Journal: Scandinavian journal of immunology
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.
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.
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.
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.
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.
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.
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.
Pemphigus vulgaris (PV) is an autoimmune disease characterized by the production of IgG auto-antibodies owing to an imbalance in the Th1/Th2 and Th17/Tregs cell pathways. The role of gut microbiota in the development of immune system as well as autoimmune diseases has been unraveled in the last two decades. However, data pertaining to gut microbiota of PV patients is largely lacking. We aimed to compare the gut microbiota of PV patients and healthy controls and assessed potential correlation with circulating cytokines of Th1/Th2/Th17 cell. Fecal bacterial diversity was analyzed in 18 PV patients and 14 age and gender matched healthy individuals using hypervariable tag sequencing of the V3-V4 region of the 16S rRNA gene. Plasma levels of 20 inflammatory cytokines were assessed using the luminex screening system. As a result, we identified 10 differentially abundant taxa between patients and controls. At the genera level, Lachnospiracea_incertae_sedis and Coprococcus decreased, while Granulicatella, Flavonifractor enriched in PV. Plasma levels of C5a, interleukin (IL)-2R, IL-6, IL-8, IL-7, IL-1β, IL17A, IL-5, and IL-21 were significantly increased in PV. Flavonifractor exhibited a positive correlation with C5a, IL-6, IL-8, IL-7, IL-1β, IL17A, and IL-21. Lachnospiracea_incertae_sedis and Coprococcus showed a negative correlation with IL-17A. Our results are consistent with the hypothesis that PV patients have gut microbial dysbiosis which might contribute to the immune disorder and the development of PV. This article is protected by copyright. All rights reserved.
CD40 ligand (CD40L) deficiency is a rare but life-threatening primary immunodeficiency caused by mutations in the CD40L gene. Here, we investigated a cohort of 40 genetically-diagnosed CD40L-deficient patients from the Chinese mainland, analyzed their clinical and genetic data, and examined CD40L expression, the proportion of T cell subsets, B cell subsets, and T follicular helper (Tfh) cells. The aim was to provide a complete picture of CD40L deficiency. Initial presentations of the patient cohort mainly involved recurrent fever (47.5%) and sinopulmonary infection (42.5%). Life-threatening infections (42.5%), caused by various pathogens, were the most serious threats faced by CD40L-deficient patients, while neutropenia (57.5%) remained the most common complication. Opportunistic infections, including Pneumocystis carinii pneumonia and invasive fungal disease associated with Talaromyces marneffei were also common in the cohort. In addition, seven patients (17.5%) suffered BCGitis /BCGosis, which is a major problem facing a planned immunization program in China. It was intriguing that reduced IgM levels were observed in 12.5% of patients, while normal or elevated IgA levels were shown in 47.5% of patients. Thirty-seven unique mutations were identified in 40 patients; of these, 10 were novel. Furthermore, we observed a lower percentage of NK cells, Tfh cells, and central memory CD4+ T cells, and an extremely small class-switched memory B cell population, in CD40L-deficient patients. Patients that underwent hematopoietic stem cell transplantation experienced better disease remission. Taken together, our data establish the largest database about CD40L deficiency in China and provide genetic, immunologic, and clinical information about Chinese CD40L-deficient patients. This article is protected by copyright. All rights reserved.
In 1964 Peter Bretscher and I began graduate studies at Cambridge University. Unaware of the other’s existence, at various times we each met with César Milstein at the MRC Laboratory of Molecular Biology (LMB, Hills Road, Cambridge) and with Avrion Mitchison at the National Institute for Medical Research (NIMR, Mill Hill, London). This article is protected by copyright. All rights reserved.