Search

Objective: Bullous pemphigoid is a rare autoimmune skin disorder characterized by blistering, urticarial lesions, which are sometimes associated with adverse drug reactions. Vildagliptin is an oral anti-diabetic agent that selectively inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme. Materials and Methods: A 75-year-old female with a known case of type 2 Diabetes Mellitus, hypertension, and hypothyroidism for the last 10 years presented with pruriginous tense bullous skin lesions over her both palms and soles. There was no mucosal involvement. Further interrogation revealed that she started taking Vildagliptin 5 days ago which was prescribed due to high levels of post-prandial blood sugar level despite already intake of Glimepiride-4 mg and Metformin-3 gm. Results: Vildagliptin was immediately advised to be stopped. She was treated with antihistamines, steroids, and conservative management which led to remission of the blisters. Conclusion: Vildagliptin is the probable causative drug for developing bullous pemphigoid skin lesion which shows temporal association in this case as other concomitant drugs has no direct correlation. Therefore physicians must be aware of this rare life-threatening side effect of this medicine and advice patients to visit the hospital even the slightest cutaneous manifestation. Bullous pemphigoid can result in fatal life-threatening conditions if not treated early. [ABSTRACT FROM AUTHOR]

In immunocompetent animals, numerous factors including the immune system of the host regulate the survival of neuro-glial precursors transplanted into the cerebellum. We transplanted human neuro-glial precursors derived in vitro from partial differentiation of IPS cells into the developing cerebellum of mice and rats before maturation of the host immune system. These approaches should facilitate the development of immune-tolerance for the transplanted cells. However, we found that human cells survived the engraftment and integrated into the host cerebellum and brain stem up to about 1 month postnatally when they were rejected in both species. On the contrary, when we transplanted the same cells in NOD-SCID mice, they survived indefinitely. Our findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts the induction of immune-tolerance to human antigens expressed before completion of the maturation of the immune system. As predicted by our hypothesis, when we engrafted the human neuro-glial precursor cells either in a more mature state or mixed with extracts from adult cerebellum, we prolonged the survival of the graft. [ABSTRACT FROM AUTHOR]

• The endogenous inhibition of IL-6 could represent a safe and effective approach for the treatment of inflammatory-associated diseases. • In endothelial cells, modifying the methylation status or enhancing the expression of TAX1BP1 has been shown to reduce the intrinsic generation of IL-6 triggered by repetitive TLR2 stimulation and restore A20's suppressive role in NF-κB signaling. • Promoting immune tolerance in endothelial cells has the potential to mitigate the inflammatory cascade mediated by IL-6, and targeting TAX1BP1/A20 could serve as a viable strategy for intervention in the treatment of inflammatory immunological conditions. The inflammatory cascade driven by interleukin-6 (IL-6) plays a crucial role in the initiation and progression of chronic inflammatory conditions such as atherosclerosis. Research has demonstrated that prolonged exposure to inflammatory stimuli leads to the development of "immune tolerance" in specialized immune cells such as monocytes and macrophages, serving as a mechanism to prevent tissue damage and curb the inflammatory cascade. However, our recent investigation revealed that immune tolerance did not effectively regulate the production of IL-6 in human umbilical vein endothelial cells (HUVECs) when stimulated by a Toll-like receptor 2 (TLR2) ligand Pam3CSK4, which is a potent activator of the pro-inflammatory transcription factor NF-κB. Furthermore, the negative regulator of NF-κB signaling, A20, was ineffective in suppressing TLR2-induced IL-6 synthesis in this context. Notably, all A20 auxiliary molecules, with the exception of TAX1BP1, were found to be significantly expressed in HUVECs. DNA methylation in TAX1BP1 was confirmed in GEO database. According to the information provided, it is hypothesized that altered DNA methylation in HUVECs could potentially lead to decreased expression of TAX1BP1, thereby impeding A20′s capacity to modulate continuous activation of the TLR2-NF-κB pathway. This may consequently lead to unregulated production of IL-6, evading immune tolerance mechanisms. Subsequent investigations suggested that demethylating TAX1BP1 could enhance its expression, potentially reducing the endogenous IL-6 levels induced by repeated TLR2 stimulation and restoring A20′s inhibitory role in NF-κB signaling. Additionally, over-expression of TAX1BP1 could decrease the production of atherosclerosis-associated cytokines like IL-6, MCP-1, ICAM-1, and VCAM-1, while increasing NO release following repeated Pam3cks4 stimulation, along with enhanced co-localization of TAX1BP1 and A20. These findings indicate that inducing immune tolerance in endothelial cells may effectively suppress endogenous IL-6 production and halt the IL-6-mediated inflammatory cascade, with TAX1BP1/A20 identified as crucial components in this process.These insights provide novel perspectives and potential targets for therapeutic strategies in inflammatory immunological disorders involving the overproduction of IL-6. [ABSTRACT FROM AUTHOR]

