Autoreactive Immune Responses Research Articles

Regulatory immune cells and functions in autoimmunity and transplantation immunology.

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies.

Immunopathogenic Oral Diseases: An Overview Focusing on Pemphigus Vulgaris and Mucous Membrane Pemphigoid.

Pemphigus vulgaris, mucosal pemphigoid (mucous membrane pemphigoid), lichen planus, discoid lupus erythematosus and erythema multiforme are a group of immune-mediated mucocutaneous disorders characterised clinically by the formation of blisters, erosions or ulcers. The oral mucosa is often affected, and sometimes the disease is limited to the mouth. The target antigens, autoreactive immune responses, microscopic features, treatment and prognosis vary from one disease to the other. Treatment aims to eliminate exogenous risk factors, suppress the pathogenic immuno-inflammatory reactions, promote healing and prevent infection. The aim of this article is to provide the general dental practitioner with a succinct overview of the diagnostic, clinical, aetiopathogenic features and characteristics of, as well as treatment guidelines for oral pemphigus vulgaris and oral mucosal pemphigoid. Early diagnosis and treatment could prevent severe consequences of the disease in their full-blown forms.

A unique CD8+ T lymphocyte signature in pediatric type 1 diabetes

Human type 1 diabetes results from a destructive auto-reactive immune response in which CD8+ T lymphocytes play a critical role. Given the intense ongoing efforts to develop immune intervention to prevent and/or cure the disease, biomarkers suitable for prediction of disease risk and progress, as well as for monitoring of immunotherapy are required. We undertook separate multi-parameter analyses of single naïve and activated/memory CD8+ T lymphocytes from pediatric and adult patients, with the objective of identifying cellular profiles associated with onset of type 1 diabetes. We observe global perturbations in gene and protein expression and in the abundance of T cell populations characterizing pediatric but not adult patients, relative to age-matched healthy individuals. Pediatric diabetes is associated with a unique population of CD8+ T lymphocytes co-expressing effector (perforin, granzyme B) and regulatory (transforming growth factor β, interleukin-10 receptor) molecules. This population persists after metabolic normalization and is especially abundant in children with high titers of auto-antibodies to glutamic acid decarboxylase and with elevated HbA1c values. These findings highlight striking differences between pediatric and adult type 1 diabetes, indicate prolonged large-scale perturbations in the CD8+ T cell compartment in the former, and suggest that CD8+CD45RA− T cells co-expressing effector and regulatory factors are of interest as biomarkers in pediatric type 1 diabetes.

Dysregulated CD8 T cells resemble Tfh-like cells and promote B cell activation during autoimmunity.

Abstract T follicular helper (Tfh) cells provide essential help for the development of antigen specific antibodies during normal and autoreactive immune responses. IL-2-deficient (KO) mice suffer from excessive lymphoproliferation and spontaneous, systemic autoimmune disease. Depletion of CD4 T cells in IL-2-KO mice eliminates the generation of RBC-specific antibodies, augmenting survival. Surprisingly, depletion of CD8 T cells in IL-2-KO mice also reduces disease and prolongs survival. Several groups have demonstrated a protective role for CD8 T cells in inflammation and autoimmunity, while others have suggested a pathogenic role. However the mechanisms of CD8 T cell influence on autoimmune disease are largely unknown. We have identified a new CD8 Tfh-like population in an autoimmune setting. RNA-sequencing of day 12 IL-2-KO CD8 T cells revealed an increase in the expression of genes associated with the CD4 Tfh lineage (Bcl-6, CXCR5, PD-1, ICOS and IL-21) compared with wild-type CD8 T cells. Flow cytometry confirmed the presence of expanded CD4 Tfh and CD8 Tfh-like cells, and the production of IL-21 in IL-2-KO mice. Germinal center tissue staining revealed localization of both CD4 and CD8 T cells to the germinal center during autoimmunity. In vitro, IL-2-KO CD8 T cells induced proliferation and activation of B cells. Our results indicate that autoreactive CD8 T cells contribute to the autoimmune disease in part through dysregulated follicular-like differentiation and function. NIH funding R00HL090706.

Adaptive immunity in the liver.

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.

Infectious Mononucleosis Triggers Generation of IgG Auto-Antibodies against Native Myelin Oligodendrocyte Glycoprotein.

