The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

The discovery of the autoimmune regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

Genetic susceptibility to fungal infection in children.

PURPOSE OF REVIEW: Fungal infections have steadily increased in incidence, emerging as a significant cause of morbidity and mortality in patients with iatrogenic immunosuppression. Simultaneously, we have witnessed a growing population of newly described inherited immune disorders that have enhanced our understanding of the human immune response against fungi. In the present review, we provide an overview and diagnostic roadmap to inherited disorders which confer susceptibility to superficial and invasive fungal infections. RECENT FINDINGS: Inborn errors of fungal immunity encompass a heterogeneous group of disorders, some of which confer fungal infection-specific susceptibility, whereas others also feature broader infection vulnerability and/or noninfectious manifestations. Infections by Candida, Aspergillus, endemic dimorphic fungi, Pneumocystis, and dermatophytes along with their organ-specific presentations provide clinicians with important clues in the assessment of patients with suspected immune defects. SUMMARY: The absence of iatrogenic risk factors should raise suspicion for inborn errors of immunity in children and young adults with recurrent or severe fungal diseases. Expeditious diagnosis and prompt initiation of antifungal therapy and management of complications are paramount to achieve remission of fungal disease in the setting of primary immunodeficiency disorders.

Extra-nigral pathological conditions are common in Parkinson's disease with freezing of gait: an in vivo positron emission tomography study.

Cholinergic denervation has been associated with falls and slower gait speed and ß-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11) C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic "off" state. A subset of subjects (n = 61) underwent [(11) C]Pittsburgh compound-B ß-amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal ß-amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non-freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ(2) = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ(2) = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical ß-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra-nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathological conditions studied. Extra-nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society.

Recent advances in understanding the role of eosinophils.

Our understanding of eosinophil biology, development, and regulation has dramatically increased in the past decade, leading to new paradigms for the role of eosinophils in human health and disease and, perhaps more importantly, providing insights toward novel treatment strategies in the fight against eosinophil-mediated inflammation. In this review, we discuss recent advances regarding the role of eosinophils in host-viral defense, eosinophil heterogeneity, and eosinophil-targeted therapies.

Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson's disease.

Clinical effects of anti-cholinergic drugs implicate cholinergic systems alterations in the pathophysiology of some cardinal motor impairments in Parkinson's disease. The topography of affected cholinergic systems deficits and motor domain specificity are poorly understood. Parkinson's disease patients (n = 108) underwent clinical and motor assessment and vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol PET imaging. Volumes-of-interest-based analyses included detailed thalamic and cerebellar parcellations. Successful PET sampling for most of the small-sized parcellations was available in 88 patients. A data-driven approach, stepwise regression using the forward selection method, was used to identify cholinergic brain regions associating with cardinal domain-specific motor ratings. Regressions with motor domain scores for model-selected regions followed by confounder analysis for effects of age of onset, duration of motor disease and levodopa equivalent dose were performed. Among 7 model-derived regions associating with postural instability and gait difficulties domain scores three retained significance in confounder variable analysis: medial geniculate nucleus (standardized ß = -0.34, t = -3.78, P = 0.0003), lateral geniculate nucleus (ß = -0.32, t = -3.4, P = 0.001) and entorhinal cortex (ß = -0.23, t = -2.6, P = 0.011). A sub-analysis of non-episodic postural instability and gait difficulties scores demonstrated significant effects of the medial geniculate nucleus, entorhinal cortex and globus pallidus pars interna. Among 6 tremor domain model-selected regions two regions retained significance in confounder variable analysis: cerebellar vermis section of lobule VIIIb (ß = -0.22, t = -2.4, P = 0.021) and the putamen (ß = -0.23, t = -2.3, P = 0.024). None of the three model-selected variables for the rigidity domain survived confounder analysis. Two out of the four model-selected regions for the distal limb bradykinesia domain survived confounder analysis: globus pallidus pars externa (ß = 0.36, t = 3.9, P = 0.0097) and the paracentral lobule (ß = 0.26, t = 2.5, P = 0.013). Emphasizing the utility of a systems-network conception of the pathophysiology of Parkinson's disease cardinal motor features, our results are consistent with specific deficits in basal forebrain corticopetal, peduncupontine-laterodorsal tegmental complex, and medial vestibular nucleus cholinergic pathways, against the background of nigrostriatal dopaminergic deficits, contributing significantly to postural instability, gait difficulties, tremor and distal limb bradykinesia cardinal motor features of Parkinson's disease. Our results suggest significant and distinct consequences of degeneration of cholinergic peduncupontine-laterodorsal tegmental complex afferents to both segments of the globus pallidus. Non-specific regional cholinergic nerve terminal associations with rigidity scores likely reflect more complex multifactorial signalling mechanisms with smaller contributions from cholinergic pathways.

