Papers by Dusanka Skundric
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous s... more Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS) of unknown etiology. MS is a leading cause of disability among young adults in the western hemisphere. Auto-reactive myelin and neuronal antigen-directed CD4 + T cells mainly contribute to initiation and/or perpetuation of neuronal damage in MS. We present the current understanding of the molecular and cellular pathways by which autoagressive T cells mediate tissue damage in experimental allergic encephalomyelitis (EAE) and MS, specifically interleukin-16 (IL-16)-related pathways. IL-16 is a CD4 + T cell-specific chemotactic factor. IL-16 regulates major biological properties of CD4 + T cells including cell activation, CD25 expression, MHC class II expression and cross receptor desensitization of chemokine-induced chemoattraction. Various approaches in halting CNS homing, or modulating immune properties of autoimmune T cells have been taken to treat MS and EAE, an animal mode...
Multiple sclerosis (MS) is an immunepathologically-mediated, putative autoimmune disease. It rank... more Multiple sclerosis (MS) is an immunepathologically-mediated, putative autoimmune disease. It ranks among the leading causes of disability in North America. Autoimmune mechanisms of central nervous system (CNS) damage are primarily mediated by auto-reactive CD4 + T cells, which are specific for encephalitogenic epitopes of myelin peptides. Migration of autoimmune T cells from the periphery into CNS parenchyma leads to inflammation, demyelination and damage of axons, oligodendrocytes and neurons . This autoimmune T cell mediated tissue damage results in impairment of motor function leading to paralysis. Disease is progressive and often takes a relapsing-remitting course. Progression and severity of the disease as well as types of CNS lesions are highly heterogeneous among patients with MS [2]. In an effort to replicate heterogeneity of clinical course and CNS lesions observed in MS patients, different types of experimental models have been developed.
Journal of neuroinflammation, Jan 22, 2015
In an important article published in Nature Medicine, Liu and colleagues described a novel CD4(+)... more In an important article published in Nature Medicine, Liu and colleagues described a novel CD4(+) FoxA1(+) regulatory T (Treg) cell population as distinct regulators of relapsing-remitting multiple sclerosis (RRMS) and experimental autoimmune encephalomyelitis (EAE). CD4(+) FoxA1(+) Treg cells appear as key regulators of responsiveness to therapy with interferon beta (IFN-β) in RRMS patients. Data indicate that CD4(+)FoxA1(+) FOXP3(-) Treg cells develop within the central nervous system (CNS), and a potential of cerebellar granule neurons (CGN) in generation of CD4(+)FoxA1(+)PD-L1(hi)FOXP3(-) Treg cells from encephalitogenic CD4(+) T cells.A CD4 co-receptor specific ligand, IL-16, governs trafficking and biological properties of CD4(+) T cells irrespective of their activation state. Functions of IL-16, relevant to Treg cells, include expansion of CD4(+)CD25(+) T cells in long-term cultures with IL-2, de novo induction of FOXP-3 and migration of FOXP-3(+) T cells. IL-16 is highly con...
Cytokine, Jan 18, 2015
Cytokines are pleiotropic soluble mediators of cellular functions. Cytokines are critical in immu... more Cytokines are pleiotropic soluble mediators of cellular functions. Cytokines are critical in immune pathogenesis of human diseases, including autoimmune CD4(+) T cell mediated chronic inflammatory, demyelinating and neurodegenerative diseases of the central nervous system (CNS), multiple sclerosis (MS). In MS and its experimental model, experimental autoimmune encephalomyelitis (EAE), chronic persistence and/or reoccurrence of inflammation in the CNS causes chronic progressive or relapsing disease, accompanied with demyelination and damage to axons and oligodendrocytes, which ultimately leads to paralysis and disability. As opposed to other cytokines, whose effects are not limited to the CD4(+) T cell subset, IL-16 exerts its biological properties by exclusive binding and signaling through CD4 receptor. IL-16 selectively regulates migration of all CD4 expressing T cells regardless of their activation state, which is of critical importance for immune modulation and potential therapy ...
