Pregnancy-related immune suppression leads to altered influenza vaccine recall responses Publication date: November 2019 Source: Clinical Immunology, Volume 208 Author(s): Nishel M. Shah, Nesrina Imami, Peter Kelleher, Wendy S. Barclay, Mark R. Johnson Abstract Pregnancy is a risk factor for severe influenza infection. Despite achieving seroprotective antibody titres post immunisation fewer pregnant women experience a reduction in influenza-like illness compared to non-pregnant cohorts. This may be due to the effects that immune-modulation in pregnancy has on vaccine efficacy leading to a less favourable immunologic response. To understand this, we investigated the antigen-specific cellular responses and leukocyte phenotype in pregnant and non-pregnant women who achieved seroprotection post immunisation. We show that pregnancy is associated with better antigen-specific inflammatory (IFN-γ) responses and an expansion of central memory T cells (Tcm) post immunisation, but low-level pregnancy-related immune regulation (HLA-G, PIBF) and associated reduced B-cell antibody maintenance (TGF-β) suggest poor immunologic responses compared to the non-pregnant. Thus far, studies of influenza vaccine immunogenicity have focused on the induction of antibodies but understanding additional vaccine-related cellular responses is needed to fully appreciate how pregnancy impacts on vaccine effectiveness.

Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis Publication date: November 2019 Source: Clinical Immunology, Volume 208 Author(s): Maiko Takakura, Masaki Shimizu, Hitoshi Irabu, Naoto Sakumura, Natsumi Inoue, Mao Mizuta, Yasuo Nakagishi, Akihiro Yachie Abstract Our study aimed to compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Serum cytokine levels (neopterin, IL-18, and CXCL9 and soluble tumor necrosis factor receptor type I (sTNFR-I) and II) were determined by enzyme-linked immunosorbent assay in 78 patients with s-JIA, including 21 with MAS. Receiver operating characteristic curve analysis revealed area under the curve values and cut off values of neopterin, IL-18, CXCL9, sTNFR-II/I ratio and ferritin were 0.9465/19.5 nmol/l, 0.8895/69250 ng/ml, 0.9333/3130 pg/ml, 0.9395/3.796 and 0.8671/2560 ng/ml, respectively. Serum neopterin levels were significantly elevated in patients with MAS and those were correlated positively with disease activity. In conclusion, serum neopterin levels may be used as a promising indicator of disease activity in s-JIA and MAS and for evaluating it. It may also be a useful marker to diagnose the transition to MAS from active-phase s-JIA.

A comprehensive analysis of antigen-specific antibody responses against human cytomegalovirus in patients with systemic sclerosis Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Georgios Efthymiou, Efthymios Dardiotis, Christos Liaskos, Emmanouela Marou, Thomas Scheper, Wolfgang Meyer, Alexandros Daponte, Dimitrios Daoussis, Georgios Hadjigeorgiou, Dimitrios P. Bogdanos, Lazaros I. Sakkas Abstract Anti-human cytomegalovirus (HCMV) antibodies are considered triggers of systemic sclerosis (SSc), but such a hypothesis has been assessed in limited sub-dominant epitopes. Our aim was to systematically assess the potential association of HCMV antibodies targeting most immunodominant and subdominant viral antigens, as this would reveal immunopathogenic associations. Our study included 110 SSc patients, 60 multiple sclerosis (MS) patients, and 51 healthy controls (HC). Anti-HCMV abs were tested by immunoblotting. IgG anti-HCMV was broader in SSc and MS compared to HC. Anti- UL57 and UL55 were more frequent in SSc versus MS forms. Reactivity to multiple viral antigens was more frequent in SSc than MS forms. Anti-viral antibodies levels were higher in specific autoantibody-positive SSc patients compared to seronegative cases. In conclusion, more prevalent and/or stronger antigen-specific HCMV responses are noted in SSc compared to controls, implying a role of these viral responses in SSc development.

Variants at potential loci associated with Sjogren's syndrome in Koreans: A genetic association study Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Qingxia Shen, Kwanghwan Lee, Seong Kyu Han, Hyung-Joon Ahn, Sanguk Kim, Jae Hoon Lee Abstract Sjogren's syndrome (SS), a chronic autoimmune disease, typically causes or involves inflammation in the salivary and lacrimal glands. Although recent genetic association studies have contributed to the discovery of SS susceptible genes, few studies have reported on the Korean population. Here, we did a genetic association study of SS in Korean patients using whole-exome sequencing data of 15 patients and 100 healthy controls. In addition to confirming previously described SS susceptibility loci MSH5 (p = 1.67 × 10–5) and RELN (p = 4.91 × 10–6), we also validated PRAMEF13 (p = 2.28 × 10–5), TARBP1 (p = 1.87 × 10–5), UGT2B28 (p = 1.33 × 10–5), TRBV5-6 (p = 2.27 × 10–5) and NAPB (p = 3.73 × 10–5) as novel susceptibility loci for SS. Furthermore, we identified UGT2B28, TARBP1 and PRAMEF13 as associated with human immune function. These findings may provide useful insight into to the pathways and pathogenesis contributing to SS susceptibility in the Korean population.

