Antigen presentation for priming T cells in central system

The International Journal of Biochemistry & Cell Biology 82 (2017) 41–48

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Antigen presentation for priming T cells in central system Shaoni Dasgupta a , Subhajit Dasgupta b,∗ a

Academic Magnet High School, Charleston, SC, United States Microbiology, Immunology and Biochemistry, Saint James School of Medicine, P.O. Box 318, Albert Lake Drive, The Quarter, AI−2640, British West Indies, Anguilla b

a r t i c l e

i n f o

Article history: Received 28 July 2016 Received in revised form 16 November 2016 Accepted 23 November 2016 Available online 27 November 2016 Keywords: Lymphocyte Dendritic cells Central nervous system Antigen MHC

a b s t r a c t Generation of myelin antigen-specific T cells is a major event in neuroimmune responses that causes demyelination. The antigen-priming of T cells and its location is important in chronic and acute inflammation. In autoimmune multiple sclerosis, the effector T cells are considered to generate in periphery. However, the reasons for chronic relapsing-remitting events are obscure. Considering mechanisms, a feasible aim of research is to investigate the role of antigen-primed T cells in lupus cerebritis. Last thirty years of investigations emphasize the relevance of microglia and infiltrated dendritic cells/macrophages as antigen presenting cells in the central nervous system. The recent approach towards circulating Blymphocytes is an important area in the context. Here, we analyze the existing findings on antigen presentation in the central nervous system. The aim is to visualize signaling events of myelin antigen presentation to T cells and lead to the strategy of future goals on immunotherapy research. © 2016 Elsevier Ltd. All rights reserved.

1. Introduction

1.1. Antigen presentation signaling for T cell priming

In autoimmune diseases, self-antigen-specific immune responses gradually establish clinical conditions through cell degeneration. The interactive events are the major causes of chronic inflammation in central nervous system (CNS). Investigation on peripheral immune responses in the CNS indicates that activated immune cells, such as lymphocytes, dendritic cells, monocytes, and macrophages enter the CNS through a leak in the blood brain barrier (Lopes Pinheiro et al., 2016; Ransohoff et al., 2015). The mechanism of CNS −specific myelin antigen(s) presentation to T cells is still unclear at this point. Different laboratories have suggested the presence of myelin mimic (including microbial peptides) or endogenously derived antigen(s) for induction of peripheral T cell activation. In fact, antigen-mimicry in T cell activation has been reported to induce CNS inflammation in multiple sclerosis (MS) murine models (Chastain and Miller, 2012; Moses and Sriram, 2001). However, genetic susceptibility factors are major regulators in such events where the interplay of signals remains largely unclear. This article focuses on different antigen presenting cells and their roles in T cell activation and consequently CNS inflamation.

Cells of myeloid origin like macrophages and dendritic cells convert antigens to epitopes through sequential time-dependent means and present these epitopes with genetically determined MHC/HLA (Major Histocompatibility Complex/Human Leukocyte Antigen) I and/or II to the T-cell receptors of CD3 and cytotoxic CD8 cells (Munz, 2016; Roche and Cresswell, 2016). The Signaling includes antigen-induced receptor-mediated activation of endocytosis in antigen presenting cells, transmission of intracellular signals from the plasma membrane-bound G-protein linked and G-protein coupled receptors to the nucleus for transcription regulation and ultimately protein synthesis in the cytoplasm. The activation of protease synthesis and processing of antigens as well as the biosynthesis of functional MHC/HLA proteins are relevant signal mechanisms for antigen presentation (Bosch et al., 2013; Inaba et al., 2000). Different co-stimulatory molecules like CD40, CD80, CD86, integrins are expressed on the surface of antigen presenting cells and interact with T cell receptor (TCR) proteinsignaling complexes in the immune synapse for successful antigen presentation during process of T cell activation (Altaf and Revell, 2013; Hochweller et al., 2010). In immunocompetent hosts, selective antigen presentation induces clonal expansion of effector T and B cells and generates a specific pool of memory cells. The signal to switch from memory to effector cells, or tolerogenic regulatory T cells (Treg), is critical in long lasting antigen-specific immune responses during

∗ Corresponding author. E-mail addresses: [email protected] (S. Dasgupta), [email protected] (S. Dasgupta). http://dx.doi.org/10.1016/j.biocel.2016.11.015 1357-2725/© 2016 Elsevier Ltd. All rights reserved.

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antimicrobial defense and self-antigen mediated autoimmune diseases (Lanzavecchia and Sallusto, 2001; Yamazaki et al., 2006). Signaling of MHC-epitope clusters and TCR interaction in the immune synapse with co-stimulatory molecules is critical for T cell–mediated immune responses. The signal cascades for antigen presentation and T cell activation in CNS thus indicate tissue/organ-specific localized immune responses for myelin antigens in chronic inflammatory clinical conditions. We hypothesize consequently that myelin antigen specific effector and memory T cells appear in peripheral circulation from CNS. 1.2. Antigen-dependent activation of T cells inside CNS Presentation of Myelin antigen(s) in association with MHC is a prerequisite step for generation of encephalitogenic effector T cells (Williams et al., 2011; Gran and Rostami, 2001). The progression of clonal expansion of these encephalitogenic T cells possibly occurs inside CNS with the generation of memory cells. These memory cells come into peripheral circulation as autoreactive lymphocytes, which are then transformed into effector cells and re-enter the CNS through the blood brain barrier. Thus, a close relationship between peripheral and CNS immune responses is established during chronic neuroinflammation. Several investigators demonstrated the presence of proinflammatory cytokines and free radicals in cerebrospinal fluid (CSF) (Sun et al., 2015; Wajgt and Gorny, 1983; Kothur et al., 2016). The isotopes of myelin basic protein (MBP) have been found in the liver (Fryxell et al., 1983; Takahashi et al., 1983), indicating a possibility of availability of myelin antigen in periphery. However, there is no such evidence of the presence of isotypes of other myelin antigens, such as myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein (PLP) in liver or any peripheral organ. This raises the question of whether major pools of encephalitogenic T cells are primed by MBP only? The myelin antigen primed T cells possibly have a profound impact on neurodegeneration in lupus cerebri-

tis although the mechanism is still not very clear. Unfortunately, testing the hypothesis on CNS antigen presentation in vivo without breaking blood brain barrier and peripheral blood contamination is still a challenge as there is a lack of sophisticated realtime imaging and functional study of T cell interaction events with cells inside CNS. Thus, three views prevail on the mechanism of CNS inflammatory responses: 1. Activated T cells (antigen specific and in majority unspecific) enter the CNS through blood brain barrier and induce inflammation upon interacting with resident microglia and astrocytes (Schmitt, 2015; Stinissen et al., 1998); 2. Glial cells (microglia and astrocytes) as well as dendritic cells, mononuclear cells, and macrophages in CNS are activated for antigen presentation (Valentin-Torres et al., 2016; Mayo et al., 2014; Benveniste, 1997); 3. Myelin antigen(s) are presented by CNS-APCs to T cells for antigen specific immune responses inside the CNS (Molnarfi et al., 2013; Almolda et al., 2011; Chastain et al., 2011). The myelin antigens in the spleen and lymph nodes prime circulatory T cells to attain encephalitogenicity. These primed cells enter the CNS and subsequently cause inflammation. Such events are demonstrated by relapsing remitting multiple sclerosis and its autoimmune encephalomyelitis (EAE) experimental model. The recurring bouts of clinical manifestations suggest that the priming and repriming of encephalitogenic T cells achieve effector specificity through clonal expansion. In Table 1, we presented the research viewpoints of various laboratories for the last thirty years (1986–2016), showing how T cells are prime targets of CNS inflammation and subsequent cause of demyelination. In the following sections, we analyzed the role of different antigen presenting cells in CNS inflammation. 2. Microglia as antigen presenting cells (APC) of central nervous system (CNS) Since their development, microglia have represented a pool of CNS resident cells with macrophage-like property. Several recent

Table 1 Impact of T cells in inflammation of central nervous system. Diseases involve inflammation in central nervous system (CNS) in animal models and human

Demonstrated Immune responses to myelin antigen

Cellular parameters, cytokines and immunoglobulin during inflammatory responses in CNS

Representative references (cited in reference section)

Adoptively transferred EAE in C57BL/6 and/or female SJL/J mice

Myelin Basic Protein (MBP), MBP peptide (1-11)

IFN␥, TNF␣, low IL4

Active immunization (Direct injection) of Lewis rats Murine EAE; EAE in B10.PL mice Murine EAE

High level antibody IgG2 to MBP68-88

Active immunization of EAE in rabbits

Peptide 68-88 amino acids of guinea pig MBP; self and non-self T cell clone T helper 1 response to MBP TH 1/TH 2 response and B7-1; B7-2 costimulatory signal; Inducible costimulator protein (ICOS); Proteolipid protein (PLP) 139-151

Bernard et al., 1976; Skundric et al., 1993, 1994; Cross et al., 1990; Sakai et al., 1986; McCarron et al., 1990; Zamvil et al., 1987; Dasgupta et al., 2004 Fritz et al., 1979; Happ and Heber-Katz, 1988; Matsumoto et al., 1990; Voskuhl et al., 1993; Ando et al., 1989 Kuchroo et al., 1995; Wiendl et al., 2003; McAdam et al., 2000

Murine EAE in SJL/J mice

TH 1 responsive to PLP

Murine EAE

TH 17, IL17, TH 22, T cell immunoglobulin Mucin-3 (Tim-3) signaling Increasing number of T and B cells in CSF than peripheral blood circulation T cell-mediated immune response

Tim-3 positive IFN␥; ROR␥t orphan receptor regulation of IL17, Tbet

Neuropsychiatric lupus (patients)

T cell-mediated immune response; unknown antigen source

Neuropsychiatric lupus (patients)

B cell activation, autoantibody in CSF

T cell response, Elevated expression of IL2, IL4, IL10, IL6, TNF-alpha, IFN␥, MCP1 Anti-ribosomalP protein autoantibody; anticardiolipin antibody; soluble terminal compliment complex, IL6, IL8

Multiple sclerosis (MS) (patients) Multiple sclerosis (MS) (patients)

IFN␥, TNF␣/lymphotoxin; IL2 Cellular phenotypes, Elevated IFN␥, low IL4, IL10; Infiltration of T cells, macrphages in CNS Cellular phenotypes, IFN␥

CD4, IgM, IgA, IgG producing cells; TH 1/TH 17, Nuclear Factor- kappaB

Sobel et al. (1986) Satoh et al., 1987; McRae and Miller, 1994; Dasgupta et al., 2007 Lee and Goverman, 2013; Yang et al., 2014; Rolla et al., 2014 Sandberg-Wollheim and Turesson, 1975; Henriksson et al., 1985 Hussman et al. 2016; Schlager et al., 2016 Fragoso-Loyo et al. (2013)

Jonsen et al., 2003; Trysberg et al., 2000

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Table 2 Impact of microglia in inflammatory and degenerative central nervous system. Different types of microglia

Cell surface markers and inflammatory mediators; cytokines/ chemokines

Activation signal pathway(s) in microglia

Major signal molecule(s) in microglia

Nuclear signal for transcriptional regulation

Representative references (cited in reference section)

Microglia in white matter (Histology and in vitro cell culture)

MHCII, HLA-I ABC; HLA-II DR, Ia; MAC-1, F4/80 Intercellular adhesion molecule-1 (ICAM1) MHCII

IL1 signal; IFN-gamma receptor-mediated signal

–

–

Woodroofe et al., 1986; van der Maesen et al., 1999; Benveniste, 1992

Prostaglandin E2 (PGE2); Cyclooxygenase2 (COX2);Nitric oxide synthase (NOS); iNOS, 15d-PGJ2

NF-␬B; p38 MAP kinase; CREB

NF-␬B

Levi et al., 1998; Ajmone-Cat et al., 2003

NF-␬B, PPAR-gamma –

NF-␬B, PPAR-gamma –

Bernardo et al., 2000; Pahan et al., 2001 Wake et al., 2009; Schilling et al., 2005; Trapp et al., 2007

Activated microglia (In vitro neonatal murine brain cell culture) Activated microglia (murine spinal cord in EAE) Resting microglia: glia neuron interaction in maintaining synaptic plasticity in murine model of focal cerebral ischemia

