Role for complement in the development of seizures following acute viral infection.

Complement, part of the innate immune system, acts to remove pathogens and unwanted host material. Complement is known to function in all tissues, including the central nervous system (CNS). In this study, we demonstrated the importance of the complement system within the CNS in the development of behavioral seizures following Theiler's murine encephalomyelitis virus (TMEV) infection. C57BL/6 mice, deficient in complement component C3, developed significantly fewer behavioral seizures following TMEV infection, whereas mice depleted of complement component C3 in the periphery through treatment with cobra venom factor had a seizure rate comparable to that of control mice. These studies indicate that C3 participates in the induction of acute seizures during viral encephalitis.

Innate but not adaptive immune responses contribute to behavioral seizures following viral infection.

PURPOSE: To examine the role of innate immunity in a novel viral infection-induced seizure model. METHODS: C57BL/6 mice, mouse strains deficient in interleukin (IL)-1RI, IL-6, tumor necrosis factor (TNF)-RI, or myeloid differentiation primary response gene 88 (MyD88), or transgenic mice (OT-I) were infected with Theiler's murine encephalomyelitis virus (TMEV) or were mock infected. Mice were followed for acute seizures. Tissues were examined for neuron loss, the presence of virus (viral RNA and antigen), perivascular cuffs, macrophages/microglia, and gliosis, and mRNA expression of IL-1, TNF-alpha, and IL-6. RESULTS: IL-1 does not play a major role in seizures, as IL-1RI- and MyD88-deficient mice displayed a comparable seizure frequency relative to controls. In contrast, TNF-alpha and IL-6 appear to be important in the development of seizures, as only 10% and 15% of TNF-RI- and IL-6-deficient mice, respectively, showed signs of seizure activity. TNF-alpha and IL-6 mRNA levels also increased in mice with seizures. Inflammation (perivascular cuffs, macrophages/microglia, and gliosis) was greater in mice with seizures. OT-I mice (virus persists) had a seizure rate that was comparable to controls (no viral persistence), thereby discounting a role for TMEV-specific T cells in seizures. DISCUSSION: We have implicated the innate immune response to viral infection, specifically TNF-alpha and IL-6, and concomitant inflammatory changes in the brain as contributing to the development of acute seizures. This model is a potential infection-driven model of mesial temporal lobe epilepsy with hippocampal sclerosis.

Seizures following picornavirus infection.

PURPOSE: We demonstrate the establishment and characterization of a novel virus infection-induced seizure model in C57BL/6 mice. METHODS: C57BL/6 mice were infected with Theiler's murine encephalomyelitis virus (TMEV) or mock infected. Mice were followed for seizures, weight change, body temperature, motor function (righting reflex, rotorod) and neurological manifestations (inflammation [perivascular cuffing], pyknotic neurons, transforming growth factor [TGF]-beta expression). RESULTS: C57BL/6 mice are susceptible to seizures induced by TMEV infection. Approximately 50% of C57BL/6 mice develop transient afebrile seizures. Motor function and coordination are impaired in seized mice. Pyramidal neuron pyknosis and TGF-beta expression correlate with seizure activity in the hippocampus. DISCUSSION: The characterization of this model will enable the investigation of viral and immune contributions in the central nervous system to the development of seizure disorders in humans.

How relevant are GFAP autoantibodies in autism and Tourette Syndrome?

Controversy exists over the role of autoantibodies to central nervous system antigens in autism and Tourette Syndrome. We investigated plasma autoantibody titers to glial fibrillary acidic protein (GFAP) in children with classic onset (33) and regressive onset (26) autism, controls (25, healthy age- and gender-matched) and individuals with Tourette Syndrome (24) by enzyme-linked immunosorbent assays. We found a significant difference in autoantibody titers to GFAP, not accounted for by age, between the Tourette (significantly lower) and regressive autism groups. However, no differences were found between: classic/regressive; classic/controls; classic/Tourette; regressive/controls; or controls/Tourette. Autoantibody responses against GFAP are unlikely to play a pathogenic role in autism or Tourette Syndrome.

Are there enhanced MBP autoantibodies in autism?

