Clues of HLAs, metabolic SNPs, and epigenetic factors in T cell-mediated drug hypersensitivity reactions.

Drug hypersensitivities are common reactions due to immunologic responses. They are of utmost importance because they may generate severe and fatal outcomes. Some drugs may cause Adverse Drug Reactions (ADRs), such as drug hypersensitivity reactions (DHRs), which can occur due to the interaction of intact drugs or their metabolites with Human Leukocyte Antigens (HLAs) and T cell receptors (TCRs). This type develops over a period of 24-72 h after exposure and is classified as type IV of DHRs. Acute generalized exanthematic pustulosis (AGEP), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are types of Severe Cutaneous Adverse Reactions (SCARs). In this review, we aim to discuss the types of ADRs, the mechanisms involved in their development, and the role of immunogenetic factors, such as HLAs in type IV DHRs, single-nucleotide polymorphisms (SNPs), and some epigenetic modifications, e.g., DNA/histone methylation in a variety of genes and their promoters which may predispose subjects to DHRs. In conclusion, development of promising novel in vitro or in vivo diagnostic and prognostic markers is essential for identifying susceptible subjects or providing treatment protocols to work up patients with drug allergies as personalized medicine.

Essential Transcription Factors and Functional Roles of Follicular Helper T Cells in Human Autoimmune Diseases.

Follicular helper T (TFH) cells are a subset of effector CD4+ T cells that support the differentiation of antigen-specific B cells in the germinal center. TFH cells are distinct from other established CD4+ T cell subsets and possess a list of transcription factors, including BCL6, IRF4, c-Maf, Batf, NFAT1-2, and STAT3. The mentioned factors direct several activities such as cell differentiation, migration to the follicles, cell-to-cell interaction, as well as cell programming. Given that TFH cells are essential for the germinal center formation, affinity maturation and the development of most high-affinity antibodies. TFH cells may play crucial roles in different pathologic conditions, particularly autoimmune diseases. However, the mechanisms that cause functional differences of TFH cell responses are not exactly defined. In this review first the immunological profile of TFH cells will be discussed then attempts will be made to give a broad picture on the role of this key subset of T cells in autoimmune diseases.

Gut Microbiota Modulates the Efficiency of Programmed Cell Death Protein 1 Cancer Immunotherapies.

Program cell death protein 1 (PD1) is considered as an inhibitory molecule that is expressed on the surface of activated T-cells and bound to PD-L1 and PD-L2 ligands. Several types of cancer cells express PD-L1 which can bind to PD1 on the surface of tumor-specific T-cells. PD1/PD-L1 ligation triggers a pathway to protect tumor cells from an effective response of tumor-specific T-cells. Different PD1/PD-L1 blocker antibodies are clinically used to promote the T-cell response against the cancer cells. Current studies suggest that the gut microbiome impacts the efficiency of PD1 blockade therapy in cancer patients. The association of several bacterial species with PD1 responder patients has been determined. The present study reviewed previous reports on the relation between the microbiome and immune checkpoint therapy (ICT). The results of studies were discussed considering adjuvant and molecular mimicry of microbial antigens by tumor-associated antigens and metabolic effects of microbial products on ICT.

The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies.

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.

The Comparison of the IFN-ɤ, TNF-α and IL-10 Cytokines in Healing and Non-healing Cutaneous Leishmaniasis.

BACKGROUND: Leishmaniasis is one of the main vectors borne and neglected tropical parasitic diseases. T cell cytokine responses are highly important in the presentations of disease such as control or progression, and understanding of the host immunological response is valuable in diagnosis, follow-up, and vaccine designs. In the current study, the profile of IFN-ɤ, TNF-α, and IL-10 cytokines was investigated through the ELISA technique in PBMCs isolated from antimony resistance and susceptible patients. METHODS: In this experimental study, 54 patients with healing (n=27) or non-healing (n=27) CL were recruited. Lesion samples were collected to determine the genotype of Leishmania spp. and peripheral blood mononuclear cells (PBMCs) were obtained to evaluate the cytokines profiles using soluble Leishmania antigen (SLA) and phytohaemagglutinin (PHA) mitogen. Cytokines were assessed by the ELISA technique. RESULTS: The IFN-ɤ and TNF-α cytokines were significantly increased in the healing group treated with both SLA antigen and PHA mitogen (P<0.001). The level of IL-10 was significantly increased in non-healing and significantly declined in healing groups (P<0.001). CONCLUSION: The profile of IFN-ɤ, TNF-α, and IL-10 cytokines are crucially associated with the response of treatment.

