Clinical and experimental immunology最新文献

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely related inflammatory disorders. Easily measurable biomarkers defining active disease and identifying patients in need of glucocorticoid sparing treatment options are highly desired. Interferon Type I (IFN-I) might be involved in disease pathology; however, evidence is limited. This study explores a systemic IFN-I signature and expression of IFN-I markers in GCA and PMR patients. Treatment naive GCA and PMR patients, and PMR patients with glucocorticoid treatment were included. Patients suspected of but not diagnosed with GCA were used as controls. Five relevant IFN-I-stimulated genes were identified in literature, and relative expression levels were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in peripheral blood mononuclear cells. An IFN-I score was generated. Serum levels of IFN-I induced C-X-C motif chemokine 10 (CXCL10) and Galectin-9 were determined by multiplex immunoassay. There were no differences in IFN-I scores between the groups. An IFN-I signature was observed in 0/9 controls, 2/11 GCA patients, 4/20 treatment naive PMR patients, and 2/10 PMR patients with treatment. Serum CXCL10 and Galectin-9 were not increased in GCA or PMR patients compared to control patients. Treated PMR patients had lower CXCL10 levels [423.2 pg/ml (375.1-491.1)] compared to treatment naive PMR patients [641.8 pg/ml (552.8-830.6)]. An IFN-I signature does not distinguish GCA and PMR patients from controls. Also, IFN-I-induced serum markers are not upregulated in GCA and PMR patients. Easily measurable IFN-I-induced serum markers will therefore probably not aid in diagnosis and additional treatment options in newly diagnosed GCA and PMR patients.

F-BAR domain only protein 1(FCHO1) contributes as a critical component to an essential cellular process, clathrin-mediated endocytosis(CME). CME involves cellular membrane invagination followed by cargo protein recruitment and adaptor protein assembly to form endocytic vesicles, maintains several cellular functions, such as signaling, differentiation, nutrition, absorption, and secretion. We aimed to determine the clinical/immunological findings in FCHO1 deficiency to generate appropriate medical approach. We present clinical/immunological/genetic findings of two FCHO1 deficiency patients together with recently reported 17 patients. We found two different variants in the patients, one previously defined and one novel homozygous mutation(c.306C>A(p.Tyr102Ter)). Recurrent sinopulmonary infections occurred in all patients, with viral(63.1%) and fungal(52.6%) infections frequently reported. Lymphopenia and CD4+T cell lymphopenia are present in 77.7%(14/18) and 100% of patients, respectively. CD8+ T cell number is low in half. Hypogammaglobulinemia and low IgM are present in 83.3%(15/18) and 61.1%(11/18) of patients, respectively. Neurological disorders(Guillian-Barre Syndrome, Moya Moya disease, encephalitis, and cranial infarction) are common(n=6(31.5%)). Malignancy is present in four(21%) patients, three suffered from diffuse large B cell lymphoma and one developed Hodgkin lymphoma. Additional clinical and laboratory results from more patients helped to define the characteristics of FCHO1 deficiency. The early application of molecular genetic analysis in CID patients is crucial. Since all transplanted patients were alive, allogeneic hematopoietic stem cell transplantation emerged as a potential curative therapy.

Systemic sclerosis is considered a rare autoimmune disease in which there are alterations of both the innate and adaptive immune response resulting in the production of autoantibodies. Abnormalities of the immune system compromise the normal function of blood vessels leading to a vasculopathy manifested by Raynaud's phenomenon, an early sign of systemic sclerosis. As a consequence of this reactive picture, the disease can evolve leading to tissue fibrosis. Several systemic sclerosis-specific autoantibodies are currently known and are associated with specific clinical manifestations and prognosis. Although the pathogenetic role of these autoantibodies is still unclear, their production by B cells and plasma cells suggests the importance of these cells in the development of systemic sclerosis. This review narratively examines B cell dysfunctions and their role in the pathogenesis of systemic sclerosis and discusses B cell-targeted therapies currently used or potentially useful for the management of end-organ complications.