A history of infectious mononucleosis (IM), symptomatic primary infection with the Epstein Barr virus, is associated with the development of autoimmune diseases and increases the risk to develop multiple sclerosis. Here, we hypothesized that immune activation during IM triggers autoreactive immune responses. Antibody responses towards cellular antigens using a HEp-2 based indirect immunofluorescence assay and native myelin oligodendrocyte glycoprotein (MOG) using a flow cytometry-based assay were determined in 35 patients with IM and in 23 control subjects. We detected frequent immunoglobulin M (IgM) reactivity to vimentin, a major constituent of the intermediate filament family of proteins, in IM patients (27/35; 77%) but rarely in control subjects (2/23; 9%). IgG autoantibodies binding to HEp-2 cells were absent in both groups. In contrast, IgG responses to native MOG, present in up to 40% of children with inflammatory demyelinating diseases of the central nervous system (CNS), were detectable in 7/35 (20%) patients with IM but not in control subjects. Normalization of anti-vimentin IgM levels to increased total IgM concentrations during IM resulted in loss of significant differences for anti-vimentin IgM titers. Anti-MOG specific IgG responses were still detectable in a subset of three out of 35 patients with IM (9%), even after normalization to increased total IgG levels. Vimentin-specific IgM and MOG-specific IgG responses decreased following clinical resolution of acute IM symptoms. We conclude from our data that MOG-specific memory B cells are activated in subset of patients with IM.

Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome.

ObjectiveGlycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation.MethodsUsing ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).ResultsMultiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).ConclusionThe IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.

Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats

Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D2 /5-HT1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]-picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), in experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation. Both compounds (10mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D2 and 5-HT1A receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM-CSF, TH 1 cytokine IFN-γ, TH 17 cytokine IL-17, as well as the signature transcription factors of TH 1 (T-bet) and TH 17 (RORγt) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The invitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic protein-activated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation. Arylpiperazine dopaminergic/serotonergic ligands reduce neurological symptoms of acute autoimmune encephalomyelitis in rats without affecting the activation of autoreactive immune response, through mechanisms involving a decrease in CNS immune infiltration, as well as direct protection of CNS from immune-mediated damage. These data indicate potential usefulness of arylpiperazine-based compounds in the treatment of neuroinflammatory disorders such as multiple sclerosis.

Putting together the autoimmunity puzzle.

Autoimmune diseases classically present with a complex etiology in which different factors concur in the generation and maintenance of autoreactive immune responses. Some mechanisms and pathways that lead to the development of imbalanced immune homeostasis and loss of self-tolerance have been identified as common to multiple autoimmune disorders. This Review series focuses on the general concepts of development and progression to pathogenic autoimmune phenotypes. A mechanistic discussion of the most recent advances in the field, together with related considerations of possible therapies, make this series of particular interest to both the basic and translational science communities.

Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke.

Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4(+) T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of 2D2 and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of 2D2 mice 14 d after middle cerebral artery occlusion. One month after experimental stroke, 2D2 mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4(+) T cells, isolated from 2D2 mice, into lymphocyte-deficient Rag-1KO mice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.

Understanding the opposing roles of the adaptive immune system in stroke (THER7P.955)

Abstract Stroke is caused by a loss of blood flow to the brain, which results in permanent neurological injury. Murine models of ischemic stroke implicate the immune system as both contributor and suppressor of neuro-inflammation following brain ischemia. Using a 60-min transient middle cerebral artery occlusion model and a recall response assay, we have detected autoreactive immune responses to myelin, neuronal and glial peptides, suggesting a possible immune involvement in further brain inflammation. We previously found that repetitive hypoxic preconditioning (RHP) prior to stroke endogenously decreases infarct volumes and creates a unique, anti-inflammatory B-cell phenotype that may contribute to RHP-mediated reversal of neuropathology. Now, we show that B(RHP)cell adoptive transfer significantly reduces infarct volumes and CNS-antigen autoreactivity in CD4+ T-cells compared to PBS- or control B-cell treatments. B(RHP)cells exhibited increased production of IL10, a neuroprotective cytokine, and IFN-γ, a cytokine that potentiates the conversion of effector to regulatory T-cells that suppress neuropathological immune cells. Co-culture of B(RHP)cells with T-cells significantly converted naïve CD4 T-cells to Foxp3+CD25+ regulatory CD4 T-cells. Based on these observations, we hypothesize that RHP induces a novel subset of neuroprotective B-cells as an important regulatory arm of the adaptive immune system that can be potentially harnessed for immunotherapeutic strategies.

Mast cell promotion of T cell-driven antigen-induced arthritis despite being dispensable for antibody-induced arthritis in which T cells are bypassed.