Moma2, CD11b, TNF-alpha; NO; CD11b

Contact signal between microglial processes and synapse in neurons; migration of bone marrow derived microglia

review articles nicely projected the biological function of microglia in CNS. Table 2 shows the several roles of microglia as distinct CNS resident cells, having definitive markers for identification. In resting stage, ramified microglia scan their surroundings for endogenously generated cell debris to clear through phagocytosis. The amoeboid, with round or oval shaped activated microglia, process antigens and clear them from the immediate vicinity. The last thirty years of research reports (1986–2016) on neuro-inflammation provide us with possible clues on the role of microglia as antigen presenting cells. Furthermore, different investigators have suggested microglial activity-mechanisms in CNS inflammation during the progression of multiple sclerosis (MS) in its susceptible animal model, experimental autoimmune encephalomyelitis (EAE) (Benveniste, 1997; Almolda et al., 2011). At this point, we have two hypothetical approaches: Firstly, T cell priming to myelin antigens and/or oligodendrocyte specific antigen(s) takes place only inside CNS in MS/EAE, and secondly, myelin antigen primed activated T cells enter into peripheral circulation from CNS get reprimed in spleen and lymph nodes by peripheral APCs to maintain encephalitogenicity. Fig. 1A demonstrates the role of microglia (CD11b) as CNS-APC for priming CD4 and CD8 cells inside CNS. The primed CD4 can take commitment towards differentiation of TH 1 or TH 17 and express IFN gamma or IL17 respectively. The mechanism of TH 1 to TH 17 switching depends on transcriptional modification signaling for Tbet to RORgamma-t followed by MHCII-myelin antigens and TCR interaction kinetics inside CNS. The CD8 cells are primed by MHCI −antigen and activated to express perforin and granzymeB to cause apoptosis in CNS. Neurons undergo apoptosis and shed degraded myelin sheath components [Myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP) CNPase and core myelin basic protein (MBP)]. The myelin proteins are processed by APCs to prime T cells. A distinct mechanism of clonal expansion of CD4 and CD8 cells in CNS parenchyma in the presence of myelin antigens is highly speculated here. In the model (Fig. 1A), CNS−APC microglia, following activation, generate interleukin 12 (IL12) family of cytokines, TNF alpha, interleukin 1 beta (IL1␤), reactive nitrogen species and nitric oxide (NO) as well as superoxide radicals that are found in the CSF. The model defines the therapeutic prospect of selective inhibitors for IL12 family cytokines, TNF alpha, IL1␤, iNOS, IFN gamma, and IL17. The screening of therapeutic compounds can restore peripheral tolerance by expanding regulatory T cells and generating CNS specific regulatory T cells and signal mechanisms. Such tolerogenic process can elevate IL10 expression in the CNS, which, objectively, is required to restore anti-inflammatory mileu in CNS.

The impact of microglia as APC greatly explains the inflammatory responses and degeneration in CNS during Alzheimer’s disease, Parkinson’s disease, and lupus cerebritis (neuro lupus) (Gyoneva et al., 2016; Schlachetzki and Hull, 2009; Sanchez-Guajardo et al., 2015; Gulinello and Putterman, 2011). The preventive strategies therefore, need to be directed to minimize the generation of these autoreactive T cells for uncontrolled microglial activation. 3. Dendritic cells as antigen presenting cells (APC) of central nervous system (CNS) Infiltrated dendritic cells create interactive cellular events of antigen priming inside the blood brain barrier of CNS. The neuroinflammatory disease models of multiple sclerosis (MS) suggest the role of dendritic cells in disease progression. The CD11c positive dendritic cells are found in the perivascular region and express chemokines CCL5, CXCL9, CXCL10 (Clarkson et al., 2015; Zozulya et al., 2010). The T cells primed by these dendritic cells express IFN-gamma and IL17 in the CNS. Recent investigations on the matter have been compiled in Table 3. Induction of IFN-gamma in CNS is a relevant mechanism of TH 1 function in neuro-inflammation. An integrated relationship exists between expression profiles of IFNgamma and IL17 with interleukin 12 and chemokines in antigen presenting cells within CNS. Table 3 presents the outcome of different investigations on the mode of action of dendritic cells and their impact on T cell commitment in CNS inflammation. Many investigators have also suggested a differential mode of action of monocyte-derived (mDC) and plasmacytoid (pDC) dendritic cells in the polarization of T cells in presence of toll-like receptor agonists. Recently, Ruocco et al. (Ruocco et al., 2015) used human dendritic cells derived from one hundred and seven relapsing-remitting MS patients and healthy donor volunteers in co-culture condition in vitro with naïve autologous CD4 cells. These dendritic cells were stimulated with toll-like receptor (TLR 7/8) agonist Resiquimod. The results showed that higher expression of IL9 from TLR7/8 agonist Resiquimod stimulated pDC–mediated differentiation of Th9 cells and inversely related to IL17 level in cerebrospinal fluid (CSF). Thus, modified antigen presentation ability of dendritic cells serves to develop possible treatment as cell-based immunotherapy. The extent of inflammation and cytokine expressions was correlated with the selection of patients with records of optical coherence tomography and Magnetic Resonance Imaging (MRI). The signaling mechanismof dendritic cells in the presence of myelin antigens is an important aspect towards regulation of inflammatory or anti-inflammatory conditions. The dendritic cells

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Fig. 1. (A). Microglia present antigen to T cells in CNS. The CNS resident macrophages microglia express MHC I and II. These glial cells can act as CNS specific antigen presenting cells presenting cells to T cell repertoires. In the figure, CD11b, marker for microglia; CD4, marker for T helper cells (TH ). The arrow head-lines indicate the fate of microglia to T cell interaction. Different pro-inflammatory cytokines are produced as a result of glial cell activation. The T helper cell activation followed by commitment to either pro inflammatory or anti inflammatory conditions balances disease versus tolerance effect in aspect of neuro immune response. The activation of cytotoxic CD8 cells produce GranzymeB and perforin, which along with Fas ligand interact with non-self autoreactive, cells and induce apoptosis. (B). B cells can act as antigen presenting cells to T helper cells in central nervous system. The B cells express MHC and process antigen for presentation. During the interactive process, the activated B cells produce immunoglobulins and antigen primed T helper cells take the committed pathways to proinflammatory TH 1, TH 17 or tolerance generating Treg cells. B cells can also activate CD8 cells for cytotoxicity.

