Clinical Immunology

Compendium of synovial signatures identifies pathologic characteristics for predicting treatment response in rheumatoid arthritis patients Publication date: May 2019 Source: Clinical Immunology, Volume 202 Author(s): Ki-Jo Kim, Minseung Kim, Iannis E Adamopoulos, Ilias Tagkopoulos Abstract Rheumatoid arthritis (RA) is therapeutically challenging due to patient heterogeneity and variability. Herein we describe a novel integration of RA synovial genome-scale transcriptomic profiling of different patient cohorts that can be used to provide predictive insights on drug responses. A normalized compendium consisting of 256 RA synovial samples that cover an intersection of 11,769 genes from 11 datasets was build and compared with similar datasets derived from OA patients and healthy controls. Differentially expression genes (DEGs) that were identified in three independent methods were fed into functional network analysis, with subsequent grouping of the samples based on a non-negative matrix factorization method. RA-relevant pathway activation scores and four machine learning classification techniques supported the generation of a predictive model of patient treatment response. We identified 876 up-regulated DEGs including 24 known genetic risk factors and 8 drug targets. DEG-based subgrouping revealed 3 distinct RA patient clusters with distinct activity signatures for RA-relevant pathways. In the case of infliximab, we constructed a classifier of drug response that was highly accurate with an AUC/AUPR of 0.92/0.86. The most informative pathways in achieving this performance were the NFκB-, FcεRI- TCR-, and TNF signaling pathways. Similarly, the expression of the HMMR, PRPF4B, EVI2A, RAB27A, MALT1, SNX6, and IFIH1 genes contributed in predicting the patient outcome. Construction and analysis of normalized synovial transcriptomic compendia can provide useful insights for understanding RA-related pathway involvement and drug responses for individual patients.

Stratum corneum interleukin-33 expressions correlate with the degree of lichenification and pruritus in atopic dermatitis lesions Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Naomi Nakamura, Risa Tamagawa-Mineoka, Risa Yasuike, Koji Masuda, Hiroshi Matsunaka, Yumi Murakami, Emiko Yokosawa, Norito Katoh

Cell mediated immune responses elicited in volunteers following immunization with candidate live oral Salmonella entericaserovar Paratyphi A attenuated vaccine strain CVD 1902 Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Rezwanul Wahid, Karen L. Kotloff, Myron M. Levine, Marcelo B. Sztein Abstract The incidence of Salmonella enterica serovar Paratyphi A (PA) infection is on the rise and no licensed vaccines are available. We evaluated cell mediated immune (CMI) responses elicited in volunteers following immunization with a single dose (109 or 1010 cfu) of a novel attenuated live oral PA-vaccine strain (CVD 1902). Results showed increases in PA-lipopolysaccharide-specific IgG- and/or IgA B-memory cells and production of IFN-γ, TNF-α, IL-10, IL-23 and RANTES following stimulation with PA-antigens by peripheral blood mononuclear cells obtained 28 days post immunization. Flow cytometry assays revealed that vaccine elicited PA-specific CD8+ and/or CD4+ T effector/memory cells were predominantly multifunctional concomitantly expressing CD107a and/or producing IFN-γ, TNF-α and/or IL-2. Similar proportions of these MF cells expressed, or not, the gut homing marker integrin α4β7. The results suggest that immunization with CVD 1902 elicits CMI responses against PA supporting its further evaluation as a potential vaccine candidate against paratyphoid A fever.

Aberrant natural killer (NK) cell activation and dysfunction among ART-treated HIV-infected adults in an African cohort Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Rose Nabatanzi, Lois Bayigga, Stephen Cose, Sarah Rowland-Jones, Glenda Canderan, Moses Joloba, Damalie Nakanjako Abstract Background We examined NK cell phenotypes and functions after seven years of ART and undetectable viral loads (<50 copies/ml) with restored CD4 T-cell counts (≥500 cells/μl) and age-matched healthy-HIV-uninfected individuals from the same community. Methods Using flow-cytometry, NK cell phenotypes were described using lineage markers (CD56+/-CD16+/−). NK cell activation was determined by expression of activation receptors (NKG2D, NKp44 and NKp46) and activation marker CD69. NK cell function was determined by CD107a, granzyme-b, and IFN-gamma production. Results CD56 dim and CD56 bright NK cells were lower among ART-treated-HIV-infected than among age-matched-HIV-negative individuals; p = 0.0016 and p = 0.05 respectively. Production of CD107a (P = 0.004) and Granzyme-B (P = 0.005) was lower among ART-treated-HIV-infected relative to the healthy-HIV-uninfected individuals. NKG2D and NKp46 were lower, while CD69 expression was higher among ART-treated-HIV-infected than healthy-HIV-uninfected individuals. Conclusion NK cell activation and dysfunction persisted despite seven years of suppressive ART with "normalization" of peripheral CD4 counts.

