IgG entry and deposition are components of the neuroimmune response in Batten disease

Lim, Ming; Alexander, Noreen A.; Benedict, Jared W.; Chattopadhyay, Subrata; Shemilt, Stephen J. A.; Guérin, Christopher J.; Cooper, Jonathan D.; Pearce, David A.

doi:10.1016/j.nbd.2006.09.005

Cited by 53 publications

(43 citation statements)

References 56 publications

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“…GAD65-antibodies became undetectable in these patients after initiation of the treatment, suggesting that systematically produced GAD65-antibodies worsen the motor symptoms of older patients. This is in agreement with an earlier study [181] that evaluated the deposition of antibodies in the CNS in one autopsy brain of a CLN3 disease, juvenile patient (no genotype specified). GAD65-antibodies were assumed to occur late in the disease process as result of the invasion of systematically produced antibodies into the CNS.…”

Section: Immune Therapysupporting

confidence: 93%

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Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Kohan¹,

Cismondi²,

Oller-Ramírez³

et al. 2011

CPB

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The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally with recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 269 mutations and 49 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

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Section: Immune Therapysupporting

confidence: 93%

“…In contrast, early systemic immune dysregulation was detected in Cln3 −/− mice. In addition, evidence for a sizeselective breach in the BBB integrity in these mice suggested that systemically produced auto-antibodies can access the CLN3 disease, juvenile CNS and contribute to a progressive inflammatory response [181].…”

Section: Immune Therapymentioning

confidence: 99%

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Kohan¹,

Cismondi²,

Oller-Ramírez³

et al. 2011

CPB

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“…This may reflect loss of barrier integrity and consequent GAD65 exposure to the immune system. Indeed, evidence of impaired barrier function has been reported recently for the Cln3 ⌬ex1-6 mouse model (Lim et al, 2007). Thus, loss of a basic function performed by CLN3 in brain endothelial cells might compromise the integrity of the BBB and contribute to JNCL pathology.…”

Section: Discussionmentioning

confidence: 93%

A Knock-In Reporter Model of Batten Disease

Eliason¹,

Stein²,

Mao³

et al. 2007

J. Neurosci.

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Juvenile neuronal ceroid lipofuscinosis is a severe inherited neurodegenerative disease resulting from mutations in CLN3 (ceroidlipofuscinosis, neuronal 3, juvenile). CLN3 function, and where and when it is expressed during development, is not known. In this study, we generated a knock-in reporter mouse to elucidate CLN3 expression during embryogenesis and after birth and to correlate expression and behavior in a CLN3-deficient mouse. In embryonic brain, expression appeared in the cortical plate. In postnatal brain, expression was prominent in the cortex, subiculum, parasubiculum, granule neurons of the dentate gyrus, and some brainstem nuclei. In adult brain, reporter gene expression waned in most areas but remained in vascular endothelia and the dentate gyrus. Mice homozygous for Cln3 deletion showed two hallmark pathological features of the neuronal ceroid lipofuscinosises: autofluorescent inclusions and lysosomal enzyme elevation. Moreover, CLN3-deficient reporter mice displayed progressive neurological deficits, including impaired motor function, decreased overall activity, acquisition of resting tremors, and increased susceptibility to pentilentetrazole-induced seizures. Notably, seizure induction in heterozygous mice was accompanied by enhanced reporter expression. This model provides us with the unique ability to correlate expression with pathology and behavior, thus facilitating the elucidation of CLN3 function and the pathogenesis of Batten disease.

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“…Over the last decade, we have been characterizing each of the available mouse models of NCL, documenting the onset and progression of pathological changes [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and testing the efficacy of a range of therapeutic interventions [35][36][37][38]. Our studies have revealed a number of new and surprising pathological features that are broadly shared by the different forms of NCL, but with subtype-specific differences in the staging of these events and some more pronounced differences between certain forms of NCL.…”

Section: What Do We Know About Ncl Pathogenesis So Far?mentioning

confidence: 99%

The neuronal ceroid lipofuscinoses: the same, but different?

Cooper

2010

Biochemical Society Transactions

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The NCLs (neuronal ceroid lipofuscinoses) (also known as Batten disease) are a group of at least ten fatal inherited storage disorders. Despite the identification of many of the disease-causing genes, very little is known about the underlying disease mechanisms. However, now that we have mouse or large-animal models for most forms of NCL, we can investigate pathogenesis and compare what happens in the brain in different types of the disease. Broadly similar neuropathological themes have emerged, including the highly selective nature of neuron loss, early effects upon the presynaptic compartment, together with an early and localized glial activation. These events are especially pronounced within the thalamocortical system, but it is clear that where and when they occur varies markedly between different forms of NCL. It is now becoming apparent that, despite having pathological endpoints that resemble one another, these are reached by a sequence of events that is specific to each subtype of NCL.

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IgG entry and deposition are components of the neuroimmune response in Batten disease

Cited by 53 publications

References 56 publications

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

A Knock-In Reporter Model of Batten Disease

The neuronal ceroid lipofuscinoses: the same, but different?

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