A novel truncating mutation in MYD88 in a patient with BCG adenitis, neutropenia and delayed umbilical cord separation Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Craig D. Platt, Fatima Zaman, Jacqueline G. Wallace, Michael Seleman, Janet Chou, Nashat Al Sukaiti, Raif S. Geha Abstract Mutations in MYD88 cause susceptibility to invasive bacterial infections through impaired signaling downstream of toll-like receptors (TLRs) and IL-1 receptors. We studied a patient presenting with neutropenia, delayed umbilical cord separation, BCG adenitis, andP. aeruginosapneumonia. Next-generation DNA sequencing identified a novel homozygous truncation mutation in MYD88 that abolishes MyD88 expression. The patient's dermal fibroblasts had severely impaired IL-6 production after stimulation with ligands for the MyD88-dependent receptors TLR2, TLR4 and IL-1R, while responses to ligands for the MyD88-independent receptors TLR3 and TNF-α were preserved. Notably, secretion of TNF-α, which is essential for BCG control, was also impaired after LPS stimulation. In this first report of BCG infection in MyD88 deficiency, data suggest that MyD88-dependent TNF-α production contributes to control of mycobacterial disease.

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.

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.

Exome sequencing confirms diagnosis of kabuki syndrome in an-adult with hodgkin lymphoma and unusually severe multisystem phenotype Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Charu Kaiwar, Teresa M. Kruisselbrink, Yogish C. Kudva, Eric W. Klee, Pavel Pichurin Abstract We report a 34-year-old male patient with a novel variant in KMT2D gene, which finally ended a quest for a diagnosis that was clinically suspected in the past, prior the molecular basis of Kabuki Syndrome (KS) was known. The patient showcases the multisystemic features, with involvement of all previously associated with KS body systems, presence of immune deficiency as well as autoimmune disorders, requiring three pancreatic transplants. We also report, for the first time to our knowledge, the presence of epidural lipomatosis and Hodgkin Lymphoma in a patient with KS.

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.

Macrophage activation syndrome in neonates born to mothers with adult-onset Still's disease: Perinatal effect of maternal IL-18 Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Masaki Shimizu, Toshitaka Kizawa, Ryota Kato, Takayuki Suzuki, Akihiro Yachie Abstract Overproduction of interleukin (IL)-18 is closely related to the pathogenesis of adult-onset Still's disease (AOSD) and the development of macrophage activation syndrome (MAS), a life-threating complication of AOSD. We reported three cases of MAS occurring in infants born to mothers with AOSD. The infants developed MAS at age 13 and 8 days and at birth. Serum IL-18 levels were extremely elevated in all infants (147,000 pg/mL; 378,000 pg/mL; 95,000 pg/mL) as well as in their mothers (58,500 pg/mL; 367,000 pg/mL; 84,000 pg/mL). Physicians should be aware that infants born to mothers with AOSD are at a risk of developing MAS. Serum IL-18 levels in mothers with AOSD and their infants should be monitored.

iNKT cells and hematopoietic stem cell transplantation: Two-phase activation of iNKT cells may improve outcome Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Mohammad Fereidouni, Afshin Derakhshani, Mark A. Exley Abstract Invariant natural killer T cells (iNKT) produce large amounts of different cytokines which can influence differentiation, polarization and activation of immune cells, particularly NK and T cells. iNKT have been shown to suppress GvHD and promote anti-tumor and anti-pathogen immunity. There are highly specific and safe synthetic ligands such as alpha-galactosylceramide (α-GalCer) and C20:2 which activate iNKT cells toward relatively Th1 and Th2 pathways, respectively. Bone marrow transplantation (BMT) or ‘hematopoietic stem cell transplantation’ (HSCT) is effective for leukemia and lymphoma through ‘graft-versus-leukemia’ (GVL) immunity. However, frequent serious complications include graft-versus-host-disease (GVHD), opportunistic infections and relapse. Both GVHD and GVL are mediated by T cells. Manipulating iNKT by different lipid analogues in early and late phases after transplantation may suppress GVHD and graft rejection and enhance GVL effect, as well as resistance to opportunistic infections and so, could be a novel and effective strategy for improving HSCT outcome.