Recent advances in understanding inherited deficiencies in immunity to infections.

The immune system is central to our interactions with the world in which we live and importantly dictates our response to potential allergens, toxins, and pathogens to which we are constantly exposed. Understanding the mechanisms that underlie protective host immune responses against microbial pathogens is vital for the development of improved treatment and vaccination strategies against infections. To that end, inherited immunodeficiencies that manifest with susceptibility to bacterial, viral, and/or fungal infections have provided fundamental insights into the indispensable contribution of key immune pathways in host defense against various pathogens. In this mini-review, we summarize the findings from a series of recent publications in which inherited immunodeficiencies have helped illuminate the interplay of human immunity and resistance to infection.

Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity.

Olfactory dysfunction is common in patients with Parkinson disease (PD) and has been attributed to early pathological deposition of Lewy bodies and Lewy neurites in primary olfactory centers. However, olfactory deficits do not always worsen over time despite progression of disease raising the possibility of additional pathobiological mechanisms contributing to olfactory functions in PD, such as changes in olfactory neurotransmitter functions. Neurotransmitter changes, such as altered dopaminergic status, may also better explain the selective nature of odor identification deficits in PD. Proper odor identification depends on higher order structures, such as the hippocampus, for olfactory cognitive or memory processing. Using the University of Pennsylvania Smell Identification Test (UPSIT), we previously identified three odors (banana, licorice, dill pickle, labeled as UPSIT-3) that PD subjects most frequently failed to recognize compared to age- and gender-matched controls. We also identified six odors that were equally successfully identified by controls and PD subjects (NPD-Olf6). A ratio of UPSIT-3 divided by NPD-Olf6 scores provides another descriptor of selective hyposmia in PD ("olfactory ratio"). In this study we investigated the pathophysiology of hyposmia in PD using dopamine transporter (DAT) PET. Twenty-nine PD patients (Hoehn and Yahr stages I-III; 7f/22m; age 60.2+/-10.8) underwent olfactory testing using the UPSIT and [(11)C]beta-CFT DAT PET. DAT binding potentials (BP) were assessed in the hippocampus, amygdala, ventral and dorsal striatum. We found that correlation coefficients between total UPSIT scores and regional brain DAT BP were highest for the hippocampus (Rs=0.54, P=0.002) and lower for the amygdala (Rs=0.44, P=0.02), ventral (Rs=0.48, P=0.008) and dorsal striatum (Rs=0.39, P=0.03). Correlations were most significant for the selective hyposmia measures and hippocampal DAT: UPSIT-3 (Rs=0.65, P=0.0001) and the olfactory ratio (Rs=0.74, P<0.0001). We conclude that selective hyposmia in PD is more robustly correlated with hippocampal rather than amygdala, ventral or dorsal striatal dopamine innervation as shown by DAT binding. These findings indicate that mesolimbic dopamine innervation of the hippocampus may be a determinant of selective hyposmia in PD.

Selective hyposmia and nigrostriatal dopaminergic denervation in Parkinson's disease.

Olfactory dysfunction is a frequent and early feature of Parkinson's disease (PD), often preceding the motor symptoms by several years. Assessment of olfactory deficits may be used in the diagnostic assessment of PD. In this study we investigated the relationship between selective deficits in smell identification and nigrostriatal dopaminergic denervation in patients with PD. Twenty-seven PD patients (Hoehn and Yahr stages I-III) and 27 healthy controls matched for gender and age underwent olfactory testing using the 40-odor University of Pennsylvania Smell Identification Test (UPSIT). PD patients underwent (11)C-beta-CFT dopamine transporter (DAT) positron emission tomography (PET) imaging and clinical motor examination. We found that total UPSIT scores were significantly lower in the PD than in the control subjects (z=4.7, p<0.0001). Analysis of the individual smell scores identified 3 odors with an accuracy of >0.75 for the diagnosis of PD. These odors were banana, licorice, and dill pickle. A PD-specific smell identification score (UPSIT-3) was calculated for these 3 odors. Analysis of the patient PET data demonstrated significant correlations between dorsal striatal DAT activity and the UPSIT-3 (R(S)=0.53, p=0.0027) and total UPSIT (R(S)=0.44, p=0.023) scores. UPSIT-3 (R(S)=0.43, p=0.027) but not total UPSIT (R(S)=0.20, ns) correlated with nigral DAT activity. We conclude that patients with PD have selective hyposmia. A simplified UPSIT smell identification test consisting of 3 PD-selective odors had more robust correlation with nigral and dorsal striatial dopaminergic activity compared with the full UPSIT scores in patients with PD. Assessment of selective olfactory deficits may be used as a simplified olfactory screening test in the evaluation of subjects with possible PD.

Grooved pegboard test as a biomarker of nigrostriatal denervation in Parkinson's disease.

Recent pharmacotherapy trials in Parkinson's disease (PD) using dopaminergic neuroimaging as outcome parameter failed to show significant relationships between imaging and clinical results. One possible explanation is that there is a non-linear relationship between striatal denervation and motor performance reflecting a statistical "floor" effect in the imaging data with advanced disease. Both the motor manifestations and the striatal dopamine denervation of idiopathic PD, however, are typically asymmetric and more meaningful associations may be found by comparing data from the least denervated striatum with motor performance in the corresponding body side. PD patients (n=28) underwent [11C]beta-CFT dopamine transporter (DAT) positron emission tomography (PET) and grooved pegboard testing. Voxel-based analysis of DAT PET and bimanual pegboard scores demonstrated significant correlation clusters within the bilateral striata (P<0.001). However, findings were most prominent in the least denervated striatum. There was a significant inverse correlation between pegboard scores of the least affected arm and DAT binding of the least denervated striatum (Rs=-0.69, P<0.0001) but no significant correlation between pegboard scores of the clinically most affected arm and DAT binding of the most denervated striatum (Rs=-0.15, ns). These data indicate that the robustness of the grooved pegboard test as a biomarker for nigrostriatal denervation in PD mainly reflects the relationship between test performance of the clinically least affected limb and the least denervated striatum. These findings indicate that there is both a statistical "floor" and "ceiling" effect for the most affected striatal and body sides that must be considered when employing imaging as an outcome measure in clinical trials in PD.

A Biohybrid Device for the Systemic Control of Acute Inflammation.

Properly regulated inflammation facilitates recognition and reaction to injury or infection, but inadequate or overly robust inflammation can lead to disease. Sepsis is an inflammatory disease that accounts for nearly 10% of total U.S. deaths, costing more than $17 billion. Acute inflammation in sepsis may evolve too rapidly to be modulated appropriately, and we suggest that therapies should focus not on abolishing inflammation, but rather on attenuating the positive feedback cycle of inflammation/damage/inflammation. In Gram-negative sepsis, bacterial endotoxin causes inflammation and is driven and regulated by the cytokine tumor necrosis factor-α (TNF-α), which is, in turn, negatively regulated via its endogenous inhibitor, soluble TNF-α receptor (sTNFR). We generated stably gene-modified variants of human HepG2 hepatocytes, using lentiviral constructs coding for mouse sTNFR driven by the constitutive cytomegalovirus promoter, and seeded them in a scaled-down, experimental liver bioreactor. When connected to anesthetized, cannulated rats subjected to endotoxin infusion and maintained solely by the animals' circulation, this biohybrid device elevated circulating sTNFR, reduced the levels of TNF-α and other key inflammatory mediators, alleviated hypotension, and reduced circulating markers of organ damage. This novel class of biohybrid devices may bemodified for patient- and disease-specific application, and, thus, may represent a disruptive strategy that offers the potential for rational inflammation reprogramming.

