www.elsevier.com/locate/yclim ISSN 1521-6616 Volume 250S, May 2023 Selected Abstracts from the 2023 Clinical Immunology Society Annual Meeting: Immune Deficiency and Dysregulation North American Conference May 18–21, 2023 St. Louis, Missouri, USA
Volume 250S, 2023 Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St. Louis Volume 250S, 2023 Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St. Louis Volume 250S, 2023 Selected Abstracts from the 2023 Clinical Immunology Society Annual Meeting: Immune Deficiency and Dysregulation North American Conference May 18–21, 2023 St. Louis, Missouri, USA Publication of this supplement was funded by the Clinical Immunology Society. All content was reviewed and approved by the Program Committee, which held full responsibility for the abstract selections.
Editor-in-Chief George Tsokos Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts 02115 Associate Editors J.S. Chou, Boston, Massachusetts, USA Jose C. Crispin, Ciudad de México, Mexico Mark Exley, Manchester, UK Samia Khoury, Boston, Massachusetts, USA Antonio La Cava, Los Angeles, California, USA Lan-juan Li, Zhejiang, China Qianjin Lu, Changsha, China Abhigyan A. Satyam, Boston, Massachusetts, USA Amr Hakim Sawalha, Pittsburgh, Pennsylvania, USA Becky M. Vonakis, Baltimore, Maryland, USA Xuan Zhang, Beijing, China Editorial Board Iannis E. Adamopoulos Tatiana Akimova David Avigan Dan H. Barouch Jenna Bergerson Elke Bergmann-Leitner George Bertsias Rhea Bhargava Perluigi Bigazzi Patrick Blanco Afroditi Boulougoura Samuele E. Burastero Roberto Caricchio Javier Chinen Daniela Cihakova Dennis Comte Guo-Min Deng Hongyan Diao Wassim Elyaman Lionel Filion Sherry Fleming Shu Man Fu Andrew Gennery Christian Hedrich Matthias von Herrath Mitsuomi Hirashima Rodrigo Hoyos Erin Janssen Hirohito Kita Tomohiro Koga Antonio Kolios Michihito Kono Vasileios Kyttaris Hao Li Stamatis Liossis Mindy Lo Vassilios Lougaris Xiao-Jie Lu Tanya Mayadas Masayuki Mizui Kamal Moudgil Kari Nadeau Haitao Niu Eric Oliver Jordan Orange Mohamed Oukka Andras Perl Shiv Pillai Antony Psarras Thomas Rauen Sergio Rosenzweig Florencia Rosetti Amir Sharabi Nan Shen Lisa A. Spencer Isaac Ely Stillman Elena Svirshchevskaya Yoshiya Tanaka Klaus Tenbrock Betty Tsao George Tsokos Tonya J. Webb Henry Wong Shinsuke Yasuda Nobuya Yoshida Takeshi Yoshida Chack-Yung Yu
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Abstracted/indexed in: Biological Abstracts, Chemical Abstracts, Current Contents/Life Sciences, Excerpta Medica, MEDLINE®, PubMed, and SIIC Databases. Also covered in the abstract and citation database Scopus®. Full text available on ScienceDirect®. CONTENTS Available online at www.sciencedirect.com Volume 250, May 2023 Review Pancreatic sympathetic innervation disturbance in type 1 diabetes Senlin Li, Huimin Yuan, Keshan Yang, Qing Li and Ming Xiang 109319 Regular Articles PPAR inhibits small airway remodeling through mediating the polarization homeostasis of alveolar macrophages in COPD Sirong He, Ruoyuan Tian, Xinying Zhang, Qingmei Yao, Quan Chen, Bicui Liu, Lele Liao, Yuxuan Gong, Hua Yang and Dan Wang 109293 STING contributes to traumainduced heterotopic ossification through NLRP3-dependent macrophage pyroptosis Ziyang Sun, Hang Liu, Yuehao Hu, Gang Luo, Zhengqiang Yuan, Bing Tu, Hongjiang Ruan, Juehong Li and Cunyi Fan 109300 Aberrant promoter methylation of Wnt inhibitory factor-1 gene is a potential target for treating psoriasis Liu Liu, Yaqiong Zhou, Dan Luo, Xiaoying Sun, Hongjin Li, Yi Lu, Jiao Wang, Miao Zhang, Naixuan Lin, Chengqian