Immunological Medicine最新文献

X-linked NF-κB essential modulator (NEMO) deficiency is a primary immunodeficiency characterized by combined immunodeficiency and ectodermal dysplasia. Monocytes from the patients demonstrate a severely impaired response to tissue necrosis factor or lipopolysaccharide, whereas hyper-inflammation is found in some patients. Juvenile myelomonocytic leukemia (JMML) is a pediatric malignancy caused by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and aberrant RAS signaling activation. Patients with JMML demonstrate characteristic manifestations such as splenomegaly, monocytosis and the presence of myeloid or erythroid precursors in the peripheral blood. Here, we present the case of a male infant with ectodermal dysplasia, bacterial septicemia, Pneumocystis pneumonia, severe inflammation and transient manifestations mimicking JMML. Genetic analysis revealed a deep intronic germline variant of IKBKG. Full-length IKBKG cDNA and NEMO protein expression were almost inexistent. Peripheral mononuclear cells (PBMCs) from the patient showed increased RAS signaling activation with GM-CSF or Phorbol 12-myristate 13-acetate without the RAS-associated gene variant, although the increased RAS signaling activation in induced-pluripotent stem cell-derived myeloid lineage and bone marrow-derived mesenchymal cells was not evident. The patient with NEMO deficiency demonstrated JMML-like manifestation and severe inflammation. PBMCs of the patient demonstrated increased RAS signaling activation with unknown pathophysiology.

The pathomechanisms of autonomic disorders in systemic lupus erythematosus (SLE) remain unclear. We herein report a patient with SLE who developed autonomic disorders presumably caused by autoimmune autonomic ganglionopathy (AAG). A 42-year-old woman with SLE under treatment with corticosteroids and hydroxychloroquine was admitted for recurrence of SLE with thrombocytopenia and nephritis. On admission, she presented with weight loss, orthostatic dizziness, abdominal distension, and difficulty urinating. Marked intestinal dilatation, kidney swelling, bilateral hydronephrosis, and ureteral dilatation were noted on ultrasonography and computed tomography. No evidence of obstruction was observed in the intestines, urinary tracts, or bladder. Transverse myelitis was also ruled out by magnetic resonance imaging. After starting the treatment for the recurrent SLE (intravenous immunoglobulin and methylprednisolone pulse therapy, followed by high-dose oral corticosteroid, mycophenolate mofetil, and tacrolimus), orthostatic dizziness, abdominal distension, and difficulty urinating subsided along with increases in platelet count and decreases in urinary protein. The intestinal dilatation, hydronephrosis, and ureteral dilatation improved. We inferred that her SLE was complicated by AAG based on a positive anti-ganglionic acetylcholine receptor antibody. This case suggested that AAG should be considered as a type of autonomic disorder in SLE.

Zinc (Zn), an essential trace element, plays a significant role in fetal development and biological defense during the embryonic and neonatal periods. Therefore, exploring the kinetics of Zn related to immune disturbances in preterm neonates is important. We here performed the measurement of Zn concentration along with immunological analysis of neonates and investigated the role of Zn in the neonatal period. Serum Zn concentrations were measured immediately after birth in neonates (329 cases). Moreover, for 25 cases, the kinetics of various immune cells and cytokines were measured by flow cytometry and electrochemiluminescence. We observed that Zn levels were inversely correlated with gestational weeks. Immune cell and cytokine analysis revealed an inverse correlation between HLA-DR on monocytes and Zn levels and between inflammatory cytokine interleukin-12 and Zn levels. Furthermore, oxidative stress status was inversely correlated with Zn levels. Our results suggested that the Zn dynamics immediately after birth, which show a negative correlation with the gestational week, can provide an anti-inflammatory and anti-oxidative environment for preterm neonates. The increased Zn concentration in the blood of preterm neonates may consequently protect neonates from perinatal stress.

Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disease, characterized by recurrent fever, arthritis, rash, and serositis, and is caused by mutations in the MEFV gene coding for the pyrin protein. The primary treatment goal is to prevent acute attacks and minimize subclinical inflammation to avoid secondary amyloidosis with colchicine as the first-line treatment. However, 10-20% of patients are colchicine-resistant or intolerant. While the therapeutic potential of IL-6 inhibitors such as tocilizumab (TCZ) has been suggested, the detailed serum cytokine profiles after TCZ treatment in patients with FMF remain largely unexplored. This study focused on a sub-analysis of a clinical trial evaluating TCZ in patients with colchicine-resistant FMF (crFMF). We analyzed the serum cytokine profiles at 0, 2, 4, 8, 12, 16, 20, and 24 weeks in the TCZ and placebo groups. Our findings revealed a decrease in serum C-X-C motif chemokine ligand 1 and vascular endothelial growth factor levels in the TCZ group at week 4 compared to baseline, which persisted until week 24, indicating the potential of TCZ to manage crFMF by modulating specific inflammatory cytokines. Further research is required to confirm these findings and optimize the treatment strategies for FMF.

In recent years, various myositis-specific and myositis-associated autoantibodies have been identified in idiopathic inflammatory myopathies, including dermatomyositis (DM), anti-synthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). These autoantibodies exhibit unique characteristics in terms of organ involvement, severity, and treatment response, making their understanding crucial for accurate diagnosis and effective therapy. This review provides a comprehensive overview of the clinical features of recently discovered myositis-specific and associated autoantibodies, while exploring their potential roles in the pathogenesis and exacerbation of myositis. Key findings include the production of anti-TIF1γ antibodies in model mice, the upregulation of Mi2-related genes in anti-Mi2 antibody-positive dermatomyositis muscle tissue, and Jo-1 antigen-induced T cell activation, shedding light on whether disease mechanisms are driven by autoantibodies or autoantigens.

We compared different antineutrophil cytoplasmic antibody (ANCA) detection methods using a predominantly myeloperoxidase (MPO)-ANCA-associated vasculitis cohort. Stored sera from 147 patients with untreated ANCA-associated vasculitis (AAV), including microscopic polyangiitis and granulomatosis with polyangiitis (n = 115 and 32, respectively), and 124 disease controls were tested for P-ANCA and C-ANCA with immunofluorescence (IIF), and for MPO-ANCA and proteinase 3 (PR3)-ANCA with different antigen-specific immunoassays: direct enzyme-linked immunosorbent assay (ELISA), chemiluminescent enzyme immunoassay (CLEIA), third-generation fluorescent enzyme immunoassay (FEIA), and latex turbidimetrical immunoassay (LTIA). In addition, MPO-ANCA and PR3-ANCA titers were calibrated using certified reference materials (CRMs). The sensitivities and specificities for AAV diagnoses were 95% and 94% (IIF), 86% and 98% (ELISA), 93% and 94% (CLEIA), 92% and 96% (FEIA), and 68% and 88% (LTIA). Dual IIF/antigen-specific immunoassay testing reduced diagnostic accuracies from 94% to 93%. The quantitative agreement between ANCA levels measured using CLEIA and FEIA and calibrated using CRMs was not good. In conclusion, this study demonstrated the high performance of antigen-specific immunoassays for AAV diagnosis in a predominantly MPO-ANCA-associated vasculitis cohort and suggested that the benefit of dual IIF/antigen-specific immunoassay testing is limited. Standardizing ANCA measurements using different immunoassays was difficult, even when using CRMs.

Glioblastoma (GBM) is the central nervous system tumor with the most aggressive behavior, and no definitive therapy has yet been found. The tumor microenvironment of GBM is immunosuppressive and is considered a 'cold tumor' with low lymphocytic infiltration, but is characterized by a high proportion of glioma-associated macrophages/microglia (GAMs). GAMs promote tumor growth and also affect treatment resistance in GBM. In this review, we describe the origin and classification of GAMs in humans and describe the mechanisms of their activation and the cell-cell interactions between tumor cells and GAMs. We also describe the history of GAM detection methods, especially immunohistochemistry, and discusses the merits and limitations of these techniques. In addition, we summarized chemotactic factors for GAMs and the therapies targeting these factors. Recent single-cell RNA analysis and spatial analysis add new insights to our previous knowledge of GAMs. Based on these studies, GBM therapies targeting GAMs are expected to be further developed.

