Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain.

Darnell, Robert B.

doi:10.1073/pnas.93.10.4529

Cited by 256 publications

(145 citation statements)

References 99 publications

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“…The fixed tissue was placed in phosphate buffered saline (PBS) containing 2% Triton X-100 for roughly 6 hr and then placed in antibody diluent (PBS with 0.3% Triton X-100, 5.0% goat serum and 0.05% sodium azide) containing HNK-1 (ascites produced from cells obtained from American Type Culture Collection ([ATCC], Manassas, VA; 1/1,000), human anti-Hu (1/1,000; Fairman et al, 1995), and mouse anti-␤ (III)-tubulin (1/500; Lee et al, 1990a,b) for 12-24 hr at 4°C. Hu recognizes a family of RNA-binding proteins (Darnell, 1996;Okano and Darnell, 1997), and ␤ (III)-tubulin is an isoform of tubulin unique to neurons (Lee et al, 1990a,b). Tissues were washed and incubated in a mixture of goat anti-mouse immunoglobulin (Ig) M-Texas Red (1/100; -specific, Jackson Labs, West Grove, PA), goat anti-mouse CY2 (1/100; ␥ specific, Jackson Labs), and goat anti-human IgG-Alexa 488 (1/100; Molecular Probes, Eugene, OR).…”

Section: Methodsmentioning

confidence: 99%

Appearance of neurons and glia with respect to the wavefront during colonization of the avian gut by neural crest cells

Conner

Focke

Noden

et al. 2002

Developmental Dynamics

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The enteric nervous system is formed by neural crest cells that migrate, proliferate, and differentiate into neurons and glia distributed in ganglia along the gastrointestinal tract. In the developing embryo some enteric crest cells cease their caudal movements, whereas others continue to migrate. Subsequently, the enteric neurons form a reticular network of ganglia interconnected by axonal projections. We studied the developing avian gut to characterize the pattern of migration of the crest cells, and the relationship between migration and differentiation. Crest cells at the leading edge of the migratory front appear as strands of cells; isolated individual crest cells are rarely seen. In the foregut and midgut, these strands are located immediately beneath the serosa. In contrast, crest cells entering the colon appear first in the deeper submucosal mesenchyme and later beneath the serosa. As the neural crest wavefront passes caudally, the crest cell cords become highly branched, forming a reticular lattice that presages the mature organization of the enteric nervous system. Neurons and glia first appear within the strands at the advancing wavefront. Later neurons are consistently located at the nodes where branches of the lattice intersect. In the most rostral foregut and in the colon, some neurons initially appear in close association with extrinsic nerve fibers from the vagus and Remak's nerve, respectively. We conclude that crest cells colonize the gut as chains of cells and that, within these chains, both neurons and glia appear close to the wavefront. Developmental Dynamics 226:91-98, 2003.

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Section: Methodsmentioning

confidence: 99%

Appearance of neurons and glia with respect to the wavefront during colonization of the avian gut by neural crest cells

Conner

Focke

Noden

et al. 2002

Developmental Dynamics

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“…Several autoantibodies associated with PND are directed against various nervous system antigens, including a group of proteins with potential roles in the signal transduction pathway (Darnell, 1996). The discovery of anti-CV2 autoantibodies allowed us to identify Ulip/CRMP proteins as potential targets for these autoantibodies (Honnorat et al, 1999).…”

Section: Molecular and Cellular Characterization Of Ulip6/crmp5mentioning

confidence: 99%

Isolation and Expression Pattern of Human Unc-33-Like Phosphoprotein 6/Collapsin Response Mediator Protein 5 (Ulip6/CRMP5): Coexistence with Ulip2/CRMP2 in Sema3A- Sensitive Oligodendrocytes

Ricard¹,

Rogemond²,

Charrier³

et al. 2001

J. Neurosci.

124

104

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The Unc-33-like phosphoprotein/collapsin response mediator protein (Ulip/CRMP) family consists of four homologous phosphoproteins considered crucial for brain development. Autoantibodies produced against member(s) of this family by patients with paraneoplastic neurological diseases have made it possible to clone a fifth human Ulip/CRMP and characterize its cellular and anatomical distribution in developing brain. This protein, referred to as Ulip6/CRMP5, is highly expressed during rat brain development in postmitotic neural precursors and in the fasciculi of fibers, suggesting its involvement in neuronal migration/differentiation and axonal growth. In the adult, Ulip6/ CRMP5 is still expressed in some neurons, namely in areas that retain neurogenesis and in oligodendrocytes in the midbrain, hindbrain, and spinal cord. Ulip2/CRMP2 and Ulip6/CRMP5 are coexpressed in postmitotic neural precursors at certain times during development and in oligodendrocytes in the adult. Because Ulip2/CRMP2 has been reported to mediate semaphorin-3A (Sema3A) signal in developing neurons, in studies to understand the function of Ulip6/CRMP5 and Ulip2/ CRMP2 in the adult, purified adult rat brain oligodendrocytes were cultured in a Sema3A-conditioned medium. Oligodendrocytes were found to have Sema3A binding sites and to express neuropilin-1, the major Sema3A receptor component. In the presence of Sema3A, these oligodendrocytes displayed a dramatic reduction in process extension, which was reversed by removal of Sema3A and prevented by anti-neuropilin-1, antiUlip6/CRMP5, anti-Ulip2/CRMP2 antibodies, or VEGF-165, another neuropilin-1 ligand. These results indicate the existence in the adult brain of a Sema3A signaling pathway that modulates oligodendrocyte process extension mediated by neuropilin-1, Ulip6/CRMP5, and Ulip2/CRMP2, and they open new fields of investigation of neuron/oligodendrocyte interactions in the normal and pathological brain.

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“…High‐titer antibodies to the neuronal protein are found in both the serum and cerebrospinal fluid (CSF) of patients with PND 1. However, antibodies are unlikely to be the sole cause of the neuronal destruction for those PNDs in which the target antigens are intracellular 2, 3. Moreover, PND antigen‐specific CD8 + T cells are present in the peripheral blood and CSF of patients with both paraneoplastic cerebellar degeneration (PCD) and the paraneoplastic Hu syndrome subtypes of PND 4, 5, 6…”

mentioning

confidence: 99%

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

Roberts

Blachère

Frank

et al. 2015

Annals of Neurology

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ObjectiveParaneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high‐titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients.MethodsCSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow‐up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen.ResultsHere we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3+ cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen‐specific cognate interactions between T cells and antigen‐presenting cells (APCs) when interferon‐γ (IFNγ) receptors were present on the T cell.InterpretationThese results support a model in which antigen‐specific T cell stimulation by PND APCs triggers IFNγ, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation. Ann Neurol 2015;78:619–629

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Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain.

Cited by 256 publications

References 99 publications

Appearance of neurons and glia with respect to the wavefront during colonization of the avian gut by neural crest cells

Appearance of neurons and glia with respect to the wavefront during colonization of the avian gut by neural crest cells

Isolation and Expression Pattern of Human Unc-33-Like Phosphoprotein 6/Collapsin Response Mediator Protein 5 (Ulip6/CRMP5): Coexistence with Ulip2/CRMP2 in Sema3A- Sensitive Oligodendrocytes

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

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