42 days) to 0.76 (0.44–1.32) compared with first IvIg use. The key conclusions from this study are that the risk of anaphylaxis has progressively reduced over the last decade, from 14.87 of 10 000 in 2009–10 to 4.39 of 10 000 IvIg administrations in 2017–18 and is rare overall, and that the risk of anaphylaxis is increased in those aged under 18 years.

Down‐regulation of PR/SET domain 10 underlies natural killer cell dysfunction in hepatocellular carcinoma

Jiantao Han, Chao Ke, Bin Jiang, Hongjian Zhou, Hanbin Xu, Xingwang Xie — Tue, 02 Nov 2021 03:35:20 -0700

PRDM10 positively regulates NK cell-mediated anti-tumor reaction. PRDM10 down-regulation causes NK cell dysfunction in hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is the world’s leading cause of tumor-related mortalities. Natural killer (NK) cells play a critical role at the first immunological defense line against HCC initiation and progression. NK cell dysfunction is therefore an important mechanism for immune evasion of HCC cells. In the present study using a murine HCC model, we revealed the down-regulation of PR/SET Domain 10 (PRDM10) in hepatic NK cells that were phenotypically and functionally exhausted. PRDM10 silencing diminished the expression of natural killer group 2 member D (NKG2D) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), augmented T cell immunoglobulin and ITIM domain (TIGIT) expression, and decreased the expression of interferon (IFN)-γ, perforin and granzyme B in normal hepatic NK cells in vitro. Consistently, PRDM10-deficient NK cells exhibited impaired cytotoxicity on target cells. In contrast, PRDM10 over-expression promoted NKG2D and Fas ligand (FasL) expression, reduced CD96 expression and enhanced transcripts of IFN-γ, perforin and granzyme B in NK cells in vivo. Moreover, PRDM10 silencing and PRDM10 over-expression down-regulated and up-regulated Eomesodermin (Eomes) expression, respectively. In summary, this study reveals PRDM10 down-regulation as a novel mechanism underlying NK cell dysfunction and identifies PRDM10 as a supporting factor of NK cell function.

Acquired angioedema in B cell lymphoproliferative disease: A retrospective case series

Alex Wonnaparhown, Alexandra Stefanovic, Patricia Lugar, Haley P. Hostetler — Tue, 02 Nov 2021 03:35:20 -0700

Abstract

Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is rare and is associated with underlying lymphoproliferative diseases. C1-INH deficiency may be due to neoplastic over-consumption of C1-INH and the generation of anti-C1-INH autoantibodies. Uncovering an occult malignancy can lead to earlier oncology referral and improvement of angioedema after treatment of the underlying lymphoproliferative disorder. We characterized seven patients with C1-INH-AAE that highlights the importance of recognizing the association between C1-INH-AAE and underlying malignancy. In acute attacks, patients may be resistant to C1-INH therapy due to the presence of anti-C1-INH autoantibodies or rapid complement consumption, and may respond better to icatibant or ecallantide, which directly affect bradykinin. Treatment of the underlying malignancy also improves AAE-C1-INH symptoms and supports the role of lymphoproliferative B cells in AAE-C1-INH pathophysiology. Monitoring levels of C4, C1-INH function and level, and C1q may be predictive of AAE-C1-INH control and be used as surrogates for treatment efficacy. With close monitoring, low-dose danazol can be effective for long-term prophylaxis. Annual evaluation in AAE-C1-INH is recommended if an underlying malignancy is not found, as angioedema may precede the development of malignancy by several years. Our single-center study has aided in standardization of comprehensive AAE-C1-INH diagnosis, treatment, and monitoring strategies towards future therapeutic clinical trials.

