TY - JOUR
T1 - IgG entry and deposition are components of the neuroimmune response in Batten disease
AU - Lim, Ming J.
AU - Alexander, Noreen
AU - Benedict, Jared W.
AU - Chattopadhyay, Subrata
AU - Shemilt, Stephen J.A.
AU - Guérin, Christopher J.
AU - Cooper, Jonathan D.
AU - Pearce, David A.
N1 - Funding Information:
We would like to thank Andrew Serour and Timothy Curran for their excellent technical assistance; Drs. Jaana Tyynelä and Matti Haltia, University of Helsinki for providing human JNCL autopsy material; Dr. James Powers for useful discussions and Dr. Alison Barnwell for constructive comments on the manuscript. These studies were supported by National Institutes of Health grants NS044310 (D.A.P.), NS041930 European Commission 6th Framework Research Grant LSHM-CT-2003-503051 (J.D.C.), the WellChild Training Fellowship of the UK Royal College of Paediatrics and Child Health (M.J.L.) and grants from the JNCL Research Fund (D.A.P.), Batten Disease Support and Research Association (J.D.C., C.J.G., D.A.P.), and grants to J.D.C. from The Natalie Fund, Batten Disease Family Association, Batten Disease Research Trust and the Remy Fund.
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - Batten disease
KW - Blood-brain barrier
KW - Brain-directed autoantibody
KW - GAD65 autoantibody
KW - Neuroinflammation
KW - Neuronal ceroid lipofuscinoses
UR - https://www.scopus.com/pages/publications/33846451748
U2 - 10.1016/j.nbd.2006.09.005
DO - 10.1016/j.nbd.2006.09.005
M3 - Article
C2 - 17070688
AN - SCOPUS:33846451748
SN - 0969-9961
VL - 25
SP - 239
EP - 251
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -