The role of orexin in Parkinson's disease.

Emerging evidence has implicated the orexin system in non-motor pathogenesis of Parkinson's disease. It has also been suggested the orexin system is involved in the modulation of motor control, further implicating the orexin system in Parkinson's disease. Parkinson's disease is the second most common neurodegenerative disease with millions of people suffering worldwide with motor and non-motor symptoms, significantly affecting their quality of life. Treatments are based solely on symptomatic management and no cure currently exists. The orexin system has the potential to be a treatment target in Parkinson's disease, particularly in the non-motor stage. In this review, the most current evidence on the orexin system in Parkinson's disease and its potential role in motor and non-motor symptoms of the disease is summarized. This review begins with a brief overview of Parkinson's disease, animal models of the disease, and the orexin system. This leads into discussion of the possible roles of orexin neurons in Parkinson's disease and levels of orexin in the cerebral spinal fluid and plasma in Parkinson's disease and animal models of the disease. The role of orexin is then discussed in relation to symptoms of the disease including motor control, sleep, cognitive impairment, psychological behaviors, and the gastrointestinal system. The neuroprotective effects of orexin are also summarized in preclinical models of the disease.

Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.

Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in transformed cells, and its dysregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals require further investigation. We have generated a Cep55 knockout (Cep55-/-) mouse model which demonstrated preweaning lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55-/- embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3ß/ß-Catenin/Myc axis in an Akt-dependent manner. The elevated apoptosis of neural stem/progenitors was recapitulated using Cep55-deficient human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3ß. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting a novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss.

Heterogeneous immunoreactivity of axonal spheroids in focal symmetrical encephalomalacia produced by Clostridium perfringens type D epsilon toxin in sheep.

Since axonal injury (AI) is an important component of many veterinary neurologic disorders, we assessed the relative ability of a panel of antibodies (amyloid precursor protein, 3 subunits of neurofilament protein, protein gene product 9.5, ubiquitin, and synaptophysin) to detect axonal swellings or spheroids. Abundant axonal spheroids found in necrotic internal capsule foci produced in 4 sheep by chronic Clostridium perfringens type D epsilon neurotoxicity provided a model system in which to evaluate this important diagnostic tool. There was heterogeneous labeling of subsets of spheroids by the respective antibodies, suggesting that, in order to detect the complete spectrum of AI in diagnostic cases, a range of antibodies should be used, not only when spheroids are plentiful but also when they are few in number or incompletely developed. The application of insufficient markers in the latter cases can potentially lead to the contribution of AI to lesion pathogenesis being underappreciated.

Animal models of pediatric abusive head trauma.

BACKGROUND: Abusive head trauma (AHT), previously known as the shaken baby syndrome, is a severe and potentially fatal form of traumatic brain injury in infant children who have been shaken, and sometimes also sustained an additional head impact. The clinical and autopsy findings in AHT are not pathognomonic and, due to frequent obfuscation by perpetrators, the circumstances surrounding the alleged abuse are often unclear. The concept has evolved that the finding of the combination of subdural hemorrhage, brain injury, and retinal hemorrhages ("the triad") is the result of shaking of an infant ("shaken baby syndrome") and has led to the ongoing controversy whether shaking alone is able to generate sufficient force to produce these lesions. OBJECTIVE: In an attempt to investigate whether shaking can engender this lesion triad, animal models have been developed in laboratory rodents and domestic animal species. This review assesses the utility of these animal models to reliably reproduce human AHT pathology and evaluate the effects of shaking on the immature brain. RESULTS: Due largely to irreconcilable anatomic species differences between these animal brains and human infants, and a lack of resemblance of the experimental head shaking induced by mechanical devices to real-world human neurotrauma, no animal model has been able to reliably reproduce the full range of neuropathologic AHT changes. CONCLUSION: Some animal models can simulate specific brain and ophthalmic lesions found in human AHT cases and provide useful information on their pathogenesis. Moreover, one animal model demonstrated that shaking of a freely mobile head, without an additional head impact, could be lethal, and produce significant brain pathology.

CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus.

Lysosomal vesicles around neuritic plaques are thought to drive Alzheimer's disease by providing ideal microenvironments for generation of amyloid-ß. Although lysosomal vesicles are present at every amyloid plaque in mouse models of Alzheimer's disease, the number of amyloid plaques that contain lysosomal vesicles in the human brain remains unknown. This study aimed to quantify lysosomal vesicles at amyloid plaques in the human hippocampus. Lysosome-associated membrane protein 1 (LAMP1)-positive vesicles accumulated in both diffuse (Aß42-positive/AT8-negative) and neuritic (Aß42-positive/AT8-positive) plaques in all regions were analysed. In contrast to mouse models of Alzheimer's disease, however, not all amyloid plaques accumulated LAMP1-positive lysosomal vesicles. Even at neuritic plaques, LAMP1 immunoreactivity was more abundant than phospho-tau (AT8). Further, lysosomal vesicles colocalised weakly with phospho-tau such that accumulation of lysosomal vesicles and phospho-tau appeared to be spatially distinct events that occurred within dystrophic neurites. This quantitative study shows that diffuse plaques, as well as neuritic plaques, contain LAMP1 immunoreactivity in the human hippocampus.

Infections and vaccinations as possible triggers of inflammatory myopathies.

INTRODUCTION: The role of vaccinations and infections in triggering idiopathic inflammatory myopathies (IIM) has not been confirmed. METHODS: Among patients with histologically confirmed myositis, infections or vaccinations administered prior to myositis onset were determined. The characteristics of this group were compared with controls (myositis patients without prior infection or vaccination). RESULTS: The frequency of IIM with a prior vaccination was 20 of 206 (9.7%), infection was 29 of 206 (14%), and either vaccination or infection was 49 of 206 (23.8%). Dermatomyositis (DM) was more frequent among patients with preceding vaccination (P = 0.03) or prior infections (P = 0.02) than among controls. Antibodies to Ro52 were more frequent among patients with preceding vaccination than among controls (P = 0.002). DISCUSSION: Although causality is not shown, the occurrence of prior infection or vaccination in 24% of patients with IIM prompts further inquiry. The overrepresentation of DM in those with preceding vaccination and the possible role of antibodies to Ro52 in susceptibility to vaccine-induced myositis require confirmation. Muscle Nerve 56: 987-989, 2017.

The PTPN22 gene is associated with idiopathic inflammatory myopathy.

INTRODUCTION: The aim of this study was to determine whether a single-nucleotide polymorphism (SNP; 1858CT, R620W) in the protein tyrosine phosphatase N22 (PTPN22) gene confers susceptibility to idiopathic inflammatory myopathy (IIM) in South Australian patients with IIM. METHODS: Genotyping was performed on stored DNA from 199 patients with histologically confirmed polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM), and then compared with 455 matched controls. Associations with the 8.1 ancestral haplotype (AH), and myositis-specific (MSA) and myositis-associated (MAA) autoantibodies were investigated. RESULTS: The PTPN22 R620W minor allele frequency was increased in IIM patients (50 of 398, 12.6%) compared with controls (75 of 910, 8.2%) (odds ratio 1.6, 95% confidence interval 1.1-2.3, P = 0.016). In IIM patients, there was no association between the R620W minor allele and detection of any MSA/MAA (P = 0.70), nor any evidence of epistasis with the 8.1 AH (P = 0.69). CONCLUSIONS: The PTPN22 R620W minor allele is associated with susceptibility to IIM in SA patients, independent of the 8.1 AH. Muscle Nerve, 2016 Muscle Nerve 55: 270-273, 2017.

Coxiella burnetii dormancy in a fatal ten-year multisystem dysfunctional illness: case report.

BACKGROUND: In a previous study of a Q fever outbreak in Birmingham, our group identified a non-infective complex of Coxiella burnetii (C.b.) antigens able to survive in the host and provoked aberrant humoral and cell-mediated immunity responses. The study led to recognition of a possible pathogenic link between C.b. infection and subsequent long-term post Q fever fatigue syndrome (QFS). This report presents an unusually severe case of C.b. antigen and DNA detection in post-mortem specimens from a patient with QFS. CASE PRESENTATION: We report a 19-year old female patient who became ill with an acute unexplained febrile encephalitis-like illness, followed by increasingly severe multisystem dysfunction and death 10 years later. During life, extensive clinical and laboratory investigations from different disciplinary stand points failed to deliver a definitive identification of a cause. Given the history of susceptibility to infection from birth, acute fever and the diagnosis of "post viral syndrome", tests for infective agents were done starting with C.b. and Legionella pneumophila. The patient had previously visited farms a number of times. Comprehensive neuropathological assessment at the time of autopsy had not revealed gross or microscopic abnormalities. The aim was to extend detailed studies with the post-mortem samples and identify possible factors driving severe disturbance of homeostasis and organ dysfunction exhibited by the course of the patient's ten-year illness. Immunohistochemistry for C.b. antigen and PCR for DNA were tested on paraffin embedded blocks of autopsy tissues from brain, spleen, liver, lymph nodes (LN), bone marrow (BM), heart and lung. Standard H&E staining of brain sections was unrevealing. Immuno-staining analysis for astrocyte cytoskeleton proteins using glial fibrillary acidic protein (GFAP) antibodies showed a reactive morphology. Coxiella antigens were demonstrated in GFAP immuno-positive grey and white matter astrocytes, spleen, liver, heart, BM and LN. PCR analysis (COM1/IS1111 genes) confirmed the presence of C.b. DNA in heart, lung, spleen, liver & LN, but not in brain or BM. CONCLUSION: The study revealed the persistence of C. b. cell components in various organs, including astrocytes of the brain, in a post-infection QFS. The possible mechanisms and molecular adaptations for this alternative C.b. life style are discussed.

Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy.

INTRODUCTION: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. METHODS: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. RESULTS: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR(+) patients there was a trend toward increased malignancy (P = 0.15). CONCLUSIONS: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA-DR11. Muscle Nerve 52: 196-203, 2015.

Effect of long-term (2 years) exposure of mouse brains to global system for mobile communication (GSM) radiofrequency fields on astrocytic immunoreactivity.

This study was designed to determine whether long-term (2 years) brain exposure to mobile telephone radiofrequency (RF) fields produces any astrocytic activation as these glia react to a wide range of neural perturbations by astrogliosis. Using a purpose-designed exposure system at 900 MHz, mice were given a single, far-field whole body exposure at a specific absorption rate of 4 W/kg on five successive days per week for 104 weeks. Control mice were sham-exposed or freely mobile in a cage to control any stress caused by immobilization in the exposure module. Brains were perfusion-fixed with 4% paraformaldehyde and three coronal levels immunostained for glial fibrillary acidic protein (GFAP). These brain slices were then examined by light microscopy and the amount of this immunomarker quantified using a color deconvolution method. There was no change in astrocytic GFAP immunostaining in brains after long-term exposure to mobile telephony microwaves compared to control (sham-exposed or freely moving caged mice). It was concluded that long-term (2 years) exposure of murine brains to mobile telephone RF fields did not produce any astrocytic reaction (astrogliosis) detectable by GFAP immunostaining.

The neuroprotective activity of the amyloid precursor protein against traumatic brain injury is mediated via the heparin binding site in residues 96-110.

We have previously shown that following traumatic brain injury (TBI) the presence of the amyloid precursor protein (APP) may be neuroprotective. APP knockout mice have increased neuronal death and worse cognitive and motor outcomes following TBI, which is rescued by treatment with exogenous sAPPα (the secreted ectodomain of APP generated by α-secretase cleavage). Two neuroprotective regions were identified in sAPPα, the N and C-terminal domains D1 and D6a/E2 respectively. As both D1 and D6a/E2 contain heparin binding activity it was hypothesized that this is responsible for the neuroprotective activity. In this study, we focused on the heparin binding site, encompassed by residues 96-110 in D1, which has previously been shown to have neurotrophic properties. We found that treatment with APP96-110 rescued motor and cognitive deficits in APP-/- mice following focal TBI. APP96-110 also provided neuroprotection in Sprague-Dawley rats following diffuse TBI. Treatment with APP96-110 significantly improved functional outcome as well as preserve histological cellular morphology in APP-/- mice following focal controlled cortical impact injury. Furthermore, following administration of APP96-110 in rats after diffuse impact acceleration TBI, motor and cognitive outcomes were significantly improved and axonal injury reduced. These data define the heparin binding site in the D1 domain of sAPPα, represented by the sequence APP96-110, as the neuroprotective site to confer neuroprotection following TBI. The product of α-secretase cleavage of the amyloid precursor protein, sAPPα is neuroprotective following traumatic brain injury (TBI). Of interest was whether this neuroprotective activity could be further delineated to a heparin binding region within sAPPα, corresponding to the region APP96-110 (see diagram demonstrating the domain structure of sAPPα). Indeed treatment with APP96-110 improved functional outcome following TBI, an effect that was not seen with a mutated version of the peptide that had reduced heparin binding affinity.

Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.

Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1-16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1-16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1-q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.

The incidence and associations of malignancy in a large cohort of patients with biopsy-determined idiopathic inflammatory myositis.

The South Australian (SA) myositis database has registered all patients with biopsy-proven inflammatory myositis in SA from 1980 to 2009. We determined the incidence and associations of malignancy in myositis by linking this database with the SA cancer registry. Standardized incidence ratios (SIR) for malignancy were determined using the total SA population over the same time period, stratified by age and gender. The SIR for cancer in the myositis population (n = 373) was 1.39, p = 0.047. There was a trend towards an increased SIR in dermatomyositis but no increased risk of malignancy in polymyositis or inclusion body myositis. Malignancies of the lung and prostate were the commonest and 28 % of malignancies occurred within one year of IIM diagnosis. The odds of developing cancer were significantly raised in the presence of a shawl sign, male gender, and in patients with overlap syndrome or rheumatoid arthritis whilst myalgia was a significant protective factor. HLA-A28 allele was overrepresented in patients with malignancy (11 vs 2 %, p = 0.006). Patients in SA with myositis are at modestly increased risk for malignancy. We report clinical and genetic risk factors allowing the identification of patients at greatest risk for malignancy.

Avian riboflavin deficiency causes reliably reproducible peripheral nerve demyelination and, with vitamin supplementation, rapid remyelination.

Riboflavin deficiency produces severe peripheral neve demyelination in young, rapidly growing chickens. While this naturally-occurring vitamin B2 deficiency can cause a debilitating peripheral neuropathy, and mortality, in poultry flocks, it can also be a useful experimental animal model to study the pathogenesis of reliably reproducible peripheral nerve demyelination. Moreover, restitution of normal riboflavin levels in deficient birds results in brisk remyelination. It is the only acquired, primary, demyelinating tomaculous neuropathy described to date in animals. The only other substance that causes peripheral nerve demyelination similar to avian riboflavin deficiency is tellurium and the pathologic features of the peripheral neuropathy produced by this developmental neurotoxin in weanling rats are also described.

sAPPα rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury.

The amyloid precursor protein (APP) is thought to be neuroprotective following traumatic brain injury (TBI), although definitive evidence at moderate to severe levels of injury is lacking. In the current study, we investigated histological and functional outcomes in APP-/- mice compared with APP+/+ mice following a moderate focal injury, and whether administration of sAPPα restored the outcomes in knockout animals back to the wildtype state. Following moderate controlled cortical impact injury, APP-/- mice demonstrated greater impairment in motor and cognitive outcome as determined by the ledged beam and Barnes Maze tests respectively (p < 0.05). This corresponded with the degree of neuronal damage, with APP-/- mice having significantly greater lesion volume (25.0 ± 1.6 vs. 20.3 ± 1.6%, p < 0.01) and hippocampal damage, with less remaining CA neurons (839 ± 245 vs. 1353 ± 142 and 1401 ± 263). This was also associated with an impaired neuroreparative response, with decreased GAP-43 immunoreactivity within the cortex around the lesion edge compared with APP+/+ mice. The deficits observed in the APP-/- mice related to a lack of sAPPα, as treatment with exogenously added sAPPα post-injury improved APP-/- mice histological and functional outcome to the point that they were no longer significantly different to APP+/+ mice (p < 0.05). This study shows that endogenous APP is potentially protective at moderate levels of TBI, and that this neuroprotective activity is related to the presence of sAPPα. Importantly, it indicates that the mechanism of action of exogenously added sAPPα is independent of the presence of endogenous APP.

Necrotizing myopathy: clinicoserologic associations.