take part in modulation of TH 1/TH 17/TH 9 axes under a bridge of endogenous TLR activation (Rampal et al., 2016). It appears that selective modulation of TLR signals in dendritic cells could be a fruitful therapeutic strategy. advancements in experimental autoimmune Recent encephalomyelitis (EAE murine model of MS), through dendritic cell-based T-cell modification, indicate a role of Wnt ligand induced activation of beta-catenin signaling. This signaling generates tolerance and consequently reduces inflammation in CNS (Swafford and Manicassamy, 2015; Oderup et al., 2013). Very recently, Yan et al. and Terness et al. (Yan et al., 2010; Terness

et al., 2006) demonstrated the benefits of Indolamine dioxygenase (IDO) on the reduction of CNS inflammation in EAE. The findings suggest that inhibition of tryptophan biosynthesis by IDO enzyme promotes regulatory T cells (Treg) differentiation, attenuating TH 17 and TH 1 cell-biased inflammation. The antigen specific expansion of regulatory T cells and IL10 expression are critical signals for restoration of peripheral tolerance (Dasgupta and Dasgupta, 2016). We consider generation of self-antigen-primed tolerance to be mandatory for therapeutic interventions of autoimmune diseases. Table 4 represents the out-

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Table 3 Infiltrated dendritic cells can present antigens in CNS. Dendritic cells (DC)

Markers

Expression of cytokines/ Chemokine/ Other compounds

T cells and TCR under interactions

Signalling in dendritic cells

Signalling in T cells

Representative references (cited in reference section)

VSV stimulated Encephalitis and DCs, pDCs (plasmacytoid DC) with microglia as APC; CD11c DC in multiple sclerosis in EAE model Glia and infiltrating macrophages in EAE pDC in EAE

CD11c; PDCA

–

CD4, CD8; T cells, low IFN-gamma expression

Class-I MHC restricted antigen presentation

MOG-induced T cells, TH1, TH 17 cytokines

Steel et al., 2009; Wlodarczyk et al., 2014

Mac + CD45 int; Mac + CD45+ hi

NO; IFN-gamma expression

MOG-induced TH1

MHC-II, B7-1; B7-2

TH 1 signal

Juedes and Ruddle, 2001

PDCA1; CX3CR+ cells

IFN-gamma, IL17

MOG-primed T cells

TH 1; TH 17

IFN gamma and IL17 signal

DCs in EAE in mice model

DEC-205, MIDC-8

Chemokine receptor expression

PLP I39-151 peptide induced DC activation in spinal cord

MHC-II, CD40, CD86

Signalling for MIP-3 alpha, CCR6

Isaksson et al., 2009; Barkauskas et al., 2013 Serafini et al. (2000)

Mature DCs in mice model

CD11c+

B-7H1 induction by IFN beta;

MHC-II, PARP

Up regulation of PD-1 receptor in antigen specific T cells, TH 1

Yogev et al., 2012; Cavone et al., 2011; Almolda et al., 2011; Greter et al., 2005; Schreiner et al., 2004

Table 4 The prospect of regulatory T cells in reduction of T cell −mediated CNS inflammation. Antigen presenting cells

Marker/cell identities

Antigen(s)

T cell status

Cytokine(s)

Representative references (cited in reference section)

Bone Marrow (BM) derived dendritic cells (DCs) in EAE mice

PD-L1

Reduced T cell proliferation and generate tolerance

Lower TH 1, TH 17 responses

Tseveleki et al., 2015

Modulation of myeloid APC subsets by laquinimod treatment in RR EAE

Increase in CD11bGr1 hi; reduction of CD11c + CD11b + CD4+ cDCs B cell-APC induced recombinant MOG-specific proinflammatory TH 1, TH 17 responses; MOG-peptide has no effect

Mannan (oxidized or reduced forms) conjugated myelin peptides Oral introduction of laquinimod

Reduction of TH 1, TH 17

Lower TH 1, TH 17 responses; decrease in IL6, Il12/23, TNF

Schulze-Topphoff et al., 2012

Recombinant MOG

Elevation of TH 1, TH 17 by B cell APC; Elimination of B cells reduced T reg cell frequency and increase disease progression

TH 1, TH 17 responses

Weber et al., 2010

CD19CD20B cells as APC in recombinant MOG and MOG peptide (p35-55)-induced EAE

come of regulatory T cells based immune response as a therapeutic prospect of neuroinflammation. 4. B- lymphocytes as antigen presenting cells of central nervous system The role of B-lymphocytes as antigen presenting cells in CNS inflammation is a newly developed concept and relatively unclear in neuro-immunology research. The presence of polyclonal antibodies against N-methyl d-aspartate (NMDA) receptors, brain phospholipids in cerebrospinal fluid (CSF), and peripheral blood circulation has been demonstrated in lupus cerebritis (neuro lupus), a neurodegenerative disease of unknown etiology. The presence of anti-myelin oligoclonal antibody has been reported in CSF of MS patients (Marchiori et al., 1990; Lolli et al., 1991). Many laboratories have been investigating the antigen presenting function of Blymphocytes due to the presence of MHC I and II molecules (Avalos and Ploegh, 2014; Siemasko and Clark, 2001). In a set of unique experiments, using globular protein cytochrome-c as an antigen and defining T cell antigenic determinant as a cognate interacting site, the B cell-APC approach was studied in the laboratory through

cell culture. The surface immunoglobulin molecules were found to facilitate internalization of the antigen and presented the processed antigen on the cell’s surface. Casten and Pierce (Casten and Pierce, 1988) demonstrated that antigen internalization occurred through a receptor-mediated mechanism. Interestingly, the encephalitogenic T cell commitment with antigen presenting ability of B cells are not detectable in CNS of neonatal brains as observed in EAE (Cravens et al., 2013). Molnarfi et al. (Molnarfi et al., 2013) suggested a mechanistic standpoint of MHCII, indicating the B cell APC mode of action towards the presentation of recombinant human MOG peptide antigen in TCR transgenic EAE mice. Thus, it is speculated that differential mode of antigen presentation and alteration in signal strength modify the nature of commitment of T cells to TH 1, TH 17, TH 9, TH 2, or Treg cells through unknown mechanisms involving B cell-APC. 5. Future research program The last thirty years of systematic literature search and analysis of existing results suggest feasibility to look for antigen presentation signaling inside CNS. However, the query, “How do these

