Hong-Liang Zhang

Th1/Th2/Th17/Treg cytokines in Guillain-Barré syndrome and experimental autoimmune neuritis.

Guillain-Barré syndrome (GBS) is an immune-mediated acute inflammatory disorder in the peripheral nervous system (PNS) of humans characterized by inflammatory infiltration and damage to myelin and axon. Experimental autoimmune neuritis (EAN) is a useful animal model for GBS. Although GBS and EAN have been widely studied, the pathophysiological basis of GBS/EAN remains largely unknown. Immunocompetent cells together with cytokines produced by various cells contribute to the inflammatory process of EAN by acting as mediators or effectors. Both GBS and EAN have hitherto been attributed to T helper (Th)1 cells-mediated disorders, however, some changes in GBS and EAN could not be explained by the pathogenic role of Th1 cells and a disturbance of the Th1/Th2 balance, which has previously been considered to be important for the homeostatic maintenance of the immune responses and to explain the adaptive immunity and autoimmune diseases. The Th1/Th2 paradigm in autoimmune diseases has been greatly challenged in recent years, with the identification of a particular T cell subset Th17 cells. Studies on the associations between Th17 cells/cytokines and GBS/EAN are reviewed. But some of them occasionally yield conflicting results, indicating an intricate network of cytokines in immune response.

Attenuated EAN in TNF-α Deficient Mice Is Associated with an Altered Balance of M1/M2 Macrophages

The role of tumor necrosis factor (TNF)-α and its receptors in neuroautoimmune and neuroinflammatory diseases has been controversial. On the basis of our previous studies, we hereby aimed to further clarify TNF-α’s mechanism of action and to explore the potential role of TNF-α receptor (TNFR)1 as a therapeutic target in experimental autoimmune neuritis (EAN). EAN was induced by immunization with P0 peptide 180–199 in TNF-α knockout (KO) mice and anti-TNFR1 antibodies were used to treat EAN. Particularly, the effects of TNF-α deficiency and TNFR1 blockade on macrophage functions were investigated. The onset of EAN in TNF-α KO mice was markedly later than that in wild type (WT) mice. From day 14 post immunization, the clinical signs of TNF-α KO mice were significantly milder than those of their WT counterparts. Further, we showed that the clinical severity of WT mice treated with anti-TNFR1 antibodies was less severe than that of the control WT mice receiving PBS. Nevertheless, no difference with regard to the clinical signs of EAN or inflammatory infiltration in cauda equina was seen between TNF-α KO and WT mice with EAN after blockade of TNFR1. Although TNF-α deficiency did not alter the proliferation of lymphocytes in response to either antigenic or mitogenic stimuli, it down-regulated the production of interleukin (IL)-12 and nitric oxide (NO), and enhanced the production of IL-10 in macrophages. Increased ratio of regulatory T cells (Tregs) and reduced production of interferon (IFN)-γ in cauda equina infiltrating cells, and elevated levels of IgG2b antibodies against P0 peptide 180–199 in sera were found in TNF-α KO mice with EAN. In conclusion, TNF-α deficiency attenuates EAN via altering the M1/M2 balance of macrophages.

Circulating Th17, Th22, and Th1 Cells Are Elevated in the Guillain-Barré Syndrome and Downregulated by IVIg Treatments

The Guillain-Barré syndrome (GBS) is considered a T helper 1 (Th1) cells-mediated acute inflammatory peripheral neuropathy. However, some changes in GBS could not be explained completely by Th1 cells pathogenic role. Recently, Th17 cells have been identified and can mediate tissue inflammation and autoimmune response. Therefore, a study on the role of Th17 and Th22 cells and their cytokines in GBS is necessary for exploring the pathogenesis of GBS. Here, we detected the frequency of Th1, Th17, and Th22 cells by using 4-color flow cytometry and we detected the plasma levels of IL-17 and IL-22 by ELISA in GBS patients, relapsing-remitting multiple sclerosis patients at the acute phase of relapse, viral encephalitis or meningitis patients and healthy controls. Our data showed that the frequency of circulating Th1, Th17, and Th22 cells was significantly increased in GBS patients. The plasma levels of IL-17 and IL-22 in GBS and relapsing-remitting multiple sclerosis at the acute phase of relapse were also markedly elevated. Enhanced circulating Th22 cells were correlated with GBS severity. Intravenous immunoglobulin therapy downregulated Th17, and Th22 cells and the plasma levels of IL-17 and IL-22 in GBS patients. Th17 and Th22 cells may be involved in the pathogenesis of GBS, and intravenous immunoglobulin mediates therapeutic effects by downregulating these cells and their cytokines.