Yin and Xin Li 109294 Myelin basic protein and index for neuro-Behçet's disease Haoting Zhan, Linlin Cheng, Xiaoou Wang, Haiqiang Jin, Yongmei Liu, Haolong Li, Dandan Liu, Xinyao Zhang, Wenjie Zheng, Hongjun Hao and Yongzhe Li 109286 PReS-endorsed international childhood lupus T2T task force definition of childhood lupus low disease activity state (cLLDAS) E.M.D. Smith, A. Aggarwal, J. Ainsworth, E. Al-Abadi, T. Avcin, L. Bortey, J. Burnham, C. Ciurtin, C.M. Hedrich, S. Kamphuis, L. Lambert, D.M. Levy, L. Lewandowski, N. Maxwell, E. Morand, S. Ozen, C.E. Pain, A. Ravelli, C. Saad Magalhaes, C. Pilkington, D. Schonenberg-Meinema, C. Scott, K. Tullus and M.W. Beresford on behalf of the International cSLE T2T Task Force 109296 Baricitinib for the treatment of refractory vascular Behçet's disease Zhimian Wang, Xiaoou Wang, Weiwei Liu, Yuhua Wang, Jinjing Liu, Li Zhang, Shangzhu Zhang, Xinping Tian, Yan Zhao and Wenjie Zheng 109298 κ (continued on inside back cover) Selected Abstracts from the 2023 Clinical Immunology Society Annual Meeting: Immune Deficiency and Dysregulation North American Conference May 18-21, 2023 St. Louis, Missouri, USA Late-Breaking Abstracts Oral Presentation Abstracts Poster Presentation Abstracts Abstracted/indexed in: Biological Abstracts, Chemical Abstracts, Current Contents/Life Sciences, Excerpta Medica, MEDLINE®, PubMed, and SIIC Databases. Also covered in the abstract and citation database Scopus®. Full text available on ScienceDirect®. CONTENTS Available online at www.sciencedirect.com Volume 250, May 2023 Review Pancreatic sympathetic innervation disturbance in type 1 diabetes Senlin Li, Huimin Yuan, Keshan Yang, Qing Li and Ming Xiang 109319 Regular Articles PPAR inhibits small airway remodeling through mediating the polarization homeostasis of alveolar macrophages in COPD Sirong He, Ruoyuan Tian, Xinying Zhang, Qingmei Yao, Quan Chen, Bicui Liu, Lele Liao, Yuxuan Gong, Hua Yang and Dan Wang 109293 STING contributes to traumainduced heterotopic ossification through NLRP3-dependent macrophage pyroptosis Ziyang Sun, Hang Liu, Yuehao Hu, Gang Luo, Zhengqiang Yuan, Bing Tu, Hongjiang Ruan, Juehong Li and Cunyi Fan 109300 Aberrant promoter methylation of Wnt inhibitory factor-1 gene is a potential target for treating psoriasis Liu Liu, Yaqiong Zhou, Dan Luo, Xiaoying Sun, Hongjin Li, Yi Lu, Jiao Wang, Miao Zhang, Naixuan Lin, Chengqian Yin and Xin Li 109294 Myelin basic protein and index for neuro-Behçet's disease Haoting Zhan, Linlin Cheng, Xiaoou Wang, Haiqiang Jin, Yongmei Liu, Haolong Li, Dandan Liu, Xinyao Zhang, Wenjie Zheng, Hongjun Hao and Yongzhe Li 109286 PReS-endorsed international childhood lupus T2T task force definition of childhood lupus low disease activity state (cLLDAS) E.M.D. Smith, A. Aggarwal, J. Ainsworth, E. Al-Abadi, T. Avcin, L. Bortey, J. Burnham, C. Ciurtin, C.M. Hedrich, S. Kamphuis, L. Lambert, D.M. Levy, L. Lewandowski, N. Maxwell, E. Morand, S. Ozen, C.E. Pain, A. Ravelli, C. Saad Magalhaes, C. Pilkington, D. Schonenberg-Meinema, C. Scott, K. Tullus and M.W. Beresford on behalf of the International cSLE T2T Task Force 109296 Baricitinib for the treatment of refractory vascular Behçet's disease Zhimian Wang, Xiaoou Wang, Weiwei Liu, Yuhua Wang, Jinjing Liu, Li Zhang, Shangzhu Zhang, Xinping Tian, Yan Zhao and Wenjie Zheng 109298 κ (continued on inside back cover) Volume 250S, May 2023 Note: The names of the main authors are underlined. When a main author is not also presenting author, the name of the presenting author is followed by an asterisk.
