Electroacupuncture at Neurogenic Spots in Referred Pain Areas Attenuates Hepatic Damages in Bile Duct-Ligated Rats.

Visceral pain frequently produces referred pain at somatic sites due to the convergence of somatic and visceral afferents. In skin overlying the referred pain, neurogenic spots characterized by hyperalgesia, tenderness and neurogenic inflammation are found. We investigated whether neurogenic inflammatory spots function as acupoints in the rat model of bile duct ligation-induced liver injury. The majority of neurogenic spots were found in the dorsal trunk overlying the referred pain and matched with locations of acupoints. The spots, as well as acupoints, showed high electrical conductance and enhanced expression of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). Electroacupuncture at neurogenic spots reduced serum hepatocellular enzyme activities and histological patterns of acute liver injury in bile duct ligation (BDL) rats. The results suggest that the neurogenic spots have therapeutic effects as acupoints on hepatic injury in bile-duct ligated rats.

Potential for Targeting Myeloid Cells in Controlling CNS Inflammation.

Multiple Sclerosis (MS) is characterized by immune cell infiltration to the central nervous system (CNS) as well as loss of myelin. Characterization of the cells in lesions of MS patients revealed an important accumulation of myeloid cells such as macrophages and dendritic cells (DCs). Data from the experimental autoimmune encephalomyelitis (EAE) model of MS supports the importance of peripheral myeloid cells in the disease pathology. However, the majority of MS therapies focus on lymphocytes. As we will discuss in this review, multiple strategies are now in place to target myeloid cells in clinical trials. These strategies have emerged from data in both human and mouse studies. We discuss strategies targeting myeloid cell migration, growth factors and cytokines, biological functions (with a focus on miRNAs), and immunological activities (with a focus on nanoparticles).

Alarmins and c-Jun N-Terminal Kinase (JNK) Signaling in Neuroinflammation.

Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of neuroinflammation and in the acute phase of ischemia. Defensins, cathelicidin, high-mobility group box protein 1, S100 proteins, heat shock proteins, nucleic acids, histones, nucleosomes, and monosodium urate microcrystals are thought to be alarmins. They are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors. Being principal sterile inflammation triggering agents, alarmins are considered biomarkers and therapeutic targets. They are recognized by host cells and prime the innate immune system toward cell death and distress. In stroke, alarmins act as mediators initiating the inflammatory response after the release from the cellular components of the infarct core and penumbra. Increased c-Jun N-terminal kinase (JNK) phosphorylation may be involved in the mechanism of stress-induced release of alarmins. Putative crosstalk between the alarmin-associated pathways and JNK signaling seems to be inherently interwoven. This review outlines the role of alarmins/JNK-signaling in cerebral neurovascular inflammation and summarizes the complex response of cells to alarmins. Emerging anti-JNK and anti-alarmin drug treatment strategies are discussed.

Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis.

Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues.

Depletion of NK Cells Improves Cognitive Function in the Alzheimer Disease Mouse Model.

Despite mounting evidence suggesting the involvement of the immune system in regulating brain function, the specific role of immune and inflammatory cells in neurodegenerative diseases remain poorly understood. In this study, we report that depletion of NK cells, a type of innate lymphocytes, alleviates neuroinflammation, stimulates neurogenesis, and improves cognitive function in a triple-transgenic Alzheimer disease (AD) mouse model. NK cells in the brains of triple-transgenic AD mouse model (3xTg-AD) mice exhibited an enhanced proinflammatory profile. Depletion of NK cells by anti-NK1.1 Abs drastically improved cognitive function of 3xTg-AD mice. NK cell depletion did not affect amyloid ß concentrations but enhanced neurogenesis and reduced neuroinflammation. Notably, in 3xTg-AD mice depleted of NK cells, microglia demonstrated a homeostatic-like morphology, decreased proliferative response and reduced expression of neurodestructive proinflammatory cytokines. Together, our results suggest a proinflammatory role for NK cells in 3xTg-AD mice and indicate that targeting NK cells might unlock novel strategies to combat AD.

Molecular hydrogen attenuates sepsis-induced neuroinflammation through regulation of microglia polarization through an mTOR-autophagy-dependent pathway.

