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  • Inflammation and Adaptive Immunityin Parkinsons Disease

    R. Lee Mosley, Jessica A. Hutter-Saunders, David K. Stone, and Howard E. Gendelman

    Movement Disorders Program, Department of Pharmacology and Experimental Neuroscience, Center forNeurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198

    Correspondence: hegendel@unmc.edu

    The immune system is designed to protect the host from infection and injury. However, whenan adaptive immune response continues unchecked in the brain, the proinflammatory innatemicroglial response leads to the accumulation of neurotoxins and eventual neurodegenera-tion. What drives such responses are misfolded and nitrated proteins. Indeed, the antigen inParkinsons disease (PD) is an aberrant self-protein, although the adaptive immune responsesare remarkably similar in a range of diseases. Ingress of lymphocytes and chronic activationof glial cells directlyaffect neurodegeneration. With this understanding, new therapies aimedat modulating the immune systems response during PD could lead to decreased neuronalloss and improved clinical outcomes for disease.

    Parkinsons disease (PD) is the second mostcommon neurodegenerative disorder affect-ing the elderly. Pathologically, the disease ischaracterized by the cytoplasmic accumulationof proteinaceous aggregates called Lewy bodies(LBs), which are mainly comprised of a-syn-uclein (a-syn) and ubiquitin (Spillantini et al.1997, 1998). Progressive degeneration of dopa-minergic neurons in the substantia nigra (SN)pars compacta and their projections into thecaudate nucleus leads to substantial decreasesin dopamine levels, which manifest as restingtremor, bradykinesia, rigidity, and gait dysfunc-tion (Dauer and Przedborski 2003). Currently,no curative treatments or treatments that in-terdict disease progression exist. Although theetiology of PD remains unknown, abundantevidence implicates immune system abnormal-ities and central nervous system (CNS) inflam-

    mation in disease pathobiology (McGeer et al.1988a; Stone et al. 2009; Kosloski et al. 2010).Harnessing inflammatory responses throughtargeted modulation of innate and adaptive im-mune responses has gained increasing interestin recent years as a potential therapeutic strat-egy. The interplay between innate and adaptiveimmunity in the pathobiology of PD, the evolu-tion and change in such immune responses, andthe means to alter it to the benefit of the dis-eased, is the focus of this article.

    ADAPTIVE IMMUNITY AND THE CNS

    William Hickey wrote, vertebrates possess twobodily systems capable of learning and remem-bering: the nervous system and the immunesystem (Hickey 2001; Weiner 2008). The CNSwas once thought to be an immune privileged

    Editor: Serge Przedborski

    Additional Perspectives on Parkinsons Disease available at www.perspectivesinmedicine.org

    Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a009381Cite this article as Cold Spring Harb Perspect Med 2012;2:a009381

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  • site, in which immune cells of the peripherycould not enter or rarely entered, and thus thetwo systems had little to no interaction. This hy-pothesis was supported by the early observationthat tissue grafts in the eye or brain survivedlonger than grafts in other areas of the body(Medawar 1948). However, today, evidence ofan interactive adaptive immune system andthe CNS abounds. Indeed, communication be-tween the CNS and peripheral immune systemis much more fluid than previously consideredand, as such, may substantially affect diseaseprogression in neurological disorders (Ferrariand Tarelli 2011). Peripheral immune responsescan trigger inflammation and exacerbation ofCNS degeneration in several neurodegenerativediseases such as Alzheimers disease (AD), mul-tiple sclerosis (MS), amyotrophic lateral sclero-sis (ALS), stroke, and prion-mediated diseases(Cunningham et al. 2005a,b; Kamer et al.2008; Fiala and Veerhuis 2009; Holmes et al.2009; Lee et al. 2009a; McColl et al. 2009; Realeet al. 2009; Stoll and Bendszus 2009; Teeling andPerry 2009; Heesen et al. 2010; Perry 2010), andparticularly PD (Hasegawa et al. 2000; Arai et al.2006). In those disorders, increasing inflam-mation and breakdown of the bloodbrain bar-rier (BBB) forces increased communication be-tween the CNS and peripheral immune systemsas evidenced in several neurodegenerative dis-eases with increased leukocyte migration withinthe brain parenchyma (Stolp and Dziegielewska2009). Under infectious or inflammatory con-ditions, peripheral immune cells have relativelyunfettered access to the CNS. These immunecells influence neuroinflammation and neuro-degeneration not only in a paracrine fashion,but also in an endocrine fashion. In turn,the CNS is capable of influencing the immuneresponse to pathogens in the periphery throughthe neuroendocrine system. Thus, the immunesystem is not only charged with protectingthe CNS from pathogens and injury, but isalso capable of affecting the functions and ho-meostasis of resident CNS cells, for better orworse. Furthermore, researchers are beginningto harness the neurotrophic effects of the im-mune system to aid in repair and regenerationin the CNS.

