Immunological Medicine最新文献

We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

Interleukin-1, a pro-inflammatory cytokine, plays a crucial role in inflammatory disease pathogenesis. Interleukin-1 receptor antagonist knockout (IL-1Ra KO) mice spontaneously develop aortitis, arthritis and dermatitis, and are employed as a model for human inflammatory diseases. Previous studies have shown that transferring total T cells from IL-1Ra KO mice into nude mice induces aortitis and arthritis; however, the roles of specific T cell subsets in these inflammatory responses remain unclear. In this study, we aimed to investigate the T cell subsets in IL-1Ra KO mice. We found that the proportion of PD-1+CD44+CD62L-CD4+ T cells in the spleen and lymph nodes of IL-1Ra KO mice was significantly higher than that of wild type mice. RNA sequencing revealed elevated expression of basic helix-loop-helix family member e40 and granulocyte macrophage colony stimulating factor (GM-CSF) in splenic CD44+CD62L-CD4+ T cells from IL-1Ra KO mice. In addition, GM-CSF production from splenic CD4+ T cells of IL-1Ra KO mice was significantly higher than that of wild type mice when stimulated with PMA and ionomycin in vitro. Notably, immunohistochemical staining showed infiltration of GM-CSF+CD4+ T cells at inflammatory sites in IL-1Ra KO mice. Our results suggest that a subset of GM-CSF+CD4 + T cells emerges under IL-1 signal-enhanced inflammatory conditions.

Immune checkpoint molecules, including both co-inhibitory molecules and co-stimulatory molecules, are known to play critical roles in regulating T-cell responses. During the last decades, immunotherapies targeting these molecules (such as programmed cell death 1 (PD-1), and lymphocyte activation gene 3 (LAG-3)) have provided clinical benefits in many cancers. It is becoming apparent that not only T cells, but also B cells have a capacity to express some checkpoint molecules. These were originally thought to be only the markers for regulatory B cells which produce IL-10, but recent studies suggest that these molecules (especially T-cell immunoglobulin and mucin domain 1 (TIM-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and PD-1) can regulate intrinsic B-cell activation and functions. Here, we focus on these molecules and summarize their characteristics, ligands, and functions on B cells.

Trained immunity (TI) is functional memory displayed by innate immune cells (IICs). TI facilitates rapid, non-specific responses to pathogens upon secondary challenge. It is driven by immunological signaling and metabolic rewriting via epigenetic alteration, triggered by recognition of certain stimuli. Recently, immune checkpoint inhibitors have come into common use in clinical oncology settings, and genetically engineered cytotoxic T cells comprise a potent cancer treatment strategy. However, the contributions of TI in the tumor microenvironment (TME) are only beginning to be uncovered. Accumulating evidence that various microorganisms and vaccines convey tumoricidal ability suggest that TI may become a useful anti-cancer tool. The expected roles of TI in tumor therapy are the 1) promotion of proinflammatory cytokine section, 2) enhancement of phagocytosis, 3) quick expansion and recruitment of cancer-specific cytotoxic T cells to the TME through neoantigen presentation, 4) reversal of immunosuppression in the TME, and 5) removal of pathogens associated with carcinogenesis or tumor development. Medium- to long-term TI durability may reduce the risk of tumor development. Recent findings on TI usher in new aspirations for cancer treatment.

T cell receptor rearrangement excision circles (TRECs) and immunoglobulin κ-deleting recombination excision circles (KRECs) represent the lymphopoiesis capacity, widely used for newborn screening of inborn errors of immunity. To clarify the significance of TRECs and KRECs as immune indicators in patients with systemic autoimmune diseases, we prospectively evaluated TREC and KREC levels with qPCR, lymphocyte phenotypes with flow cytometry, along with lymphocyte counts and serum immunoglobulin levels in peripheral blood samples from newly diagnosed patients. Each variable was assessed before immunosuppressive treatments (baseline), 3-, 6-, and 12-months after the treatment. Severe infections were recorded until 6 months after treatment. Among 35 patients, TREC and KREC levels were associated positively with the proportion of recent thymic emigrants, naïve T and B cells at all the timepoints. TREC and KREC levels decreased after treatment. The ratios of TREC and KREC levels under treatment to baseline were significantly lower in patients with severe infection than those without. In conclusion, TREC and KREC levels reflect peripheral blood immunophenotypes, specifically recent-emigrated T and B cells, in patients under treatment-naïve and immunosuppressive conditions. The longitudinal changes in TREC and KREC levels were beneficial markers for predicting the risk of severe infection during immunosuppressive treatments.