The expression of miRNA-152-3p and miRNA-185 in tumor tissues versus margin tissues of patients with chemo-treated breast cancer.

OBJECTIVE: Breast cancer (BC) is the most significant and lethal type of cancer in women. Although there are many newly develop chemotherapy drugs for patients with BC treating at various stages, drug resistance is the most important obstacle in their effectiveness for BC treatment. On the other hand, microRNAs are considered key regulators of genes involved in carcinogenesis and chemoresistance in cancers. The purpose of this study was to evaluate the role of miR-152-3p and miR-185 in intrinsic chemoresistance and proliferation of BC. In addition, the potential role of these miRNAs during chemoresistance was evaluated through possible signaling pathways. RESULTS: Here, miR-152-3p was significantly downregulated in tumor tissues compared to the corresponding margin tissues in patients with BC (p-value ≥ 0.04407 and fold change = - 2.0552). In contrast, no statistically significant difference was observed in the miR-185 expression between the two groups. Furthermore, no significant correlation was found between the expression of these two miRNAs and subfactors, including cancer family history, abortion, and age. Downregulation of miR-152-3p could be considered a promising regulator of BC chemoresistance.

Clinical and In Silico Outcomes of the Expression of miR-130a-5p and miR-615-3p in Tumor Compared with Non-Tumor Adjacent Tissues of Patients with BC.

BACKGROUND: Breast Cancer (BC) is the most common malignancy among women with a high mortality rate. The blockade of asparagine-related pathways may be an effective measure to control the progression and reduction of BC metastasis potential. Recently, it has been shown that various miRNAs, as part of small non-coding RNAs, have a great role in cancer development, especially asparagine-related pathways, to modulate the invasiveness. OBJECTIVE: This study aimed to evaluate the expression of miR-130a-5p and miR-615-3p in tumoral and nontumoral adjacent tissues of patients with BC. METHODS: There is a chance that asparagine metabolism is influenced by miR-130a-5p and miR-615-3p as confirmed by bioinformatics analysis. Hence, real-time PCR was conducted on eighty BC tumoral and non-tumoral adjacent tissues to evaluate the expression level of the two miRNAs. To predict the potential biological process and molecular pathways of miR-130a-5p, an in silico analysis was performed. RESULTS: This study indicated that miR-130a was downregulated in tumoral tissues compared to non-tumoral adjacent tissues (P-value= 0.01443 and fold change= -2.5137), while miR-615-3p did not show a significant difference between the two groups. Furthermore, the subgroup studies did not reveal any significant correlation between the expression of these two miRNAs and subfactors. Furthermore, in silico studies unraveled several biological processes related to amino-acid metabolism, as well as pathways related to tumor development such as Phosphatase and Tensin Homolog (PTEN) and JAK-STAT pathways among miR-130a-5p target genes. CONCLUSION: Our findings indicate that miRNA-130a-5p is downregulated in BC tissues and may play a tumor suppressor role in patients with BC. Therefore, it may be suggested as a potential diagnostic and therapeutic target for BC.

Evaluating the Immunoreactivity of Ailanthus Altissima (The Tree of Heaven) Pollen Extract in Atopic Patients.

IgE-mediated hypersensitivity reaction to pollens is a common health problem in atopic patients. In this regard, the assessment of the allergenicity of highly pollinating plants would be demanding. Based on the increment of Ailanthus altissima (A. altissima) tree in some parts of Iran and considering its probable role in respiratory allergy, in this study, we aimed to investigate its IgE-immunoreactivity and in diagnostic applications. One hundred and twenty-five allergic rhinitis patients who were diagnosed as high IgE responders and demonstrated seasonal rhinitis or rhinoconjunctivitis, as well as 20 healthy controls (HCs) with no allergic symptoms, were enrolled in this study. Total protein extract was prepared from A. altissima pollens and subjected to quality control experiments and finally used in ELISA and western blotting studies. Approximately 24% of the atopic patients (30 from 125) showed positive immunoreactivity to A. altissima extract. The median (IQR) of absorbance (450 nm) of the specific IgE against A. altissima pollen extract in HCs and positive groups were 0.33 (0.28-0.42) and 0.59 (0.36-0.79), respectively (p<0.001). Receiver operating characteristics (ROC) curve analysis of the specific ELISA results, revealed a cut-off value of 0.46 and a sensitivity of 70% and specificity of 100%. Western blotting with the sera positive cases revealed that the main immunoreactive proteins range from 10 to 70 kDa. This study revealed that some of A. altissima pollen proteins ranging from 10 to 70 kDa show IgE-reactivity in atopic patients and may play a role in their allergic reaction symptoms.