The Plasmodium parasite has to cross various immunological barriers for successful infection. Parasites have evolved mechanisms to evade host immune responses, which hugely contributes to the successful infection and transmission by parasites. One way in which a parasite evades immune surveillance is by expressing molecular mimics of the host molecules in order to manipulate the host responses. In this study, we report a Plasmodium berghei hypothetical protein, Pb TIP (PbANKA_124360.0), which is a Plasmodium homolog of the human T-cell immunomodulatory protein (TIP). The latter possesses immunomodulatory activities and suppressed the host immune responses in a mouse acute graft- versus -host disease (GvHD) model. The Plasmodium berghei protein, Pb TIP, is expressed on the merozoite surface and exported to the host erythrocyte surface upon infection. It is shed in the blood circulation by the activity of an uncharacterized membrane protease(s). The shed Pb TIP could be detected in the host serum during infection. Our results demonstrate that the shed Pb TIP exhibits binding on the surface of macrophages and reduces their inflammatory cytokine response while upregulating the anti-inflammatory cytokines such as TGF-β and IL-10. Such manipulated immune responses are observed in the later stage of malaria infection. Pb TIP induced Th2-type gene transcript changes in macrophages, hinting toward its potential to regulate the host immune responses against the parasite. Therefore, this study highlights the role of a Plasmodium -released protein, Pb TIP, in immune evasion using macrophages, which may represent the critical strategy of the parasite to successfully survive and thrive in its host. This study also indicates the human malaria parasite TIP as a potential diagnostic molecule that could be exploited in lateral flow-based immunochromatographic tests for malaria disease diagnosis. [ABSTRACT FROM AUTHOR]