Systemic lupus erythematosus (SLE) is a typical autoimmune disease; although severe disease and refractoriness to existing therapies are still experienced, the number of cases resistant to remission induction has decreased with the establishment of various therapies. However, improving long-term prognosis remains a challenge due to the unavoidable prolonged use of non-selective glucocorticoids. To investigate the additional effect of belimumab in the chronic phase, we included 28 of 46 patients with SLE who were initiated on belimumab between January 2018 and October 2022 for glucocorticoid reduction. The efficacy of tacrolimus and mycophenolate mofetil in combination with belimumab was also compared. In the stable chronic phase, the combination with belimumab improved the SLE Disease Activity Index and reduced glucocorticoid requirement. The tacrolimus with belimumab group was not significantly inferior to the mycophenolate mofetil with belimumab group and was effective in treatment and glucocorticoid sparing including cases at all phases of SLE. To improve the long-term prognosis of SLE, it is crucial to introduce highly selective biological agents and reduce glucocorticoids whenever possible. Belimumab is effective with or without hydroxychloroquine and Tac was effective as concomitant drugs.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory condition of unknown etiology characterized by lymphocytic infiltration, fibrosis, and infiltration of IgG4-positive plasma cells. It affects various organs, including the pancreas and salivary glands. Immunological abnormalities are suspected to play a role in its pathogenesis, and there is an epidemiological link to allergic conditions and type 2 inflammation. This study focused on the expression of thymus and activation-regulated chemokine (TARC)/CCL17, which is involved in the migration of T helper 2 and/or regulatory T cells, in salivary gland tissues of patients with IgG4-RD. We analyzed 60 salivary gland biopsy samples obtained from patients at Sapporo Medical University Hospital between 2015 and 2020. Immunohistochemical analysis revealed TARC/CCL17 positivity in 87.2% of histologically confirmed IgG4-RD cases and negativity in 84.6% of histologically unconfirmed but clinically suspected IgG4-RD cases. There was a significant correlation between histologically confirmed IgG4-RD and TARC/CCL17 expression, suggesting its potential diagnostic utility and possible involvement in the pathogenesis of IgG4-RD.

Rituximab (RTX) has been reported to effectively maintain remission in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). In this multicenter study involving 57 patients who achieved remission after 24 weeks, we evaluated the effectiveness of RTX in maintaining remission in patients with AAV. Patients were divided into three groups based on RTX administration: continuous, induction phase-only, and maintenance phase-only groups. The continuous group had a remission maintenance rate after 48 weeks of treatment compared with the induction phase-only group (100% vs. 88.2%, p = 0.29). More patients in the continuous group received three or more RTX doses during the induction period (82.4% vs. 52.9%, p = 0.06), and this group had a lower incidence of infection (5.9% vs. 29.4%, p = 0.08). Compared with the maintenance-only group, the continuous group had a numerically higher proportion of patients in remission after 48 weeks of treatment (100% vs. 83.3%, p = 0.26) and a lower incidence of infection (5.9% vs. 50%, p = 0.04); however, the N in the maintenance phase was small and suspected to have low power. Regardless of the method of RTX administration (induction phase-only or continuous), administering RTX during the induction phase may be crucial for achieving remission.

Recent evidence indicates an increased risk of chronic kidney disease (CKD) in patients with rheumatoid arthritis (RA), with prevalence rates ranging from 20.8% to 24.5%. Risk factors for CKD among RA patients include advancing age, diabetes, cardiovascular disease, hypertension and RA disease activity. Medications such as glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) may also accelerate CKD progression. Inflammatory cytokines, notably interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and IL-1, play significant roles in the pathogenesis of both RA and CKD, promoting systemic inflammation and renal impairment. Elevated levels of various cytokines have been detected in the plasma and urine of CKD patients, and they raise morbidity and mortality rates, even during early disease stages. Effective management of RA activity and modifications in treatment to reduce renal burden are essential for lowering CKD risk and improving patient outcomes. Biological disease-modifying antirheumatic drugs (DMARDs), particularly those targeting IL-6 and TNF-α, show potential in mitigating CKD progression in RA patients. However, individualized treatment and careful kidney function monitoring are critical, as CKD may impact RA management. Future research should focus on therapeutic strategies that address inflammation in both RA and CKD to optimize patient care.

Chronic Fatigue Syndrome (CFS) is a complex disorder characterized by prolonged, unexplained fatigue and challenging diagnosis. We report the case of a 35-year-old Japanese woman with CFS who had experienced chronic fatigue since the age of 11 years. Despite treatment with modafinil, methylphenidate, levocarnitine, and ubiquinone, the symptoms persisted. Introduction of oral 5-aminolevulinic acid with sodium ferrous citrate (5-ALA/SFC) led to significant improvements in daily activities, mobility, and psychosocial functioning. Genetic analysis revealed a novel heterozygous frameshift deletion in ADCK1 (p.Asn280fs), a gene related to mitochondrial function, which was confirmed using cDNA sequencing. ADCK1 deficiency has been associated with developmental disabilities, mitochondrial dysfunction, increased reactive oxygen species levels, and apoptosis in Drosophila and muscle cells. This case supports the hypothesis that ADCK1 mutations contribute to mitochondrial dysfunction and CFS pathogenesis. The patient's significant clinical improvement with 5-ALA/SFC and ubiquinone suggests their potential for addressing mitochondrial dysfunction. Further functional and familial analyses are required to confirm the role of this heterozygous ADCK1 mutation in CFS. This case highlights the importance of considering mitochondrial dysfunction in CFS, and the potential therapeutic benefits of 5-ALA/SFC and ubiquinone.