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.

Autosomal recessive agammaglobulinemic patient with a novel large deletion in IGHM presenting with mild clinical phenotype Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Ercan Nain, Ozge Ulgen, Ayca Kiykim, Elif Karakoc Aydiner, Ahmet Ozen, Safa Baris

IL-38 is a biomarker for acute respiratory distress syndrome in humans and down-regulates Th17 differentiation in vivo Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Yu-sen Chai, Shi-hui Lin, Mu Zhang, Liangyong Deng, Yanqing Chen, Ke Xie, Chuan-jiang Wang, Fang Xu

JNK and phosphorylated Bcl-2 predict multiple sclerosis clinical activity and glatiramer acetate therapeutic response Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Freidrich Anselmo, Alexandru Tatomir, Dallas Boodhoo, Armugam P. Mekala, Vinh Nguyen, Violeta Rus, Horea Rus Abstract In this study, we investigated the role of JNK and phospho-Bcl-2 as possible biomarkers of multiple sclerosis (MS) relapse and of glatiramer acetate (GA) therapeutic response in relapsing-remitting MS patients. We enrolled a cohort of 15 GA-treated patients and measured the expression of JNK1, JNK2, phospho-JNK and phospho-Bcl-2 through Western blotting of lysates from peripheral blood mononuclear cells collected at 0, 3, 6, and 12 months after initiating GA therapy. We found significantly higher levels of JNK1 p54 and JNK2 p54 and significantly lower levels of p-Bcl-2 in relapse patients and in GA non-responders. By using receiver operating characteristic analysis, we found that the probability of accurately detecting relapse and response to GA was: 92% and 75.5%, respectively, for JNK1 p54 and 86% and 94.6%, respectively, for p-Bcl-2. Our data suggest that JNK1 and p-Bcl-2 could serve as potential biomarkers for MS relapse and the therapeutic response to GA. Graphical abstract

Clinicopathological characteristics of dysplastic teratomous neuroglia with anti-N-methyl-d-aspartate receptor encephalitis Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Yangyang Xiao, Jian Li, Lingjuan Liu, Jie Xiong, Jie Xu, Qingchun Liang, Xiaoling She, Hong Tan, Yong Ma, Ding’an Mao, Liqun Liu Abstract In this study, we investigated whether unique pathological characteristics exist in teratomas that can trigger autoimmune anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. We compared a case of retroperitoneal teratoma associated with anti-NMDAR encephalitis and four control cases. The encephalitis-positive case showed that (i) more dysplastic neuroglia with higher Ki-67 labeling index values than the control cases, which met the diagnostic criteria of astrocytoma, (ii) the NMDAR subunit NR1 was expressed more abundantly in neuroglial tissue where many neuroglial cells co-expressed glial fibrillary acidic protein (GFAP) and NR1 and formed abnormally large cellular masses, (iii) intense NR1 expression occurs in squamous epithelium near neuroglial tissue and lymphocyte infiltration. This study showed that dysplastic neuroglial tissue resembling central nervous system tumors, which might promote autoimmunity, distinguished the case with NMDAR encephalitis from the controls. Additionally, abnormal expression of NR1 occurs in non-neural tissues and could be triggered by inflammation and participate in autoimmunity.

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.

Elevated levels of circulating invariant natural killer cell subsets are skewed toward Th2-like phenotype in children with sickle cell disease Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Mohamed-Rachid Boulassel, Abeer Al-Zubaidi, Shoaib Al-Zadjali, Zahra Al-Qarni, Nidaa Al-Naamany, Ahmed Al-Yarabi, Mohamed Elshinawy, Yasser Wali Abstract Invariant natural killer T (iNKT) cells are being considered as potential targets for immunotherapeutic strategies in a variety of conditions including sickle cell disease (SCD). However, relatively little is known about the fate of iNKT cell subsets in children with SCD. Herein, quantitative and qualitative analyses of circulating iNKT cell subsets were carried out in 120 children in steady state and 30 healthy controls. Children with SCD displayed significantly elevated levels of circulating iNKT cell subsets with a preferential polarization toward Th2-like cells. The known SCD modifiers did not influence levels of iNKT cell subsets, except that children carrying the Bantu haplotype exhibited elevated levels of CD4iNKT cells, and to a lesser degree CD8iNKT cells. Collectively, these findings indicate that circulating iNKT cell subsets are significantly increased in children with SCD, and highlight the existence of imbalanced production of cytokines toward Th2-like phenotype, which seems to be associated with genetic polymorphisms.

NFKB2 regulates human Tfh and Tfr pool formation and germinal center potential Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Pasqualina De Leo, Luisa Gazzurelli, Manuela Baronio, Davide Montin, Silvia Di Cesare, Carmen Giancotta, Francesco Licciardi, Caterina Cancrini, Alessandro Aiuti, Alessandro Plebani, Maria Pia Cicalese, Vassilios Lougaris, Georgia Fousteri Abstract Mutations affecting the non-canonical pathway of NF-κB were recently identified to underlie a form of common variable immunodeficiency strongly associated with autoimmunity. Although intrinsic B-cell abnormalities explain most of the humoral defects of this disease, detailed data on the impact of NFKB2 on follicular helper (Tfh) and regulatory (Tregs) T cells are scarce. Here, we show that Tfh, CXCR5+, and CXCR5− Treg cell subsets were significantly reduced in patients heterozygous for a truncating mutation of NFKB2. Plasma CXCL13 levels were reduced, underlining an important role for NFKB2 in regulating the germinal center (GC) response. Proinflammatory IFNγ, IL-17 and IL-10 cytokine production by CD4 T cells was lower in the mutated patients, but the production of IL-4 and IL-21 was not altered. Taken together, our findings show that NFKB2 influences the quality and efficiency of human GC reaction, by affecting not only the B cells but also GC-relevant T cell subsets. Graphical abstract

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.

Recombinant human granulocyte macrophage-colony stimulating factor expressed in yeast (sargramostim): A potential ally to combat serious infections Publication date: January 2020 Source: Clinical Immunology, Volume 210 Author(s): Giovanni Damiani, Thomas S. McCormick, Luis O. Leal, Mahmoud A. Ghannoum Abstract Granulocyte-macrophage-colony stimulating factor (GM-CSF), can direct the activation, proliferation and differentiation of myeloid-derived cells. It is also responsible for maturation and function of professional antigen presenting cells thereby impacting adaptive immune responses, while assisting to maintain epithelial barrier function. GM-CSF in combination with other endogenous cytokines and secondary stimuli, such as tumor necrosis factor can modulate pro-inflammatory monocyte priming via chromatin remodeling and enhanced transcriptional responses, a concept termed “trained immunity”. An increase in the incidence of opportunistic fungal infections was recently reported in patients with hematological cancers receiving treatment with the BTK inhibitor, Ibrutinib. Tec Kinase BTK is known to influence the expression of GM-CSFRα and regulates downstream signaling pathways, suggesting a role for GM-CSF in maintenance of defense against fungal infections in immune competent hosts. Further examination of the potential mechanism(s) of action for naturally occurring GM-CSF and recombinant human GM-CSF (rhu-GM-CSF) expressed in yeast (sargramostim) are reviewed.