autoimmunity refers to the immunological destruction of the own cells and tissues due to the failure of the organism to recognize these as self .
autoimmune diseases cover a great variety of symptoms reaching from diffuse inflammatory symptoms involving components of the innate immune system to highly antigen - specific t- and b - lymphocyte responses . both types of autoimmunity can appear restricted to defined structures in local tissues or systemically ( mcgonagle and mcdermott 2006 ) .
genetic predisposition to overshooting immunity either by a loss of tolerance to self - antigens ( e.g. by deficit of thymic selection , regulatory t cells ) or increased sensitivity thresholds ( e.g. by increased immune receptor signaling ) may explain why some but not all individuals develop autoimmunity at one point of their life time .
however , it can not explain why the symptoms start at a certain time point .
therefore , additional environmental factors such as noxes , injury or infections have been discussed to trigger the loss of self - tolerance and thereby the onset of disease ( bach 2005 ; chervonsky 2010 ) .
the same recognition system responsible to initiate anti - microbial immune responses against foreign antigens may then be triggered in a bystander fashion against harmless auto - antigens or the infectious environment may modify auto - antigens into chemically altered self - antigens that then appear as foreign antigens . evolutionarily conserved pathogen - associated molecular patterns ( pamps ) on microbes or danger - associated molecular patterns ( damps ) released after tissue damage are recognized by different families of immune receptors , summarized under the name pattern recognition receptors ( prrs ) , with the toll - like receptors ( tlrs ) as their most prominent representatives ( mills 2011 ) .
first , genetic alterations in such receptors or other immune - related genes could lower the threshold for immune activation against harmless self - antigens .
second , cross - reactivity of microbial structures with self - antigens ( molecular mimicry ) may occur ( chastain and miller 2012 ) and , finally , exogenous noxes or infections by viruses ( bianchi et al .
2007 ; ferri et al . 2008 ; lunemann and munz 2007 ; munz et al .
2009 ) , bacteria ( root - bernstein et al . 2009 ) or fungi ( romani 2008 ) may be responsible for chronic inflammatory processes promoting auto - aggression via bystander activation or epitope - spreading ( delogu et al .
more recent data indicate that proteins may in fact represent only a minor source of antigens that contribute to molecular mimicry . with the increasing identification of c - type lectin receptors as prrs for sugars and lipids , their role as auto - antigens turned into the center of attention ( buzas et al .
antibodies against campylobacter jejuni gangliosides cross react with some human gangliosides , mostly gm1 and gd1 ( hughes and cornblath 2005 ; nores et al . 2008 ) .
the antibodies found are igg type produced only after the isotype switch of b cells ( yuki and odaka 2005 ) , which strictly require cd4 t - cell help .
t - cell activation of dendritic cell ( dc ) can occur by c. jejuni gangliosides , but presentation of the glycolipids on mhc class ii molecules is not possible ( kuijf et al .
2010 ) . how can igg antibodies then be generated against glycolipids that are not presented on mhc ii molecules to differentiate t helper cells ?
nkt cells recognize glycolipids and can produce similar cytokine patterns as cd4 t cells that are involved in b - cell cytokine switches ( brigl and brenner 2004 ) .
they may be substitute the classical cd4 t - helper cells as shown after injection of mice with -galactosylceramide , a prototype glycolipid antigen for nkt cells ( lang et al .
2006 ) and thereby help to generate glycolipid - specific igg antibodies without antigen - specific cd4 t - cell help .
alternatively , soluble factors present in the supernatant of the glycolipid - activated dcs may directly be able to circumvent both t cell and nkt cell help ( kuijf et al .
despite the fact that the cns is the target organ for auto - reactive t cells in multiple sclerosis ( ms ) , the t - cell priming event is postulated to occur in peripheral tissues ( goverman 2009 ) . whether these primed t cells and subsequently b cells have been primed directly against cns antigens
it is also conceivable that they responded to a virus infection , where specific viruses gained access to the cns .
