Autoreactive T Cells Research Articles

Autoantigen Exposure in Murine Fetuses Elicited Nonpathogenic Autoimmunity

Autoimmunity refers to the presence of autoantibodies and autoreactive lymphocytes against the structural molecules of an individual's cells or tissues, known as self-antigens or autoantigens. It might exist in the absence of autoimmune disease. However, how autoimmunity develops remains a mystery, despite the discovery of autoantibodies in human cord blood. Murine fetuses on day 14 of gestation were subjected to intraperitoneal injection of murine thyroid peroxidase (TPO) peptides or collagen type II (CII) at graded doses via transuterine approach. Postnatally, the recipients were examined for autoantibodies by ELISA and autoreactive lymphocytes by in vitro incorporation of tritium and for the development of autoimmune thyroiditis or arthritis. At one month of age, the recipients did not secrete significant levels of anti-TPO or CII IgG2a in sera until a dose of 0.5 µg TPO or 5.0 µg CII was injected in utero. Serum anti-TPO or CII IgG2a persisted for at least two to four months postnatally. In recipients with elevated autoantibodies, their lymphocytes also showed proliferative responses specifically to TPO or CII. However, the development of autoantibodies and autoreactive lymphocytes was not associated with inflammatory cell infiltration of thyroid glands or paw joints even though anti-TPO or CII IgG2a was enhanced by postnatal TPO or CII challenge. Fetal exposure to free autoantigens could be immunogenic, shedding new light on the in utero origin of autoantibodies and autoreactive lymphocytes. The development of autoimmunity requires a threshold intensity of autoantigen exposure in the fetus.

Primary immunodeficiency as a cause of immune-mediated kidney diseases.

Primary immunodeficiency (PID) is no longer defined by infections alone, and autoimmunity is an accompanying manifestation of PID. Recurrent infections may trigger autoimmunity through molecular mimicry, bystander activation, or superantigens. The diagnosis of PID is still challenging, but genetic analysis reveals the underlying link between PID and autoimmunity. Mutations in relevant genes affecting central and peripheral immune tolerance, regulatory T-cell function, expansion of autoreactive lymphocytes, antigen clearance, hyperactivation of type I interferon, and NF-κB pathways have all been implicated in triggering autoimmunity in PID. Autoimmunity in PID leads to chronic inflammation, tissue damage, and organ failure and increases the mortality of patients with PID. The kidneys are inextricably linked with the immune system, and kidney diseases can be mediated by both infection and autoimmunity/inflammation in PID patients. The manifestations of kidney involvement in PID patients are very heterogeneous and include lupus nephritis, C3 glomerulopathy, kidney thrombotic microangiopathy, vasculitis, and interstitial nephritis.Patients with PID-caused kidney diseases have defined immune function defects and may benefit from pathway-based biologics, stem cell transplantation, or gene therapy. Early diagnosis and appropriate treatment of PID are crucial for reducing the mortality rate and improving organ function and quality of life.

Single-cell RNA sequencing reveals an immunomodulatory population of double negative T-cells in the diabetic NOD mouse

Abstract NOD mice are a widely used model of type 1 diabetes, an inflammatory autoimmune condition characterized by autoreactive T-cells that target insulin producing beta cells of the pancreatic islets. While T cell biology in the context of this disease is important it is unclear why autoreactive T-cells develop in this model or what they do within the islets themselves. We have designed a single cell sequencing experiment where enriched T-cells taken from diabetic and non-diabetic NOD mice are sequenced for mRNA expression and TCR sequence concurrently. The resulting sequencing data shows abnormal representation of Double Negative (DN) T-cells in all tissues and conditions (~30%). We have observed that like CD8+ and CD4+ T-cells, this population displays normal maturation phenotypes, but experience reduced exhaustion of effector subsets after infiltration of the pancreatic islets. Looking at clonal subpopulations of T-cells we have discovered a subset of CD8+ T-cells that have high expression of GzmA even after loss of the survival signal marker, IL7r. Through investigation of these aberrant T-cell populations, we have found that the diabetic NOD mouse pancreatic is highly immunosuppresive and expression of T-cell co-receptors may have a significant impact on diabetic onset.