TWO AUTOCOVARIANCE-BASED MEASURES OF BALANCE IN PARKINSONIANS AND NORMAL CONTROLS.

Center of pressure electronic platform testing is proposed as an affordable early diagnostic tool for persons at risk of Parkinson's disease. A stiffness measures and crossing time statistic are studied for possible use in such a diagnosis.

Age-associated striatal dopaminergic denervation and falls in community-dwelling subjects.

Older adults have a high prevalence of gait and balance disturbances and falls. Normal aging is associated with significant striatal dopaminergic denervation, which might be a previously unrecognized additional contributor to geriatric falls. This study investigated the relationship between the severity of age-associated striatal dopaminergic denervation (AASDD) and falls in community-dwelling subjects. Community-dwelling subjects who did not have a clinical diagnosis to explain falls (n = 77: 43 female, 34 male; mean age 61.4 +/- 16.4; range 20-85) completed clinical assessment and brain dopamine transporter (DAT) [(11)C]beta-CFT (2-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane) positron emission tomography imaging followed by 6 months of prospective fall monitoring using diaries. Results showed a significant inverse relationship between striatal DAT activity and age (r = -0.82, p < 0.001). A total of 26 subjects (33.8%) reported at least one fall, with 5 subjects (6.5%) reporting two or more falls. While no significant difference was noted in striatal DAT activity between nonfallers (n = 51) and fallers (n = 26; f = 0.02, not significant), striatal DAT activity was modestly reduced in the small subgroup of recurrent fallers compared with the other subjects (f = 5.07, p < 0.05). Findings indicate that AASDD does not explain isolated self-reported falls in community-dwelling subjects. However, it may be a contributing factor in the small subgroup of subjects with recurrent falls.

Predictive models of postural control based on electronic force platform measures in patients with Parkinson's disease.

The human postural control system is difficult to quantify since it seems to be subject to both deterministic forces as well as stochastic effects. The attempt made in this paper is to study postural control under quiet stance on the one hand, and by engaging the brain through a fluency test, on the other. A Kistler electronic platform is the vehicle by way of which we gather observations in the form of center of pressure (COP) trajectories. From these two-dimensional trajectories we extract several measures that describe various features of the postural control system. Some of the measures are descriptive, while others incorporate physical forces that enter the process. From these measures we then build predictive models and apply them to a set of patients with Parkinson's disease (PD) and a set of normal control subjects to validate and calibrate them. We further use the measures built out of the center of pressure trajectories to test the significance of the fluency (cognitive-motor dual task) effect on the two groups. The fluency effect is found significant in the parkinsonian group as well as the normal controls. The clinical importance of these findings lies in the fact that the models may be used as a more objective assessment of postural control that may either replace or supplement the more subjective Unified Parkinson's Disease Rating Scale (UPDRS). The models may also be used as an assessment tool for the evaluation of patients subsequent to pharmacological and surgical treatment.

ELECTRONIC PLATFORM MEASURES OF BALANCE IMPAIRMENT IN PARKINSONIANS AND FIRST DEGREE RELATIVES.

Several measures of balance obtained from quiet stance on an electronic platform are described. These measures were found to discriminate patients with Parkinson disease (PD) from normal control subjects. First degree relatives of patients with PD show greater variability on these measures. A primary goal is to develop sensitive measures that would be capable of identifying impaired balance in early stages of non-clinical PD.