The function of mast cells (MCs) in autoimmune disorders has been a subject of controversy recently. MC-deficient Kit(W/W-v) mice were found to be resistant to K/BxN serum-transfer arthritis, whereas Kit(W-sh/W-sh) mice and a genetic model of MC deficiency independent of the Kit mutation were found to be fully susceptible. This debate might lead to the assumption that MCs are dispensable in autoimmunity in general. Thus, the purpose of this study was to examine the relevance of MCs to arthritis using a genetic model of inducible MC deficiency without compromised Kit signaling. We compared MC functions in K/BxN serum-induced arthritis and in collagen-induced arthritis (CIA) in a mouse model of inducible MC deficiency by analyzing joint inflammation, parameters of cartilage degradation and bone erosion, and the autoreactive adaptive immune response. We observed a redundant role of MCs in K/BxN serum-induced arthritis, where joint inflammation is triggered by cartilage-bound immune complexes independently of T cells. In contrast, we found MCs to be critically relevant in CIA, which is provoked by two arms of autoimmune attack: autoreactive antibodies and effector T cells. In addition to diminished joint inflammation in the absence of MCs, we found a dramatic loss of T cell expansion upon immunization, accompanied by reduced T cell cytokine responses. In this analysis of an arthritis model in which the cellular arm of adaptive immunity was not bypassed, we identified MCs as important promoters of T cell-conditioned autoimmune disorders and, consequently, as potential therapeutic targets in rheumatoid arthritis.

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Background: Accumulating evidence shows that the pathological autoreactive immune response is responsible for plaque rupture and the subsequent onset of acute coronary syndrome (ACS). Naturally occurring CD4⁺CD25⁺regulatory T cells (nTregs) are indispensable in suppressing the pathological autoreactive immune response and maintaining immune homeostasis. However, the number and the suppressive function of glycoprotein-A repetitions predominant (GARP) ⁺ CD4⁺ CD25⁺ activated nTregs were impaired in patients with ACS. Recent evidence suggests that heme oxygenase-1 (HO-1) can regulate the adaptive immune response by promoting the expression of Foxp3. We therefore hypothesized that HO-1 may enhance the function of GARP⁺ CD4⁺ CD25⁺Tregs in patients with ACS and thus regulate immune imbalance. Methods: T lymphocytes were isolated from healthy volunteers (control, n=30) and patients with stable angina (SA, n=40) or ACS (n=51). Half of these cells were treated with an HO-1 inducer (hemin) for 48 h, and the other half were incubated with complete RPMI-1640 medium. The frequencies of T-helper 1 (Th1), Th2, Th17 and latency-associated peptide (LAP) ⁺CD4⁺ T cells and the expression of Foxp3 and GARP by CD4⁺CD25⁺T cells were then assessed by measuring flow cytometry after stimulation in vitro. The suppressive function of activated Tregs was measured by thymidine uptake. The levels of transforming growth factor-1 (TGF-β1) in the plasma were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of the genes encoding these proteins were analyzed by real-time polymerase chain reaction. Results: Patients with ACS exhibited an impaired number and suppressive function of GARP⁺ CD4⁺ CD25⁺Tregs and a mixed Th1/Th17-dominant T cell response when compared with the SA and control groups. The expression of LAP in T cells was also lower in patients with ACS compared to patients with SA and the control individuals. Treatment with an HO-1 inducer enhanced the biological activity of GARP⁺ CD4⁺ CD25⁺Tregs and resulted in increased expression of LAP and GARP by activated T cells. Conclusions: The reduced number and impaired suppressive function of GARP⁺ CD4⁺ CD25⁺Tregs result in excess effector T cell proliferation, leading to plaque instability and the onset of ACS. HO-1 can effectively restore impaired GARP⁺ CD4⁺ CD25⁺Tregs from patients with ACS by promoting LAP and GARP expression on activated T cells.

Diversity and clonal selection in the human T-cell repertoire.

T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.

Mesenchymal stem cell-based therapy in a mouse model of experimental autoimmune encephalomyelitis (EAE).

Multiple sclerosis (MS) is a common neurodegenerative disease that presents after an auto-reactive immune response against constituents of the central nervous system. Demyelination, inflammation, and white matter lesions are all hallmarks of this disease. Clinical research supports the use of mesenchymal stem cells (MSCs) as therapy for MS to ameliorate symptoms and pathology. MSCs can be isolated from multiple tissues, including adipose and bone marrow, and are able to migrate to sites of pathology, release anti-inflammatory factors, and provide immunomodulatory and neuroprotective effects once administered. Numerous studies have demonstrated the beneficial effects of MSCs in experimental autoimmune encephalomyelitis (EAE), an induced model of MS. EAE can be induced in several species; however, the mouse is commonly used for therapeutic testing. In the following chapter, scientists will be able to learn how to prepare reagents and MSCs (e.g., isolate, culture, and expand) as well as skillfully execute induction of EAE in mice and administer stem cell-based treatments. Standard methods used to evaluate the disease progression and analyze postmortem tissues are also included.

High Fat Diet Exacerbates Neuroinflammation in an Animal Model of Multiple Sclerosis by Activation of the Renin Angiotensin System

Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND) or HFD and subsequently induced with EAE. Immunohistochemical staining and real-time PCR were used to determine immune cell infiltration and inflammatory mediators in the central nervous system (CNS). Our data show that HFD increases immune cell infiltration and inflammatory mediator production in the CNS and thereby aggravates EAE. Moreover, our data demonstrate that activation of the renin angiotensin system (RAS) is associated with the HFD-mediated effects on EAE severity. These results show that HFD exacerbates an autoreactive immune response within the CNS. This indicates that diets containing excess fat have a significant influence on neuroinflammation in EAE, which may have important implications for the treatment and prevention of neuroinflammatory disorders.