Current Vaccination Practice in Diabetic (Diabetes I) Patients.

The worldwide prevalence of diabetes, an endocrine condition, is rising quickly. The alarming rise of diabetes in recent years has emerged as a major contributor to premature death and illness among persons of working age. The potential use of immunomodulatory drugs to prevent diabetes has been a source of worry in light of recent advances in our understanding of the role of autoimmune responses in the development of diabetes. Vaccines can work in a variety of ways, including by eliminating autoreactive T-cells or by blocking the connections between immune cells. Most diabetes vaccines that have been created so far have only been evaluated in animal models, with just a small number having undergone successful human trials. In this article, the authors also look at the clinical trial research that are currently being conducted to create a prototype diabetes vaccine.

Somatic variant profiling of a thymoma in Good syndrome

Good syndrome (GS) is a combined immunodeficiency that is associated with thymomas. The cause of the reduction in B-cells in patients with GS may be multifactorial and may include dysregulated T-cell responses. It has been proposed that tumorigenesis in a normal thymus alters thymic epithelial cell function, which leads to attenuated elimination of T-cells autoreactive to B-cells. Although the comprehensive genetic analysis of thymoma has been performed and reported in many articles, the comprehensive genetic analysis specified for GS-related thymoma has not been reported. Herein, we report comprehensive genetic analysis of a thymoma taken from a patient with GS. Oncogenesis-associated genes that may contribute to thymoma development were detected. Additionally, alteration of VCAM1, which is required in the interaction between T-cells and thymic epithelial cells, was observed. Aberrantly expressed VCAM1 in thymic epithelial cells may decrease the efficacy of negative of selection autoreactive T-cells and contribute to autoimmunity to B-cells.

The Prognostic Value of Extended Inflammation Parameters and Soluble Fibrin Monomer Complex in Covid-19 Patients in The Intensive Care Unit

Objective: This study aimed to investigate how extended inflammation markers (EIM) and soluble fibrin monomer complex (SFMC) affected the prognosis of COVID-19-infected patients in the intensive care unit (ICU). Methods: In this study, 73 adults with COVID-19 were included. Patients were divided into two groups: those who died (Group 1; n = 45) and those who survived (Group 2; n = 28). SFMC and EIM [neutrophil reactivity index (NEUT-RI) and neutrophil granularity index (NEUT-GI), reactive lymphocyte (RE-LYMPH), antibodies synthesizing lymphocyte (AS-LYMP), neutrophil/lymphocyte ratio (NLR) and immature granulocyte/lymphocyte ratio (IGLR)], were analyzed in the first 28 days of these patients' follow-up. Results: The median NLR during the first four weeks, IGLR in the first two weeks, RE-LYMPH in the first three weeks, NEUT-RI and NEUT-GI values in the second week, and AS-LYMP in the third week of follow-up were significantly higher in Group 1 than in Group 2 (p<0.05). The median D-Dimer level during the first three weeks and SFMC value in the first week of follow-up were significantly higher in Group 1 than in Group 2 (p<0.05). In patients with COVID-19, older age (≥65 years), nosocomial infection, blood product use, longer ICU stay (>7 days), high DIC (>5), and comorbidities (>3) scores were all risk factors for mortality. In ROC analysis, the cut-off values for NLR and SFMC to predict mortality were 6 and 6.5, respectively. Conclusion: Our data show that elevated NLR and SFMC values in the first week should alert physicians to the risk of life-threatening COVID-19 complications.

Unraveling the complex interplay between anti-tumor immune response and autoimmunity mediated by B cells and autoantibodies in the era of anti-checkpoint monoclonal antibody therapies.