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antigen presenting cells function specifically inside CNS?” is not addressed in an adequate manner till today. It is evident that microglia and astrocytes have enormous beneficial properties in maintaining the physiology and integrity of CNS. The role of B cells as antigen presenting cells is a new perspective of neuroimmunology. Thus, T and B cell interaction inside the CNS is one of the relevant aspects to consider for future research. We propose that B cells act as antigen-presenting cells to prime T cells inside CNS. Future research should focus primarily on CNS specific clonal expansion and memory cell formation of these interacting B and T cells (Fig. 1B). The implications of the neuro-immune aspect can be found in the development of therapeutic strategies of chronic inflammatory and degenerative diseases of the central nervous system. Conflicts of interests We do not have any conflict of interests. Acknowledgements I (S.D.G) acknowledge College of Dentistry, University of Nebraska Medical Center, Holdrege, Lincoln, Nebraska for the initial phase of concept development. This is a small, analysis based review project for Ms. Shaoni Dasgupta. Ms. Dasgupta put her effort in literature search, analysis of statement in manuscript, formatting and preliminary draft preparation. We are thankful to Oscar Andrade, Chief Librarian of Saint James School of Medicine (Main Campus, Park Ridge, IL); Department of Medicine, Rheumatology Division; Department of Neurosciences and N.N.R.I (Strom Thurmond Building), Medical University of South Carolina (MUSC) for research support. References Ajmone-Cat, M.A., De Simone, R., Nicolini, A., Minghetti, L., 2003. Effects of phosphatidylserine on p38 mitogen activated protein kinase: cyclic AMP responding element binding protein and nuclear factor-kappaB activation in resting and activated microglial cells. J. Neurochem. 84, 413–416. Almolda, B., Gonzalez, B., Castellano, B., 2011. Antigen presentation in EAE: role of microglia: macrophages and dendritic cells. Front. Biosci. (Landmark Ed) 16, 1157–1171. Altaf, H., Revell, P.A., 2013. Evidence for active antigen presentation by monocyte/macrophages in response to stimulation with particles: the expression of NFkappaB transcription factors and costimulatory molecules. Inflammopharmacology 21, 279–290. Ando, D.G., Clayton, J., Kono, D., Urban, J.L., Sercarz, E.E., 1989. Encephalitogenic T cells in the B10: PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell. Immunol. 124, 132–143. Avalos, A.M., Ploegh, H.L., 2014. Early BCR events and antigen capture, processing, and loading on MHC class II on B cells. Front. Immunol. 5, 92. Barkauskas, D.S., Evans, T.A., Myers, J., Petrosiute, A., Silver, J., Huang, A.Y., 2013. Extravascular CX3CR1+ cells extend intravascular dendritic processes into intact central nervous system vessel lumen. Microsc. Microanal. 19, 778–790. Benveniste, E.N., 1992. Inflammatory cytokines within the central nervous system: sources, function and mechanism of action. Am. J. Physiol. 263, C1–16. Benveniste, E.N., 1997. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J. Mol. Med. (Berl.) 75, 165–173. Bernardo, A., Levi, G., Minghetti, L., 2000. Role of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its natural ligand 15-deoxy-Delta12, 14-prostaglandin J2 in the regulation of microglial functions. Eur. J. Neurosci. 12, 2215–2223. Bosch, B., Heipertz, E.L., Drake, J.R., Roche, P.A., 2013. Major histocompatibility complex (MHC) class II-peptide complexes arrive at the plasma membrane in cholesterol-rich microclusters. J. Biol. Chem. 288, 13236–13242. Casten, L.A., Pierce, S.K., 1988. Receptor-mediated B cell antigen processing: increased antigenicity of a globular protein covalently coupled to antibodies specific for B cell surface structures. J. Immunol. 140, 404–410. Cavone, L., Aldinucci, A., Ballerini, C., Biagioli, T., Moroni, F., Chiarugi, A., 2011. PARP-1 inhibition prevents CNS migration of dendritic cells during EAE: suppressing the encephalitogenic response and relapse severity. Mult. Scler. 17, 794–807. Chastain, E.M., Miller, S.D., 2012. Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease. Immunol. Rev. 245, 227–238.