Unbalanced expression of membrane-bound and soluble inducible costimulator and programmed cell death 1 in patients with myasthenia gravis Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Xiaoming Yan, Yanzheng Gu, Caiqin Wang, Simao Sun, Xiaozhu Wang, Jingluan Tian, Mingyuan Wang, Xiaopei Ji, Xiaoyu Duan, Hanqing Gao, Qi Fang, Wanli Dong, Xueguang Zhang, Qun Xue Abstract This study aimed to investigate the possible functions and mechanisms of positive and negative costimulatory molecules in the pathological process of myasthenia gravis (MG). The expression levels of membrane-bound inducible costimulator (ICOS) and programmed cell death 1 (PD-1) in peripheral blood T cells, their corresponding ligands ICOSL and PDL-1 on B cells, and their soluble forms (sICOS, sPD-1, sICOSL, and sPDL-1) in plasma were detected in patients with untreated-stage MG (USMG) and remission-stage MG (RSMG). The results showed that the expression levels of membrane-bound ICOS and PD-1 in the peripheral blood T cells of the USMG group and their corresponding ligands ICOSL and PD-L1 on B cells were significantly increased compared to those in the RSMG group and healthy controls (HCs). The levels of sICOSL and sPD-1 were significantly upregulated in USMG patients compared to those in the RSMG and HC groups, while the levels of sICOS and sPD-L1 were not different. The expression of PD-L1 on CD19+ B cells was positively correlated with the concentrations of AchR Ab in the USMG group. The expression of ICOS and PD-1 in CD4+ T cells and the expression of ICOSL and PD-L1 on CD19+ B cells were positively correlated with the quantitative myasthenia gravis (QMG) scores in the USMG group. Also, in the USMG group, the plasma levels of sICOSL and sPD-1 were positively correlated with the QMG scores. In addition, the percentage of peripheral blood follicular helper T (Tfh) cells in the USMG group was positively correlated with ICOS and PD-1 expression on CD4+ T cells and ICOSL and PD-L1 expression on CD19+ B cells. There were positive correlations between sICOSL and sPD-1 levels and the percentage of peripheral blood Tfh cells and plasma interleukin-21 (IL-21) levels in the USMG group. The results suggest that the positive ICOS/ICOSL and negative PD-1/PD-L1 costimulatory molecule pairs participate in the pathological process of MG. Abnormal sICOSL and sPD-1 expression might interfere with the normal signal transduction of ICOS and PD-1 on Tfh cells, causing excessive activation of Tfh cells and promotion of disease progression. sICOSL and sPD-1 have potential value in monitoring MG disease states.

Metabolic reprogramming in memory CD4 T cell responses of old adults Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Rolando E. Yanes, Huimin Zhang, Yi Shen, Cornelia M. Weyand, Jorg J. Goronzy Abstract To determine whether aging affects the ability of T cells to undergo metabolic reprogramming upon activation, we compared CD4 T cell responses after polyclonal in vitro stimulation. Compared to younger adults, CD4 memory T cells from healthy older individuals exhibited a higher upregulation of oxidative phosphorylation with increased production of reactive oxygen species and intracellular and secreted ATP. Increased ATP secretion led to increased purinergic signaling and P2X7-dependent increases in cytoplasmic calcium. The increased mitochondrial activity was not due to a difference in activation-induced mitochondrial biogenesis. Expression of carnitine palmitoyl transferase 1 was higher, conversely that of fatty acid synthase was reduced in older T cells, resulting in increased fatty acid oxidation, while depleting intracellular lipid stores. The aged CD4 memory T cells therefore maintain a more catabolic state in lipid metabolism, while their ability to upregulate glycolysis upon activation is preserved.

Engineered ovalbumin-expressing regulatory T cells protect against anaphylaxis in ovalbumin-sensitized mice Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Maha Abdeladhim, Ai-Hong Zhang, Laura E. Kropp, Alyssa R. Lindrose, Shivaprasad H. Venkatesha, Edward Mitre, David W. Scott Abstract Allergy is a major public health concern, the main treatment for which is symptomatic relief with anti-inflammatory drugs. A key clinical challenge is to induce specific tolerance in order to control allergen-specific memory B and T cells, and specifically block effector cell responses. Our lab recently developed antigen-specific regulatory T-cell (Treg) therapies as a treatment for adverse responses. Recently, we created a chimeric antigen receptor (CAR) approach in which we engineered a target protein antigen, ovalbumin (OVA), linked with the transmembrane and signal transduction domains, CD28-CD3ζ to directly target B cells and sensitized mast cells in an allergy model. We named this receptor “BAR” for B-cell Antibody Receptor. Murine or human Tregs, transduced with a BAR containing OVA or control Tregs expressing an unrelated antigen, were successfully expanded in vitro and tested in the murine OVA-alum allergy model with measurable titers of anti-OVA IgE. Because BAR Tregs express the target antigen and could interact with specific IgE on sensitized mast cells, we first demonstrated that intravenously injected OVA-BAR Tregs did not directly lead to a drop in temperature or release of mediators in plasma indicative of anaphylaxis. Forty-eight hours later, mice were challenged intraperitoneally with 200 μg OVA to induce an anaphylactic reaction, and temperature immediately measured for 30 min. We found that OVA-BAR Tregs protected mice from hypothermia, whereas mice given control BARs (expressing an unrelated antigen) or PBS showed substantial temperature drops indicative of anaphylaxis when systemically challenged with OVA. Importantly, this effect was also demonstrated in a passive anaphylaxis model in which mice that received anti-OVA IgE antibody were protected from hypothermia when treated with OVA-BAR Tregs prior to systemic OVA challenge. These results provide proof of principle that engineered allergen-specific T-regulatory cells can provide clinical protection against severe allergic reactions in individuals already IgE-sensitized to an allergen.