The intricate relationship between anti-tumor immunity and autoimmunity is a complex yet crucial aspect of cancer biology. Tumor microenvironment often exhibits autoimmune features, a phenomenon that involves natural autoimmunity and the induction of humoral responses against self-antigens during tumorigenesis. This induction is facilitated by the orchestration of anti-tumor immunity, particularly within organized structures like tertiary lymphoid structures (TLS). Paradoxically, a significant number of cancer patients do not manifest autoimmune features during the course of their illness, with rare instances of paraneoplastic syndromes. This discrepancy can be attributed to various immune-mediated locks, including regulatory or suppressive immune cells, anergic autoreactive lymphocytes, or induction of effector cells exhaustion due to chronic stimulation. Overcoming these locks holds the risk to induce autoimmune mechanisms during cancer progression, a phenomenon notably observed with anti-immune checkpoint therapies, in contrast to more conventional treatments like chemotherapy or radiotherapy. Therefore, the challenge arises in managing immune-related adverse events (irAEs) induced by immune checkpoint inhibitors treatment, as decoupling them from the anti-tumor activity poses a significant clinical dilemma. This review summarizes recent advances in understanding the link between B-cell driven anti-tumor responses and autoimmune reactions in cancer patients, and discusses the clinical implications of this relationship.

Lymphocyte apoptosis and its association with the inflammatory markers and disease severity in juvenile-onset systemic lupus erythematosus patients

BackgroundThe defective clearance of apoptotic bodies in juvenile-onset systemic lupus erythematosus (jSLE) potentially leads to the persistence of autoreactive lymphocytes and the perpetuation of the autoimmune response. These factors contribute to the disturbance in lymphocyte apoptosis and show potential as key determinants in the clinical course and severity of jSLE. This study evaluates the role of peripheral blood (PB) lymphocyte apoptosis in prognosis of jSLE and as a predictor for disease activity.MethodsThe study involved 100 jSLE patients and 50 healthy controls. Flow cytometry was used to analyze percentages of lymphocyte apoptosis in PB of all study participants. Plasma levels of pro-inflammatory cytokines were determined using ELISA.ResultsOur results showed that percentages of lymphocyte apoptosis in PB of jSLE patients are significantly higher than those of healthy controls. These percentages are significantly positively associated with disease activity of patients (SLEDAI-2 K). Furthermore, plasma cytokine levels (IL-17, IFN-γ and TNF-α) are significantly elevated in jSLE patients compared to their levels in healthy controls. Also, there are weak significant positive correlations between percentages of PB lymphocyte apoptosis and each of IL-17 and IFN-γ plasma levels in jSLE patients. Moreover, PB lymphocyte apoptosis percentages among jSLE patients are higher in the presence of some clinical and laboratory features than those in their absence.ConclusionPeripheral apoptotic lymphocytes could contribute to the prognosis of jSLE and could be used as a predictor for disease activity in jSLE patients.

The role of autoimmune processes in demyelinating diseases of the nervous system: focus on multiple sclerosis

Background. Demyelinating diseases of the central nervous system (CNS) are a heterogeneous group of disorders characterized by a damage to the myelin sheath of nerve cell axons. Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS affecting more than 2.9 million people worldwide. The purpose was to summarize current information about the features of the immunopathogenesis of multiple sclerosis according to the data from open sources of information. Materials and methods. The selection of publications covering the features of the immunopathogenesis of multiple sclerosis was carried out in the PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection and Google Scholar databases using the following keywords: multiple sclerosis, demyelinating diseases, neurodegeneration, oligodendrocytes. Results. The course of MS has three successive phases/forms known as relapsing-remitting, primary progressive and secondary progressive. Abnormalities of immune mechanisms are proposed as protagonists of the pathogenesis of MS. Autoreactive myelin-specific lymphocytes are activated outside the CNS, they cross the blood-brain barrier and form new inflammatory demyelinating lesions. The myelinating oligodendrocyte is a target during the adaptive immune response in MS. The inflammatory reaction in the brain of patients with progressive MS is observed mainly in the large connective tissues of the meninges and the periventricular space. Treatment of MS can be divided into three categories: treatment of acute relapse, disease-modifying treatment, and symptomatic treatment. Conclusions. On the T cell side, both hel-per (CD4+) and cytotoxic (CD8+) T cells are involved in the CNS damage in MS. Peripherally activated subsets of T cells (CD4+ Th1 and Th17, CD8+) migrate through the blood-brain barrier and activate B-cells and macrophages, which causes a neuroinflammatory reaction and leads to demyelination and neurodegeneration in the CNS. Oligodendrocyte progenitor cells, which are widely distributed throughout the CNS, mediate myelination and remyelination. One of the desired features of new methods for treating MS is the restoration of antigen-specific tolerance.