Chastain, E.M., Duncan, D.S., Rodgers, J.M., Miller, S.D., 2011. The role of antigen presenting cells in multiple sclerosis. Biochim. Biophys. Acta 1812, 265–274. Clarkson, B.D., Walker, A., Harris, M.G., Rayasam, A., Sandor, M., Fabry, Z., 2015. CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. J. Immunol. 194, 531–541. Cravens, P.D., Kieseier, B.C., Hussain, R., Herndon, E., Arellano, B., Ben, L.H., Timmons, B.C., Castro-Rojas, C., Hartung, H.P., Hemmer, B., Weber, M.S., Zamvil, S.S., Stuve, O., 2013. The neonatal CNS is not conducive for encephalitogenic Th1 T cells and B cells during experimental autoimmune encephalomyelitis. J. Neuroinflamm. 10, 67. Cross, A.H., Dolich, S., Raine, C.S., 1990. Antigen processing of myelin basic protein is required prior to recognition by T cells inducing EAE. Cell. Immunol. 129, 22–31. Dasgupta, S., Dasgupta, S., 2016. Therapeutic interventions of tissue specific autoimmune onset in systemic lupus erythematosus. Mini Rev. Med. Chem. Dasgupta, S., Jana, M., Zhou, Y., Fung, Y.K., Ghosh, S., Pahan, K., 2004. Antineuroinflammatory effect of NF-kappaB essential modifier-binding domain peptides in the adoptive transfer model of experimental allergic encephalomyelitis. J. Immunol. 173, 1344–1354. Dasgupta, S., Roy, A., Jana, M., Hartley, D.M., Pahan, K., 2007. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-alpha. Mol. Pharmacol. 72, 934–946. Fragoso-Loyo, H., Atisha-Fregoso, Y., Llorente, L., Sanchez-Guerrero, J., 2013. Inflammatory profile in cerebrospinal fluid of patients with headache as a manifestation of neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 52, 2218–2222. Fritz, R.B., Chou, F.C., Chou, C.H., Kibler, R.F., 1979. The immune response of Lewis rats to peptide 68-88 of guinea pig myelin basic protein II. B cell determinants. J. Immunol. 123, 1544–1547. Fryxell, K.J., Balzer Jr., D.R., Brockes, J.P., 1983. Development and applications of a solid-phase radioimmunoassay for the PO protein of peripheral myelin. J. Neurochem. 40, 538–546. Gran, B., Rostami, A., 2001. T cells, cytokines: and autoantigens in multiple sclerosis. Curr. Neurol. Neurosci. Rep. 1, 263–270. Greter, M., Heppner, F.L., Lemos, M.P., Odermatt, B.M., Goebels, N., Laufer, T., Noelle, R.J., Becher, B., 2005. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334. Gulinello, M., Putterman, C., 2011. The MRL/lpr mouse strain as a model for neuropsychiatric systemic lupus erythematosus. J. Biomed. Biotechnol. 2011, 207504. Gyoneva, S., Swanger, S.A., Zhang, J., Weinshenker, D., Traynelis, S.F., 2016. Altered motility of plaque-associated microglia in a model of Alzheimer’s disease. Neuroscience. Happ, M.P., Heber-Katz, E., 1988. Differences in the repertoire of the Lewis rat T cell response to self and non-self myelin basic proteins. J. Exp. Med. 167, 502–513. Henriksson, A., Kam-Hansen, S., Link, H., 1985. IgM: IgA and IgG producing cells in cerebrospinal fluid and peripheral blood in multiple sclerosis. Clin. Exp. Immunol. 62, 176–184. Hochweller, K., Wabnitz, G.H., Samstag, Y., Suffner, J., Hammerling, G.J., Garbi, N., 2010. Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc. Natl. Acad. Sci. U. S. A. 107, 5931–5936. Hussman, J.P., Beecham, A.H., Schmidt, M., Martin, E.R., McCauley, J.L., Vance, J.M., Haines, J.L., Pericak-Vance, M.A., 2016. GWAS analysis implicates NF-kappaB-mediated induction of inflammatory T cells in multiple sclerosis. Genes Immun. 17, 305–312. Inaba, K., Turley, S., Iyoda, T., Yamaide, F., Shimoyama, S., Reis e Sousa, C., Germain, R.N., Mellman, I., Steinman, R.M., 2000. The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. J. Exp. Med. 191, 927–936. Isaksson, M., Ardesjo, B., Ronnblom, L., Kampe, O., Lassmann, H., Eloranta, M.L., Lobell, A., 2009. Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE. Eur. J. Immunol. 39, 2925–2935. Jonsen, A., Bengtsson, A.A., Nived, O., Ryberg, B., Truedsson, L., Ronnblom, L., Alm, G.V., Sturfelt, G., 2003. The heterogeneity of neuropsychiatric systemic lupus erythematosus is reflected in lack of association with cerebrospinal fluid cytokine profiles. Lupus 12, 846–850. Juedes, A.E., Ruddle, N.H., 2001. Resident and infiltrating central nervous system APCs regulate the emergence and resolution of experimental autoimmune encephalomyelitis. J. Immunol. 166, 5168–5175. Kothur, K., Wienholt, L., Brilot, F., Dale, R.C., 2016. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: a systematic review. Cytokine 77, 227–237. Kuchroo, V.K., Das, M.P., Brown, J.A., Ranger, A.M., Zamvil, S.S., Sobel, R.A., Weiner, H.L., Nabavi, N., Glimcher, L.H., 1995. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80, 707–718. Lanzavecchia, A., Sallusto, F., 2001. Antigen decoding by T lymphocytes: from synapses to fate determination. Nat. Immunol. 2, 487–492. Lee, S.Y., Goverman, J.M., 2013. The influence of T cell Ig mucin-3 signaling on central nervous system autoimmune disease is determined by the effector function of the pathogenic T cells. J. Immunol. 190, 4991–4999.