especially for ebv , higher igg antibody titers had been measured in cerebrospinal fluid as compared to peripheral blood ( haahr and hollsberg 2006 ) , potentially indicating that a cerebral infection would be target also for a t - cell response .
the intrathecal demonstration of oligoclonal igg bands from ms patients by electrophoretic profiling can be used for diagnosis .
however , the simultaneous increase of iggs against different viruses may rather indicate a generalized inflammatory reponse , because infections enhance only monospecific iggs directed against the pathogen ( boucquey et al .
in fact , binding of these antibodies to viral target structures in the cns has not been demonstrated .
nevertheless , indirect microbial promotion of autoimmunity is highly evident , as , for example , impressively shown by clear influence of intestinal tract commensals on experimental autoimmune encephalomyelitis ( eae ) , a murine model for the early inflammatory stages of ms ( berer et al .
together , a definitive proof , which directly links virus infections with cns autoimmunity , is still lacking .
more recent data indicate that cerebrospinal fluid of ms patients also contains increased levels of selected glycolipids such as sulfatide and , interestingly , oxidized cholesterol and phosphocholine as well as asialo gm1 when compared to healthy controls ( kanter et al .
sulfatide has been shown to associate with cd1d antigen - presenting molecules of mice ( zajonc et al .
thus , also in ms rather glycolipids than proteins might represent targets of autoimmune attack , especially when oxidation of glycolipids converts them to altered self - antigens .
more recent data indicate that proteins may in fact represent only a minor source of antigens that contribute to molecular mimicry . with the increasing identification of c - type lectin receptors as prrs for sugars and lipids , their role as auto - antigens turned into the center of attention ( buzas et al .
antibodies against campylobacter jejuni gangliosides cross react with some human gangliosides , mostly gm1 and gd1 ( hughes and cornblath 2005 ; nores et al . 2008 ) .
the antibodies found are igg type produced only after the isotype switch of b cells ( yuki and odaka 2005 ) , which strictly require cd4 t - cell help .
t - cell activation of dendritic cell ( dc ) can occur by c. jejuni gangliosides , but presentation of the glycolipids on mhc class ii molecules is not possible ( kuijf et al .
2010 ) . how can igg antibodies then be generated against glycolipids that are not presented on mhc ii molecules to differentiate t helper cells ?
nkt cells recognize glycolipids and can produce similar cytokine patterns as cd4 t cells that are involved in b - cell cytokine switches ( brigl and brenner 2004 ) .
they may be substitute the classical cd4 t - helper cells as shown after injection of mice with -galactosylceramide , a prototype glycolipid antigen for nkt cells ( lang et al . 2006 ) and thereby help to generate glycolipid - specific igg antibodies without antigen - specific cd4 t - cell help . alternatively
, soluble factors present in the supernatant of the glycolipid - activated dcs may directly be able to circumvent both t cell and nkt cell help ( kuijf et al .
despite the fact that the cns is the target organ for auto - reactive t cells in multiple sclerosis ( ms ) , the t - cell priming event is postulated to occur in peripheral tissues ( goverman 2009 ) . whether these primed t cells and subsequently b cells have been primed directly against cns antigens
it is also conceivable that they responded to a virus infection , where specific viruses gained access to the cns .
especially for ebv , higher igg antibody titers had been measured in cerebrospinal fluid as compared to peripheral blood ( haahr and hollsberg 2006 ) , potentially indicating that a cerebral infection would be target also for a t - cell response .
the intrathecal demonstration of oligoclonal igg bands from ms patients by electrophoretic profiling can be used for diagnosis .
however , the simultaneous increase of iggs against different viruses may rather indicate a generalized inflammatory reponse , because infections enhance only monospecific iggs directed against the pathogen ( boucquey et al .
in fact , binding of these antibodies to viral target structures in the cns has not been demonstrated .
nevertheless , indirect microbial promotion of autoimmunity is highly evident , as , for example , impressively shown by clear influence of intestinal tract commensals on experimental autoimmune encephalomyelitis ( eae ) , a murine model for the early inflammatory stages of ms ( berer et al .
together , a definitive proof , which directly links virus infections with cns autoimmunity , is still lacking .