The Neuroprotective Role of BCG Vaccine in Movement Disorders: A Review.

Bacillus Calmette-Guérin (BCG) is the first developed vaccine to prevent tuberculosis (TB) and is the world's most widely used vaccine. It has a reconcilable defense in opposition to tuberculosis, meningitis, and miliary disease in children but changeable protection against pulmonary TB. Immune activation is responsible for regulating neural development by activating it. The effect of the BCG vaccine on neuronal disorders due to subordinate immune provocation is useful. BCG vaccine can prevent neuronal degeneration in different neurological disorders by provoking auto-reactive T-cells. In the case of TB, CD4+ T-cells effectively protect the immune response by protecting the central defense. Because of the preceding fact, BCG induces protection by creating precise T-cells like CD4+ T-cells and CD8+ T-cells. Hence, vaccination-induced protection generates specific T-cells and CD4+ T-cells, and CD8+ T-cells. The BCG vaccine may have an essential effect on motor disorders and play a crucial role in neuroprotective management. The present review describes how the BCG vaccine might be interrelated with motor disorders and play a key role in such diseases.

Immunomodulatory effect of Tityus sp. in mononuclear cells extracted from the blood of rheumatoid arthritis patients.

Pathophysiological mechanisms of rheumatoid arthritis arise because of a proinflammatory environment, generated by the interaction of autoreactive lymphocytes and proinflammatory mediators. Current strategies to mitigate the progression of the disease produce adverse effects, so there is a need for new therapeutic strategies and molecular targets to treat this disease. In this context, evidence suggests that scorpion venoms could modulate the immune response and some important cellular mechanisms of pharmacological interest. To evaluate the immunomodulatory effect of the venom of Tityus sp. (a possible new species close to Tityus metuendus) peripheral blood mononuclear cells of women diagnosed with RA were compared to cells of a control group. A case-control study was conducted with a sample of 10 women with a confirmed diagnosis of RA and controls matched by sex and age. The cytotoxicity of the venom was evaluated to find sublethal concentrations of the venom, and subsequently, their immunomodulatory capacity in terms of percentage of proliferation, cell activation, and cytokines production. the venom of Tityus sp. produced a decrease in the percentage of proliferation in the CD3+, CD3+CD4+, and CD3+CD8+ cell subpopulations of RA patients and healthy controls, at concentrations of 252 and 126 µg/mL. However, the venom did not induce significant differences in the percentage of cell activation markers. The venom caused a decrease in IL-10 at a concentration of 252 µg/mL compared to untreated cells from patients and controls. The remaining cytokines did not show significant differences. the venom of Tityus sp. is a potential source of molecules with immunomodulatory ability in CD4 and CD8 T lymphocytes. This result directs venom characterization studies to identify pharmacological targets with immunomodulatory capacity in T lymphocytes to enhance research in the treatment of autoimmune disorders such as RA.

Assembling the thymus medulla: Development and function of epithelial cell heterogeneity.

The thymus is a unique primary lymphoid organ that supports the production of self-tolerant T-cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus-dependent T-cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T-cell clones, thereby counterbalancing the potential for random T-cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self-tolerant T-cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function.

Decision support system for the classification of Downey cells as a pre-diagnostic tool