S. Dasgupta, S. Dasgupta / The International Journal of Biochemistry & Cell Biology 82 (2017) 41–48 Levi, G., Minghetti, L., Aloisi, F., 1998. Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie 80, 899–904. Lolli, F., Mata, S., Baruffi, M.C., Amaducci, L., 1991. Cerebrospinal fluid anti-cardiolipin antibodies in neurological diseases. Clin. Immunol. Immunopathol. 59, 314–321. Lopes Pinheiro, M.A., Kooij, G., Mizee, M.R., Kamermans, A., Enzmann, G., Lyck, R., Schwaninger, M., Engelhardt, B., de Vries, H.E., 2016. Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim. Biophys. Acta 1862, 461–471. Marchiori, P.E., Dos Reis, M., Quevedo, M.E., Callegaro, D., Hirata, M.T., Scaff, M., De Oliveira, R.M., 1990. Cerebrospinal fluid and serum antiphospholipid antibodies in multiple sclerosis: Guillain-Barre syndrome and systemic lupus erythematosus. Arq. Neuropsiquiatr. 48, 465–468. Matsumoto, Y., Kawai, K., Fujiwara, M., 1990. Analysis of the T cell repertoire for myelin basic protein in thymus-grafted and other types of chimera: evidence that major histocompatibility complex molecules on accessory cells rather than T cell specificity mainly regulate susceptibility to autoimmune encephalomyelitis. Eur. J. Immunol. 20, 2119–2126. Mayo, L., Trauger, S.A., Blain, M., Nadeau, M., Patel, B., Alvarez, J.I., Mascanfroni, I.D., Yeste, A., Kivisakk, P., Kallas, K., Ellezam, B., Bakshi, R., Prat, A., Antel, J.P., Weiner, H.L., Quintana, F.J., 2014. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med. 20, 1147–1156. McAdam, A.J., Chang, T.T., Lumelsky, A.E., Greenfield, E.A., Boussiotis, V.A., Duke-Cohan, J.S., Chernova, T., Malenkovich, N., Jabs, C., Kuchroo, V.K., Ling, V., Collins, M., Sharpe, A.H., Freeman, G.J., 2000. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165, 5035–5040. McCarron, R.M., Fallis, R.J., McFarlin, D.E., 1990. Alterations in T cell antigen specificity and class II restriction during the course of chronic relapsing experimental allergic encephalomyelitis. J. Neuroimmunol. 29, 73–79. McRae, B.L., Miller, S.D., 1994. Fine specificity of CD4+ T cell responses to the dominant encephalitogenic PLP 139–151 peptide in SJL/J mice. Neurochem. Res. 19, 997–1004. Molnarfi, N., Schulze-Topphoff, U., Weber, M.S., Patarroyo, J.C., Prod’homme, T., Varrin-Doyer, M., Shetty, A., Linington, C., Slavin, A.J., Hidalgo, J., Jenne, D.E., Wekerle, H., Sobel, R.A., Bernard, C.C., Shlomchik, M.J., Zamvil, S.S., 2013. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med. 210, 2921–2937. Moses Jr., H., Sriram, S., 2001. An infectious basis for multiple sclerosis: perspectives on the role of Chlamydia pneumoniae and other agents. BioDrugs 15, 199–206. Munz, C., 2016. Autophagy beyond intracellular MHC class II antigen presentation. Trends Immunol. Oderup, C., LaJevic, M., Butcher, E.C., 2013. Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J. Immunol. 190, 6126–6134. Pahan, K., Sheikh, F.G., Liu, X., Hilger, S., McKinney, M., Petro, T.M., 2001. Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells. J. Biol. Chem. 276, 7899–7905. Rampal, R., Awasthi, A., Ahuja, V., 2016. Retinoic acid-primed human dendritic cells inhibit Th9 cells and induce Th1/Th17 cell differentiation. J. Leukoc. Biol. 100, 111–120. Ransohoff, R.M., Schafer, D., Vincent, A., Blachere, N.E., Bar-Or, A., 2015. Neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics 12, 896–909. Roche, P.A., Cresswell, P., 2016. Antigen processing and presentation mechanisms in myeloid cells. Microbiol. Spectr., 4. Rolla, S., Bardina, V., De Mercanti, S., Quaglino, P., De Palma, R., Gned, D., Brusa, D., Durelli, L., Novelli, F., Clerico, M., 2014. Th22 cells are expanded in multiple sclerosis and are resistant to IFN-beta. J. Leukoc. Biol. 96, 1155–1164. Ruocco, G., Rossi, S., Motta, C., Macchiarulo, G., Barbieri, F., De Bardi, M., Borsellino, G., Finardi, A., Grasso, M.G., Ruggieri, S., Gasperini, C., Furlan, R., Centonze, D., Battistini, L., Volpe, E., 2015. T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis. Clin. Sci. (Lond.) 129, 291–303. Sakai, K., Namikawa, T., Kunishita, T., Yamanouchi, K., Tabira, T., 1986. Studies of experimental allergic encephalomyelitis by using encephalitogenic T cell lines and clones in euthymic and athymic mice. J. Immunol. 137, 1527–1531. Sanchez-Guajardo, V., Tentillier, N., Romero-Ramos, M., 2015. The relation between alpha-synuclein and microglia in Parkinson’s disease: recent developments. Neuroscience 302, 47–58. Sandberg-Wollheim, M., Turesson, I., 1975. Lymphocyte subpopulations in the cerebrospinal fluid and peripheral blood in patients with multiple sclerosis. Scand. J. Immunol. 4, 831–836. Satoh, J., Sakai, K., Endoh, M., Koike, F., Kunishita, T., Namikawa, T., Yamamura, T., Tabira, T., 1987. Experimental allergic encephalomyelitis mediated by murine encephalitogenic T cell lines specific for myelin proteolipid apoprotein. J. Immunol. 138, 179–184. Schilling, M., Besselmann, M., Muller, M., Strecker, J.K., Ringelstein, E.B., Kiefer, R., 2005. Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp. Neurol. 196, 290–297.