Initial safety analysis of a randomized phase II trial of nelipepimut-S + GM-CSF and trastuzumab compared to trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): G. Travis Clifton, Kaitlin M. Peace, Jarrod P. Holmes, Timothy J. Vreeland, Diane F. Hale, Garth S. Herbert, Jennifer K. Litton, Rashmi K. Murthy, Jason Lukas, George E. Peoples, A. Mittendorf Elizabeth Abstract The development of HER2-targeted therapy has decreased recurrence rates and improved survival, transforming the natural history of HER2-positive breast cancer. However only a minority of breast cancer patients benefit as these agents are not used in patients with tumors expressing low levels of HER2. Preclinical data suggests a synergistic action of HER2-targeted vaccination with trastuzumab. We report the initial safety interim analysis of a phase II trial that enrolled patients with HER2 low-expressing (IHC 1+/2+) breast cancer who were clinically disease-free after standard therapy. Patients were randomized to receive the HER2-peptide vaccine nelipepimut-S + GM-CSF with trastuzumab (vaccine arm) or trastuzumab + GM-CSF (control arm) and were followed for recurrence. A planned analysis that occurred after enrollment of 150 patients showed no significant differences in toxicity between the two arms, including cardiac toxicity. The clinical efficacy of this combination will be reported 6 months after the final patient was enrolled.

Hydroxyfasudil alleviates demyelination through the inhibition of MOG antibody and microglia activation in cuprizone mouse model Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Jing Wang, Ruo-Xuan Sui, Qiang Miao, Qing Wang, Li-Juan Song, Jie-Zhong Yu, Yan-Hua Li, Bao-Guo Xiao, Cun-Gen Ma Abstract Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system characterized by oligodendrocyte loss and progressive neurodegeneration. The cuprizone (CPZ)-induced demyelination is widely used to investigate the demyelination/remyelination. Here, we explored the therapeutic effects of Hydroxyfasudil (HF), an active metabolite of Fasudil, in CPZ model. HF improved behavioral abnormality and reduced myelin damage in the corpus callosum. Splenic atrophy and myelin oligodendrocyte glycoprotein (MOG) antibody were observed in CPZ model, which were partially restored and obviously inhibited by HF, therefore reducing pathogenic binding of MOG antibody to oligodendrocytes. HF inhibited the percentages of CD4+IL-17+ T cells from splenocytes and infiltration of CD4+ T cells and CD68+ macrophages in the brain. HF also declined microglia-mediated neuroinflammation, and promoted the production of astrocyte-derived brain derived neurotrophic factor (BDNF) and regeneration of NG2+ oligodendrocyte precursor cells. These results provide potent evidence for the therapeutic effects of HF in CPZ-induced demyelination. Graphical abstract

Identification and mutational analysis of continuous, immunodominant epitopes of the major oyster allergen Crag 1 Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Lei Fang, Guoming Li, Jiangtao Zhang, Ruizeng Gu, Muyi Cai, Jun Lu Abstract Shellfish, including oysters, often cause allergic reactions in children and adults. Oysters are inevitably consumed because of its delicacy and nutritional benefit, leading to frequent occurrence of severe clinical symptoms observed in patients with oyster hypersensitivity. We aimed to identify the immunodominant epitopes of oyster tropomyosin and crucial amino acids for IgE binding, which will help us to further understand the immunochemical characteristics of Cra g 1. The potential epitopes were predicted by immunoinformatics tools and the resultant immunodominant epitopes were identified by inhibition ELISA with pooled sera and individual serum from oyster allergic patients. Surprisingly, homologous substitution of multiple amino acids led to obviously decrease affinity of IgE antibodies, but this manner did not abrogate binding completely. Five major linear epitopes were evenly distributed on the surface of homology-based Cra g 1 model and hydrophilic residues appeared to be the most important for IgE binding. These results not only offer a better understanding of the molecular mechanism of interaction between Cra g 1 and oyster-specific IgE but also have significance in clinical diagnosis and immunotherapy.