OP0053 Cremalpha destabilizes FOXP3 expression in regulatory T cells

BackgroundThe transcription factor cAMP response element modulator (CREM) is a widely expressed transcriptional repressor. CREMα is overexpressed in SLE (Systemic Lupus erythematosus) T cells and CREMα promoter activity correlates with...

A novel subset of functional interleukin-10 secreting CD8 regulatory T cells infiltrate human hepatocellular carcinoma

BackgroundTumour specific effector T cells can be detected in the blood and tumours of patients with hepatocellular carcinoma but they fail to mount effective immune responses. Attempts to amplify anti-tumour immune responses using immunotherapy show promise, but are hampered by the presence of suppressive regulatory T cells (Tregs) that inhibit anti-tumour immune responses. Tregs are crucial in the maintenance of immune homoeostasis and in the prevention of autoreactive immune response but in the context of cancer they can suppress beneficial anti-tumour immunity leading to tumour progression. A novel subset of CD8 expressing Tregs has recently been described and we now report the presence of such cells in human hepatocellular carcinoma and define their functional and homing properties. MethodsFresh tissue from hepatocellular carcinoma and matched distal non-involved tissue were obtained from patients undergoing liver resection or transplantation at the Queen Elizabeth Hospital, Birmingham, after informed consent. Liver-derived T cells were isolated and phenotyped with multicolour flow cytometry including intracellular cytokine staining. CD8+Tregs were isolated with a Mo-Flow cell sorter for functional assays. Distribution of CD8+Tregs was investigated by immunohistochemistry and immunofluorescence. FindingsThe percentage of CD8+Tregs (defined as CD8+CD25highCD127lowFoxP3+) infiltrating hepatocellular carcinoma tumours was significantly greater than matched non-involved liver. Tumour-derived CD8+Treg isolated by Mo-Flo sorting suppressed allogeneic effectors cells in vitro and secreted interleukin (IL) 10. By contrast, T-cell interferon-γ production was decreased within the tumour compared with matched non-involved liver. The chemokine receptor CXCR3 which is involved in T-cell recruitment to the inflamed liver was highly expressed on tumour-derived CD8+Tregs. InterpretationA novel subset of functional IL-10 secreting CD8+Tregs may suppress anti-tumour immunity in hepatocellular carcinoma. Their expression of CXCR3 provides a potential mechanism for recruitment into the tumour environment. FundingWellcome Trust.

Myeloid-derived Suppressor Cells in Autoimmune Diabetes: Their Antidiabetic Potential and Mechanism

Autoimmune diabetes is caused by a destruction of pancreatic β-cells by autoreactive immune response, leading to insulin insufficiency/deficiency and hyperglycemia and fatal complications. This disease afflicts up to 10 million people worldwide. There is no cure for autoimmune diabetes. Insulin injection is the only supportive medication, which always accompanies fatality. Apart from replacement therapy using insulin and/or β-cells, immune interventions hold the key to stopping this illness. Myeloid-derived suppressor cells have emerged as a new regulator in harnessing immune response. In this review, we first up-dated the advances on etiology, development and immune interventions of autoimmune diabetes. Next, we highlighted the origin, development, tolerogenic mechanisms of myeloid-derived suppressor cells with an emphasis of the signaling pathways in their development and action. Finally, we summarized and discussed the recent progress in exploring the potential and mechanism of myeloid-derived suppressor cells in autoimmune diabetes. A novel vista on MDSC-based immune intervention with AID development was also discussed.

Neuroendocrine Immunoregulation in Multiple Sclerosis

Currently, it is generally accepted that multiple sclerosis (MS) is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses that lead to damage of myelin. In this respect, intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress as well as a variety of other lifestyle interventions can influence the neuroendocrine system. On its turn, it has been demonstrated that the neuroendocrine system has immunomodulatory potential. Moreover, the neuroendocrine and immune systems communicate bidirectionally via shared receptors and shared messenger molecules, variously called hormones, neurotransmitters, or cytokines. Discrepancies at any level can therefore lead to changes in susceptibility and to severity of several autoimmune and inflammatory diseases. Here we provide an overview of the complex system of crosstalk between the neuroendocrine and immune system as well as reported dysfunctions involved in the pathogenesis of autoimmunity, including MS. Finally, possible strategies to intervene with the neuroendocrine-immune system for MS patient management will be discussed. Ultimately, a better understanding of the interactions between the neuroendocrine system and the immune system can open up new therapeutic approaches for the treatment of MS as well as other autoimmune diseases.