Sepsis-associated encephalopathy (SAE) is the cognitive impairment resulting from sepsis and is associated with increased morbidity and mortality. Hydrogen has emerged as a promising therapeutic agent to alleviate SAE. The mechanism, however, remains unclear. This research aimed to determine whether hydrogen alleviates SAE by regulating microglia polarization and whether it is mediated by the mammalian target of rapamycin (mTOR)-autophagy pathway. Septic models were established by cecal ligation and puncture (CLP) performed on mice. The Morris Water Maze was used to evaluate cognitive function. M1/M2 microglia polarization was assessed by immunofluorescence. Inflammatory cytokines were determined by ELISA. Septic cell models were established using BV-2 cells incubated with 1 µg/ml lipopolysaccharide (LPS). M1/M2 microglia polarization was assessed by flow cytometry. Inflammatory cytokines from culture medium supernatant were determined by ELISA, and associated protein expression levels of mTOR-autophagy pathway were assessed by Western blot. Hydrogen inhalation attenuated sepsis-induced cognitive impairment with improved escape latency, time spent in the target platform quadrant and number of times crossing the target platform. In both animal and cell research, hydrogen reduced TNF-α, IL-6 and HMGB1 levels and M1 polarization, but increased IL-10 and TGF-ß levels and M2 polarization. Hydrogen treatment decreased the ratio of p-mTOR/mTOR and the expression of p62 and increased the ratio of p-AMPK/AMPK, LC3II/LC3I and the expression of TREM-2 and Beclin-1 in LPS-treated BV-2 cells. MHY1485, an mTOR activator, abolished the protective effects of hydrogen in vitro. Taken together, these results demonstrated that hydrogen attenuated sepsis-induced neuroinflammation by modulating microglia polarization, which was mediated by the mTOR-autophagy signaling pathway.

[Migraine epidemiological, clinical and therapeutic data]. / Migraine : données épidémiologiques, cliniques et thérapeutiques.

Burden of disease study ranks headache disorders as the second leading cause of years lived with disability worldwide. Migraine has an estimated prevalence of 10 to 14% and is therefore the most common neurological pathology. It concerns young populations, with a female/male ratio of 3/1, and its impact in economic terms is mainly related to indirect costs. Migraine can be episodic or chronic depending on the frequency of headache days (≥ 15 days per month). The diagnosis of migraine is made according to international criteria, which are easy to use, with essential questions to be asked to patients in a logical order and structure. The migraine is explained by an activation of the so-called trigeminocervical system, with release of neuromediators participating in neurogenic inflammation and activation of second-order neurons. Migraine with aura is manifested by neurological symptoms, lasting less than 60 minutes, explained by the phenomenon of cortical spreading depression. Visual symptoms are the most commonly described aura event of migraine, other auras include sensory and speech disturbance. Cortical spreading depression is a slowly propagating wave of near-complete depolarization of neurons and glial cells spreading over the cortex at a speed of ∼3-5 mm/min. First-line acute treatment for migraine consists of nonsteroidal anti-inflammatory drugs (NSAID), triptans and antiemetics. Patients with frequent or chronic headaches warrant prophylactic therapy. Various classes of preventives can be used (ß-blockers, tricyclics, antiepileptics), with the choice of therapy tailored to the patient's risk factors and symptoms. In practice, treatment has two axes: NSAID or triptans for crisis treatment and for background treatment prescribed case by case, the first-intention molecules according to the French recommendations are beta-blockers, then, in case of failure, topiramate, oxetorone or amitriptyline.

Auricular vagus nerve stimulation protects against postoperative cognitive dysfunction by attenuating neuroinflammation and neurodegeneration in aged rats.

Postoperative cognitive dysfunction (POCD) has been increasingly recognized as a significant complication after surgery, especially in senior patients. Vagus nerve stimulation (VNS) reportedly provides beneficial effects against various brain disorders, supporting a hypothesis of its protective role in POCD. However, direct stimulation of the vagus nerve is invasive, as it requires a surgical incision in the neck. Thus, we employed a non-invasive VNS method by stimulating the dermatome in the external ear, which is innervated by the vagus nerve (auricular vagus nerve stimulation; aVNS) and sought to investigate the efficacy of this method in treating surgery-induced cognitive dysfunction in an aged rat model of POCD. We observed that the treatment of aVNS alleviated postoperative memory impairment after exploratory laparotomy surgery, as demonstrated by the shorter swimming latency and distance in Morris water maze tests. Moreover, aVNS also reduced postoperative apoptosis in the hippocampus of the aged rats. Concomitant with these beneficial effects, we found that treatment with aVNS attenuated postoperative neuroinflammation (i.e., the protein level of interleukin-1ß and tumor necrosis factor-α, along with the nuclear protein expression of NF-κB) and Alzheimer's-related pathology (tau phosphorylation at AT-8 and Ser396, as well as the levels of Aß40 and Aß42) in the hippocampus of the aged rats. In conclusion, our study is the first to reveal the neuroprotective effect of aVNS against POCD. This effect might be attributed to the inhibition of neuroinflammation and Alzheimer's-related pathology. This study suggests non-invasive aVNS may serve as a promising method for clinical treatment of POCD.

