IgG entry and deposition are components of the neuroimmune response in Batten disease.
Patients and a mouse model of Batten disease, the juvenile form of neuronal ceroid lipofuscinosis (JNCL), raise autoantibodies against GAD65 and other brain-directed antigens. Here we investigate the adaptive component of the neuroimmune response. Cln3(-/-) mice have autoantibodies to GAD65 in their cerebrospinal fluid and elevated levels of brain bound immunoglobulin G (IgG). IgG deposition was found within human JNCL autopsy material, a feature that became more evident with increased age in Cln3(-/-) mice. The lymphocyte infiltration present in human and murine JNCL occurred late in disease progression, and was not capable of central/intrathecal IgG production. In contrast, we found evidence for an early systemic immune dysregulation in Cln3(-/-) mice. In addition evidence for a size-selective breach in the blood-brain barrier integrity in these mice suggests that systemically produced autoantibodies can access the JNCL central nervous system and contribute to a progressive inflammatory response.
Lim
Ming J
MJ
Pediatric Storage Disorders Laboratory, Department of Neuroscience and Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
Alexander
Noreen
N
Benedict
Jared W
JW
Chattopadhyay
Subrata
S
Shemilt
Stephen J A
SJ
Guérin
Christopher J
CJ
Cooper
Jonathan D
JD
Pearce
David A
DA
D000818:Animals; D001323:Autoantibodies / Q000134:cerebrospinal fluid*; D001812:Blood-Brain Barrier / Q000276:immunology / Q000503:physiopathology; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D004660:Encephalitis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007527:Isoenzymes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics; D015213:Neuroimmunomodulation / Q000276:immunology*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000503:physiopathology
D001323:Autoantibodies; C102229:CLN3 protein, mouse; D007074:Immunoglobulin G; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2