Rheumatoid arthritis (RA) is associated with high-risk HLA class II alleles known as the "RA shared epitope." Among prevalent shared epitope alleles, study of DRB1*04:04 has been limited. To define relevant epitopes, we identified citrullinated peptide sequences from synovial antigens that were predicted to bind to HLA-DRB1*04:04 and utilized a systematic approach to confirm their binding and assess their recognition by CD4 T cells. After confirming the immunogenicity of 13 peptides derived from aggrecan, cartilage intermediate layer protein (CILP), α-enolase, vimentin, and fibrinogen, we assessed their recognition by T cells from a synovial tissue sample, observing measurable responses to 8 of the 13 peptides. We then implemented a multicolor tetramer panel to evaluate the frequency and phenotype of antigen-specific CD4 T cells in individuals with anti-citrullinated protein antibody (ACPA)-positive RA and controls. In subjects with RA, CILP-specific T cell frequencies were significantly higher than those of other antigens. The surface phenotypes exhibited by antigen-specific T cells were heterogeneous, but Th1-like and Th2-like cells predominated. Stratifying based on disease status and activity, antigen-specific T cells were more frequent and most strongly polarized in RA subjects with high disease activity. In total, these findings identify novel citrullinated epitopes that can be used to interrogate antigen-specific CD4 T cells and show that antigen-specific T cell frequency is elevated in subjects with high disease activity.

To evaluate neuropsychiatric manifestations in the pristane-induced lupus (PIL) model, as well as to evaluate immunoregulatory effects of vitamin D (vit-D) in the brain of mice with PIL. Eighty female BALB/c mice were divided into six groups with 90 (3 months) and 180 (6 months) days of experimentation: CO3, CO6 (controls), PIL3, PIL6 (pristane-induced lupus), VD3 and VD6 (PIL supplemented with 1,25-dihydroxyvitamin D). Forced-swim, elevated plus maze and Barnes maze were the behavioral tests performed. Expression of pVDR was assessed by immunofluorescence. Brain IgM and IgG deposits were evaluated by double staining fluorescence. Serum IL-6 and IFN-α1 were quantified by ELISA. AUC-ROC curve was also performed for immunoglobulins. PIL and VD showed depressive-like behavior in the forced-swim test and anxious-like behavior in the elevated plus maze test. PIL also presented cognitive and memory impairment in the Barnes maze test. Additionally, PIL and VD presented higher levels of serum IFN-α1, but not IL-6. Mice supplemented with vit-D had reduced IgM and IgG deposits and increased pVDR expression in the brain after 180 days. The AUC-ROC curve demonstrated high sensitivity and specificity for IgM and IgG in the brain. We observed neuropsychiatric manifestations in this model of systemic lupus erythematosus (SLE), strongly corroborating to PIL model being suitable as a neuropsychiatric lupus (NPSLE) model. Vit-D was able to reduce immunoglobulin deposits in the brain and influenced the levels of serum IL-6 in the animals assessed. Also, it improved memory, but it had no effect on depressive and anxious-like behavior.

Primary Sjogren's syndrome is a chronic inflammatory disease characterised by the destruction of exocrine glands. We have previously shown significantly upregulated levels of CXCL10 and CCL3 chemokines in saliva from Sjogren's syndrome patients. In this study, we examined the expression pattern and localisation of these chemokines at the site of inflammation in patients' minor salivary glands using novel RNAscope® in situ hybridisation. Minor salivary glands from 33 primary Sjogren's syndrome patients and 22 non-Sjogren's syndrome sicca controls were included. The biopsies were formalin- fixed, paraffin-embedded and histopathologically evaluated. The CXCL10 and CCL3 mRNA expression in the glandular tissue was investigated using reverse transcription quantitative real-time polymerase chain reaction followed by RNAscope® in situ hybridisation. The mRNA expression of CXCL10 was higher than CCL3 in all patients. Significantly elevated expression of CXCL10 and CCL3 was detected in patients that also expressed autoantibody positivity and a positive biopsy for mononuclear cell infiltrates when compared to controls. CXCL10 was localised as clusters within focal infiltrates as well as adjacent to acinar and ductal epithelium, while CCL3 was expressed as scattered single mRNA molecules in focal infiltrates and in acinar cells. Our findings suggest CXCL10 as a possible disease biomarker in primary Sjogren's syndrome due to its upregulated expression in both saliva and minor salivary glands of patients and the localisation in the tissue. This should be re-assessed in a larger primary Sjogren's syndrome patient cohort, followed by additional functional studies to further validate its potential as a disease biomarker.