Autoantibodies to central nervous system antigens, such as myelin basic protein (MBP), may play a role in autism. We measured autoantibody titers to MBP in children with autism, both classic onset and regressive onset forms, controls (healthy age- and gender-matched) and individuals with Tourette syndrome via enzyme-linked immunosorbent assays. We found a significant difference in autoantibody titers to MBP, not accounted for by age or medication, between Tourette and classic autism (both significantly lower) when compared to regressive autism, but not when compared to controls. Autoantibody responses against MBP are unlikely to play a pathogenic role in autism.

Are there altered antibody responses to measles, mumps, or rubella viruses in autism?

The role that virus infections play in autism is not known. Others have reported that antibodies against measles virus are higher in the sera/plasma of children with autism versus controls. The authors investigated antibody titers to measles, mumps, and rubella viruses and diphtheria toxoid in children with autism, both classic onset (33) and regressive onset (26) forms, controls (25, healthy age- and gender-matched) and individuals with Tourette's syndrome (24) via enzyme-linked immunosorbent assays. No significant differences in antibody titers to measles, mumps, and rubella viruses and diphtheria toxoid were found among the four groups. Additionally, there were no significant differences between the four groups for total immunoglobulin (Ig)G or IgM. Interestingly, the authors did find a significant number (15/59) of autism subjects (classic and regressive onset combined) who had a very low or no antibody titer against rubella virus, compared to a combine control/Tourette's group (2/49).

The mouse germ-cell-specific leucine-rich repeat protein NALP14: a member of the NACHT nucleoside triphosphatase family.

Microscopy of sectioned neonatal mouse ovaries established the predominance of primordial follicles in Day 3 samples and the predominance of primary follicles by Day 8. To identify genetic determinants of the primordial to primary follicle transition, the transcriptome of Day 1 or Day 3 mouse ovaries was contrasted by differential display with that of Day 8 ovaries. This manuscript examines one of the up-regulated genes, the novel Nalp14 gene, whose transcript displayed 18- and 127-fold increments from Day 1 to Days 3 and 8, respectively. First noted by in situ hybridization in oocytes encased by primary follicles, Nalp14 transcripts were continuously expressed through the preovulatory stage. The transcripts declined when meiotic maturation resumed, and they were markedly diminished by the 2-cell embryo stage. The corresponding 3281-base pair, full-length cDNA coded for a 993 residue/104.6-kDa germ cell-specific protein. A member of the multifunctional NACHT NTPase family, the NALP14 protein featured 14 iterations of the leucine-rich-repeat domain, a region implicated in protein-protein interaction. Protein BLAST analysis of the NALP14 sequence revealed 2 previously reported germ cell-specific homologs (i.e., MATER [Maternal Antigen That Embryos Require], RNH2 [RiboNuclease/Angiogenin Inhibitor 2], and NALP4c). The structural attributes, expression pattern, and cellular localization of MATER and RNH2 largely conformed to those reported for NALP14.

H1FOO is coupled to the initiation of oocytic growth.

We previously reported the discovery of a novel mammalian H1 linker histone termed H1FOO (formerly H1OO), a replacement H1, the expression of which is restricted to the growing/ maturing oocyte and to the zygote. The significance of this pre-embryonic H1 draws on its substantial orthologous conservation, singular structural attributes, selectivity for the germ cell lineage, prolonged nucleosomal residence, and apparent predominance among germ cell H1s. Herein, we report that the intronic, single-copy, five-exon (> or =5301 base pair) H1foo gene maps to chromosome 6 and that the corresponding primary H1foo transcript gives rise to two distinct, alternatively spliced mRNA species (H1foo(alpha) and H1foo(beta)). The expression of the oocytic H1FOO transcript and protein proved temporally coupled to the recruitment of resting primordial follicles into a developing primary follicular cohort and thus to the critical transition marking the onset of oocytic growth. The corresponding potential protein isoforms (H1FOO(alpha) and H1FOO(beta)), both nuclear localization sequence-endowed but export consensus sequence-free and possessing a significant net positive charge, localized primarily to perinucleolar heterochromatin in the oocytic germinal vesicle. Further investigation will be required to define the functional role of the H1FOO protein in the ordering of the chromatin of early mammalian development as well as its potential role in defining the primordial-to-primary follicle transition.