Mitigated Tregs and Augmented Th17 Cells and Cytokines are Associated with Severity of Experimental Autoimmune Neuritis

Experimental autoimmune neuritis (EAN), an animal model of human Guillain–Barré syndrome, has long been considered as a T helper (Th) 1 cell–mediated autoimmune disorder. However, deficiency of IFN‐γ, a signature Th1 cytokine, aggravated EAN, with features of elevated production of IL‐17A, despite an alleviated systemic Th1 immune response. We hypothesized that Th17 cells and their cytokines might play a pathogenic role in EAN. To further clarify the roles of these Th and regulatory T cell (Treg) cytokines in the pathogenesis of EAN and their interrelationship, we investigated the expression of Th1/Th2/Th17/Treg cytokines in EAN in this study. We found that the levels of Th17 cells and IL‐17A in cauda equina (CE)‐infiltrating cells and splenic mononuclear cells (MNCs) as well as in serum paralleled the disease evolution, which increased progressively during the initiation stage and reached higher value at the peak of EAN. The same pattern was also noticed for the expression of IL‐22. The diverse expression profiles of FoxP3, IL‐17 receptors A and C were seen in CE‐infiltrating cells and splenic MNCs in EAN. These findings indicate a major pro‐inflammatory role of Th17 cells and IL‐17A in the pathogenesis of EAN. Therapeutic interventions may be focused upon inhibiting Th17 cells and their cytokines in the early phase of EAN, so as to delay and suppress clinical signs of the disease, which has relevance for future studies on pathogenesis and treatment of GBS in humans.

Olfactory dysfunctions in neurodegenerative disorders

Olfactory dysfunction is a common symptom in the patients with neurodegenerative disorders, particularly in Parkinsons disease (PD) and Alzheimers disease (AD). Recently, studies of olfactory dysfunction have focused on its potential as a medication‐independent biomarker for disease progression and as an early indicator for the diagnosis of neurodegenerative disorders. In the past decades, great achievements have been obtained in elucidating the neuroanatomy and the function of olfactory system, yet the pathogenesis of olfactory dysfunction in neurodegenerative disorders remains elusive. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb, primary olfactory cortices, and their secondary targets changes. This article summarizes the up‐to‐date knowledge on pathophysiological changes of the olfactory system in neurodegenerative disorders and attempts to find the association between olfactory dysfunction and neurodegenerative disorders.

IFN-γ deficiency exacerbates experimental autoimmune neuritis in mice despite a mitigated systemic Th1 immune response

Previous studies have shown that interferon-gamma (IFN-γ) is a proinflammatory cytokine that contributes to the pathogenesis of Guillain-Barré syndrome and its animal model, experimental autoimmune neuritis (EAN). Treatments with anti-IFN-γ antibodies improve clinical outcome in GBS patients and EAN animals and administration of IFN-γ markedly worsens EAN. Paradoxically, the mice deficient in IFN-γ remain susceptible to experimental autoimmune encephalomyelitis, an analogous disease in the central nervous system. These observations raise a question whether IFN-γ might be protective in autoimmune demyelinating diseases. To clarify the role of IFN-γ in the pathogenesis of autoimmune demyelinating diseases, we used P0 protein peptide 180-199 to induce EAN in IFN-γ knockout (KO) mice. After the acute phase of EAN, the clinical signs of IFN-γ KO mice were significantly more severe than those of wild type (WT) controls. After antigenic stimulation, the proliferation of splenic mononuclear cells was significantly higher in IFN-γ KO than in WT mice with EAN. At the peak of EAN, the proportion of interleukin (IL)-17A expressing cells in cauda equina (CE) infiltrating cells, and the levels of IL-17A in sera were elevated in IFN-γ KO mice when compared with their WT counterparts. The proportions of major histocompatibility complex (MHC) II, macrosialin, and IL-12/IL-23p40 expressing cells, relative to total CE infiltrating cells were correspondingly higher in IFN-γ KO than in WT mice with EAN. However, IFN-γ deficiency reduced the production of NO by cultured macrophages in response to proinflammatory stimuli and induced a systemic Th2-oriented immune response. In conclusion, IFN-γ deficiency exacerbates EAN via upregulating Th17 cells despite a mitigated systemic Th1 immune response.