Late-Breaking Abstracts (1) Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency Zhiyong Liu1, Eduardo Garcia Reino2, Hongyan Guo3, Oliver Harschnitz4, Yi-Hao Chan5, Shuxiang Zhao6, Darawan Rinchai7, Jean-Laurent Casanova8, Shen-Ying Zhang9 1Postdoctoral Associate/The Rockefeller University 2PhD student/The Rockefeller University 3Assistant Professor/6. Louisiana State University Health Sciences Center at Shreveport 4Assistant Professor/Human Technopole 5Postdoctoral Fellow/The Rockefeller University 6Research Assistant/The Rockefeller University 7Research Associate/The Rockefeller University 8Professor Head of Laboratory/Rockefeller University, Imagine Institute for Genetic Diseases, University of Paris Cité, Howard Hughes Medical Institute 9Associate Professor of Clinical Investigation/The Rockefeller University Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who is compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impair cellular apoptosis and necroptosis upon TLR3, TLR4 or TNFR1 stimulation, and ZBP1/DAImediated necroptotic cell death following HSV-1 infection. The patient’s fibroblasts display no detectable RIPK3 expression. Following TNFR1 or TLR3 stimulation, the patient’s cells do not undergo apoptosis or necroptosis. Following HSV-1 infection, the cells support excessive viral growth despite normal induction of antiviral IFN-β and interferonstimulated genes (ISGs). This phenotype is, nevertheless, rescued by the application of exogenous type I IFN. The patient’s human pluripotent stem cell (hPSC)-derived cortical neurons display impaired cell death and enhanced viral growth following HSV-1 infection, as do isogenic RIPK3knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE, by impairing the cell deathdependent control of HSV-1 in cortical neurons independently of type I IFN immunity. Keywords: Herpes simplex encephalitis, RIPK3, HSV-1, Cell death, Necroptosis, Apoptosis Disclosures: The authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109348 https://doi.org/10.1016/j.clim.2023.109348 (2) Results of a Phase 3 Trial of an Oral CXCR4 Antagonist, Mavorixafor, for Treatment of Patients With WHIM Syndrome Raffaele Badolato1, Jean Donadieu2, 4WHIM Study Group3 1Professor of Pediatrics at the University of Brescia/Department of Clinical and Experimental Sciences, University of Brescia & ASST Spedali Civili, Brescia, Italy 2Pediatrician, Hemato Oncologist and Epidemiologist/CHU Paris Est - Hôpital d’Enfants Armand-Trousseau, France 3n/a/n/a Background: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency presenting with leukopenia and infections, predominately caused by gainof-function variants in CXCR4. Mavorixafor, an investigational oral CXCR4 antagonist, demonstrated promising efficacy and safety profiles in a phase 2 trial for participants with WHIM syndrome. Objective: To report results of the randomized, double-blind, multicenter, placebo-controlled period of a phase 3 study evaluating the efficacy and safety of mavorixafor in participants with WHIM syndrome (NCT03995108). Methods: Participants aged ≥12 years with clinical diagnosis of WHIM syndrome, confirmed CXCR4 variant, and absolute neutrophil count (ANC) or total white blood cell (WBC) count ≤400 cells/µL at screening were eligible. Participants were randomized 1:1 to receive mavorixafor (>50 kg, 400 mg once daily [QD]; ≤50 kg, 200 mg QD) or placebo for 52 weeks. The primary endpoint was time above threshold ANC (TAT-ANC). Figure 1 shows study design and select secondary endpoints. Results: Overall, 31 participants were randomized (mavorixafor, n = 14; placebo, n = 17) and received ≥1 dose of treatment (intent-to-treat population). The primary endpoint, mean TAT-ANC, was 15.04 (mavorixafor-group) vs 2.75 hours (placebo-group; P < .0001). Additionally, mean TAT absolute lymphocyte count (TAT-ALC) was 15.80 (mavorixafor-group) vs 4.55 hours (placebo-group; P < .0001). Mean absolute WBC count, ANC, and ALC increased from baseline into normal range and sustained at each timepoint assessed over 52 weeks with mavorixafor versus placebo. Compared with placebo-group, mavorixafor-group showed 60% lower annualized infection rate (least squares [LS] mean: mavorixafor, 1.7; placebo, 4.2; nominal P = .0072), and 40% lower total infection score, a combination of infection number and severity (LS mean [95% CI]: mavorixafor, 7.41 [1.64–13.19]; placebo, 12.27 [7.24–17.30]). Greater reduction in infection duration and type and antibiotic use was observed with mavorixafor versus placebo. No discontinuations occurred due to adverse events (AEs). No treatmentrelated serious AEs or treatment-limiting toxicities were observed (Table 1). Clinical Immunology 250S (2023) Abstracts CIS 2023 Contents lists available at ScienceDirect Clinical Immunology journal homepage: https://www.elsevier.com/locate/yclim 1521-6616/© 2023 Elsevier Inc. All rights reserved. 1
