Dendritic cells in autoimmune disorders and cancer of the thyroid

Dendritic cells (DCs), considered as one of the crucial immune regulatory populations, are implicated in the immune pathology of various disorders. Also in the thyroid gland, DCs were shown to be involved in early and chronic phases of various types of autoimmunity — including Hashimoto’s thyroiditis and Graves’ disease. In thyroid malignant processes, DCs are suggested as an important element of both tumour defence and tumour immune evasion mechanisms. Recent findings emphasize a crucial role of interactions between particular DC subsets and other regulatory cell populations (e.g. FoxP3+ regulatory T cells) in thyroid pathology. Additionally, an increasing attention has been paid to the control of DC function by thyrometabolic conditions. (Folia Histochemica et Cytobiologica 2014, Vol. 52, No. 1, 18–28

Immunohistochemical analysis of spinal cord components in mouse model of experimental autoimmune encephalomyelitis

Introduction. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for studying immunopathology of multiple sclerosis (MS) because it repeats the hallmarks of the human disease, such as focal inflammation and demyelination of the central nervous system, subsequently leading to axonal and neuronal loss. The interrelationships, timing and sequence of different pathological processes that lead to histologically observed lesions in SM are still incompletely understood.Material and methods. EAE was induced in female C57Bl/6 mice by active immunization with MOG35-55 antigen. Development of the neurological symptoms in the animals was monitored and on that basis spinal cords were collected in three successive phases of the disease (onset, peak, chronic). Total leukocytes, T cells, macrophages/microglia, oligodendrocytes, damaged axons and surviving neuronal cell bodies were visualized using appropriate immunohistochemical markers and their density was quantitatively assessed using image analysis software.Results. The density of all studied cells except neurons was significantly higher in EAE mice than in the control mice. The density of total leukocytes, T cells, and damaged axons increased from the onset to the peak phase and decreased in the chronic phase to reach values lower than those in the peak phase. The density of macrophages/microglia increased in the peak phase and remained at the elevated level in the chronic phase. Oligodendrocytes showed the highest density in the onset phase and gradually decreased afterwards. The density of neuronal cell bodies decreased only in the chronic phase of the disease.Conclusions. In mouse model of EAE, inflammatory cells predominate in the early phases of the disease. This study shows for the first time that inflammation precedes oligodendrocyte death and neuronal loss and that macrophages/ microglia are the only cells persisting in large numbers in the chronic phase of the disease, probably because of the switch from proinflammatory to anti-inflammatory phenotype

Effect of L-thyroxine treatment on peripheral blood dendritic cell subpopulations in patients with Hashimoto’s thyroiditis

Recent reports suggested dendritic cells (DCs) to be important players in the pathogenesis of autoimmune thyroid processes in humans. However, there are virtually no data addressing the influence of thyroid autoaggression-associated disturbances of thyrometabolic conditions on DCs biology. The aim of the study was to evaluate the influence of L-thyroxine supplementation on conventional and plasmacytoid peripheral blood DCs subtypes in patients with hypothyroidism due to Hashimoto’s thyroiditis (HT). Eighteen patients with newly diagnosed hypothyroidism due to HT were included into the study. All patients received L-thyroxine treatment with doses adjusted to reach euthyroidism. Peripheral blood DC subtypes structure and immunoregulatory phenotype were analyzed by flow cytometry in the same patient prospectively at two time points: (i) beforeand (ii) 3 months after beginning of L-thyroxine treatment (hypothyroidism vs. euthyroidism, respectively). Percentage of plasmacytoid DCs in peripheral blood mononuclear cells fraction was significantly decreased in the course of L-thyroxine treatment (0.27 ± 0.19 vs. 0.11 ± 0.08; p < 0.05), whereas we did not observe any changes in the number of conventional DCs. However, the phenotypic analysis showed a significant increase of conventional DCs expressing CD86 and CD91 (64.25 ± 21.6% vs. 86.3 ± 11%; p < 0.05 and 30.75 ± 11.66% vs. 44.5 ± 13.3%; p < 0.05; respectively) in euthyroid patients. Standard L-thyroxine supplementation in HT patients exerted significant immunoregulatory effects, associated with quantitative and phenotypic changes of peripheral blood DC subpopulations

MHC class II–restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell–mediated autoimmunity

Although plasmacytoid dendritic cells (pDCs) express major histocompatibility complex class II (MHCII) molecules, and can capture, process, and present antigens (Ags), direct demonstrations that they function as professional Ag-presenting cells (APCs) in vivo during ongoing immune responses remain lacking. We demonstrate that mice exhibiting a selective abrogation of MHCII expression by pDCs develop exacerbated experimental autoimmune encephalomyelitis (EAE) as a consequence of enhanced priming of encephalitogenic CD4+ T cell responses in secondary lymphoid tissues. After EAE induction, pDCs are recruited to lymph nodes and establish MHCII-dependent myelin-Ag–specific contacts with CD4+ T cells. These interactions promote the selective expansion of myelin-Ag–specific natural regulatory T cells that dampen the autoimmune T cell response. pDCs thus function as APCs during the course of EAE and confer a natural protection against autoimmune disease development that is mediated directly by their ability to present of Ags to CD4+ T cells in vivo

