Neoantigen-activated haploidentical T cell therapy for angioimmunoblastic T-cell lymphoma Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Yuan Chen, Haimei Chen, Weiyue Gu, Guoyu Hu

Screening of tumor-associated antigens based on Oncomine database and evaluation of diagnostic value of autoantibodies in lung cancer Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Tingting Wang, Hongchun Liu, Lu Pei, Kaijuan Wang, Chunhua Song, Peng Wang, Hua Ye, Jianying Zhang, Zhenyu Ji, Songyun Ouyang, Liping Dai Abstract Objectives The purpose of this study is to discover novel tumor-associated antigens (TAAs) to improve the diagnosis of lung cancer (LC). Materials and methods Oncomine database was used to discover potential TAAs from LC tissues, enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of autoantibodies against TAAs in two independent sets (identification set, n = 368; validation set, n = 1011). Results Analyses of sera from identification set showed that the sensitivity of autoantibodies against five TAAs (HMGB3, ZWINT, GREM1, NUSAP1 and MMP12) reached 57.1%, 42.4%, 38.0%, 36.4% and 20.7%, with area under ROC curve (AUC) of 0.85, 0.75, 0.71, 0.73 and 0.70, respectively. It also validated the diagnostic performances of these autoantibodies with AUC of 0.72, 0.65, 0.61, 0.64 and 0.64, respectively. Autoantibody against HMGB3 exhibited significantly increased frequency in early LC (53.3%) compared to advanced LC (29.3%) (P < .05). The positive rates of autoantibody against HMGB3 and NUSAP1 in serum of LC patients without distant metastasis were significantly higher than that of distant metastatic LC (P < .05). When each of the three protein biomarkers (CEA, CA125 and CYFRA21-1) was combined with anti-HMGB3 autoantibody, the sensitivity of early LC increased to 72.7%, 63.3% and 75.9% from 36.4%, 13.3% and 27.6%, respectively. Conclusion Autoantibodies against 5 TAAs (HMGB3, ZWINT, GREM1, NUSAP1 and MMP12) might have favorable diagnostic values in LC detection, and autoantibody against HMGB3 has the potential to serve as a serological biomarker in early-stage LC. The combination of protein biomarkers and anti-HMGB3 might contribute to detection of early-stage LC.

A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Georgios Sogkas, Ignatius R. Adriawan, Felix C. Ringshausen, Ulrich Baumann, Claudia Schröder, Christian Klemann, Sandra von Hardenberg, Gunnar Schmidt, Auber Bernd, Alexandra Jablonka, Diana Ernst, Reinhold E. Schmidt, Faranaz Atschekzei Abstract Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.

An update on genetic susceptibility in lupus nephritis Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Kangkang Song, Lu Liu, Xuejun Zhang, Xiangmei Chen Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multiple system involvement and positive serum autoantibodies. Lupus nephritis (LN) is the most common and serious complication of SLE, and it is the main cause of death in patients with SLE. Abnormalities in the immune system lead to LN and involve a variety of cells (T cells, B cells, macrophages, NK cells, etc.), cytokines (interleukin, tumor necrosis factor α, etc.) and their related pathways. Previous studies have shown that the interactions of genetic, epigenetic and environmental factors contribute to the pathogenesis and development of LN. In recent years, one genome-wide association study (GWAS) and a number of gene association studies have explored the susceptibility genes of LN, including immunization-, inflammation-, adhesion- and other pathway-related genes. These genes participate in or suggest the pathogenesis and progression of LN. In this review, we summarize the genetic susceptibility of LN and discuss the possible mechanism underlying the susceptibility genes of LN.

Sepsis roadmap: What we know, what we learned, and where we are going Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Vijay Kumar Abstract Sepsis is a life-threatening condition originating as a result of systemic blood infection causing, one or more organ damage due to the dysregulation of the immune response. In 2017, the world health organization (WHO) declared sepsis as a disease of global health priority, needing special attention due to its high prevalence and mortality around the world. Most of the therapeutics targeting sepsis have failed in the clinics. The present review highlights the history of the sepsis, its immunopathogenesis, and lessons learned after the failure of previously used immune-based therapies. The subsequent section, where to go describes in details the importance of the complement system (CS), autophagy, inflammasomes, and microbiota along with their targeting to manage sepsis. These systems are interconnected to each other, thus targeting one may affect the other. We are in an urgent need for a multi-targeting therapeutic approach for sepsis. Graphical abstract

Prognostic role of circulating neutrophil extracellular traps levels for long-term mortality in new end-stage renal disease patients Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Jwa-Kyung Kim, Hoi Woul Lee, Narae Joo, Hyung Seok Lee, Young Rim Song, Hyung Jik Kim, Sung Gyun Kim Abstract Dysregulation of innate immunity has been proposed as an important contributing factor for advanced atherosclerosis and resultant high mortality in hemodialysis (HD) patients. To evaluate the long-term prognostic role of in vivo neutrophil extracellular traps (NETs), we measured circulating serum nucleosome, myeloperoxidase (MPO), and DNase I levels in 281 incident HD patients. Circulating nucleosome level was significantly higher in HD patients compared to controls, and it was closely associated with MPO levels, suggesting increased in vivo NETs in uremia. Patients in the nucleosome Q4 group had significantly increased all-cause and adverse CV mortality compared to those in the Q1–3 group even after adjusting traditional risk factors Also, serum DNase I level was significantly higher in HD patients than controls (2.76 ± 1.02 ng/ml and 1.93 ± 0.85 ng/ml), but it had no correlation with NETs. Interestingly, it serves an additive biomarker for predicting poor CV outcomes. The two novel biomarkers might provide an importance independent prognostic significance in incident HD patients.