Figure 1. Study design for randomized, double-blind, multicenter, placebo-controlled period of a phase 3 study evaluating the efficacy and safety of mavorixafor in participants with WHIM syndrome (NCT03995108). ALC, absolute lymphocyte count; ANC, absolute neutrophil count; QD, daily; TAT, time above threshold; WBC, white blood cell. aAdults and adolescents (aged 12–17 years) weighing >50 kg received 400 mg mavorixafor QD; adolescents aged 12–17 years weighing ≤50 kg received 200 mg QD bTAT ANC(primary endpoint) defined as time (in hours) above threshold ANC≥500cells/ μL over a 24-hour period, assessed every 3 months for 52 weeks. cSecondary endpoints were analyzed per a hierarchical approach prespecified in the study protocol; not all key and other secondary endpoints included in the hierarchical sequence are shown or listed in the order of the sequence. dTAT ALC (first key secondary endpoint) defined as time (in hours) above threshold ALC ≥1000 cells/µL over a 24-hour period, assessed every 3 months for 52 weeks. eTotal infection score is based on number and severity of infections adjudicated by a blinded, independent adjudication committee. Table 1. Overall summary of AEs from the randomized, placebo-controlled period Participants, n (%)a–d Mavorixafor (n=14) Placebo (n=17) Total (n=31) Any TEAEe 14 (100.0) 17 (100.0) 31 (100.0) Treatment-related TEAEe 7 (50.0) 3 (17.6) 10 (32.3) Any SAE 5 (35.7) 2 (11.8) 7 (22.6) Treatment-related SAE 0 (0) 0 (0) 0 (0) TEAE leading to treatment discontinuatione,f 0 (0) 0 (0) 0 (0) Treatment-limiting toxicity 0 (0) 0 (0) 0 (0) AE, adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event. Data cutoff November 11, 2022. aSafety was evaluated in the safety population, defined as all participants who received ≥1 dose of study medication (either mavorixafor or placebo). Participants were analyzed according to the treatment they actually received. bPercentages were based on the number of participants in each analysis group. cAll AEs were coded using Medical Dictionary for Regulatory Activities Version 25.0. dIf a participant had≥2 AEs, the participant is counted only once in a category for the n. The same participant may appear in different categories. eTEAEs were defined as any AEs that begin or worsen on or after the start of study drug through 10 days after the last dose of study drug. fOne participant had a TEAE that emerged during the randomized, placebo-controlled period but leading to treatment discontinuation after entering the open-label period. Conclusions: Primary and first key secondary endpoints were met. Mavorixafor-group showed significantly higher mean TAT-ANC and TATALC and greater reduction in infection frequency, severity, and duration versus placebo-group. Mavorixafor was generally well tolerated over the 52-week treatment period. About 87% of eligible participants enrolled in the open-label extension. Keywords: WHIM syndrome, Combined immunodeficiency, CXCR4 antagonist, Mavorixafor, Phase 3 clinical trial, Neutropenia, Lymphopenia Disclosures: Raffaele Badolato: I have relevant financial relationships with proprietary interests: Angelini (Consultant); Janssen (Consultant); X4 Pharmaceuticals Inc. (Consultant). The other authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109349 https://doi.org/10.1016/j.clim.2023.109349 (3) Newborn screening has improved the survival of infants with severe combined immunodeficiency (SCID) –a Primary Immune Deficiency Treatment Consortium (PIDTC) study Monica Thakar1, Brent R. Logan2, Jennifer Puck3, Elizabeth Dunn4, Rebecca Buckley5, Morton Cowan6, Sung-Yun Pai7, Jennifer Heimall8, Michael Pulsipher9, Linda Griffith10, Elie Haddad11, Christopher C. Dvorak12, Luigi Notarangelo13, PIDTC Contributing Investigators14 1Associate Professor/Fred Hutch Cancer Center 2Director and Professor/Division of Biostatistics, Medical College of Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee, WI 3Professor, Division of Pediatric Allergy, Immunology, and Blood and Marrow Transplantation/University of California San Francisco 4PIDTC Strategic Advisor, Division of Pediatric Allergy, Immunology & Blood & Marrow Transplantation/University of California San Francisco 5Professor Emeritus of Pediatrics, Division of Allergy and Immunology/ Department of Pediatrics, Duke University 6Professor/University of California San Francisco 7Chief Immune Deficiency Cellular Therapy Program, Senior Investigator/ Center for Cancer Research, National Cancer Institute 8Associate Professor/Department of Pediatrics, University of Pennsylvania, Division of Allergy