Saliva, as a diagnostic medium, offers a promising alternative to blood by virtue of its non-invasive collection, which enhances patient compliance, especially in paediatric and geriatric populations. In this study, we assessed the utility of saliva as a non-invasive medium for measuring V. cholerae-specific serum antibodies in naturally infected individuals. We tested paired serum and saliva samples obtained from a total of 63 cholera patients enrolled in a cohort study. Vibriocidal antibodies assay (IgM/IgG) as markers for accurate determination was used to determine cholera specific antibody levels. Using receiver operating characteristics (ROC) curve, we found that the best cut-off that maximizes (sensitivity + specificity) is 10 titres. At this saliva titre, the sensitivity is 76.9% (95%CI: 60.9%, 87.7%) and specificity is 80.0% (95%CI: 56.6%, 92.5%). Using Spearman's correlation coefficient, we also found evidence of a positive correlation between Vibrio Cholerae saliva and serum antibodies (rho=0.66, p<0.001). In conclusion, saliva-based diagnostic cholera tests has high diagnostic accuracy, and would be advantageous, cheaper, and quicker for early diagnosis of severe cholera outcomes.

Coronary artery involvement (CAI) is a special but not rare manifestation of Takayasu arteritis (TAK). Granzyme B (GzmB) is a multifunctional protease associated with the immune system and coronary artery disease. However, its role in patients with TAK and CAI remains unclear. This study investigates the role of GzmB+ cell subsets in TAK. The study included 105 TAK patients and 58 healthy controls. The percentages of different GzmB+ cells in blood samples were analyzed by flow cytometry. We found that age, age at onset, BMI, disease duration month, hypertension, and hyperlipidemia were significantly different between TAK patients with and without CAI (P=0.000, P=0.038, P=0.003, P=0.031, P=0.039, P=0.000). The proportions of CD3+CD8+cells (P=0.001) and CD3+CD4+cells (P=0.000) in GzmB+ cells were significantly increased, while the proportion of CD3-CD56+cells (P=0.001) in GzmB+ cells was decreased in TAK patients. The proportions of three types of GzmB+ subsets in lymphocytes (CD3+CD4+GzmB+, CD3+CD8+GzmB+, CD3+CD56+ GzmB+) were higher in TAK patients with CAI compared to those without CAI (P=0.021, P=0.007, P=0.007). The increased proportion of CD3+CD8+GzmB+cells/lymphocytes was an independent risk factor for coronary involvement in TAK (OR=4.990 [1.766-14.098], P=0.002). Additionally, patients with a high CD3+CD8+GzmB+cells/lymphocytes ratio had a higher MACE rate than those with a low ratio in TAK (P=0.019). Our results indicate that CD8 cell-derived Gzm B may be a predictor for CAI and MACE in TAK patients. Targeting CD3+CD8+GzmB+ lymphocytes or using GzmB inhibitors could be a potential therapeutic approach for the treatment of CAI in TAK.

Granulomatosis with polyangiitis (GPA) is a B cell-mediated, relapsing, autoimmune disease. There is a need for novel therapeutic approaches and relapse markers to achieve durable remission. B cells express immune regulatory molecules that modulate their activation and maintain tolerance. While recent studies show dysregulation of these molecules in other autoimmune diseases, data on their expression in GPA are limited. This study aimed to map the expression of surface immune regulatory molecules on circulating B cell subsets in GPA and correlate their expression with clinical parameters. Immune regulatory molecule expression on circulating B cell subsets was comprehensively examined in active GPA (n=16), GPA in remission (n=16), and healthy controls (HCs, n=16) cross-sectionally using a 35-color B cell-specific spectral flow cytometry panel. Our supervised and unsupervised in-depth analysis revealed differential expression of inhibitory and stimulatory immune molecules on distinct B cell populations in GPA, with the most notable differences observed in active GPA. These differences include the upregulation of FcγRIIB on non-mature B cells, downregulation of CD21 and upregulation of CD86 on antigen-experienced B cells, and elevated CD22 expression on various populations. Additionally, we found a strong association between FcγRIIB, BTLA, and CD21 expression on specific B cell populations and disease activity in GPA. Together, these findings provide novel insights into the immune regulatory molecule expression profile of B cells in GPA, and could potentially form the foundation for new therapeutic approaches and disease monitoring markers.