Clinical and experimental immunology最新文献

Neutralizing autoantibodies against type I interferons are a risk factor for multiple severe viral diseases. The timely detection of these autoantibodies remains an unmet need. We hypothesized that paradoxically low expression of type I IFN-induced CD169/SIGLEC1 expression analyzed by flow cytometry may allow rapid screening for the presence of these autoantibodies. In a prospective cohort study, we quantified monocytic CD169/SIGLEC1 expression and neutralizing autoantibodies against type I interferons in 808 patients who presented to the emergency room with signs of acute infections during the second wave of the SARS-CoV-2 pandemic in Germany in 2021. In patients, elevated CD169/SIGLEC1 (>2400 mAb/cell) demonstrated a negative predictive value of 100% for the detection of neutralizing autoantibodies against type I interferons. Low CD169/SIGLEC1 (<2400 mAb/cell) and a CRP >50 mg/L exhibited a positive predictive value of 70% for neutralizing autoantibodies against type I interferons. We further compared the adjusted odds ratio for mortality in patients with these autoantibodies to that in patients without autoantibodies against type I interferons. Neutralizing autoantibodies against type I interferons were associated with a worse clinical outcome, independent of SARS-CoV-2 infection, implying their presence is a risk factor for a worse general outcome.

Immune Checkpoint Inhibitors (ICIs) have become a mainstay in the treatment of various solid tumors. At present, commonly used predictive biomarkers include tumor mutation burden, programed death-ligand 1 expression levels, and microsatellite instability. However, these biomarkers face inherent limitations, such as the challenges associated with tumor tissue sampling and the inability to provide dynamic monitoring. In recent years, significant efforts have been undertaken for the precise characterization of circulating T-lymphocyte subsets, with their classification offering the potential to reflect the functional state of T cells and predict responses to ICI therapy. Its advantages in terms of sampling convenience and minimally invasive nature further highlight its feasibility as a dynamic monitoring tool. This review expounds on current research progress on the use of "circulating" T-lymphocyte subsets as predictors of ICI efficacy and discusses their reliability and potential as predictive tools.

Psoriasis is a chronic disease caused by abnormal immune system response, which is characterized by excessive keratinocyte proliferation and the activation of cytokine signaling pathways. In a previous study, we demonstrated in a psoriasis mouse model that hydrogen-rich water, an effective reactive oxygen species (ROS) scavenger, significantly improves disease severity. However, the precise molecular mechanism by which hydrogen helps in psoriasis treatment remains inadequately understood. This study assessed the role of hydrogen in suppressing keratinocyte hyperproliferation. We observed that the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon gene signaling was activated in psoriasis-like skin inflammation, which was dramatically inhibited by hydrogen treatment both in vitro and in vivo. Consistently, hydrogen decreased proliferative marker expression, including BCL2, BAX, and Ki-67, and significantly reduced ROS and inflammatory cytokines production. Our study suggests that molecular hydrogen could function as a potential treatment for psoriasis.

Autoreactive B cells that remain in lymphatic tissue after anti-CD20 antibody therapy are considered a major contributing factor to relapse in patients with autoimmune diseases. Natural killer (NK) cells contribute to the depletion of autoreactive B cells by anti-CD20 antibodies via antibody-dependent cellular cytotoxicity (ADCC). However, the impact of germinal centre-associated signals CD40 ligand (CD40L) and interleukin-4 (IL-4) on ADCC was unknown. This study used a combination of flow cytometry, immunohistochemistry, and ex vivo functional assays using peripheral blood mononuclear cells to investigate how CD40L and IL-4 affect NK cell-B cell interactions. CD40L and IL-4 significantly upregulate human leukocyte antigen (HLA)-E and total HLA Class I expression on the surface of B cells from healthy donors, as well as patients with rheumatoid arthritis and systemic lupus erythematosus. The upregulation of HLA-E and total HLA functions to inhibit B-cell depletion by NK cell-mediated ADCC induced by rituximab via NKG2A and killer cell immunoglobulin-like receptors (KIR). Moreover, B cells that have differentiated through the germinal centre have higher expression of HLA-E and total HLA compared with naive B cells and are more resistant to depletion by rituximab. In accordance with this, blockade of NKG2A and inhibitory KIRs by monalizumab and lirilumab, respectively, increased antibody-dependent cellular cytotoxicity against autologous B cells in vitro. Overall, this study identifies a novel mechanism of resistance of B cells to NK cell cytotoxicity and indicates that blockade of the HLA-E:NKG2A and HLA:KIR checkpoint axes could be beneficial for improving B-cell depletion in patients with autoimmune diseases.