Abstract Objectives Epstein–Barr virus (EBV) is a member of the herpes virus that causes infectious mononucleosis (IM). Downey cell is the atypical lymphocyte of IM and can be seen in various conditions. Peripheral blood smear (PBS) microscopic evaluation is used to identify Downey cells. A lack of experienced professionals or professional errors may obstruct early and accurate diagnostics for the microscopic evaluation. The main objective of this study is to create a decision support system by digitizing the PBS samples. A general tool providing an inexpensive and measurable solution is envisioned to analyze the PBS samples in detail to give alerting flags to prevent missing Downey cells in manual analysis. Methods The PBS dataset collected was split into Downey positives and negatives. The negative set consisted of 5 leucocyte subtypes. Mantiscope, a cloud-based slide scanner system, was used to collect images from the physical PBS samples. Clinically and laboratory-confirmed 35 IM patients and 124 healthy PBS slides were selected for this procedure. A number of cell counts were obtained after the application of annotation and augmentation methods, and a partially balanced dataset was created for the artificial intelligence (AI) network training. The verification steps included the calculation of sensitivity, specificity, and Cohen’s kappa metrics from the partitioned testing set that was not used during training. A validation process was also performed over the manually identified PBS samples to measure whether the algorithm noticed the samples or not. Results After testing this setup, we have observed 98 % sensitivity and 99 % specificity for Downey cells. According to the validation procedure of Downey positive and negative samples that were carried out by the physicians, a sensitivity of 57 %, specificity of 100 %, and Cohen’s kappa value of 0.5 were observed. Besides, the accuracy was found to be 66 % according to the physicians’ evaluations employing the digital images which were identified by Mantiscope, Conclusions Decision support systems can alert the physician for Downey cells and increase the rate of true diagnosis in PBS evaluation. A higher sensitivity and specificity for the detection of Downey cells would be achieved. However, the variance over the dataset is a constraint for effective diagnosis. As the annotation and AI development process continues to collect more data from patients, the model can be updated for future releases.

Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system.

Regulatory T cells (Tregs) can eliminate autoreactive lymphocytes, induce self-tolerance, and suppress the inflammatory response. Mitochondria, as the energy factories of cells, are essential for regulating the survival, differentiation, and function of Tregs. Studies have shown that patients with autoimmune diseases of the central nervous system, such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis, have aberrant Tregs and mitochondrial damage. However, the role of mitochondrial-regulated Tregs in autoimmune diseases of the central nervous system remains inconclusive. Therefore, this study reviews the mitochondrial regulation of Tregs in autoimmune diseases of the central nervous system and investigates the possible mitochondrial therapeutic targets.

Anti-GAD encephalitis in a child with beta-thalassemia after allogeneic hematopoietic stem cell transplantation

Glutamic acid decarboxylase (GAD) is an intracellular enzyme expressed in brain neurons and insulin-secreting β-cells of the pancreas. Anti-GAD-anitibodies are associated with type 1 diabetes mellitus, limbic encephalitis, cerebellar ataxia, temporal autoimmune epilepsy, and rigid man syndrome. We present a rare clinical case of anti-GAD-anitibodies- associated immune encephalitis in a child with beta-thalassemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT).A 3-year-old boy diagnosed with beta-thalassemia underwent allo-HSCT from a 9/10 compatible unrelated donor. The macrophage activation syndrome occurred during the early post-transplantation period. The seizure with a focal onset happened on day +65. The cytotoxic edema in the region of the left hippocampus without signs of accumulation of a contrast agent was revealed at the magnetic resonance imaging of the brain. Pleocytosis, increase in protein levels, infection and antibodies to receptors and synaptic proteins of neurons were not detected at the analysis of cerebrospinal fluid. A positive titer to anti-GAD-anitibodies was detected in the blood – 315.82 IU/ml (the norm is up to 10 IU/ml). The child was treated with cyclophosphamide 750 mg/m2, rituximab 375 mg/m2, and tocilizumab 8 mg/kg. The cytotoxic edema in the left hippocampus regressed at the control magnetic resonance imaging on day +117.Infectious, immune and toxic agents can cause the damage of central nervous system in patients after allo-HSCT. The mechanism of immune damage to the central nervous system S in such patients is still being studied and may be different: expansion of autoreactive lymphocytes due to failure of T-cell regulation due to chemo- or immunosuppressive therapy, “passenger lymphocyte” syndrome, violation of T-cell regulation due to the course of infectious complications and acute graft versus host disease.In a series of diagnostic searches in patients with central nervous system lesions after allo-HSCT, it is necessary to include immune damage to the nervous system. Diagnosis of such conditions is a difficult task due to comorbidity and multicomponent accompanying therapy, including immunosuppressive therapy, administered to patients.