The Journal of Immunology
Molecular neurodegeneration, 2008
Experimental autoimmune encephalomyelitis (EAE) is commonly used to investigate mechanisms of aut... more Experimental autoimmune encephalomyelitis (EAE) is commonly used to investigate mechanisms of autoimmune-mediated damage to oligodendrocytes, myelin, and axons in multiple sclerosis (MS). Four distinct autoimmune mechanisms with subsequently distinct patterns of demyelination have been recognized in acute MS lesions. EAE correlates for those distinct patterns of MS lesions are unknown. An excessive loss of myelin-associated glycoprotein (MAG), as a result of distal oligodendrogliopathy, is found exclusively in the subtype III lesion. We sought to answer if types of demyelination in acute lesions during onset and relapse of EAE can replicate the specific patterns observed in MS acute lesions. In parental H-2b (C57BL/6, B6) and hybrid H-2b/s [(B6 x SJL) F1] EAE mice, we examined spinal cord levels of MOG, MAG, and myelin basic protein (MBP), and compared to levels of axonal neurofilament (NF160) to assess axonal function, and levels of PARPp85 as an indicator of irreversible apoptosis...
Experimental Diabesity Research, 2003
Diabetic neuropathy develops as a result of hyperglycemia-induced local metabolic and microvascul... more Diabetic neuropathy develops as a result of hyperglycemia-induced local metabolic and microvascular changes in both type I and type II diabetes mellitus. Diabetic neuropathy shows slower impulse conduction, axonal degeneration, and impaired regeneration. Diabetic neuropathy affects peripheral, central, and visceral sensorimotor and motor nerves, causing improper locomotor and visceral organ dysfunctions. The pathogenesis of diabetic neuropathy is complex and involves multiple pathways. Lack of success in preventing neuropathy, even with successful treatment of hyperglycemia, suggests the presence of early mediators between hyperglycemia-induced metabolic and enzymatic changes and functional and structural properties of Schwann cells (SCs) and axons. It is feasible that once activated, such mediators can act independently of the initial metabolic stimulus to modulate SC-axonal communication. Neuropoietic cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), tumor necrosis factor alpha (TNF-α), and transforming growth factor beta (TGFβ), exhibit pleiotrophic effects on homeostasis of glia and neurons in central, peripheral, and autonomic nervous system. These cytokines are produced locally by resident and infiltrating macrophages, lymphocytes, mast cells, SCs, fibroblasts, and sensory neurons. Metabolic changes induced by hyperglycemia lead to dysregulation of cytokine control. Moreover, their regulatory roles in nerve degeneration and regeneration may potentially be utilized for the prevention and/or therapy of diabetic neuropathy.
Journal of Neuroinflammation, 2006
BACKGROUND: Multiple sclerosis (MS) is a central nervous system-specific autoimmune, demyelinatin... more BACKGROUND: Multiple sclerosis (MS) is a central nervous system-specific autoimmune, demyelinating and neurodegenerative disease. Infiltration of lesions by autoaggressive, myelin-specific CD4+Th1 cells correlates with clinical manifestations of disease. The cytokine IL-16 is a CD4+ T cell-specific chemoattractant that is biased towards CD4+ Th1 cells. IL-16 precursor is constitutively expressed in lymphocytes and during CD4+ T cell activation; active caspase-3 cleaves
Journal of Neuroimmunology, 1993
MHC induction in microglia cell location in perinuclear CNS areas. The general ability of electri... more MHC induction in microglia cell location in perinuclear CNS areas. The general ability of electrically active neurons to affect the antigen-presenting potential of glia cells has been recently demonstrated in a tissue culture system allowing co-culture of rat CNS neurons and syngeneic glia cells with or without direct cell-to-cell contact. Viable, but not fixed, neurons suppress constitutive expression of class 1 and inducibility of class I and class II determinants on astrocytes. This regulation requires intercellular contact between neurons and glia.
Journal of Neuroimmunology, 2001
We reported Schwann cell (SC)-specific autoregulation of IL-1 in vitro [J. Neuroimmunol. 74 (1997... more We reported Schwann cell (SC)-specific autoregulation of IL-1 in vitro [J. Neuroimmunol. 74 (1997a)]. Whether SC resume this autoregulatory potential in vivo and what significance it may have for processes leading to inflammation and demyelination of the peripheral nerve remain obscure. Therefore, we examine SC-specific autoregulation of IL-1alpha, IL-1beta and their natural antagonist IL-1 receptor antagonist (IL-1Ra) during experimental autoimmune neuritis (EAN), a model for the human Guillain-Barre syndrome. Autoregulation of IL-1 by SC was analyzed in both, actively induced and adoptively transferred, EAN. Sciatic nerves were sampled before the onset of clinical signs, 2 to 11 days post immunization (dpi), with P2 peptide, and during clinically manifest disease, 11 to 15 dpi. In adoptively transferred EAN, sciatic nerves were analyzed at preclinical stage, 2 to 4 days post P2 peptide-specific cell transfer (dpt) and during clinical manifested phase, 5 to 10 dpt. In both models, IL-1alpha and IL-1beta were expressed by SC, during preclinical EAN. IL-1Ra was not detectable in SC at preclinical stage. Further development and progression to clinically manifest disease was accompanied by SC-specific expression of IL-1Ra. Although present in other cells in the nerve, IL-1alpha and IL-1beta were hardly detectable in SC during clinical EAN. IL-1Ra immunoreactivity highly co-localized with myelin associated glycoprotein (MAG), one of the markers for paranodal regions, sites essential for proper impulse transmission. Paranodes are also primary sites where activated macrophages make contact with SC, prior to infiltration.SC-specific autoregulation of IL-1 and IL-1Ra is suggestive of its relevance for immune regulation at paranodes during EAN.