• The clinical response and T cells were tested in DM1 children treated with Tregs and rituximab. • Successful treatment was associated with increased levels of PD-1 receptor (+) T cells. • Immunotherapy with Tregs and rituximab significantly remodelled humoral immunity. • A higher level of PD-1 receptor (+) Treg correlated with better suppressive activity in vitro. • The PD-1 receptor (+) T cells may be used as a biomarker of Tregs and rituximab combined therapy outcome. An imbalance between exaggerated autoaggressive T cell responses, primarily CD8 + T cells, and impaired tolerogenic mechanisms underlie the development of type 1 diabetes mellitus. Disease-modifying strategies, particularly immunotherapy focusing on FoxP3 + T regulatory cells (Treg), and B cells facilitating antigen presentation for T cells, show promise. Selective depletion of B cells may be achieved with an anti-CD20 monoclonal antibody (mAb). In a 2-year-long flow cytometry follow-up, involving 32 peripheral blood T and B cell markers across three trial arms (Treg + rituximab N = 12, Treg + placebo N = 13, control N = 11), we observed significant changes. PD-1 receptor (+) CD4 + Treg, CD4 + effector T cells (Teffs), and CD8 + T cell percentages increased in the combined regimen group by the end of follow-up. Conversely, the control group exhibited a notable reduction in PD-1 receptor (+) CD4 + Teff percentages. Considering clinical endpoints, higher PD-1 receptor (+) expression on T cells correlated with positive responses, including a higher mixed meal tolerance test AUC, and reduced daily insulin dosage. PD-1 receptor (+) T cells emerged as a potential therapy outcome biomarker. In vitro validation confirmed that successful Teff suppression was associated with elevated PD-1 receptor (+) Treg levels. These findings support PD-1 receptor (+) T cells as a reliable indicator of treatment with combined immunotherapy consisting of Tregs and anti-CD20 mAb efficacy in type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B is an immune response-mediated disease. The aim of this study was to explore the differences of ratios of T-helper (Th) 2 cells to Th1 cells and cytokine levels in acute hepatitis B (AHB) patients and chronic hepatitis B virus (HBV)-infected patients in immune-tolerance and immune-active phases. Methods: Thirty chronic HBV-infected patients in the immune-tolerant phase (IT group) and 50 chronic hepatitis B patients in the immune-active (clearance) phase (IC group), 32 AHB patients (AHB group), and 13 healthy individuals (HI group) were enrolled in the study. Th cell proportions in peripheral blood, cytokine levels in plasma, and serum levels of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen were detected. Results: The Th1 cell percentage and Th2/Th1 ratio in the HBV infection group (including IT, IC, and AHB groups) were significantly different from those in HI group (24.10% ± 8.66% and 1.72 ± 0.61 vs. 15.16% ± 4.34% and 2.40 ± 0.74, respectively; all P < 0.001). However, there were no differences in the Th1 cell percentages and Th2/Th1 ratios among the IT, IC, and AHB groups. In HBV infection group, the median levels of Flt3 ligand (Flt3L), interferon (IFN)-γ, and interleukin (IL)-17A were significantly lower than those in HI group (29.26 pg/ml, 33.72 pg/ml, and 12.27 pg/ml vs. 108.54 pg/ml, 66.48 pg/ml, and 35.96 pg/ml, respectively; all P < 0.05). IFN-α2, IL-10, and transforming growth factor (TGF)-β2 median levels in hepatitis group (including patients in AHB and IC groups) were significantly higher than those in IT group (40.14 pg/ml, 13.58 pg/ml, and 557.41 pg/ml vs. 16.74 pg/ml, 6.80 pg/ml, and 419.01 pg/ml, respectively; all P < 0.05), while patients in hepatitis group had significant lower Flt3L level than IT patients (30.77 vs. 59.96 pg/ml, P = 0.021). Compared with IC group, patients in AHB group had significant higher median levels of IL-10, TGF-β1, and TGF-β2 (22.77 pg/ml, 10,447.00 pg/ml, and 782.28 pg/ml vs. 8.66 pg/ml, 3755.50 pg/ml, and 482.87 pg/ml, respectively; all P < 0.05). Conclusions: Compared with chronic HBV-infected patients in immune-tolerance phase, chronic HBV-infected patients in immune-active phase and AHB patients had similar Th2/Th1 ratios, significantly higher levels of IFN-α2, IL-10, and TGF-β. AHB patients had significantly higher IL-10 and TGF-β levels than chronic HBV-infected patients in immune-active phase.

Highlights • Peripheral pDC, DC and B cells migrate to the thymus. • Activated peripheral conventional and regulatory T cells recirculate back to the thymus. • Peripheral immune responses shape thymic selection. Abstract Hematopoietic precursors entering the thymus undergo a maturation process leading to the generation of a variety of T cell subsets that migrate to the periphery to perform their effector functions. This maturation process is strictly regulated by multiple interactions of developing T cells with thymic stroma cells. Signals received via the T cell receptor for antigen, co-stimulatory molecules and cytokines will determine, through thymic selection and lineage choice, thymocyte-fate. Recently, different populations of peripheral antigen presenting cells and T cells have been reported to enter the thymus. Here we review how these cells migrating from the periphery to the thymus modulate T cell development. [ABSTRACT FROM AUTHOR]

The treatment paradigm in hepatitis B virus is on the cusp of major development, with a multitude of novel agents undergoing testing for clinical efficacy. Such new immune therapies are urgently required for the treatment of chronic hepatitis B virus. The current direct antiviral therapies, although able to control viral replication and limit the progression to cirrhosis, require lifelong administration due to frequent viral rebound on treatment cessation, and immune modulation with interferon is only effective in a subpopulation of patients. Here the authors discuss novel agents in the pipeline along with whom and how best to utilize these immune therapies to achieve functional cure with defined treatment endpoints in chronic hepatitis B virus. [ABSTRACT FROM AUTHOR]