The protective effect of interfering TLR9-IRF5 signaling pathway on the development of CVB3-induced myocarditis Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Shu Nie, Boqi Dong, Shuang Gao, Yan Zhou, Wenting Lu, Mingli Fang, Shucheng Hua, Yongli Yu, Liying Wang Abstract Since toll-like receptor 9 (TLR9) or interferon regulatory factor 5 (IRF5) was reported to be associated with the development of myocarditis, we wondered if the TLR9-IRF5 pathway could contribute to the development of coxsackievirus B3 (CVB3)-induced myocarditis. We detected signaling molecules of TLR9-IRF5 pathway in CVB3-infected patients and mice. The results showed that TLR9, IRF5 and its downstream molecules such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly increased, and the increase was correlated with the severity of heart injury during CVB3 infection. In addition, we demonstrated that an AAAG ODN with IRF5 interfering activities significantly decreased the levels of the TLR9-IRF5 pathway molecules in hearts, spleens as well as white blood cells, and alleviated the myocarditis in CVB3-infected mice. The data suggest that interfering TLR9-IRF5 pathway could be an approach to treat CVB3-induced myocarditis.

Reactivation of BK virus after double umbilical cord blood transplantation in adults correlates with impaired reconstitution of CD4+ and CD8+ T effector memory cells and increase of T regulatory cells Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Theodoros Karantanos, Haesook T. Kim, Natalia M. Tijaro-Ovalle, Lequn Li, Corey Cutler, Joseph H. Antin, Karen Ballen, Francisco M. Marty, Chen Sabrina Tan, Jerome Ritz, Ioannis Politikos, Vassiliki Boussiotis Abstract BK virus (BKV), a human polyomavirus that remains latent in renal epithelial cells, can be reactivated after hematopoietic stem cell transplantation (HSCT) leading to hemorrhagic cystitis. The incidence of BK viremia is higher after Umbilical cord blood transplantation (UCBT) than HSCT from adult donors. Data regarding the role of immune recovery after UCBT in BKV reactivation is lacking. We examined the correlation between the development of BK viremia and immune reconstitution in 27 adult recipients of UCBT. The incidence of BK viremia was 52% and developed most frequently within the first 8 weeks after the transplantation, but persisted in seven patients at 6 months, and three patients at 1-year post UCBT. Detection of BK viremia 1 year after transplant was negatively associated with the number of CD8+ cells (p = 0.03) and CD8+CD45RO+ cells (p = 0.05) at 6 months, and the number of CD4+ (p = 0.03) and CD4+CD45RO+ cells (p = 0.03) at 12 months after UCBT. Conversely, BK viremia at 6 and 12 months was positively correlated with the number of T regulatory (Treg) cells at 1 month (p = 0.005 and p = 0.016, respectively). Because UCB Treg have highly potent immunosuppressive function, our findings indicate that sustained BK viremia in UCBT recipients might be associated with the increase of Treg cells early after transplantation, which mediate impaired and delayed reconstitution of CD4+ and CD8+ T effector cells.

Clinical manifestations and gastrointestinal pathology in 40 patients with autoimmune enteropathy Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Vincenzo Villanacci, Vassilios Lougaris, Alberto Ravelli, Elisabetta Buscarini, Tiziana Salviato, Paolo Lionetti, Marianna Salemme, Stefano Martelossi, Costantino De Giacomo, Diego Falchetti, Gloria Pelizzo, Gabrio Bassotti Abstract Autoimmune enteropathy (AIE) is a rare condition that may affect pediatric and adult patients, frequently associated with primary immunodeficiencies. We performed a retrospective study on clinical and histological findings from 40 AIE patients. Histological presentation showed a prevalent celiac disease pattern (50%), followed by the mixed pattern (35%), independently of age, chronic active duodenitis (10%), and GVHD-like pattern (5%). Patients with primary immunodeficiencies (24/40) presented mainly with the celiac disease pattern (72.2% versus 22.2%; p < .0001), while patients without primary immunodeficiencies presented with a mixed histological pattern (61.1% versus 13.6%; p < .0001). Our study shows that the prevalent histological presentation is the celiac disease-like pattern, independently of age, and, for the first time, that the histological presentation of AIE differs significantly between patients with and without primary immunodeficiencies. These findings may be helpful for more precise and timely diagnosis and management of this rare disorder.