more recent data indicate that cerebrospinal fluid of ms patients also contains increased levels of selected glycolipids such as sulfatide and , interestingly , oxidized cholesterol and phosphocholine as well as asialo gm1 when compared to healthy controls ( kanter et al .
sulfatide has been shown to associate with cd1d antigen - presenting molecules of mice ( zajonc et al .
thus , also in ms rather glycolipids than proteins might represent targets of autoimmune attack , especially when oxidation of glycolipids converts them to altered self - antigens .
dcs are heterogenous antigen - presenting cells of the immune system that play an important role in the initiation of innate and adaptive immune responses . from one side ,
dcs are being considered as inflamers of immune response against microbial pathogens but also unwanted organ graft rejection and autoimmunity , on the other side they are supposed to induce and even maintain tolerance to antigens ( morelli and thomson 2007 ; steinman and nussenzweig 2002 ) .
tolerogenic or immunogenic functions of dcs depend on their stage of differentiation / maturation but are independent of hematopoietic origin or subset classification ( thomson and robbins 2008 ) .
some authors claim that the endogenous environment itself may generate factors , which decide for an immune response initiated by the dcs or the maintenance of tolerance ( matzinger 2002 ) .
although immature mdcs capture and process antigens to present them to nave t cells to low extends , effector t cells are not generated by them and rather tolerogenic mechanisms such as t - cell anergy or induction of regulatory t cells dominate to downregulate immune responses .
these dcs can inhibit alloantigen - specific t - cell responses , reverse autoimmune diseases in murine models and induce antigen - specific t - cell tolerance ( thomson and robbins 2008 ) .
in contrast , following a powerful immunological stimulus ( such as contact with transplants or allergens , products associated with microbes or inflammation ) immature dcs become mature and migrate to the respective lymph node , prime and stimulate expansion of antigen - specific t cells , and present intact proteins to b cells for their activation and subsequent antibody production ( cravens and lipsky 2002 ) . activated t cells and antibodies
are carried by blood to affected tissues . in autoimmune responses , these attack host proteins .
dendritic cells also regulate immune responses against self - antigens via mechanisms such as differentiation of t - regulatory cells , t - cell anergy and clonal deletion of effector t cells which are specific for such antigens ( platt and randolph 2010 ) .
autoimmunity happens in environments where these regulatory mechanisms fail to control t - cell responses directed against the self - antigens . whereas subclinical forms of autoimmunity are frequent processes , prolonged activation of autoreactive lymphocytes
is requested for the development of an autoimmune disease and accompanies ongoing tissue damage ( ludewig et al .
although genetic components predispose people or animals for autoimmune diseases , trauma or tissue injury further contributes to promote autoimmunity through damps ( manfredi et al .
, however , is associated with viral and bacterial infections ( regner and lambert 2001 ) , which either trigger ( miller et al .
manifested autoimmunity may also depend on the number of dcs presenting self - antigens and the duration of antigen presentation by dcs , suggesting a crucial role of dcs for the development of clinical autoimmune diseases ( ludewig et al .
the involvement of dcs in autoimmune diseases includes hashimoto thyroiditis and grave s disease , psoriasis , sjgren s syndrome , rheumatoid arthritis and multiple sclerosis ( cravens and lipsky 2002 ) .
the presence of dcs in the healthy cns is restricted to the vascular - rich compartments such as the choroid plexus and meninges ( mcmenamin 1999 ) .
2001 ) . upon local inflammation of the cns due to infection , cell death or autoimmunity ,
there is so far no consensus on whether dcs in the cns parenchyma come from the periphery ( lande et al . 2008 ; zozulya et al .
2010 ) or may arise from resident microglia ( fischer and reichmann 2001 ) and monocytes ( randolph et al .
1998 ) or whether they migrate from immature dc in the choroid plexus and meninges .
the problem arises from the common surface markers on macrophages , microglia and dc subpopulations as well as that they all require the same survival factors in cultures ( mcmahon et al .
