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Journal: Scandinavian journal of immunology

147

Psoriasis is a chronic inflammatory immune-mediated autoimmune skin disorder. The histamine H4 receptor (H4R) agonist 4-methylhistamine (4-MH) plays an important role in immunomodulation of inflammatory responses associated with allergic inflammatory diseases. In this study, we investigated the effects of H4R agonist 4-MH on the development of imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice and explored the immunoregulatory mechanism involved. The total clinical severity scores were significantly ameliorated by treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Histological analysis of the skin revealed that 4-MH (20 mg/kg) and 4-MH (40 mg/kg) significantly attenuated the psoriatic phenotypes, including epidermal hyperplasis, hyperkeratosis, and lymphocytes infiltration. Treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg) led to reductions in the levels of Th1 cytokines (TNF-α, IFN-α, and IL-27) in the serum and dorsal skin, whereas Th17 cytokines levels (IL-17A and IL-23) did not change in response to treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Furthermore, the number of CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells was significantly increased by treatment with 4-MH (40 mg/kg). Taken together, these results imply that H4R agonist 4-MH might be an effective immunomodulatory approach for treatment of patients with psoriasis and the effects may be related to inhibited epidermal alteration, selectively reduced Th1 pro-inflammatory cytokines, and recruited CD4(+) CD25(+) FoxP3(+) Treg cells. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Inflammation, Asthma, Receptor antagonist, Inverse agonist, Copyright, Histamine H4 receptor, 4-Methylhistamine

28

OBJECTIVE: Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. Immunophenotypic classification schemes were developed to categorise CVID patients into phenotypic and prognostic groups based on different memory B cell subsets. Whether the B cell subset analysis is stable over time has not been investigated. METHODS: B cell phenotyping in CVID patients (n=15) and sex- and age-matched controls (n=26) were carried out according to the three B cell classifications. CVID patients were evaluated monthly over six months. Controls were assessed once during the study. RESULTS: We scored how often each patient was assigned to the same group within each classification. The Freiburg classification assigned patients to the same group at a rate of 73% and the Paris classification at 88%. The EUROclass classification of smB- vs smB+ was at 90%. The two sub-classifications [(smB-21low or smB-21norm) and transitional B] were at 87% and 97% respectively. The level of naïve B cells measured in all CVID patients during the 6 month evaluation was the most stable B cell subset. CONCLUSION: We conclude that all classifications systems show considerable variability but the EUROclass classification was the most reliable scheme for our 15 CVID and 26 healthy cohorts. Our results indicate that phenotypic classifications within CVID will be difficult while there is variability of commonly used assays.

Concepts: Immune system, Gene, B cell, Immunodeficiency, Memory B cell, Primary immunodeficiency, Common variable immunodeficiency

28

The mitogenic lectins are invaluable tools to study the biochemical changes associated with lymphocyte activation and proliferation of various immune cells. Rachycentron canadum lectin (RcaL) was detected and purified from serum of cobia fish. The aim of this study was to evaluate the proliferative response and cytokine production in splenocytes of mice in vitro stimulated with RcaL lectin; Canavalia ensiformis lectin (Con A) was used as positive control. A high proliferation index was induced by RcaL in relation to control cells. Furthermore, RcaL induced higher IL-2 and IL-6 production in relation to control. The cell viability was 90% in splenocytes treated with RcaL lectin, but RcaL promoted significant late apoptosis after 24 and 48 h in relation to control. RcaL induced proliferative responses suggesting that this lectin can be used as a mitogenic agent in immunostimulatory assays.