Imaging immune responses in neuroinflammatory diseases

Sandra Amor, Erik Nutma, David Owen — Tue, 02 Nov 2021 03:35:20 -0700

Abstract

Innate and adaptive immune responses in the central nervous system (CNS) play critical roles in the pathogenesis of neurological diseases. In the first of a two-part special issue, leading researchers discuss how imaging modalities are used to monitor immune responses in several neurodegenerative diseases and glioblastoma and brain metastases. While comparative studies in humans between imaging and pathology are biased towards the end stage of disease, animal models can inform regarding how immune responses change with disease progression and as a result of treatment regimens. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are frequently used to image disease progression, and the articles indicate how one or more of these modalities have been applied to specific neuroimmune diseases. In addition, advanced microscopical imaging using two-dimensional photon microscopy and in vitro live cell imaging have also been applied to animal models. In this special issue (Parts 1 and 2), as well as the imaging modalities mentioned, several articles discuss biomarkers of disease and microscopical studies that have enabled characterization of immune responses.

Future developments of imaging modalities should enable tracking of specific subsets of immune cells during disease allowing longitudinal monitoring of immune responses. These new approaches will be critical to more effectively monitor and thus target specific cell subsets for therapeutic interventions which may be applicable to a range of neurological diseases.

Issue Information

Tue, 02 Nov 2021 03:35:20 -0700

Clinical &Experimental Immunology, Volume 206, Issue 3, December 2021.

Towards PET imaging of the dynamic phenotypes of microglia

Tue, 02 Nov 2021 03:35:20 -0700

The development of therapeutics targeting the deleterious glial activity and modulating it into a regenerative phenotype heavily relies on a better understanding of the microglia dynamics during disease progression and the ability to monitor therapeutic outcome in vivo. In this review, we will highlight the current knowledge on the microglia phenotypes in the major neuroinflammatory and neurodegenerative diseases. We will also discuss the current and emerging PET imaging targets, the tracers, and their potential in discriminating between the pro- and anti-inflammatory microglia activation states.

Abstract

There is increasing evidence showing the heterogeneity of microglia activation in neuroinflammatory and neurodegenerative diseases. It has been hypothesized that pro-inflammatory microglia are detrimental and contribute to disease progression, while anti-inflammatory microglia play a role in damage repair and remission. The development of therapeutics targeting the deleterious glial activity and modulating it into a regenerative phenotype relies heavily upon a clearer understanding of the microglia dynamics during disease progression and the ability to monitor therapeutic outcome in vivo. To that end, molecular imaging techniques are required to assess microglia dynamics and study their role in disease progression as well as to evaluate the outcome of therapeutic interventions. Positron emission tomography (PET) is such a molecular imaging technique, and provides unique capabilities for non-invasive quantification of neuroinflammation and has the potential to discriminate between microglia phenotypes and define their role in the disease process. However, several obstacles limit the possibility for selective in vivo imaging of microglia phenotypes mainly related to the poor characterization of specific targets that distinguish the two ends of the microglia activation spectrum and lack of suitable tracers. PET tracers targeting translocator protein 18 kDa (TSPO) have been extensively explored, but despite the success in evaluating neuroinflammation they failed to discriminate between microglia activation statuses. In this review, we highlight the current knowledge on the microglia phenotypes in the major neuroinflammatory and neurodegenerative diseases. We also discuss the current and emerging PET imaging targets, the tracers and their potential in discriminating between the pro- and anti-inflammatory microglia activation states.

‘A picture is worth a thousand words’: The use of microscopy for imaging neuroinflammation

Tue, 02 Nov 2021 03:35:20 -0700

Microscopy allows the assessment of cell targets in a spatiotemporal manner. Therefore, it can integrate a large amount of data from omic methods and provide information considering the morphology and location of cells. Important advances in the field of neuroinflammation have been possible due to advances in microscopy techniques.