An oligomer-specific antibody improved motor function and attenuated neuropathology in the SOD1-G93A transgenic mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by motor neuron loss in the brain and spinal cord. Mutations in Cu-Zn superoxide dismutase (SOD1) are the first identified genetic mutations that are causative for familial ALS. Soluble SOD1 oligomers are considered the most toxic species and play a key role in the pathologic process of ALS. Here we present a therapeutic strategy for ALS with an oligomer-specific antibody (W20) targeting toxic SOD1 oligomers. Our study showed that W20 significantly improved motor neuron survival and motor performance in SOD1-G93A mouse model of ALS when administrated even at low dose within short time. Further investigation demonstrated that the beneficial effects of W20 resulted from the reduction of SOD1 oligomer levels and the inhibition of gliosis and neuroinflammation in the spinal cords and brain stems of ALS model mice. These findings for the first time suggest that an oligomer-specific antibody has promising therapeutic potential for ALS and open a new way for ALS treatment.

Understanding the Role of T Cells in CNS Homeostasis.

T cells within the central nervous system (CNS) have been generally considered pathogenic, especially in the context of neuroinflammatory disease. However, recent findings have revealed varied functions for T cells in the healthy CNS, as well as more complex roles for these cells in infection and injury than previously appreciated. Here we review evidence indicating important roles for different T cell subsets in the maintenance of CNS homeostasis. We examine the contribution of T cells in limiting inflammation and damage upon CNS injury, infection, and in neurodegeneration, and discuss the current understanding of the cellular and molecular mechanisms involved. Insight into these processes will shed light on the adverse effects of T cell-depleting therapies and present inroads into new therapeutic approaches for treating diseases affecting the CNS.

[Effects of Suspending Moxibustion at "Dazhui" (GV 14) on Neurogenic Inflammation in Asthma Rats].

OBJECTIVE: To observe the effect of suspending-moxibustion stimulation of "Dazhui" (GV 14) with different quantities on the levels of nerve growth factor(NGF) , substance P(SP) , calcitonin gene-related peptide (CGRP), neurokinin A (NKA) , neurokinin B (NKB) and phosphorylated extracellular signal-regulated kinases (pERK) in the bronchoalveolar lavage fluid (BALF) of asthma rats, so as to analyze its mechanisms underlying improving asthma. METHODS: Sixty male SD rats were randomly divided into six groups: blank control, model, 15 min-moxibustion (15 min-moxi), 30 min-moxi, 60 min-moxi and 90 min-moxi (n = 10 rats in each group). The asthma model was established by intraperitoneal injection of suspension of egg protein, magaldrate, and inactivated Bacillus pertussis (on day 1 and 8), and inhaling the atomized ovalbumin saline (from day 15 on for 14 days). Mild moxibustion was conducted at "Dazhui" (GV 14) for 15 min, 30 min, 60 min and 90 min, respectively, once daily for 7 days. The levels of NGF, SP, CGRP, NKA, NKB, and pERK in the BALF were detected by ELISA (enzyme-linked immuno sorbent assay). RESULTS: The contents of NGF, SP, CGRP, NKA, NKB and pERK in the BALF in the model group were obviously higher than those in the blank control group (P < 0.01), suggesting an apparent inflammatory reaction in rats after modeling. Following moxibustion, the levels of NGF, SP, CGRP, NKA, NKB and pERK of the four treatment groups were significantly down-regulated compared with the model group (P < 0.01). The effect of 30 min-moxi group was obviously superior to that of 15 min-moxi group (P < 0.01), and those of 60 min-moxi and 90 min-moxi groups were markedly superior to those of 15 min-moxi and 30 min-moxi groups (P < 0.01) in down-regulating NGF, SP, CGRP, NKA, NKB, and pERK levels in the BALF. No significant differences were found between the 60 min-moxi and 90 min-moxi groups in down-regulating NGF, SP, CGRP, NKA, NKB, and pERK levels (P > 0.05). CONCLUSION: Suspending-moxibustion stimulation of GV 14 can down-regulate the contents of NGF, SP, CGRP, NKA, NKB, and pERK levels in the BALF in asthma rats, suggesting a relief of neurogenic inflammation reaction after moxibustion. The effect of moxibustion presents a time-dependant manner and peaks at 60 min.