Chronic granulomatous disease (CGD) patients develop repeated infections and inflammatory complications. Underlying pathogenesis of hyperinflammation in CGD is not clearly characterized. To assess type-1 interferon signature and measure Siglec-1/CD169 expression on monocytes in patients with CGD. mRNA sequencing of PBMCs in five CGD patients and three controls was analysed for differentially expressed genes. Subsequently, 20 patients with CGD, 10 heterozygous carriers of CYBB mutations, 11 healthy controls and 11 patients of systemic lupus erythematosus (disease controls) were enrolled. Expression of CD169 on monocytes was measured using flowcytometry. Expression of five type 1 interferon signature genes (ISGs) was measured using RT-PCR. On transcriptome analysis of peripheral blood mononuclear cells, increased expression of type-1 ISGs were seen in CGD patients. Monocyte CD169 expression was compared across three subgroups of CGD patients (10 = inflammatory disease, 5 = infectious disease, 5 = asymptomatic disease). CD169 expression on monocytes (percentage and ΔMFI) was significantly high in inflammatory disease subgroup in comparison to asymptomatic disease subgroup of CGD (P = <0.001 and P = <0.001). Similarly, the expression was significantly high in inflammatory disease subgroup when compared to infection subgroup of CGD (P = 0.033 and P = 0.017). An elevated type-1 interferon score by RT-PCR was found in inflammatory disease subgroup in comparison to infection subgroup of CGD (P = 0.029) and healthy controls (P = 0.021). Percentage and ΔMFI of monocyte CD169 correlated with type 1 interferon scores, rp = 0.38 (P = 0.049) and rp = 0.46 (P = 0.017), respectively. CGD patients with hyperinflammatory manifestations exhibited a high type 1 interferon signature. CD169 is a reliable surrogate marker for estimation of type 1 interferon signature.

In recent years, research on innate lymphoid cells (ILCs) in pericardial adipose tissue has advanced significantly. These studies have revealed their dual role in maintaining cardiovascular homeostasis and mediating disease progression. Although the contribution of ILCs to cardiovascular diseases (CVDs) has garnered increasing attention, their heterogeneous nature complicates the analysis of their phenotypic and developmental characteristics. Furthermore, substantial differences in their composition, distribution, and function exist between murine and human hearts, highlighting the need for further investigation into how the high plasticity of ILCs influences disease processes. In this review, we examine the subpopulations, distribution patterns, and multifaceted roles of ILCs in the heart during CVDs, and discuss potential strategies to modulate ILC plasticity. We anticipate that, in the future, more precise immune modulation of ILCs will emerge as a promising therapeutic approach for CVDs, ultimately benefiting public health.