Abstract

Since the first studies of the nervous system by the Nobel laureates Camillo Golgi and Santiago Ramon y Cajal using simple dyes and conventional light microscopes, microscopy has come a long way to the most recent techniques that make it possible to perform images in live cells and animals in health and disease. Many pathological conditions of the central nervous system have already been linked to inflammatory responses. In this scenario, several available markers and techniques can help imaging and unveil the neuroinflammatory process. Moreover, microscopy imaging techniques have become even more necessary to validate the large quantity of data generated in the era of ‘omics’. This review aims to highlight how to assess neuroinflammation by using microscopy as a tool to provide specific details about the cell’s architecture during neuroinflammatory conditions. First, we describe specific markers that have been used in light microscopy studies and that are widely applied to unravel and describe neuroinflammatory mechanisms in distinct conditions. Then, we discuss some important methodologies that facilitate the imaging of these markers, such as immunohistochemistry and immunofluorescence techniques. Emphasis will be given to studies using two-photon microscopy, an approach that revolutionized the real-time assessment of neuroinflammatory processes. Finally, some studies integrating omics with microscopy will be presented. The fusion of these techniques is developing, but the high amount of data generated from these applications will certainly improve comprehension of the molecular mechanisms involved in neuroinflammation.

Magnetic resonance imaging in neuromyelitis optica spectrum disorder

Tue, 02 Nov 2021 03:35:20 -0700

This review summarises the clinical and radiological aspects of AQP4 antibody positive NMOSD focusing on the implication for pathophysiology. Common MR imaging features of NMOSD are reviewed in detail and illustrated. The potential future role of advanced MR imaging techniques in diagnosing and characterising NMOSD are discussed.

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) associated with antibodies to aquaporin-4 (AQP4), which has distinct clinical, radiological and pathological features, but also has some overlap with multiple sclerosis and myelin oligodendrocyte glycoprotein (MOG) antibody associated disease. Early recognition of NMOSD is important because of differing responses to both acute and preventive therapy. Magnetic resonance (MR) imaging has proved essential in this process. Key MR imaging clues to the diagnosis of NMOSD are longitudinally extensive lesions of the optic nerve (more than half the length) and spinal cord (three or more vertebral segments), bilateral optic nerve lesions and lesions of the optic chiasm, area postrema, floor of the IV ventricle, periaqueductal grey matter, hypothalamus and walls of the III ventricle. Other NMOSD-specific lesions are denoted by their unique morphology: heterogeneous lesions of the corpus callosum, ‘cloud-like’ gadolinium (Gd)-enhancing white matter lesions and ‘bright spotty’ lesions of the spinal cord. Other lesions described in NMOSD, including linear periventricular peri-ependymal lesions and patch subcortical white matter lesions, may be less specific. The use of advanced MR imaging techniques is yielding further useful information regarding focal degeneration of the thalamus and optic radiation in NMOSD and suggests that paramagnetic rim patterns and changes in normal appearing white matter are specific to MS. MR imaging is crucial in the early recognition of NMOSD and in directing testing for AQP4 antibodies and guiding immediate acute treatment decisions. Increasingly, MR imaging is playing a role in diagnosing seronegative cases of NMOSD.

Clinical and neuroimaging findings in MOGAD–MRI and OCT

Tue, 02 Nov 2021 03:35:20 -0700

Myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin-4 autoantibody associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord, optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and neuroimaging characteristics of paediatric and adult MOGAD.

Abstract

Myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin-4 autoantibody-associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In-vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord and optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and neuroimaging characteristics of paediatric and adult MOGAD. We describe how these imaging techniques may be used to study this group of disorders and discuss how image analysis methods have led to recent insights for consideration in future studies.

Neuroinflammation and immunoregulation in glioblastoma and brain metastases: Recent developments in imaging approaches

Rafael Roesler, Simone Afonso Dini, Gustavo R. Isolan — Tue, 02 Nov 2021 03:35:20 -0700

Brain tumors induce immune and inflammatory changes in the brain tissue that influence invasion and metastasis. Neuroinflammatory and necrotic lesions also occur in patients with brain cancer, as a result of radiotherapy. We review advances in imaging techniques help to differentiate primary brain tumors and metastases from neuroinflammation.