Impact of the therapy that changes the clinical course of multiple sclerosis using allogeneic mesenchymal stem cell transplantation on the immunological parameters of patients

Impact of the therapy that changes the clinical course of multiple sclerosis using allogeneic mesenchymal stem cell transplantation on the immunological parameters of patients

Real-Life Data of Cyclosporine (CsA) Tapering in Patients with Very/ Severe Aplastic Anemia (v/sAA) Treated with Horse Anti-Thymocyte Globulin (hATG/CsA) Suggest Higher Risk of AA Relapse at Cyclosporine Plasma Levels below 100 Nanogram per Milliliter

Introduction: Aplastic anemia (AA) is an acquired bone marrow failure syndrome (BMFS) mediated by autoreactive T-cells. In adults with severe (s) or very severe (vs) AA >40-50 years or ineligible for transplant for other reasons immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), cyclosporine A (CsA) and Eltrombopag (Epag) has recently become the actual standard of care. With CsA treatment maintained for 6 to 24 months followed by CsA tapering hematologic response is achieved in 60-70 % of AA patients (pts.), while 30-40 % are primary refractory. Approximately 40% of pts. relapse during CsA tapering and most relapsed AA pts. remain CsA dependent. In vitro data indicate a dose dependent inhibition of T cell activity induced by CsA, suggesting the presence of a therapeutic CsA threshold around 100 ng/mL (Flores et al. Front Immunol 2019). Pts. with CsA related side effects such as renal insufficiency would benefit from an established lowest efficient CsA plasma level preventing relapse and reducing CsA related toxicity. As data about correlation of CsA plasma levels and the occurrence of relapse during tapering are sparse, we analyzed data from our registries including CsA plasma levels of 20 s/vsAA pts. with and without relapse during CsA tapering after treatment with horse ATG/CsA. Methods: Descriptive retrospective analysis of 20 AA pts. (17 sAA/ 3 vsAA) from the AA-BMF/Basel AA registry treated with horse ATG/CsA and sufficient clinical data during CsA tapering. Results are given as mean ± standard deviation. Mean age of the 13 female and 7 male pts. was 53 ± 19 years. Follow-up data over 59 ±17 months were compiled between 2010 and 2023. Results: All 20 pts. achieved a hematological response i.e. partial (PR) or complete remission (CR) (as defined in Peffault de Latour et al., 2022) at 3/6/9 months after ATG as follows: PR 90%/ 75%/ 55% and CR 0%/ 20%/ 45%. Relapse of AA occurred in 60 % (12 pts.) at 24 ± 11 months after ATG, while 40 % (8 pts.) remained relapse-free during a follow up period of 59 ±17 months. In the 8 pts. without relapse, dose reduction was initiated 14 ± 6 months after ATG at a hematological response of CR in 4 pts. and PR in 4 pts. In two pts. with PR, early decrease of CsA was required due to renal insufficiency (1 month after ATG) or CsA related adverse drug reaction (4 months after ATG), respectively. The average time of CsA maintenance was 32 ± 13 months. In pts. with relapse (60%, 12 pts.), dose reduction was started after reaching best hematological response i.e. CR (9 pts.) or PR (3 pts.) at 11 ± 7 months after ATG. Relapse i.e. recurrent thrombocytopenia occurred 12 ± 9 months after start of tapering at CsA plasma levels of 44.0 ± 29.2 ng/mL and a daily CsA dosage of 1.01 ± 0.70 mg/kg. In one case, relapse occurred one month after stopping CsA. No patient with CsA levels continuously > 100 ng/mL relapsed, whereas thrombocytopenia was observed with a latency of 2.8 ± 1.6 months after first decrease below 100 ng/mL CsA in pts. with relapse. While 58% (7 pts.) of the relapsed pts. responded to salvage-therapy with CsA+Epag (age 58 ± 16 years), 42 % (5 pts.) required a second course of ATG/CsA, or transplant (age 44 ± 22 years). Conclusion: In s/vsAA pts. with hematological response to ATG/CsA, closer monitoring for relapse is recommended reaching CsA plasma levels <100 ng/mL, as CsA <100 ng/mL was associated with higher risk of relapse during CsA tapering in line with previous reported in vitro data. Pending prospective validation, CsA plasma levels >100 ng/mL might serve as threshold in pts. requiring accelerated tapering due to renal insufficiency or CsA related side effects.