Concepts: Immune system, Antibody, Immunology, Concanavalin A, Cobia

25

Autoimmune regulator’s (AIRE) best characterized role is in the generation immunological tolerance but it is also involved in many other processes such as spermatogenesis. Loss-of-function mutations in AIRE cause a disease called Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED; also called Autoimmune Polyendocrinopathy Syndrome type 1, APS-1) that is dominated by various autoimmune manifestations, mainly endocrinopathies. Both APECED patients and Aire(-/-) mice suffer from varying levels of infertility but it is not clear if it is a result of an autoimmune tissue damage or more of a developmental defect. In this study we wanted to resolve whether or not the reduced fertility of Aire(-/-) mice is dependent on the adaptive immune system and therefore a manifestation of autoimmunity in these mice. We generated lymphopenic mice without Aire expression that were devoid of the autoimmune manifestations previously reported in immunocompetent Aire(-/-) mice. These Aire(-/-) Rag1(-/-) mice regained full fertility. This confirms that the development of infertility in Aire(-/-) mice requires a functional adaptive immune system. We also show that only the male Aire(-/-) mice are subfertile, whereas Aire(-/-) females produce litters normally. Moreover, the male subfertility can be adoptively transferred with lymphocytes from Aire(-/-) donor mice to previously fertile lymphopenic Aire(-/-) recipients. Our data shows that subfertility in Aire(-/-) mice is dependent on a functional adaptive immune system thus confirming its autoimmune etiology. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Mutation, Endocrinology, Immunology, Humoral immunity, Autoimmune diseases, Addison's disease, Autoimmune polyendocrine syndrome

2

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Multiple Sclerosis (MS) patients suffer from debilitating fatigue which is not alleviated by rest. In addition to the fatigue related symptoms suffered by CFS/ME and MS patients, dysfunction of the immune system and in particular, reduced Natural Killer (NK) cell cytotoxic activity has also been reported in CFS/ME and MS. The purpose of this pilot study was to compare NK cellular mechanisms in CFS/ME and MS patients to investigate potential dysfunctions in the NK cell activity pathway. Flow cytometry protocols assessed CD56(dim) CD16(+) and CD56(bright) CD16(+/-) NK cell expression of adhesion molecules, NK activating and inhibiting receptors, NK cell maturation and lytic proteins. All participants in this study were female and included 14 CFS/ME patients, 9 MS patients and 19 non-fatigued controls. The patient groups and the non-fatigued controls were not taking any immunosuppressive or immune enhancing medications. In the MS cohort, KIR2DL5 was significantly increased on CD56(bright) CD16(+/-) NK cells and expression of CD94 was significantly increased on CD56(dim) CD16(+) NK cells in comparison to the controls. Co-expression of CD57 and perforin was significantly increased on CD56(dim) CD16(+) NK cells from CFS/ME patients compared to the MS and non-fatigued control participants. The results from this pilot study suggest that NK cells from CFS/ME and MS patients may have undergone increased differentiation in response to external stimuli which may affect different mechanisms in the NK cell cytotoxic activity pathway. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Lymphocyte, Antibody, Natural killer cell, Interferon, Interleukin, Cytotoxicity, Perforin

2

Farm environment has been shown to protect from childhood asthma. Underlying immunological mechanisms are not clear yet, including the role of dendritic cells (DCs). The aim was to explore if asthma and farm exposures are associated with the proportions and functional properties of DCs from 4.5 year old children in a subgroup of the Finnish PASTURE birth cohort study. Myeloid DCs (mDCs), plasmacytoid DCs (pDCs) and CD86 expression on mDCs ex vivo (n=100) identified from peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. MDCs and production of interleukin (IL)-6 and tumour necrosis factor alpha (TNF-α) by mDCs were analysed after 5 hour in vitro stimulation with lipopolysaccharide (LPS) (n=88). Prenatal and current farm exposures (farming, stables, hay barn and farm milk) were assessed from questionnaires. Asthma at age 6 years was defined as a doctor’s diagnosis and symptoms; atopic sensitization was defined by antigen-specific IgE measurements. Asthma was positively associated with CD86 expression on mDCs ex vivo [Adjusted odds ratio (aOR) 4.83, 95 % confidence interval (CI) 1.51-15.4] and inversely with IL-6 production in mDCs after in vitro stimulation with LPS (aOR 0.19, 95 % CI 0.04-0.82). In vitro stimulation with LPS resulted in lower percentage of mDCs in the farm PBMC cultures as compared to non-farm PBMC cultures. Our results suggest an association between childhood asthma and functional properties of DCs. Farm exposure may have immunomodulatory effects by decreasing mDC proportions. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Cohort study, Immunology, Allergy, In vitro, PBMC, Copyright, Barn