Abstract

Brain tumors and brain metastases induce changes in brain tissue remodeling that lead to immunosuppression and trigger an inflammatory response within the tumor microenvironment. These immune and inflammatory changes can influence invasion and metastasis. Other neuroinflammatory and necrotic lesions may occur in patients with brain cancer or brain metastases as sequelae from treatment with radiotherapy. Glioblastoma (GBM) is the most aggressive primary malignant brain cancer in adults. Imaging methods such as positron emission tomography (PET) and different magnetic resonance imaging (MRI) techniques are highly valuable for the diagnosis and therapeutic evaluation of GBM and other malignant brain tumors. However, differentiating between tumor tissue and inflamed brain tissue with imaging protocols remains a challenge. Here, we review recent advances in imaging methods that have helped to improve the specificity of primary tumor diagnosis versus evaluation of inflamed and necrotic brain lesions. We also comment on advances in differentiating metastasis from neuroinflammation processes. Recent advances include the radiosynthesis of ¹⁸F-FIMP, an L-type amino acid transporter 1 (LAT1)-specific PET probe that allows clearer differentiation between tumor tissue and inflammation compared to previous probes, and the combination of different advanced imaging protocols with the inclusion of radiomics and machine learning algorithms.

Imaging immunological processes from blood to brain in amyotrophic lateral sclerosis

Sandra Amor, Erik Nutma, Manuel Marzin, Fabiola Puentes — Tue, 02 Nov 2021 03:35:20 -0700

Here, we discuss the different imaging modalities e.g., MRI, MRS, PET as well as other approaches including biomarkers of inflammation in ALS that aid the understanding of the underlying immune mechanisms associated with motor neurone degeneration in the disease.

Abstract

Neuropathology studies of amyotrophic lateral sclerosis (ALS) and animal models of ALS reveal a strong association between aberrant protein accumulation and motor neurone damage, as well as activated microglia and astrocytes. While the role of neuroinflammation in the pathology of ALS is unclear, imaging studies of the central nervous system (CNS) support the idea that innate immune activation occurs early in disease in both humans and rodent models of ALS. In addition, emerging studies also reveal changes in monocytes, macrophages and lymphocytes in peripheral blood as well as at the neuromuscular junction. To more clearly understand the association of neuroinflammation (innate and adaptive) with disease progression, the use of biomarkers and imaging modalities allow monitoring of immune parameters in the disease process. Such approaches are important for patient stratification, selection and inclusion in clinical trials, as well as to provide readouts of response to therapy. Here, we discuss the different imaging modalities, e.g. magnetic resonance imaging, magnetic resonance spectroscopy and positron emission tomography as well as other approaches, including biomarkers of inflammation in ALS, that aid the understanding of the underlying immune mechanisms associated with motor neurone degeneration in ALS.

Immune responses against islet allografts during tapering of immunosuppression – A pilot study in 5 subjects

Wed, 25 Apr 2012 00:00:00 -0700

Abstract

Transplantation of isolated islet of Langerhans cells has great potential as a cure for type 1 diabetes but continuous immune suppressive therapy often causes considerable side effects. Tapering of immunosuppression in successfully transplanted patients would lower patients’ health risk.

To identify immune biomarkers that may prove informative in monitoring tapering, we studied the effect of tapering on islet auto- and alloimmune reactivity in a pilot study in five transplant recipients in vitro. Cytokine responses to the graft were measured using Luminex technology. Avidity of alloreactive cytotoxic T Lymphocytes (CTL) was determined by CD8 blockade. The influence of immunosuppression was mimicked by in vitro replenishment of tacrolimus and MPA, the active metabolite of mycophenolate mofetil.

Tapering of tacrolimus was generally followed by decreased C-peptide production. T-cell autoreactivity increased in four out of five patients during tapering. Overall alloreactive CTL precursor frequencies did not change, but their avidity to donor mismatches increased significantly after tapering (p=0.035). In vitro addition of tacrolimus but not MPA strongly inhibited CTL alloreactivity during tapering and led to a significant shift to anti-inflammatory graft-specific cytokine production.

Tapering of immunosuppression is characterized by diverse immune profiles that appear to relate inversely to plasma C-peptide levels. Highly avid allospecific CTLs that are known to associate with rejection increased during tapering, but could be countered by restoring immune suppression in vitro. Immune monitoring studies may help guiding tapering of immunosuppression after islet cell transplantation, even though we do not have formal prove yet that the observed changes reflect direct effects of immune suppression on immunity.