Antagonistic role of IL-1ß and NLRP3/IL-18 genetics in chronic HIV-1 infection Publication date: December 2019 Source: Clinical Immunology, Volume 209 Author(s): Edione C. Reis, Vinicius N.C. Leal, Lais T. da Silva, Marilia M.L. dos Reis, Enrique R. Argañaraz, Telma M. Oshiro, Alessandra Pontillo Abstract Host genetics affects both susceptibility and progression of HIV-1 infection. NLRP3 inflammasome provides a first-line defense in viral infections, and, accordingly, gain-of-function variants in NLRP3 have been associated with protection against HIV-1. Despite antiretroviral treatment (ART), HIV-infected patients continue to present systemic inflammation with a heterogeneous prognosis. As NLRP3 inflammasome is involved in several chronic diseases by amplifying “sterile” inflammation, its role in chronic phase of HIV infection has been postulated. Little is known about inflammasome genetics in HIV-infected patients and whether it may play a role in the different clinical outcomes. Therefore, we questioned whether NLRP3 inflammasome genetics could affect the clinical course of HIV-1 infection as it does in host/virus interaction. For this purpose, we analyzed selected single nucleotide polymorphisms (SNPs) in ART-treated HIV-infected patients (n = 300), in Long Term Non-Progressors/Elite Controllers and progressors (n = 133), and in HIV-infected individuals submitted to dendritic cell (DC)-based immunotherapy (n = 19). SNPs leading to increased activation of NLRP3 inflammasome are beneficial for patients, while SNPs that negatively affect NLRP3 activation or IL-18 production, detrimental. In contrast, gain-of-function variant in IL1B is also detrimental for patients, suggesting that while IL-1ß possible contributes to immune exhaustion, the axis NLRP3-inflammasome/IL-18 could act positively in chronic infection. Functional assays supported genetic results: NLRP3 variants associated with good quality HIV+ DC, and IL1B -511C > T with a poor one. Loss-of-function SNPs affect HIV+ T cells proliferation. These findings proposed for the first time that NLRP3 inflammasome, mainly through IL-18, play a protective role in chronic HIV infection.

Independent association of low IFNλ1 gene expression and type I IFN score/IFNλ1 ratio with obstetric manifestations and triple antiphospholipid antibody positivity in primary antiphospholipid syndrome Publication date: December 2019 Source: Clinical Immunology, Volume 209 Author(s): Christina-Maria Flessa, Stelios Vlachiotis, Adrianos Nezos, Evangelos Andreakos, Clio P. Mavragani, Maria G. Tektonidou Abstract Recent data suggest an important role of type I interferons (IFN) in antiphospholipid syndrome (APS). Here we aimed to evaluate the interplay of type I and type III (or IFNλs) IFNs in APS and potential clinical and serological associations. Our findings suggest that patients with primary APS (PAPS) and systemic lupus erythematosus (SLE)/APS displayed increased type I IFN scores but decreased IFNλ1 gene expression levels compared to healthy individuals, as assessed with real-time qPCR analysis in isolated peripheral blood mononuclear cells (PBMCs). Type I IFN score/IFNλ1 ratio was remarkably higher in patients with PAPS and SLE/APS as well as in SLE patients with or without antiphospholipid antibodies (aPL) vs controls. In conclusion, our results reveal an association between low IFNλ1 expression and obstetric APS. Moreover, the type I IFN score/IFNλ1 ratio seems to be a potential marker of high risk APS given its associations with triple aPL positivity.

A novel tool for clinical diagnosis of allergy operating a microfluidic immunoaffinity basophil activation test technique Publication date: December 2019 Source: Clinical Immunology, Volume 209 Author(s): Zenib Aljadi, Frida Kalm, Caroline Nilsson, Ola Winqvist, Aman Russom, Joachim Lundahl, Anna Nopp Abstract The Basophil Activation Test (BAT) is a valuable allergy diagnostic tool but is time-consuming and requires skilled personnel and cumbersome processing, which has limited its clinical use. We therefore investigated if a microfluidic immunoaffinity BAT (miBAT) technique can be a reliable diagnostic method. Blood was collected from allergic patients and healthy controls. Basophils were challenged with negative control, positive control (anti-FcεRI), and two concentrations of a relevant and non-relevant allergen. CD203c and CD63 expression was detected by fluorescent microscopy and flow cytometry. In basophils from allergic patients the CD63% was significantly higher after allergen activation as compared to the negative control (p<.0001–p=.0004). Activation with non-relevant allergen showed equivalent CD63% expression as the negative control. Further, the miBAT data were comparable to flow cytometry. Our results demonstrate the capacity of the miBAT technology to measure different degrees of basophil allergen activation by quantifying the CD63% expression on captured basophils.

Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine Publication date: December 2019 Source: Clinical Immunology, Volume 209 Author(s): Antonio Gonzalez-Lopez, Jaap Oostendorp, Thomas Koernicke, Tommaso Fadini, Ugo D'Oro, Sherryl Baker, Derek T. O’Hagan, Giuseppe Del Giudice, Emilio Siena, Oretta Finco, Duccio Medini Abstract An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 μg). All vaccines were well tolerated, apart from in the TLR7a 100 μg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56–81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 μg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.