High-dimensional immune profiling using mass cytometry reveals IL-17A-producing γδ T cells as biomarkers in patients with T-cell-activated idiopathic severe aplastic anemia

Severe aplastic anemia (SAA) is a bone marrow failure syndrome characterized by activated T cells. Features of T-cell activation in the pathophysiology of SAA remain unknown. To understand T cell activation states, we investigated the atlas of peripheral immune cells and the secreted cytokine network with single cell mass cytometry analysis. We found decreased γδ T-cell frequencies in all patients with SAA, together with a significantly increased proportion of interleukin (IL)-17A-producing cell subsets. Cytokine network analysis of immune cells showed significant positive relationship between IL and 17A production from immune cells and disease severity of severe aplastic anemia. On separating SAA into two distinct subgroups based on T-cell activation stage, the proportion of γδ T cells tended to decrease in the T-cell-activated SAA group compared with non-T-cell-activated group. And the proportion of IL-17A-producing γδ T cells (γδT17) within γδ T cells was newly found to be significantly higher in the T-cell-activated SAA group, implying that IL-17A production by γδ T cells was associated with T-cell activation. Overall, our study revealed a role of γδT17 cells in mediating autoreactive T-cell activation in SAA and provided a novel diagnostic indicator for monitoring autoreactive T-cell activation status during the progression of aplastic anemia in the clinic.

Neurological risks of COVID-19 in women: the complex immunology underpinning sex differences.

The COVID-19 pandemic has uncovered many mysteries about SARS-CoV-2, including its potential to trigger abnormal autoimmune responses. Emerging evidence suggests women may face higher risks from COVID-induced autoimmunity manifesting as persistent neurological symptoms. Elucidating the mechanisms underlying this female susceptibility is now imperative. We synthesize key insights from existing studies on how COVID-19 infection can lead to immune tolerance loss, enabling autoreactive antibodies and lymphocyte production. These antibodies and lymphocytes infiltrate the central nervous system. Female sex hormones like estrogen and X-chromosome mediated effects likely contribute to dysregulated humoral immunity and cytokine profiles among women, increasing their predisposition. COVID-19 may also disrupt the delicate immunological balance of the female microbiome. These perturbations precipitate damage to neural damage through mechanisms like demyelination, neuroinflammation, and neurodegeneration - consistent with the observed neurological sequelae in women. An intentional focus on elucidating sex differences in COVID-19 pathogenesis is now needed to inform prognosis assessments and tailored interventions for female patients. From clinical monitoring to evaluating emerging immunomodulatory therapies, a nuanced women-centered approach considering the hormonal status and immunobiology will be vital to ensure equitable outcomes. Overall, deeper insights into the apparent female specificity of COVID-induced autoimmunity will accelerate the development of solutions mitigating associated neurological harm.

An overlooked cause of hepatitis and thrombocytopenia with clinico-biochemical discrepancy: A case of infectious mononucleosis

A 22-year-old male was admitted to the outpatient clinic with fatigue, fever, and a sore throat. High transaminase levels, moderate thrombocytopenia, and elevated acute phase reactants were detected ten times. Ultrasound imaging revealed hepatosplenomegaly and a peripheral blood smear showed Downey cells. Epstein-Barr virus (EBV) infection was considered the definite diagnosis, and EBV serology was performed. His mild clinic improved to normal within days, but the patient's clinical progression and laboratory findings were incompatible. Laboratory results were on the extreme side, while the clinic was mildly deteriorating. EBV viral capsid antigen IgM was high, supporting the initial diagnosis. Biochemical normalization followed clinical improvement many days later. Clinicians should know that EBV infection may be mild, while laboratory results illustrate extreme findings.