The immunopathobiology of T cells in stress condition: a review.

Several factors impact the immune responses such as the chemical nature of antigens, the physiologic and metabolic condition of the responsive cells, the site of antigen recognition, and neuroendocrine and pharmacological received agents. Incompatibility of host immune responses to the entrapped antigens leads to an immune pathological manner instead of an immune protection which results in the disharmony of the immune effective factors. Besides the fact that stress is one of the most common effective factors in human life, it also contributed to the protection, suppression, and pathology of the immune system. In this review article, the direct and indirect effects of the stress on the function of T cells and the contributed mechanism of action will be discussed.

Oridonin Could Inhibit Inflammation and T-cell Immunoglobulin and Mucin-3/Galectin-9 (TIM-3/Gal-9) Autocrine Loop in the Acute Myeloid Leukemia Cell Line (U937) as Compared to Doxorubicin.

The T-cell immunoglobulin and mucin-3 (TIM-3)/galectin-9 (Gal-9) autocrine loop is an indispensable signaling in acute myeloid leukemia (AML) cells, which induces their self-renewal through activation of nuclear factor-kappa b (NF-kB) and ß-catenin pathways. In this study, we evaluated the effects of oridonin and doxorubicin on the TIM-3/Gal-9 autocrine loop. We also evaluated oridonin anti-inflammatory and anti-cancer properties on U937 cells, as an AML cell line in comparison to doxorubicin as a common anthracycline drug for AML treatment. Cell counting kit-8 (CCK-8) was applied to evaluate the cytotoxicity of oridonin and doxorubicin on U937 cells and also to determine the impact of galectin-9 (Gal-9) on their proliferation. The effects of oridonin and doxorubicin on Gal-9, TIM-3, and interleukin-1ß (IL-1ß) gene expression were determined by real-time polymerase chain reaction (RT-PCR). The Gal-9 secretion level was measured by enzyme-linked immunosorbent assay (ELISA) and activation of NF-kB pathway was assessed by western blotting. In a dose-dependent manner, oridonin and doxorubicin were capable to eradicate U937 cells while Gal-9 expanded them. Following the treatment of U937 cells with oridonin, the expression of Gal-9, TIM-3, and IL-1ß genes was down-regulated, and the Gal-9 secretion and NF-kB phosphorylation were diminished, whereas doxorubicin increased all of these factors. Doxorubicin is a common treatment agent in AML, but it may induce inflammation and up-regulate the TIM3/Gal-9 autocrine loop, consequently can enhance the possibility of disease relapse. Meanwhile, oridonin is capable to inhibit the essential signaling pathways in AML cells and reduce the inflammation and expansion of tumor cells and postpone AML recurrence.

Serum levels of adiponectin and vitamin D correlate with activity of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which numerous cells and mediators affect inflammatory conditions and disease severity. To compare the serum levels of adiponectin, vitamin D, copper, and zinc in patients with RA and to investigate the relationship between these parameters and RA severity. Ninety patients with RA and 30 healthy controls participated in this cross-sectional case-control study between November 2016 and April 2017; according to the ACR/EULAR criteria for RA. Serum levels of adiponectin were determined by ELISA; copper and zinc by colorimetric spectrophotometry; and vitamin D by HPLC. Kruskal-Wallis and Spearman tests were performed using SPSS software and data were depicted by GraphPad Prism software. Compared with healthy controls, the serum level of adiponectin was significantly increased, whereas vitamin D was significantly decreased in patients with RA. Adiponectin and vitamin D levels were inversely correlated in RA subgroups (P < 0.001, r = - 0.410). Adiponectin and vitamin D correlated with RA severity. Furthermore, no significant difference was found in copper and zinc levels between RA groups and controls. The definitive roles of adiponectin, vitamin D, copper, and zinc are not completely determined in RA development. Based on disease activity, these parameters can modulate inflammatory conditions, thus they have the potential to be used as promising therapeutic biomarkers to follow up the severity of disease, as well as the progression and treatment success in patients with RA.