Neural circuitry and immunity.

Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuro-immune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex, are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases define the emerging field of Bioelectronic Medicine.

Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective.

The immune system is inextricably linked with many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder affecting motor cell function with an average survival of 3 years from symptoms onset. In ALS, there is a dynamic interplay between the resident innate immune cells, that is, microglia and astrocytes, which may become progressively harmful to motor neurons. Although innate and adaptive immune responses are associated with progressive neurodegeneration, in the early stages of ALS immune activation pathways are primarily considered to be beneficial promoting neuronal repair of the damaged tissues, though a harmful effect of T cells at this stage of disease has also been observed. In addition, although auto-antibodies against neuronal antigens are present in ALS, it is unclear whether these arise as a primary or secondary event to neuronal damage, and whether the auto-antibodies are indeed pathogenic. Understanding how the immune system contributes to the fate of motor cells in ALS may shed light on the triggers of disease as well as on the mechanisms contributing to the propagation of the pathology. Immune markers may also act as biomarkers while pathways involved in immune action may be targets of new therapeutic strategies. Here, we review the modalities by which the immune system senses the core pathological process in motor neuron disorders, focusing on tissue-specific immune responses in the neuromuscular junction and in the neuroaxis observed in affected individuals and in animal models of ALS. We elaborate on existing data on the immunological fingerprint of ALS that could be used to identify clues on the disease origin and patterns of progression.

[2013: what's new in inflammatory neuropathies]. / Revue de la littérature 2013--les neuropathies inflammatoires.

Several high-quality publications were published in 2013 and some major trials studies were started. In Guillain-Barré syndrome, events included the launch of IGOS and a better understanding of diagnostic limits, the effect of influenza vaccination, and better care, but uncertainty remains about analgesics. A new mouse model was also described. In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), diagnostic pitfalls can be recalled. Our knowledge of underlying pathophysiological processes has improved, and the value of monitoring with function and deficit scores has been demonstrated. IVIG can sometimes be effective longer than expected, but CIDP remains sensitive to corticosteroids, particularly with the long-term beneficial effects of megadose dexamethasone. The impact of fingolimod remains to be demonstrated in an ongoing trial. Advances concerning multifocal motor neuropathy, inflammatory plexopathy, and neuropathy with anti -MAG activity are discussed but treatments already recognized as effective should not be changed. Imaging of peripheral nerve progresses.

Involvement of the janus kinase/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE) are characterized by focal inflammatory infiltrates into the central nervous system, demyelinating lesions, axonal damage, and abundant production of cytokines that activate immune cells and damage neurons and oligodendrocytes, including interleukin-12 (IL-12), IL-6, IL-17, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and interferon-gamma. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway mediates the biological activities of these cytokines and is essential for the development and regulation of immune responses. Dysregulation of the JAK/STAT pathway contributes to numerous autoimmune diseases, including MS/EAE. The JAK/STAT pathway is aberrantly activated in MS/EAE because of excessive production of cytokines, loss of expression of negative regulators such as suppressors of cytokine signaling proteins, and significant enrichment of genes encoding components of the JAK/STAT pathway, including STAT3. Specific JAK/STAT inhibitors have been used in numerous preclinical models of MS and demonstrate beneficial effects on the clinical course of disease and attenuation of innate and adaptive immune responses. In addition, other drugs such as statins, glatiramer acetate, laquinimod, and fumarates have beneficial effects that involve inhibition of the JAK/STAT pathway. We conclude by discussing the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases.

Management of glia-mediated neuroinflammation and related patents.

