Table 1.

Main autoantibodies suspected to play a direct role in neurological symptoms

Antigen	Nature of the antigen	Number of described cases	Clinical syndrome	Tumour association	Described mechanisms
NMDAR	Ionotropic Glutamate Receptor	> 500 (Titulaer et al., 2013)	Psychiatric symptoms (anxiety, abnormal behaviour, delusion) and/or neurological symptoms (seizures, movement disorders, altered mental state, short-term memory loss), autonomic instabilities (Titulaer et al., 2013).	Age-dependent, up to 40% (ovarian teratoma) in young women (Titulaer et al., 2013)	Antibodies disrupt NMDAR function by cross-linking and internalization of receptors (Hughes et al., 2010; Mikasova et al., 2012). In vitro: reduced surface expression (Hughes et al., 2010), disrupted interaction with EphB2R (Mikasova et al., 2012). In vivo: hyperactivity of glutamatergic pathway (Manto et al., 2010), reduced number of NMDAR clusters (Hughes et al., 2010), impaired memory and depression-like behaviour (Planaguma et al., 2014).
AMPAR	Ionotropic Glutamate Receptor	≈58 (Lai et al., 2009; Bataller et al., 2010; Graus et al., 2010; Wei et al., 2013; Gleichman et al., 2014; Spatola et al., 2014; Hoftberger et al., 2015; Joubert et al., 2015)	Four distinct clinical presentations: classical limbic encephalitis, diffuse encephalitis, fulminant encephalitis, psychiatric presentation (Hoftberger et al., 2015; Joubert et al., 2015)	34% (thymus, breast, lung)	In vitro: antibody-induced internalization of AMPAR (Lai et al., 2009; Peng et al., 2015), reduced excitatory transmission (Gleichman et al., 2014).
mGluR1	Metabotropic Glutamate Receptor	5 (Sillevis Smitt et al., 2000; Marignier et al., 2010; Lancaster et al., 2011b; Iorio et al., 2013)	Cerebellitis with cerebellar ataxia, balance and gait disturbances, dysarthria and nystagmus	2 cases with Hodgkin’s lymphoma (Sillevis Smitt et al., 2000), 1 case with prostate adenocarcinoma (Iorio et al., 2013)	In vitro: blockage of mGluR1 activation (Sillevis Smitt et al., 2000), reduced cerebellar LTD (Coesmans et al., 2003). In vivo: severe but transient ataxia induced by patients’ IgG infusion in mice (Sillevis Smitt et al., 2000), impaired compensatory eye movement (Coesmans et al., 2003).
mGluR5	Metabotropic Glutamate Receptor	4 (Lancaster et al., 2011b; Mat et al., 2013; Pruss et al., 2014)	Limbic encephalitis	3 cases with Hodgkin’s lymphoma (Lancaster et al., 2011b; Mat et al., 2013)	No experimental study available.
GABAAR	Ligand-gated ion Channel	≈35 (Ohkawa et al., 2014; Petit-Pedrol et al., 2014; Pettingill et al., 2015)	Encephalitis with refractory seizures	2 cases with thymoma (Ohkawa et al., 2014), 1 case with a neuroepithelial tumour (Pettingill et al., 2015)	In vitro: reduction of GABAAR synaptic density (Ohkawa et al., 2014; Petit-Pedrol et al., 2014; Pettingill et al., 2015), reduced inhibitory currents (Ohkawa et al., 2014).
GABABR	Metabotropic Receptor	≈67 (Lancaster et al., 2010; Boronat et al., 2011; Höftberger et al., 2013a,b; Jeffery et al., 2013; Kim et al., 2014)	Limbic encephalitis with prominent seizures	50% (small-cell lung cancer) (Höftberger et al., 2013a,b)	In vitro: blockage of GABABR activation by baclofen without decrease of surface GABABRs (Jain et al., 2015)
GlyR	Chloride pentameric channel	≈77 (Hutchinson et al., 2008; Clerinx et al., 2011; Mas et al., 2011; Turner et al., 2011; Iizuka et al., 2012; Damásio et al., 2013; Kyskan et al., 2013; McKeon et al., 2013; Carvajal-González et al., 2014; Kenda et al., 2015; Bourke et al., 2014; Carvajal-González et al., 2014)	Stiff-person syndrome & progressive encephalomyelitis with rigidity and myoclonus	≈20% (thymoma, lymphoma, malignant melanoma, breast cancer)	In vitro: internalization of GlyR by GlyR in recombinant cellular model (Wuerfel et al., 2014).
LGI1	Secreted Protein	> 150 (Irani et al., 2010, 2011; Lai et al., 2010; Ohkawa et al., 2013; Shin et al., 2013)	Encephalitis with limbic (amnesia, behavioural alterations, seizures) and extra-limbic symptoms	No consistent tumour association	In vitro: patients’ LGI1 antibodies impair LGI1 binding to partner proteins and decrease synaptic AMPAR expression (Ohkawa et al., 2013)
Caspr2	Adhesion Protein	95 (Irani et al., 2010, 2012; Lancaster et al., 2011a; Klein et al., 2013)	Limbic encephalitis, Morvan’s syndrome	50% (thymoma) (Irani et al., 2012)	In vitro: Caspr2 antibodies from patients with limbic encephalitis alter gephyrin clusters (Pinatel et al., 2015).
DPPX	Membrane glycoprotein	28	Pronounced gastrointestinal symptoms, agitation, hallucinations, confusion, myoclonus, tremor and seizures, sleep-disturbance, PERM-like syndrome	No tumour associations reported	In vitro: patient’s IgG reduce expression of DPPX and Kv4.2 in cultured neurons (Piepgras et al., 2015).
Amphiphysin	Synaptic vesicle protein	> 35 (Antoine et al., 1999; Murinson & Guarnaccia, 2008; Moon et al., 2014)	Stiff-person syndrome	≈90% (breast cancer)	In vivo: transfer of IgG from patients to rat causes muscles stiffness and spasms (Sommer et al., 2005).
GAD	GABA synthesis enzyme	> 100 (Saiz et al., 2008; Ariño et al., 2015; Fouka et al., 2015)	Limbic encephalitis, cerebellitis	Usually none. Associated with neuroendocrine tumours and lung cancer (Ariño et al., 2014) in 2 case series (Saiz et al., 2008; Ariño et al., 2014).	In vitro: autoantibodies uptake in heterologous cell systems expressing GAD-65 (Hampe et al., 2013). In vivo: altered behaviour induced by GAD antibodies transfer to rodents (Manto et al., 2007, 2015; Hampe et al., 2013).
VGCC	Calcium channel	> 40 (Mason et al., 1997; Lorenzoni et al., 2008; Bürk et al., 2010; Ogawa et al., 2011)	Cerebellar ataxia	Small cell lung carcinoma	In vivo: passive transfer of patients’ antibodies to mice induces acute ataxia (Martín-García et al., 2013).
Tr/DNER	Neuron-specific signalling protein	> 40 (Graus et al., 1997; de Graaff et al., 2012; Probst et al., 2015)	Cerebellar ataxia	≈90% (Hodgkin’s lymphoma)	No experimental study available.