Journal of Neuroimmunology, 1998
Similarly to the human ~isease Duchenne muscular dystrophy(DMD),mdx mice lack dystrophin and deve... more Similarly to the human ~isease Duchenne muscular dystrophy(DMD),mdx mice lack dystrophin and develop an X-linked recessive inflammatory myopathy. During onset of disease and height of myoneerosls, a period characterized by conspicuous inflammatory reaction nearby altered myofibres expression intense MHC class II molecules, it was noticeable marked changes in the microenvironment of lymphoid tissues. Thymus, spleen and draining lymph nodes (poptitesL axillar, brachial) showed reduced cellularity and characteristic atrophy accompanied by increased deposition Of extracellu[ar matrix components (ECM) fibronectin, laminin and type IV collagen. During the height of myonecresia, Mac-1 positive cells producing large amounts of TNF alpha and VLA-6 positive cells represented the predominant mononuclear population in the lesioned muscle Furthermore, intense ECM and VLA-6 immunolabelling was also observed in interfollicular areas and high endothelial venules of draining lymph nodes. Fellowtng clinical amelioration of dystrophy, mdx mice showed increased cellularity but only mild changes in the cytoarehitecture of lymphoid tissue. The results indicate that during distinct pheses of mdx muscular dystrophy, altered expression of ECM components and locally produced cytokines alter the integrity of lymphoid microenvironment, influence adhesion and mrgration of mononuclear cells into the lesioned tissue and towards local draining lymphoid tissue for subsequent activation of the immune system. Financial support: CNPq, PADCT, PRONEX, FINEP.
Journal of Neuroimmunology, 1993
Chronic relapsing experimental allergic encephalomyelitis (EAE) was induced in Thy-l.1 congenic S... more Chronic relapsing experimental allergic encephalomyelitis (EAE) was induced in Thy-l.1 congenic SJL/J mice by the adoptive transfer of myelin basic protein (MBP)-responsive lymph node cells from Thy-l.2 SJL/J mice. The Thy-1 congenic mouse strain was constructed on the SJL (Thy-l.2) background by the initial cross with the AKR (Thy-l.1) strain and does not reject Thy-l.2 + T ceils. Quantitative immunocytochemical analysis of the central nervous system (CNS) of Thy-l.1 recipients showed preferential trafficking of Thy-l.2 + T cells to the meninges and white matter, beginning prior to onset of clinical signs. At 7 days post-transfer (dpt), Thy-l.2 + donor cells constituted 2.5% of the infiltrating cells and reached peak values (ca. 10%) during the first attack. At later stages (up to ten relapses), Thy-l.2 ÷ T cells constituted 2-5% of the infiltrate. In control mice injected with irrelevant antigen-stimulated Thy-l.2 ÷ T cells, only the occasional Thy-l.2 + T cell could be demonstrated up to 14 dpt. This is the first study showing unequivocally the presence of MBP-stimulated, adoptively transferred T cells within the CNS of recipients throughout the course of EAE, particularly during later relapsing stages. These results indicate that the persistent presence of antigen-specific T cells may be required for the recruitment of non-CNS antigen-responsive immune cells.
Journal of Neuroimmunology, 1994
Journal of Neuroimmunology, 2003
To find immune mechanisms underlying relapse regulation, we developed a model of relapsing -remit... more To find immune mechanisms underlying relapse regulation, we developed a model of relapsing -remitting experimental autoimmune encephalomyelitis (EAE) in (B6 Â SJL) F1 (H-2 b/s ) mice by immunization with myelin oligodendrocyte glycoprotein peptide 35 -55 (MOG 35 -55 ) and compared with low/non-relapsing B6 (H-2 b ) mice.