Glia-mediated or glia-propagated inflammation, which acts as the central component in the progression of several brain diseases, is a milestone in the pathophysiological process contributing to the onset or progression of neurodegeneration. Excessive and prolonged neuroinflammation compromises cell and brain function, resulting in fatal brain anomalies. Glial research has garnered attention recently following breakthroughs in neuroinflammation-targeting therapeutics. Activation of microglia and astrocytes, and the attendant expression of proinflammatory cytokines and chemokines, is often associated with disease-, trauma-, and toxicant-induced damage to the central nervous system. A cause-and-effect relationship exists between neuroinflammation and neurotoxic outcomes. In clinical settings, pharmacological antagonists and immunosuppressive regimens can be used to prevent proinflammatory responses and attenuate subsequent neurotoxicity. Current research is focused on the exploration of existing drugs approved for other clinical purposes and on the development of novel synthetic compounds that may selectively downregulate neuroinflammation. The development of innovative therapeutic classes based on targeted selection of glial activation pathways and glia-mediated pathophysiology seems to be a promising approach, and may lead to more effective prevention and treatment of neuroinflammation and resulting maladies. This review focuses on recent patents and emerging therapeutics related to the management of glia-mediated neuroinflammation.

Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease.

Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent.

Treatment of spinal cord injury with intravenous immunoglobulin G: preliminary evidence and future perspectives.

Neuroinflammation plays an important role in the secondary pathophysiological mechanisms of spinal cord injury (SCI) and can exacerbate the primary trauma and thus worsen recovery. Although some aspects of the immune response are beneficial, it is thought that leukocyte recruitment and activation in the acute phase of injury results in the production of cytotoxic substances that are harmful to the nervous tissue. Therefore, suppression of excessive inflammation in the spinal cord could serve as a therapeutic strategy to attenuate tissue damage. The immunosuppressant methylprednisolone has been used in the setting of SCI, but there are complications which have attenuated the initial enthusiasm. Hence, there is interest in other immunomodulatory approaches, such as intravenous Immunoglobulin G (IVIg). Importantly, IVIg is used clinically for the treatment of several auto-immune neuropathies, such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIPD) and Kawasaki disease, with a good safety profile. Thus, it is a promising treatment candidate for SCI. Indeed, IVIg has been shown by our team to attenuate the immune response and result in improved neurobehavioral recovery following cervical SCI in rats through a mechanism that involves the attenuation of neutrophil recruitment and reduction in the levels of cytokines and cytotoxic enzymes Nguyen et al. (J Neuroinflammation 9:224, 2012). Here we review published data in the context of relevant mechanisms of action that have been proposed for IVIg in other conditions. We hope that this discussion will trigger future research to provide supporting evidence for the efficiency and detailed mechanisms of action of this promising drug in the treatment of SCI, and to facilitate its clinical translation.

Mechanistic effects of IVIg in neuroinflammatory diseases: conclusions based on clinicopathologic correlations.

The mechanisms of action of IVIg on immunoregulatory and neuroinflammatory network have been predominantly based on in vitro experiments and animal studies, rather than direct effects on human tissues. Based on clinicopathologic correlations and tissues obtained before and after IVIg therapy, the better documented and clinically-relevant in-vivo actions of IVIg include effects on: a) Antibodies. An extracted antigen-specific anti-immunoglobulin (idiotypic) fraction appears partially responsible for its effect in myasthenia gravis and GBS; b) Complement. Sera from Dermatomyositis (DM) patients responding to IVIg, inhibit complement consumption and intercept MAC formation leading to disappearance of MAC deposits in the repeated muscle biopsies and normalization of muscle tissue; c) Genes. In repeated muscle biopsies from DM patients who improved after IVIg, but not from Inclusion-Body-Myositis (IBM) who did not improve, there is a 2-fold alteration of 2206 tissue genes associated with inflammation, fibrosis, tissue remodeling and regeneration; and d) degenerative-proinflammatory molecules and ß-amyloid, implicated in neurodegenerative CNS diseases and IBM. In repeated muscle biopsies of IBM patients who did not respond to IVIg, the mRNA or protein expression for chemokines, IFN-γ, TGF-ß, IL-10, Ubiquitin and aB-crystallin is reduced, but not for the key molecules ICOS, ICOSL, IL-6, IL1-ß, perforin, APP, nitric oxide synthase and nitrotyrosine, in spite of good IVIg penetration in muscles. Collectively, the selective effectiveness of IVIg in human diseases seems to correlate in vivo with inhibition of causative inflammatory mediators. Study of accessible tissues before and after therapy and clinicopathologic correlations, may help explain the differential effect of IVIg in autoimmune or neuroinflammatory diseases.