Long-Term Decrease in VLA-4 Expression and Functional Impairment of Dendritic Cells during Natalizumab Therapy in Patients with Multiple Sclerosis

Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are central to the initiation and the regulation of immune processes in multiple sclerosis (MS). Natalizumab (NTZ) is a humanized monoclonal antibody approved for the treatment of MS that acts by blocking expression of VLA-4 integrins on the surface of leukocytes. We determined the proportions of circulating DC subsets and analyzed expression of VLA-4 expression in 6 relapsing-remitting MS patients treated with NTZ for 1 year. VLA-4 expression levels on pDCs and mDCs decreased significantly during follow-up. In vitro coculture of peripheral blood mononuclear cells and pDCs, with different doses of NTZ in healthy controls (HC) and MS patients showed dose-dependent down-regulation of VLA-4 expression levels in both MS patients and HC, and reduced functional ability to stimulate antigen-specific T-lymphocyte responses. The biological impact of NTZ may in part be attributable to inhibition of transmigration of circulating DCs into the central nervous system, but also to functional impairment of interactions between T cells and DC

CCL5-glutamate cross-talk in astrocyte-neuron communication in multiple sclerosis

The immune system (IS) and the central nervous system (CNS) are functionally coupled, and a large number of endogenous molecules (i.e., the chemokines for the IS and the classic neurotransmitters for the CNS) are shared in common between the two systems. These interactions are key elements for the elucidation of the pathogenesis of central inflammatory diseases. In recent years, evidence has been provided supporting the role of chemokines as modulators of central neurotransmission. It is the case of the chemokines CCL2 and CXCL12 that control pre- and/or post-synaptically the chemical transmission. This article aims to review the functional cross-talk linking another endogenous pro-inflammatory factor released by glial cells, i.e., the chemokine Regulated upon Activation Normal T-cell Expressed and Secreted (CCL5) and the principal neurotransmitter in CNS (i.e., glutamate) in physiological and pathological conditions. In particular, the review discusses preclinical data concerning the role of CCL5 as a modulator of central glutamatergic transmission in healthy and demyelinating disorders. The CCL5-mediated control of glutamate release at chemical synapses could be relevant either to the onset of psychiatric symptoms that often accompany the development of multiple sclerosis (MS), but also it might indirectly give a rationale for the progression of inflammation and demyelination. The impact of disease-modifying therapies for the cure of MS on the endogenous availability of CCL5 in CNS will be also summarized. We apologize in advance for omission in our coverage of the existing literature

Self-tolerance in multiple sclerosis

During the last decade, several defects in self-tolerance have been identified in multiple sclerosis. Dysfunction in central tolerance leads to the thymic output of antigen-specific T cells with T cell receptor alterations favouring autoimmune reactions. In addition, premature thymic involution results in a reduced export of naïve regulatory T cells, the fully suppressive clone. Alterations in peripheral tolerance concern costimulatory molecules as well as transcriptional and epigenetic mechanisms. Recent data underline the key role of regulatory T cells that suppress Th1 and Th17 effector cell responses and whose immunosuppressive activity is impaired in patients with multiple sclerosis. Those recent observations suggest that a defect in self-tolerance homeostasis might be the primary mover of multiple sclerosis leading to subsequent immune attacks, inflammation and neurodegeneration. The concept of multiple sclerosis as a consequence of the failure of central and peripheral tolerance mechanisms to maintain a self-tolerance state, particularly of regulatory T cells, may have therapeutic implications. Restoring normal thymic output and suppressive functions of regulatory T cells appears an appealing approach. Regulatory T cells suppress the general local immune response via bystander effects rather than through individual antigen-specific responses. Interestingly, the beneficial effects of currently approved immunomodulators (interferons β and glatiramer acetate) are associated with a restored regulatory T cell homeostasis. However, the feedback regulation between Th1 and Th17 effector cells and regulatory T cells is not so simple and tolerogenic mechanisms also involve other regulatory cells such as B cells, dendritic cells and CD56bright natural killer cells

Regulation of inflammatory transcription factors by heat shock protein 70 in primary cultured astrocytes exposed to oxygen–glucose deprivation

Inflammation is an important event in ischemic injury. These immune responses begin with the expression of pro-inflammatory genes modulating transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and signal transducers and activator of transcription-1 (STAT-1). The 70-kDa heat shock protein (Hsp70) can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. Since Hsp70 are induced under heat stress, we investigated the link between Hsp70 neuroprotection and phosphorylation of inhibitor of κB (IκB), c-Jun N-terminal kinases (JNK) and p38 through co-immunoprecipitation and enzyme-linked immunosorbent assay (ELISA) assay. Transcription factors and pro-inflammatory genes were quantified by immunoblotting, electrophoretic-mobility shift assay and reverse transcription-polymerase chain reaction assays. The results showed that heat stress led to Hsp70 overexpression which rendered neuroprotection after ischemia-like injury. Overexpression Hsp70 also interrupts the phosphorylation of IκB, JNK and p38 and blunts DNA binding of their transcription factors (NF-κB, AP-1 and STAT-1), effectively downregulating the expression of pro-inflammatory genes in heat-pretreated astrocytes. Taken together, these results suggest that overexpression of Hsp70 may protect against brain ischemia via an anti-inflammatory mechanism by interrupting the phosphorylation of upstream of transcription factors