Journal of Neuroimmunology, 1997
We analyzed two distinct phenotypes of Schwann cells (SC), non-differentiated and differentiated,... more We analyzed two distinct phenotypes of Schwann cells (SC), non-differentiated and differentiated, for their ability to produce IL-1alpha and IL-1beta, and to express message for IL-1 receptor antagonist (IL-IRA) and IL-1R type I, in vitro. SC were stimulated with: lipopolysaccharide (LPS), products of activated splenocytes (ASP), products from LPS stimulated SC (SCP), rat recombinant IL-1beta (rrIL-1beta) or dexamethasone. IL-1alpha, IL- 1beta and IL-1RA mRNA levels were highly upregulated after stimulation with LPS, ASP, SCP or rrIL-1beta. SC constitutively expressed low levels of message for IL-1alpha and IL-1beta but not IL-1RA. Specific mRNAs for both IL-1 isotypes were highly upregulated 2 to 4 h after LPS stimulation and then decreased and were undetectable by 24 h. IL-1RA mRNA was detectable after 6 h of LPS stimulation and was maximally upregulated at 24 h. IL-1 gene expression was inducible in both SC phenotypes. IL-1beta could be detected by immunofluorescence in SC, one to three days after LPS stimulation. At the same time IL-1 bioactivity was maximal in SC supernatants. Treatment with either SCP, rrIL-1beta or dexamethasone induced upregulation of IL-1R type I mRNA with maximal expression between 2 to 4 h, in SC. Inducible expression of genes for IL-1alpha, IL-1beta, IL-1RA and IL-1R type I in both differentiated and non-differentiated SC suggest autocrine and paracrine regulation of IL-1 by SC.
The Journal of Infectious Diseases, 1997
Cytokines, proteins that are secreted by many cells, including inflammatory and glial cells, medi... more Cytokines, proteins that are secreted by many cells, including inflammatory and glial cells, mediate interactions between cells, generally through paracrine and autocrine networks. Their effects are highly pleiotropic, with overlap of some activities. The pathogenesis of Guillain-Barré syndrome (GBS), especially the classic inflammatory demyelinating polyneuropathy form, seems to involve lymphocytes and macrophages, which are rich sources of cytokines. Macrophages likely have a role in the pathogenesis of the primarily axonal, less inflammatory forms of GBS. Cytokines appear to be involved in damage to Schwann cells, myelin, and axons, although the exact roles of the different cytokines is uncertain. There is increasing evidence that cytokines, including some proinflammatory cytokines that ordinarily cause damage, may also protect the cells of the peripheral nervous system and aid in its repair. The evolution of inflammatory and demyelinating disorders, including the degree of recovery, is probably dependent on the interactions of the different cytokines.
Journal of Autoimmunity, 2005
Experimental autoimmune encephalomyelitis (EAE) is a CD4C T-cell mediated disease, which resemble... more Experimental autoimmune encephalomyelitis (EAE) is a CD4C T-cell mediated disease, which resembles immunopathology of multiple sclerosis (MS). Interleukin (IL)-16 is a CD4C cell-specific chemoattractant cytokine. In CD4C T cells, production of bioactive IL-16 from constitutive pro-IL-16 requires cleavage by active caspase-3. We reported reversal of established relapsing disease by IL-16 neutralization. To better understand role(s) of IL-16 in regulation of relapsing EAE, we comparatively analyzed levels of IL-16, active caspase-3 and CD4 in mice with severe relapsing-remitting [(B6 ! SJL) F1], and low-relapsing (B6), disease. Elevated levels of IL-16 along with an increase in active-caspase-3 and CD4 levels correlated with stages of clinically active disease in both strains. CNS levels of bioactive IL-16 were notably higher in F1 compared to B6 mice at all stages, being most prominent during relapse. Similar patterns of regulation for IL-16 and active caspase-3 were observed in peripheral lymphoid organs, and in T cells isolated from lymph nodes following T-cell activation in vitro. IL-16 was coimmunoprecipitated with CD4 from CNS of relapsing mice. Our data suggest that caspase-3 mediated production of IL-16 by infiltrating CD4C T cells, contributes to ongoing neuroinflammation by chemoattraction of additional waves of CD4C T cells.
Annals of the New York Academy of Sciences, 2003
Annals of the New York Academy of Sciences, 2006
Our results show activation of the IL-1 signaling pathway in Schwann cells (SC), prior to and dur... more Our results show activation of the IL-1 signaling pathway in Schwann cells (SC), prior to and during early stages of diabetic neuropathy, thus suggesting its role in the initiation of SC-axonal miscommunication.
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Papers by Dusanka Skundric