Role of the immunogenic and tolerogenic subsets of dendritic cells in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disorder in the central nervous system (CNS) characterized by inflammation and demyelination as well as axonal and neuronal degeneration. So far effective therapies to reverse the disease are still lacking; most therapeutic drugs can only ameliorate the symptoms or reduce the frequency of relapse. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are key players in both mediating immune responses and inducing immune tolerance. Increasing evidence indicates that DCs contribute to the pathogenesis of MS and might provide an avenue for therapeutic intervention. Here, we summarize the immunogenic and tolerogenic roles of DCs in MS and review medicinal drugs that may affect functions of DCs and have been applied in clinic for MS treatment. We also describe potential therapeutic molecules that can target DCs by inducing anti-inflammatory cytokines and inhibiting proinflammatory cytokines in MS.

Biomarkers of Guillain-Barré Syndrome: Some Recent Progress, More Still to Be Explored

Guillain-Barré syndrome (GBS), the axonal subtype of which is mainly triggered by C. jejuni with ganglioside-mimicking lipooligosaccharides (LOS), is an immune-mediated disorder in the peripheral nervous system (PNS) accompanied by the disruption of the blood-nerve barrier (BNB) and the blood-cerebrospinal fluid barrier (B-CSF-B). Biomarkers of GBS have been extensively explored and some of them are proved to assist in the clinical diagnosis and in monitoring disease progression as well as in assessing the efficacy of immunotherapy. Herein, we systemically review the literature on biomarkers of GBS, including infection-/immune-/BNB, B-CSF-B, and PNS damage-associated biomarkers, aiming at providing an overview of GBS biomarkers and guiding further investigations. Furthermore, we point out further directions for studies on GBS biomarkers.

Acute Necrotizing Encephalopathy: An Underrecognized Clinicoradiologic Disorder

Acute necrotizing encephalopathy (ANE) is a rare but distinctive type of acute encephalopathy with global distribution. Occurrence of ANE is usually preceded by a virus-associated febrile illness and ensued by rapid deterioration. However, the causal relationship between viral infections and ANE and the exact pathogenesis of ANE remain unclear; both environmental and host factors might be involved. Most cases of ANE are sporadic and nonrecurrent, namely, isolated or sporadic ANE; however, few cases are recurrent and with familial episodes. The recurrent and familial forms of ANE were found to be incompletely autosomal-dominant. Further the missense mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) were identified. Although the clinical course and the prognosis of ANE are diverse, the hallmark of neuroradiologic manifestation of ANE is multifocal symmetric brain lesions which are demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI). The treatment of ANE is still under investigation. We summarize the up-to-date knowledge on ANE, with emphasis on prompt diagnosis and better treatment of this rare but fatal disease.

Overexpression of apolipoprotein E4 increases kainic-acid-induced hippocampal neurodegeneration.

Apolipoprotein E (apoE) has an intricate biological function in modulating immune responses and apoE isoforms exhibit diverse effects on neurodegenerative and neuroinflammatory disorders. In the present study, we investigated the individual roles of apoE isoforms in the kainic acid (KA)-induced hippocampal neurodegeneration with focus on immune response and microglia functions. ApoE2, 3 and 4 transgenic mice as well as wild-type (WT) mice were treated with KA by intranasal route. ApoE4 overexpressing mice revealed several peculiarities as compared with other transgenic mice and WT mice, i.e. (1) they had more severe KA-induced seizures than apoE2 and 3 mice, (2) they exhibited neuron loss in hippocampus that was higher than in apoE2, 3 and WT mice, (3) KA administration resulted in higher counts of their head drops in the cross-area of elevated plus-maze, (4) they showed lower KA-induced rearing activity than apoE2 mice in the open-field test, (5) their KA-induced microglial expression of MHC-II and CD86 was elevated compared to apoE3 mice, (6) the KA-induced increase of microglial iNOS was higher than that in the other groups of mice, and (7) the TNF-α and IL-6 expression was decreased 7 days after KA application compared to untreated mice and mice treated 1 day with KA. However, the signaling pathway of NFκB or Akt seemed not to be involved in apoE-isoform dependent susceptibility to KA-induced neurotoxicity. In conclusion, over-expression of apoE4 deteriorated KA-induced hippocampal neurodegeneration in C57BL/6 mice, which might result from a higher up-regulation of microglia activation compared to apoE2 and 3 transgenic mice and WT mice.