1

Parkinson’s Disease (PD) is the second most common neurodegenerative disease in the world, however, there is no cure for it. Current treatments only relieve some of the symptoms, without ceasing the disease, and lose efficacy with prolonged treatment. Considerable evidence shows that persistent inflammatory responses, involving T cell infiltration and glial cell activation, are common characteristics of human patients and play a crucial role in the degeneration of dopaminergic neurons. Therefore, it is important to develop therapeutic strategies that can impede or halt the disease through the modulation of the peripheral immune system by aiming at controlling the existing neuroinflammation. Most of the immunomodulatory therapies designed for the treatment of Parkinson’s Disease are based on vaccines using AS or antibodies against it; yet, it is of significant interest to explore other formulations that could be used as therapeutic agents. Several vaccination procedures have shown that inducing regulatory T cells in the periphery is protective in PD animal models. In this regard, the formulation glatiramer acetate (Copaxone(®) ), extensively used for the treatment of multiple sclerosis, could be a suitable candidate due to its capability to increase the number and suppressor capacity of regulatory T cells. In this review, we will present some of the recent immunomodulatory therapies for PD including vaccinations with AS or glatiramoids, or both, as treatments of PD pathology. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Neuron, Vaccination, Cure, Immunology, Multiple sclerosis, Neurodegenerative disorders, Dopamine

0

The suppressor of cytokine signaling-3 (SOCS3) is well-known as a feedback inhibitor of the Janus kinases-signal transducer and activator of transcription-3 (JAK/STAT3) signaling pathway, which mediates the signal transduction of many cytokines, growth factors and hormones during many cellular processes. The critical role of SOCS3 is manifested by its binding to both the JAK kinase and the cytokine receptor, which can result in the inhibition of STAT3 phosphorylation. STAT3 triggers variety of genes expression in response to cytokine (IL-6 family, IL-10) and growth factor stimulation, and thus plays a critical role in many cellular biological processes involved in anti/pro-inflammatory responses, cell growth and cell death. SOCS3 might either act directly by hampering JAK activation or by mediating the ubiquitination and subsequent proteasome degradation of the cytokine/growth factor/hormone receptor. Generally, SOCS3 is a negative regulator for cytokine or hormone signaling. But in some cases, SOCS3 regulates the inflammatory responses positively through inhibiting STAT3. An increasing number of reports showed abnormal expression levels of SOCS3/STAT3 in different myeloid and lymphoid cells as well as in various non-hematopoietic cells, which suggested its involvement in various infection and inflammatory diseases. In this review, we described the role of SOCS3 and STAT3 expression in different cell populations in regulating the outcomes of infection and inflammatory diseases. This article is protected by copyright. All rights reserved.

0

Can we formulate a framework that would provide an agreed upon basis for discussions of immune behavior? An attempt to do this is, in the end, the main goal of this essay. If you tell a physicist that you have invented a perpetual motion machine, he wouldn’t spend any time trying to reveal the flaw. Rather, he would shrug you off because in his framework, such a machine is an impossibility. However, immunologists lacking an agreed upon, preferably default, framework spend their time chasing into dead end alleys or take refuge in descriptive empiricism. This will be illustrated using Danger theory, which ignores fundamentals to generate a framework believed to obviate the need for a Self(S)-Nonself(NS) discrimination and which is claimed to be bolstered with monogamous data (observation married to a single explanation). The arguments presented here apply to all NS-marker theories (pathogenicity, discontinuity, localization, danger, etc.). This article is protected by copyright. All rights reserved.

0

IL-33 is a recently discovered cytokine which plays an important role in asthma pathogenesis.