INTRODUCTION: Necrotizing myopathy (NM) is distinguished from idiopathic inflammatory myositis (IIM) by dominance of myofiber necrosis, lack of mononuclear inflammatory infiltrates, and presence of antibodies to signal recognition particle (SRP). METHODS: The clinical features of 64 cases of NM were determined. Measurement of autoantibodies was undertaken on stored sera from 23 patients with NM. The incidence of malignancy was determined from the South Australian Cancer Registry. RESULTS: NM patients showed male predominance (61%), more frequent myalgias, and higher creatine kinase (CK) levels compared with IIM patients. Patients with NM had a high incidence of systemic lupus erythematosus (SLE) (21%), hypertension (11 of 17, 65%), and diabetes mellitus (3 of 13, 23%). No patient had antibodies to SRP. NM patients showed no altered risk for malignancy compared with the South Australian population (P = 0.86). CONCLUSIONS: NM is associated with SLE, hypertension, and diabetes mellitus. Comprehensive assessment of cardiovascular risk is indicated in NM, which raises the possibility of targeted interventions.

A three-way interplay of DR4, autoantibodies and synovitis in biopsy-proven idiopathic inflammatory myositis.

The aim of this study was to determine the HLA and autoantibody associations of patients with histologically confirmed idiopathic inflammatory myositis (IIM). Serum and DNA were archived from South Australian patients with biopsy-proven dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). HLA typing for Class I and II alleles was performed by serology and DNA-based technology, respectively, for 133 myositis patients and 166 Caucasian population-based controls. Myositis-specific and myositis-associated autoantibodies were detected by line immunoblot. All alleles of the 8.1AH were associated with myositis susceptibility. The B8-DR3 haplotype fragment conferred the strongest susceptibility (OR 2.9, 95% CI 1.8-4.6), and the B-DR region of other ancestral haplotypes was associated with myositis subgroups. Autoantibodies were present in 42/130 (32%) IIM patients and were more frequent in DM (11/17, 65%) than PM (23/70, 33%) or IBM (8/43, 19%), P = 0.002. Autoantibodies were associated with DRB1 03 (P = 0.0005) but also with DRB1 04 (P = 0.004). The frequency of autoantibodies in the three myositis subgroups mirrored the frequency of DR4. Polyarthralgia (±synovitis) was more common in DM/PM (30/76, 39%) than IBM (3/32, 9%), P = 0.004, and there was a strong ordinal association between the prevalence of autoantibodies and polyarthralgia ± synovitis (proportional OR = 5.5, 95% CI 2.3-13.7, P = 0.0004). The central MHC region confers the strongest susceptibility for IIM and also modulates disease phenotype. Our findings reveal a novel association of autoantibodies with DR4 and with arthralgia/synovitis in IIM and raise the possibility of a genetically (DR4) determined citrullination of myositis autoantigens expressed in muscle and synovium.

Characterization of the host immune response in human Ganglia after herpes zoster.

Varicella-zoster virus (VZV) causes varicella (chicken pox) and establishes latency in ganglia, from where it reactivates to cause herpes zoster (shingles), which is often followed by postherpetic neuralgia (PHN), causing severe neuropathic pain that can last for years after the rash. Despite the major impact of herpes zoster and PHN on quality of life, the nature and kinetics of the virus-immune cell interactions that result in ganglion damage have not been defined. We obtained rare material consisting of seven sensory ganglia from three donors who had suffered from herpes zoster between 1 and 4.5 months before death but who had not died from herpes zoster. We performed immunostaining to investigate the site of VZV infection and to phenotype immune cells in these ganglia. VZV antigen was localized almost exclusively to neurons, and in at least one case it persisted long after resolution of the rash. The large immune infiltrate consisted of noncytolytic CD8(+) T cells, with lesser numbers of CD4(+) T cells, B cells, NK cells, and macrophages and no dendritic cells. VZV antigen-positive neurons did not express detectable major histocompatibility complex (MHC) class I, nor did CD8(+) T cells surround infected neurons, suggesting that mechanisms of immune control may not be dependent on direct contact. This is the first report defining the nature of the immune response in ganglia following herpes zoster and provides evidence for persistence of non-latency-associated viral antigen and inflammation beyond rash resolution.