BCG-induced formation of neutrophil extracellular traps play an important role in bladder cancer treatment Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Kangkang Liu, Erlin Sun, Mingde Lei, Limin Li, Jingda Gao, Xuewu Nian, Lining Wang Abstract Bacillus Calmette-Guerin (BCG) is one of the most effective treatments for bladder cancer. Little attention has been paid to the possible role of neutrophils in BCG immunotherapy. In this study, we examined neutrophil extracellular traps (NETs) formation induced by BCG stimulation, and found that BCG-induced NETs exerted cytotoxicity, induced apoptosis and cell-cycle arrest, and inhibited migration in bladder tumor cells. BCG-activated tumor cells but not non-activated ones elicited NETs formation, in which IL-8 and TNF-α from activated tumor cells both took effect. Moreover, NETs activated peripheral blood mononuclear cells (PBMCs) exhibited a higher expression of CD4 and Th1 cytokines. Additionally, the role of NETs in vivo contributed to the recruitment of T cells and monocytes-macrophages and tissue damage, thus preventing tumor growth. NETs proteins mainly caused these effects on tumor and cellular immunity. In conclusion, we demonstrated a novel immunoregulatory role for NETs in the early stages of BCG immunotherapy.

Increased proportions of γδ T lymphocytes in atypical SCID associate with disease manifestations Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Inga Tometten, Kerstin Felgentreff, Manfred Hönig, Fabian Hauck, Michael H. Albert, Tim Niehues, Ruy Perez, Sujal Ghosh, Capucine Picard, Jan Stary, Renata Formankova, Austen Worth, Pere Soler-Palacín, Marina García-Prat, Luis M. Allende, Luis Ignacio Gonzalez-Granado, Polina Stepensky, Silvia Di Cesare, Alessia Scarselli, Caterina Cancrini Abstract Severe combined immunodeficiencies (SCID) comprise a group of genetic diseases characterized by abrogated development of T lymphocytes. In some case reports of atypical SCID patients elevated proportions of γδ T lymphocytes have been reported. However, it is unknown whether these γδ T cells modulate or reflect the patient's clinical phenotype. We investigated the frequency of elevated γδ T cell proportions and associations with clinical disease manifestations in a cohort of 76 atypical SCID patients. Increased proportions of γδ T lymphocytes were present in approximately 60% of these patients. Furthermore, we identified positive correlations between elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias. We discuss that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune cytopenias. We advocate that atypical SCID patients should be screened for elevated proportions of γδ T lymphocytes, CMV infection and autoimmune cytopenias.

Repository corticotropin injection reverses critical elements of the TLR9/B cell receptor activation response in human B cells in vitro Publication date: April 2019 Source: Clinical Immunology, Volume 201 Author(s): Nancy J. Olsen, Ann L. Benko, Carl A. McAloose, Patrice M. Becker, Dale Wright, Teresa Sunyer, Yuka Imamura Kawasawa, William J. Kovacs Abstract We sought evidence for direct effects of repository corticotropin (RCI; an FDA-approved treatment for selected cases of SLE) on isolated human B lymphocytes activated by engagement of TLR9 and B cell receptors. ODN 2395/αIgM treatment was found to result in induction of 162 distinct mRNAs and suppression of 80 mRNAs at 24 h. RCI treatment resulted in suppression of 14 of the ODN 2395/αIgM -induced mRNAs (mean suppression to 23.6 ± 3.1% of stimulated value). The RCI-suppressed mRNAs included two critical regulators of class switch recombination, AICDA and BATF. RCI treatment also resulted in induction of 5 of the ODN 2395/αIgM -suppressed mRNAs (mean induction by RCI = 7.65 ± 2.34-fold). The RCI-induced mRNAs included SLAMF3, a cell surface receptor capable of inhibiting autoantibody responses. These studies reveal that RCI treatment of human B cells reverses key elements of the early mRNA response to TLR9 and B cell receptor engagement.