This study aimed to identify biomarkers to distinguish adult-onset Still's disease (AOSD) and to predict disease phenotypes. In total, 49 patients diagnosed with AOSD and 200 patients with common diseases (controls) were included in the analysis. The levels of 69 cytokines were analyzed using a multi-suspension cytokine array. Cytokine cluster analysis was performed to identify specific molecular networks. Furthermore, random forest analysis and logistic regression analysis were used to rank cytokines based on their importance and to determine specific biomarkers for identification of AOSD patients and phenotypes. Patients with AOSD demonstrated significantly higher macrophage migration inhibitory factor (MIF) and interleukin (IL)-12(p40) serum levels than controls and patients with rheumatoid arthritis. Serum levels of chemokine (C-C motif) ligand (CCL) 8 and CCL22 were significantly lower in AOSD patients with a polycyclic systemic disease phenotype and could be differentiated with high accuracy from the other phenotypes (cutoff value for CCL8 = 122.7 pg/mL, CCL22 = 593.3 pg/mL, sensitivity 66.7%, specificity 87.1%, area under the curve 0.843). Combined MIF and IL-12(p40) levels may represent a biomarker for differentiating patients with AOSD from those with other diseases. The chemokine profiles of AOSD with a polycyclic systemic disease phenotype may differ from other phenotypes.

IgG4-related disease (IgG4-RD) is an immune disorder characterized by organ enlargement and fibrosis leading to functional impairment. Key immune cell subsets contributing to the pathogenesis of IgG4-RD include T follicular helper 2 cells (Tfh2), Tfh1, CX3CR1 + cytotoxic T cells (CX3CR1 + CTLs), Tregs and IgG4 + B cells. Tfh2 and Tregs are commonly involved in inducing IgG4 class-switching in this disease. Importantly, IgG4-RD can be classified into four clinical phenotypes based on the distribution of affected organs, with each phenotype showing different dominant immune cell subsets involved in its pathogenesis. Specifically, the clinical phenotype of retroperitoneal fibrosis/aortitis is characterized by CX3CR1 + CTLs as the dominant key immune cell subset, while Mikulicz disease with systemic involvement is dominated by Tfh2. In addition to classification based on organ distribution, IgG4-RD can also be categorized into phenotypes associated with malignancy or allergy. The malignancy phenotype is characterized by an increase in CXCR5 + CD2-double negative T cells compared to the allergy phenotype, along with a decrease in naive CD8 + T cells. Moreover, several autoantigens have been identified, and the presence of autoimmune phenotype has been revealed. Due to the pathogenicity of IgG1-type autoantibodies, Tfh1 may be important inducing IgG1 class-switching by IFNγ in autoimmune phenotype. In IgG4-RD with hypocomplementemia, activation of the complement pathway is thought to be induced by IgG1 or IgG2 antibodies, suggesting the involvement of Tfh1 in the disease pathogenesis. Therefore, elucidating the immunological features specific to each clinical characteristic is believed to lead to a deeper understanding of the pathogenesis of IgG4-RD and the discovery of novel therapeutic targets. This review provides an overview of the immunological mechanisms common to IgG4-RD as well as those specific to each clinical characteristic.

Anti-aminoacyl-tRNA synthetase (ARS) antibodies are myositis-specific antibodies associated with anti-synthetase syndrome (ASSD). Some patients are positive for anti-ARS antibodies on enzyme-linked immunosorbent assay (ELISA) but negative on RNA-immunoprecipitation (RNA-IP) (the gold standard method). Whether these patients should be considered truly positive for anti-ARS antibodies remains unclear. Therefore, we investigated the clinical characteristics of these patients and verified the authenticity of their anti-ARS positivity. Patients who were positive for anti-ARS antibodies on ELISA were divided into the non-discrepant (positive on RNA-IP, n = 52) and discrepant (negative on RNA-IP, n = 8) groups. Patient clinical characteristics were compared between the groups. For each positive individual, the authenticity of anti-ARS antibody positivity on ELISA was cross-examined using protein-IP and western blotting. All patients in the discrepant group had lung involvement, including five (63%) with interstitial lung disease. The overall survival time was significantly lower in the discrepant group than in the non-discrepant group (p < 0.05). Validation tests confirmed the presence of anti-ARS antibodies in the sera of the discrepant group but indicated different reactivity from typical anti-ARS antibodies. In conclusion, some anti-ARS antibodies are detected by ELISA but not RNA-IP. Such anti-ARS antibody discrepancies need further elucidation to attain validation of the diagnostic process in ASSD.