    Even under normal conditions, activated Tand B lymphocytes patrol the CNS in low num-bers, whereas nave lymphocytes are excluded(Hickey 1999; Togo et al. 2002; Engelhardt andRansohoff 2005). Although fewer activated Tcells infiltrate the normal CNS than other tis-sues (Yeager et al. 2000), this may be owing tothe low level of adhesion molecules expressedon endothelial cells under normal conditions(Hickey 2001), whereas increased expressionof adhesion molecules leads to increased lym-phocyte infiltration. When cytokines such asinterleukin (IL)-1 and tumor necrosis factor(TNF)-a are secreted by activated glia in thebrain, or are present in circulating blood, per-meability of the BBB is increased and the ex-pression of cellular adhesion molecules (suchas selectins) on microvascular endothelial cellsare up-regulated (Wong et al. 1999). ActivatedT cells and B cells are then able to extravasateand migrate to the site of neuronal injury in in-creased numbers (Aloisi et al. 1999; McGeer andMcGeer 2003; Olson and Miller 2004).

    Indeed, abnormalities in the BBB have beenshown where T-cell infiltration occurs in neuro-AIDS (Petito and Cash 1992; Petito et al. 2003),AD (Rogers et al. 1988; Togo et al. 2002; Desaiet al. 2007), and PD (Farkas et al. 2000). Fur-thermore, whereas the CNS lacks a definedlymphatic system, antigens do exit the CNSvia arachnoid villi, cranial nerves, and spinalnerve root ganglia to lymph (Cserr and Knopf1992). Once in the lymph, these antigens maybe taken up by dendritic cells, processed, andpresented to T and B cells to mobilize an adap-tive immune response to the CNS. Whereasacute neuroinflammation is beneficial to re-gaining homeostasis and normal function ofthe CNS after injury or infection, chronic neu-roinflammation is damaging to the CNS andmay initiate or amplify neurodegeneration as-sociated with HIV-1 encephalitis, AD, or PD.

    Cross-Regulation of Adaptive and InnateImmunity in the CNS

    Innate immunity consists of the immune mech-anisms that are encoded in the germline and arepossessed at birth, and work in a nonspecific

    R.L. Mosley et al.

    2 Cite this article as Cold Spring Harb Perspect Med 2012;2:a009381

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  • manner, for immediate defense against micro-bial infection, notably sepsis (Perry 2011; Ste-arns-Kurosawa et al. 2011). A hosts first lineof defense consists of physical barriers such asskin- and cell-regulated enzymes used to clearpathogens and debris, and serves to remove for-eign substances by phagocytosis, to recruit im-mune cells to sites of infection, to activate thecomplement cascade, but most importantly, toprocess and present antigens for activation ofand recognition by the adaptive immune re-sponse (Kim 2005; Filias et al. 2011; Sakaguchi2011; Sly and Holt 2011; Veerhuis et al. 2011).Its conservation is matched only by its simplic-ity, except for a broad range of selfnonselfpattern-recognition receptors. Such immuneactivation functions are through nonspecific,generic recognition of common cell signalingpathways shared through a host of endogenousand exogenous factors. These pathways aregaining considerable interest in therapeutic de-velopment (Goldman 2007; Basith et al. 2011).Cell debris and foreign matter within the CNSengage toll-like receptors (TLRs), which are ex-pressed by microglia, astrocytes, oligodendro-cytes, as well as by neurons (Lv et al. 2011; Zur-olo et al. 2011). Engagement of TLRs activatessignaling cascades that result in proinflamma-tory cytokine and chemokine production andin effects on the brain directly or indirectlythrough glial or BBB function (Franklin et al.2011; Greenwood et al. 2011; Holman et al.2011; Kacimi et al. 2011).

    The innate immune system also is linked toits adaptive arm through the abilities to providerequired signals for antigen presentation andto act as final effectors by T-cell-mediated re-sponses in the CNS. The interrelationships be-tween innate and adaptive immunity permitthe host to recognize environmental and exoge-nous cues and work in concert to protect andsustain the host. Central to the innate immunenetwork are microglia (Perry 2011). They se-crete bot

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