The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway critical for several biological processes. An aberrant Wnt/β-catenin signaling is linked to several human diseases. Emerging studies have highlighted the regulatory role of the Wnt/ β-catenin signaling pathway in normal physiological processes of parenchymal and hematopoietic cells. Recent studies have shown that the activation of Wnt/β-catenin pathway in dendritic cells (DCs) play a critical role in mucosal tolerance and suppression of chronic autoimmune pathologies. Alternatively, tumors activate Wnt/β-catenin pathway in DCs to induce immune tolerance and thereby evade antitumor immunity through suppression of effector T cell responses and promotion of regulatory T cell responses. Here, we review our work and current understanding of how Wnt/β-catenin signaling in DCs shapes the immune response in cancer and autoimmunity and discuss how Wnt/β-catenin pathway can be targeted for successful therapeutic interventions in various human diseases. [ABSTRACT FROM AUTHOR]

In the past decade our understanding of idiosyncratic drug induced liver injury ( IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen ( HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptation. Failure to adapt or defective adaptation leads to clinically significant liver injury. In this review we explore the immuno-tolerant microenvironment of the liver and the mechanisms of clinical adaptation in IDILI with a focus on the role of immune-tolerance and cellular adaptive responses. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward. The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course. Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) endotoxin from the membrane of Gram-negative bacteria is often used to simulate bacterial infection in mammals. Repeated exposure to LPS over a short period of time, however, is reported to result in an attenuated acute-phase response. This "LPS tolerance" is an essential immune-homeostatic response that can protect against over-activation of the inflammatory response during chronic exposure to LPS. In the present study, Holstein calves (n=20) were initially intramuscularly challenged with either saline, or 100, 200 or 400 ng/kg of LPS and then all animals were re-challenged with 200 ng/kg of LPS 2-weeks later to assess potential LPS tolerance in ruminants. Serum was collected every 2 hrs for 6 hrs to profile changes in circulatory stress biomarkers. In comparison to the first challenge and saline control animals that received LPS for the first time, heifers re-challenged with LPS demonstrated significantly attenuated cortisol responses in the second LPS challenge (p < 0.05). Blood cell populations were also attenuated in animals receiving their second LPS challenge, in that re-challenged animals showed significantly less severe thrombocytopenic (p < 0.05), and leukopenic responses to their second LPS challenge as compared to their first (p < 0.05); this trend was also apparent when comparing newly LPSchallenged animals to the LPS re-challenged animals. MicroRNA expression profiles were determined to assess a potential epigenetic response to repeated LPS exposure, which may help identify therapeutic targets to protect against LPS-associated diseases including clinical mastitis and sepsis. The present study demonstrated that LPS tolerance occurs in dairy cattle, and understanding the roles of various miRNAs in the context of innate immune cell tolerance is essential for evaluating their impact on immune system homeostasis. [ABSTRACT FROM AUTHOR]

It has been hypothesized that anterior chamber-associated immune deviation (ACAID) to neural antigens induced prior to central nervous system injury can inhibit self-reactivity and lessen secondary degeneration. This work evaluated the effect of ACAID induced to three neural tissue-derived extracts (whole extract, cytosolic extract, CE; or organelle-membrane extract) prior to optic nerve injury on retinal ganglion cell (RGC) survival. The results show that only ACAID to the CE increased RGC survival at 7 and14 days post-injury (dpi). This effect was achieved by retinal polarization towards an anti-inflammatory profile, driven by regulatory T cells and M2-type macrophages at 7 dpi. Unlabelled Image • ACAID to the CE induced prior to optic nerve injury inhibits self-reactivity. • ACAID to the CE increases RGC survival after optic nerve injury. • ACAID to the CE induces an anti-inflammatory profile in the retina early after injury. • ACAID to the CE increases neurotrophic factors and decreases apoptotic mediators. • ACAID to the CE recruits regulatory T cells and M2-type macrophages into the retina. [ABSTRACT FROM AUTHOR]