, it has been shown that dcs recruited to the inflammation sites in cns maintain their ability to migrate to the periphery with cns autoantigens and prime nave t cells ( de vos et al .
involvement of dcs has been described in rodents with eae , an animal model that resembles ms in humans , where they are discussed as the likely candidate for the initiation and progression of autoimmune reactions by t cells ( mcmahon et al .
studies showed that an expansion of dcs following flt3-ligand treatment ( flt3l / cd135 , a growth factor that regulates proliferation of early hematopoietic cells ) is associated with enhancement of clinical symptoms and increase of t cell and dcs infiltrates in cns ( greter et al .
2005 ) . on the other hand , a reduction of dcs after flt3-l inhibition has been shown to correlate with reduction of severity of disease ( whartenby et al .
elevated numbers of dcs that secreted pro - inflammatory cytokines were found in peripheral blood of humans suffering from ms ( huang et al .
also in csf , increased numbers of dcs were observed and correlated with common factors of cns inflammation ( pashenkov et al .
although active recruitment and accumulation of dcs into cns lesions of ms patients ( lande et al . 2008 ) as well as alterations in the interaction between dcs and t cells in ms patients have been reported ( stasiolek et al .
2006 ) , details in the involvement of dcs in ms are so far unknown .
the destruction of dopaminergic neurons in pd has been connected to a variety of factors , including genetic , environmental and immunologic conditions .
genetic factors have been identified in familiar forms of pd , which contribute to about 10  % of pd cases ( lesage and brice 2009 ; rosner et al .
2008 ) , and pesticides have been identified as environmental risk factors in pd pathogenesis ( liu et al . 2003 ; uitti and calne 1993 ) . moreover , intravenous drug abuse with meperidine - related substances contaminated with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine ( mptp ) triggers acute destruction of dopaminergic neurons and pd ( langston et al .
, evidence for an immunologic background of pd has been accumulated , on which we will focus here .
several studies show that pd pathogenesis is associated with neuroinflammation ( mcgeer and mcgeer 2004 ) , which is the prerequisite for the maturation of dcs and their migration to the respective sites in the brain . following these steps , dcs could be able to trigger an autoimmune response by transferring brain antigens into the cervical lymph nodes and presenting them to t- and b - cells .
early experimental evidence in favor of an autoimmune background of pd came from chen et al .
( 1998 ) who reported that the transfer of plasma antibodies isolated from pd patients to the substantia nigra of rats induced a marked loss of dopaminergic neurons .
in contrast , animals treated with antibodies from healthy controls exhibited much lower neuronal damage , suggesting that autoantibodies that recognize dopaminergic cells are present in patients with pd ( chen et al . 1998 ) . in the last decade ,
several autoantibodies directed at antigens associated or related to pd pathogenesis have been identified in pd patients , including antibodies directed at melanin ( double et al .
reversible parkinsonian syndrome together with the presence of anti - neuronal antibodies has been observed in an ebv - infected patient ( roselli et al .
autoreactive antibodies associated with pd have not only been found in plasma but also in brain : post - mortem analysis of brains from pd patients and controls showed binding of igg to dopaminergic neurons in tissues from patients with pd ( orr et al .
one potential target structure for an immune attack against dopaminergic neurons is the pigment neuromelanin ( nm ) that accumulates in dopaminergic neurons as a byproduct of catecholamine metabolism from oxidative polymerization of dopamine and norepinephrine to quinones ( graham 1979 ) .
we described recently that nm triggers maturation of dcs in vitro and that this maturation is functional as nm - treated dcs were able on their turn to trigger a proliferative t response .
these experiments demonstrate that the first necessary criteria for dcs to initiate an adaptive autoimmune response directed against nm - associated structures are fullfilled . as depicted in fig .  1 , we hypothesize that activated dcs migrate from the brain into the cervical lymph node where they present the potential ( auto- ) antigens to t and b cells .
the recognition of nm as a pathogen or dangerous molecule and its uptake by dcs would allow dc migration and its presentation in the cervical lymph nodes , thereby triggering an adaptive autoimmune response if nm - reactive t or b cells are present .
this autoimmune response against nm would be directed against nm - rich cells in the brain , leading to dopaminergic cell death ( fig .  1 ) .
this auto - aggressive loop would be enhanced by a nm - triggered activation of microglia , which has been described before ( wilms et al .
