CNS Autoimmune Disease after
            <i>Streptococcus Pyogenes</i>
            Infections: Animal Models, Cellular Mechanisms and Genetic Factors

Cutforth, Tyler; DeMille, Mellissa M C; Agalliu, Ilir; Agalliu, Dritan

doi:10.2217/fnl.16.4

Cited by 50 publications

(48 citation statements)

References 83 publications

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“…Aberrant regulation of T lymphocyte activation during the adaptive immune response to infections or to self-antigens may trigger a strong immune reaction and result in uncontrolled inflammation. This mechanism is evident in several chronic inflammatory autoimmune disorders, including those of the central nervous system (CNS) like multiple sclerosis (MS), Sydenham's chorea, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections, which are characterized by pronounced neurodegeneration due to a chronic T lymphocytedriven inflammation (Cutforth et al, 2016;Dendrou et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson’s Disease

et al. 2018

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD. Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls. After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL-17R) and NFκB activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD.

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Section: Introductionmentioning

confidence: 99%

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson’s Disease

et al. 2018

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“…Data supporting this model come from epidemiological, clinical, paraclinical, translational, and basic science investigations of PANDAS and SC. In both PANS and PANDAS, clinical evaluations (Frankovich et al 2015a;Murphy et al 2015) and research data (Hornig 2013;Hornig and Lipkin 2013;Cutforth et al 2016) suggest that immune dysfunction may occur at multiple levels: local (targeted) dysfunction relating to cross-reactive antibodies that recognize specific CNS antigens; regional dysfunction relating to inflammation within neuronal tissues or vasculature of the basal ganglia; and systemic abnormalities of cytokine and chemokine production, with resultant disruption of the blood-brain barrier (BBB) and CNS functions (Williams and Swedo 2015). Animal models of PANDAS and SC point to an essential role of the adaptive immune response (autoantibodies and Th17 cells) as possible contributors to disease pathogenesis and neurovascular damage (Hoffman et al 2004;Yaddanapudi et al 2010;Brimberg et al 2012;Cox et al 2013;Lotan et al 2014;Cutforth et al 2016;Dileepan et al 2016).…”

Section: Rationale For Using Immunomodulatory Therapy In Pansmentioning

confidence: 99%

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II—Use of Immunomodulatory Therapies

FrankovichJennifer

SwedoSusan

MurphyTanya

et al. 2017

Journal of Child and Adolescent Psychopharmacology

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Introduction: Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%-80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections). Methods: The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared webbased document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with

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“…Since the BBB is the primary protective barrier for neurons in central nervous system (CNS), BBB dysfunctions may contribute to the etiology of several neuropsychiatric disorders (Almutairi et al, 2016 ). In particular, in PANDAS and SC, after crossing the damaged BBB, cross-reactive antibodies may bind specific brain targets at the level of Basal Ganglia (BG), a brain structure involved in motor control (Martino et al, 2009 ; Murphy et al, 2010 ; Cutforth et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

2016

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Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes.

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CNS Autoimmune Disease after Streptococcus Pyogenes Infections: Animal Models, Cellular Mechanisms and Genetic Factors

Cited by 50 publications

References 83 publications

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson’s Disease

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson’s Disease

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II—Use of Immunomodulatory Therapies

Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

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