47

Schlachetzki, J.C., Hull, M., 2009. Microglial activation in Alzheimer’s disease. Curr. Alzheimer Res. 6, 554–563. Schlager, C., Korner, H., Krueger, M., Vidoli, S., Haberl, M., Mielke, D., Brylla, E., Issekutz, T., Cabanas, C., Nelson, P.J., Ziemssen, T., Rohde, V., Bechmann, I., Lodygin, D., Odoardi, F., Flugel, A., 2016. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530, 349–353. Schmitt, N., 2015. Role of T follicular helper cells in multiple sclerosis. J. Nat. Sci. 1, e139. Schreiner, B., Mitsdoerffer, M., Kieseier, B.C., Chen, L., Hartung, H.P., Weller, M., Wiendl, H., 2004. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1): a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J. Neuroimmunol. 155, 172–182. Schulze-Topphoff, U., Shetty, A., Varrin-Doyer, M., Molnarfi, N., Sagan, S.A., Sobel, R.A., Nelson, P.A., Zamvil, S.S., 2012. Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that modulate central nervous system autoimmunity. PLoS One 7, e33797. Serafini, B., Columba-Cabezas, S., Di Rosa, F., Aloisi, F., 2000. Intracerebral recruitment and maturation of dendritic cells in the onset and progression of experimental autoimmune encephalomyelitis. Am. J. Pathol. 157, 1991–2002. Siemasko, K., Clark, M.R., 2001. The control and facilitation of MHC class II antigen processing by the BCR. Curr. Opin. Immunol. 13, 32–36. Skundric, D.S., Kim, C., Tse, H.Y., Raine, C.S., 1993. Homing of T cells to the central nervous system throughout the course of relapsing experimental autoimmune encephalomyelitis in Thy-1 congenic mice. J. Neuroimmunol. 46, 113–121. Skundric, D.S., Huston, K., Shaw, M., Tse, H.Y., Raine, C.S., 1994. Experimental allergic encephalomyelitis: T cell trafficking to the central nervous system in a resistant Thy-1 congenic mouse strain. Lab. Invest. 71, 671–679. Sobel, R.A., van der Veen, R.C., Lees, M.B., 1986. The immunopathology of chronic experimental allergic encephalomyelitis induced in rabbits with bovine proteolipid protein. J. Immunol. 136, 157–163. Steel, C.D., Hahto, S.M., Ciavarra, R.P., 2009. Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system. Virology 387, 117–126. Stinissen, P., Medaer, R., Raus, J., 1998. Myelin reactive T cells in the autoimmune pathogenesis of multiple sclerosis. Mult. Scler. 4, 203–211. Sun, X., Bakhti, M., Fitzner, D., Schnaars, M., Kruse, N., Coskun, U., Kremser, C., Willecke, K., Kappos, L., Kuhle, J., Simons, M., 2015. Quantified CSF antibody reactivity against myelin in multiple sclerosis. Ann. Clin. Transl. Neurol. 2, 1116–1123. Swafford, D., Manicassamy, S., 2015. Wnt signaling in dendritic cells: its role in regulation of immunity and tolerance. Discov. Med. 19, 303–310. Takahashi, K., Odani, S., Ono, T., 1983. Isolation and characterization of the three fractions (DE-I: DE-II and DE-III) of rat-liver Z-protein and the complete primary structure of DE-II. Eur. J. Biochem. 136, 589–601. Terness, P., Chuang, J.J., Opelz, G., 2006. The immunoregulatory role of IDO-producing human dendritic cells revisited. Trends Immunol. 27, 68–73. Trapp, B.D., Wujek, J.R., Criste, G.A., Jalabi, W., Yin, X., Kidd, G.J., Stohlman, S., Ransohoff, R., 2007. Evidence for synaptic stripping by cortical microglia. Glia 55, 360–368. Trysberg, E., Carlsten, H., Tarkowski, A., 2000. Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 9, 498–503. Tseveleki, V., Tselios, T., Kanistras, I., Koutsoni, O., Karamita, M., Vamvakas, S.S., Apostolopoulos, V., Dotsika, E., Matsoukas, J., Lassmann, H., Probert, L., 2015. Mannan-conjugated myelin peptides prime non-pathogenic Th1 and Th17 cells and ameliorate experimental autoimmune encephalomyelitis. Exp. Neurol. 267, 254–267. Valentin-Torres, A., Savarin, C., Hinton, D.R., Phares, T.W., Bergmann, C.C., Stohlman, S.A., 2016. Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis. J. Neuroinflamm. 13, 46. Voskuhl, R.R., Martin, R., Bergman, C., Dalal, M., Ruddle, N.H., McFarland, H.F., 1993. T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity 15, 137–143. Wajgt, A., Gorny, M., 1983. CSF antibodies to myelin basic protein and to myelin-associated glycoprotein in multiple sclerosis. Evidence of the intrathecal production of antibodies. Acta Neurol. Scand. 68, 337–343. Wake, H., Moorhouse, A.J., Jinno, S., Kohsaka, S., Nabekura, J., 2009. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980. Weber, M.S., Prod’homme, T., Patarroyo, J.C., Molnarfi, N., Karnezis, T., Lehmann-Horn, K., Danilenko, D.M., Eastham-Anderson, J., Slavin, A.J., Linington, C., Bernard, C.C., Martin, F., Zamvil, S.S., 2010. B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. Ann. Neurol. 68, 369–383. Wiendl, H., Neuhaus, O., Mehling, M., Wintterle, S., Schreiner, B., Mitsdoerffer, M., Wienhold, W., Weissert, R., Wessels, J., Hartung, H.P., Weller, M., Tolosa, E., Melms, A., 2003. The CD28 related molecule ICOS: T cell modulation in the presence and absence of B7.1/2 and regulational expression in multiple sclerosis. J. Neuroimmunol. 140, 177–187. Williams, J.L., Kithcart, A.P., Smith, K.M., Shawler, T., Cox, G.M., Whitacre, C.C., 2011. Memory cells specific for myelin oligodendrocyte glycoprotein (MOG) govern the transfer of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 234, 84–92.

48

S. Dasgupta, S. Dasgupta / The International Journal of Biochemistry & Cell Biology 82 (2017) 41–48

Wlodarczyk, A., Lobner, M., Cedile, O., Owens, T., 2014. Comparison of microglia and infiltrating CD11c(+) cells as antigen presenting cells for T cell proliferation and cytokine response. J. Neuroinflamm. 11, 57. Woodroofe, M.N., Bellamy, A.S., Feldmann, M., Davison, A.N., Cuzner, M.L., 1986. Immunocytochemical characterisation of the immune reaction in the central nervous system in multiple sclerosis. Possible role for microglia in lesion growth. J. Neurol. Sci. 74, 135–152. Yamazaki, S., Inaba, K., Tarbell, K.V., Steinman, R.M., 2006. Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol. Rev. 212, 314–329. Yan, Y., Zhang, G.X., Gran, B., Fallarino, F., Yu, S., Li, H., Cullimore, M.L., Rostami, A., Xu, H., 2010. IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J. Immunol. 185, 5953–5961. Yang, H., Qiu, Q., Gao, B., Kong, S., Lin, Z., Fang, D., 2014. Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4T cell priming during inflammation. J. Exp. Med. 211, 2467–2479.

Yogev, N., Frommer, F., Lukas, D., Kautz-Neu, K., Karram, K., Ielo, D., von Stebut, E., Probst, H.C., van den Broek, M., Riethmacher, D., Birnberg, T., Blank, T., Reizis, B., Korn, T., Wiendl, H., Jung, S., Prinz, M., Kurschus, F.C., Waisman, A., 2012. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 37, 264–275. Zamvil, S.S., Mitchell, D.J., Moore, A.C., Schwarz, A.J., Stiefel, W., Nelson, P.A., Rothbard, J.B., Steinman, L., 1987. T cell specificity for class II (I-A) and the encephalitogenic N-terminal epitope of the autoantigen myelin basic protein. J. Immunol. 139, 1075–1079. Zozulya, A.L., Clarkson, B.D., Ortler, S., Fabry, Z., Wiendl, H., 2010. The role of dendritic cells in CNS autoimmunity. J. Mol. Med. (Berl.) 88, 535–544. van der Maesen, K., Hinojoza, J.R., Sobel, R.A., 1999. Endothelial cell class II major histocompatibility complex molecule expression in stereotactic brain biopsies of patients with acute inflammatory/demyelinating conditions. J. Neuropathol. Exp. Neurol. 58, 346–358.