Radiation-induced lymphopenia following brain irradiation may influence tumor response to cancer treatment. Interactions between the immune system, tumor, and radiotherapy manifest as global lymphopenia and result in changes in B-lymphocyte and T-lymphocyte levels. We assessed the longitudinal effects of brain irradiation on B-lymphocyte and T-lymphocyte concentrations in mice with and without glioblastoma. C57BL/6 mice were either tumor-free or tumor-bearing with GL-261 glioma cells and underwent brain irradiation with 2.5 Gy fractions in an 8-fraction irradiation regimen. We employed a tree-based model to analyze the acute impact of radiation and tumor volume on B-lymphocyte and T-lymphocyte reduction (total N = 130). Next, we developed semimechanistic models to describe the recovery patterns of B-lymphocyte and T-lymphocyte postdepletion after brain irradiation in tumor-free rodents (N = 40). Finally, we applied these models to predict B- and T-lymphocyte kinetics in tumor-bearing rodents. Brain irradiation induced a 50% reduction in B-lymphocyte and T-lymphocyte. Tumor volumes exceeding 59 mm³ caused B-lymphopenia but not T-lymphopenia during brain irradiation. Radiation exposure of lymph nodes resulted in both B- and T-lymphopenia. Our models successfully described the recovery of B/T-lymphocytes following their depletion induced by irradiation. Simulations revealed that all mice experienced B-lymphopenia, with recovery occurring within 8 days. 80% of mice experienced T-lymphopenia, with an average recovery time of 3.6 days. When tumor volumes exceeded 59 mm³, mice suffered prolonged B-lymphopenia. In conclusion, this study highlights the impact of lymph node radiation exposure and tumor volume on lymphocyte reduction and the utility of modeling in predicting long-term lymphocyte levels following brain irradiation.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement. It is known that cytokines produced from activated CD4+ T cells play a pivotal role in the development of SLE; however, the details of pathological processes remain unclear. The purpose of this study is to elucidate the role of activated CD4+ T cells on the pathogenesis of lupus using SLE murine models induced by toll like receptor 7 agonist imiquimod (IMQ). Lupus was induced in wild-type (WT) and interferon γ (IFNγ)-deficient (IFNγ-/-) mice by topical IMQ treatment. Splenic T and B cell subsets were analyzed by flow cytometry. CD4+ T cells and B cells were isolated for co-culture to assess B cell differentiation and IgG production. Comprehensive lupus-like phenotypes were evaluated. Single-cell RNA sequencing (scRNA-seq) was performed to characterize IFNγ-associated cellular and molecular pathways. IMQ treatment increased IFNγ-producing CD4+ T cells, along with Tfh cells, Tph cells, age-associated B cells, and plasma cells in WT mice. CD4+ T cells from IMQ-treated WT mice promoted B-cell differentiation and IgG production in co-culture assays. In IFNγ-/- mice, lupus-like phenotypes were significantly attenuated, and co-cultured B cells showed reduced differentiation and IgG production. Single-cell RNA sequencing revealed that IFNγ plays a critical role in promoting B cell differentiation and autoantibody production. IFNγ derived from activated CD4+ T cells plays a critical role in driving B-cell differentiation and promoting autoantibody production in IMQ-induced lupus.

Lysophosphatidic acid (LPA) is a crucial bioactive lipid mediator involved in various physiological processes; however, its role in macrophage polarization remains poorly understood; therefore, this study aimed to elucidate the modulatory effect of LPA on macrophage polarization, particularly its ability to shift M1 macrophages towards an M2-like phenotype, using murine macrophage RAW264.7 cells to confirm the expression of LPA receptor 1 (LPAR1) through immunofluorescence staining, which revealed that treatment of resting MO macrophages with LPA decreased inflammatory cytokines (IL-6, TNF-α) and increased TGF-β, with similar effects observed in LPS-stimulated cells and reversed by the LPAR1 inhibitor AM095, and immunostaining demonstrated a notable shift from an M1- to M2-like phenotype, as evidenced by an increase in the arginase-1/CD68 ratio; furthermore, LPA significantly decreased lactate production and increased ATP production in M1 macrophages, promoting a shift towards oxidative phosphorylation and suggesting metabolic reprogramming towards an M2-like phenotype, significantly influencing macrophage polarization and promoting a shift from a pro-inflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype; these results suggest that treatment with LPA may help ameliorate diseases characterized by aberrant macrophage polarization, providing insights for the development of potential therapeutic strategies for inflammatory and autoimmune diseases.

Patients with systemic lupus erythematosus (SLE) exhibit significant susceptibility to severe bacterial infections, a leading cause of mortality. A key host defence mechanism is immunothrombosis, wherein activated monocytes rapidly upregulate tissue factor (TF) to initiate localized fibrin deposition that traps and contains pathogens. Effective immunothrombosis is therefore critical for preventing microbial dissemination. This process appears deficient in SLE, a disease defined by a systemic prothrombotic state, yet poor infection outcomes. A recently discovered molecular interaction suggests that TF directly binds to the interferon-α receptor (IFNAR1), acting as a rheostat to suppress interferon signalling. We hypothesize that in SLE, this regulatory axis is disrupted. The dominant, sustained interferon-stimulated gene (ISG) signatures in monocytes limit their capacity for TF upregulation in response to bacterial challenge, thereby impairing immunothrombosis and compromising bacterial containment. Supporting this, SLE patients with secondary antiphospholipid syndrome who have lower interferon signatures display markedly elevated TF levels and a different thrombotic profile, demonstrating the inverse relationship in a clinical subset. Furthermore, TF induction in monocytes is glycolysis-dependent, and SLE monocytes are known to have profound metabolic alterations. The chronic interferon state may thus impose a metabolic constraint that further limits the bioenergetic capacity for a robust TF response. Therefore, the confluence of interferon-driven suppression and metabolic dysfunction in SLE monocytes provides a compelling explanation for the failure of immunothrombosis, directly linking a core disease feature to infection susceptibility.