2011 ) , resulting in an amplification of the adaptive immune response against nm and the local reactivation of immigrating effector t cells ( fig .  1 ) .
there is accumulating evidence for an immunogenic role of nm in pd pathogenesis : in sera from pd patients antibodies directed at catecholamine - based melanins have been detected ( double et al .
2009 ) . moreover , post - mortem analysis of brains from pd patients reveals the opsonization of nm with complement c1q ( depboylu et al .
2011 ) , indicating that nm is recognized by the classical complement pathway as a target structure and shows the capacity to cause neuroinflammation ( mcgeer and mcgeer 2004 ) .
opsonization with c1q is either mediated by previous antibody coating of the target structure followed by recruitment of c1q to the fc - part of the antibody or by direct binding to c1q ligands ( kojouharova et al .
it remains to be elucidated whether c1q - binding of nm is antibody - dependent or independent and to what extend this complement binding contributes to neuronal cell death .
danger transmitters  to evoke immune responses following danger signals has been discussed thoroughly elsewhere ( kohl 2006 ) .
in addition to an immune response directed at nm itself , the high protein affinity of nm ( zecca et al . 2000 ) , together with the efficient phagocytosis of nm by dcs ( oberlander et al .
2011 ) would allow a dc - mediated presentation of neuronal proteins to the adaptive immune system that are primarily unrelated to nm . in this scenario , nm would act like a trojan horse , providing access of otherwise unrecognized brain proteins to the dc - triggered adaptive immune response.fig . 
contact of dcs with nm triggers maturation of these cells that subsequently migrate from the brain into the cervical lymph nodes where they present nm to b- and t - lymphocytes .
if nm - reactive lymphocytes are present , they get activated ( primed ) and secrete nm - specific antibodies ( b cells ) or exert nm - specific cytotoxic functions ( t cells ) .
activation of microglia by nm would result in a proliferation of nm - specific t cells after contact with nm - presenting microglia .
nm - specific antibodies and t cells may recognize nm - positive neurons and trigger their degradation how activation of dcs by nm could trigger autoimmunity directed at dopaminergic neurons .
contact of dcs with nm triggers maturation of these cells that subsequently migrate from the brain into the cervical lymph nodes where they present nm to b- and t - lymphocytes .
if nm - reactive lymphocytes are present , they get activated ( primed ) and secrete nm - specific antibodies ( b cells ) or exert nm - specific cytotoxic functions ( t cells ) .
activation of microglia by nm would result in a proliferation of nm - specific t cells after contact with nm - presenting microglia .
nm - specific antibodies and t cells may recognize nm - positive neurons and trigger their degradation
the past decade has provided accumulating evidence for a significant role of the immune system in pd pathogenesis , be it either through inflammation or by an autoimmune response .
thus , immunomodulating therapy strategies aiming to attenuate pd disease progression become an attractive option and warrant further investigation .
 innate and adaptive immune responses in neurodegenerative diseases have become recently a focus of research and discussions . 
 parkinson s disease ( pd ) is a neurodegenerative disorder without known etiopathogenesis . 
 the past decade has generated evidence for an involvement of the immune system in pd pathogenesis . 
 both inflammatory and autoimmune mechanisms have been recognized and studies have emphasized the role of activated microglia and t - cell infiltration . in this short review , 
 we focus on dendritic cells , on their role in initiation of autoimmune responses , we discuss aspects of neuroinflammation and autoimmunity in pd , and we report new evidence for the involvement of neuromelanin in these processes . 
Theories on initiation of autoimmunity
Glycolipids as a source of autoantigens
Oxidized glycolipids as altered self-antigens
Relevance of dendritic cells (DCs) in autoimmunity
DCs and CNS autoimmunity
Autoimmunity in Parkinsons disease
Conclusions