and Immunology, Children’s Hospital of Philadelphia 9Full Professor, Chief, Division of Hematology & Oncology/Pediatric Immunology and Blood and Marrow Transplant Program, University of Utah, Intermountain Primary Children’s Hospital 10Employee/Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases 11Professor of Pediatrics, Head, Pediatric Immunology and Rheumatology Division/Department of Pediatrics and Department of Microbiology, Immunology and Infectious Diseases, University of Montreal, Montreal, Quebec, Canada; CHU Sainte-Justine, Montreal, Quebec, Canada 12Professor and Chief Division of Pediatric Allergy, Immunology, & Bone Marrow Transplant/Division of Pediatric Allergy, Immunology, and Blood and Marrow Transplantation, University of California San Francisco; UCSF Benioff Children’s Hospital San Francisco, CA 13Chief of Laboratory of Clinical Immunology and Microbiology/NIAID, NIH 14collaborative consortium/PIDTC Background: Prospective/retrospective protocols of the PIDTC have collected detailed data from children undergoing allogeneic hematopoietic cell transplantation (HCT) for SCID at 33 North American centers since 1982. We previously reported that from 1982 to 2009, overall survival (OS) after HCT was unchanged. Newborn screening (NBS) for SCID, initiated in 2010, was hypothesized to improve SCID OS following HCT. Methods: Children born and receiving HCT during 4 time intervals (1982– 89; 1990–99; 2000–09; and 2010–18) were analyzed for categorial variables (chi-square test), continuous outcomes (Kruskal-Wallis test), and OS (Kaplan-Meier method). Results: 902 children with typical (n = 747) and atypical (n = 155) SCID were included. Unlike years 1982–2009 when 5-year OS after HCT was stagnant (72–73%), improvement was seen for the first time beginning in 2010, when 5-year OS increased to 87% (p < 0.001). To determine what contributed to Abstracts / Clinical Immunology 250S (2023) 2
this finding, multiple factors were evaluated to identify differences between children transplanted between 2010–18 compared to prior time intervals. Significant differences (all p < 0.001) were found in the trigger for diagnosis being NBS or family history as opposed to clinical illness, age at HCT, active infection at HCT, and transplant characteristics including conditioning intensity, stem cell source, and donor source. On multivariable analysis, which excluded matched sibling donors due to their consistently high rates of OS (≥92%) in all time intervals, active infection (HR 2.41, 95% CI 1.53–3.72; p < 0.001), age ≥3.5 months at HCT (HR 2.21, 95% CI 1.38–3.24; p = 0.001), certain genotypes (ADA, DCLRE1C/LIG4/NHEJ, and other rare genotypes) (HR 2.22–3.67, 95% CI 1.23–7.45; p < 0.001), and Black/African American race (HR 2.33, 95% CI 1.56–3.54; p < 0.001) were associated with lower survival rates. A subgroup multivariable analysis examining the effect of trigger for diagnosis in the era of NBS, adjusting for genotype and race, confirmed that improved OS with NBS was related to earlier age and fewer infections at time of HCT. Conclusion: This study confirmed for the first time the direct benefit of population-based SCID NBS in improving OS after HCT. Our findings support adoption of SCID NBS worldwide, but also point out that persistent racial disparities in survival despite universal availability of screening must be addressed. Keywords: Newborn screening, Severe combined immunodeficiency, Hematopoietic cell transplantation Disclosures: Monica Thakar: I have relevant financial relationships with proprietary interests: Infectious Disease Research Institute (Consultant); Proteios Technology, Inc. (Advisory Board). Jennifer Puck: I have relevant financial relationships with proprietary interests: UpToDate (Royalties). Morton Cowan: I have relevant financial relationships with proprietary interests: Homology Medicines, Inc. (Scientific Advisory Board); Up-toDate (Royalties). Jennifer Heimall: I have relevant financial relationships with proprietary interests: ADMA (Grants/Research Support Recipient); CSL Behring (Grants/Research Support Recipient, Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); Enzyvant (Grants/Research Support Recipient, Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); Regeneron (Grants/Research Support Recipient); Wolters Kluwer (UpToDate) (Royalties). Michael Pulsipher: I have relevant financial relationships with proprietary interests: Adaptive (Clinical Trial Investigator); Equillium (Advisory Board); Medexus (Advisory Board); Mesoblast (Advisory Board); Miltenyi Biotech (Clinical Trial Investigator, Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); Novartis (Advisory Board, Speaker/Honoraria (includes speakers bureau, symposia, and expert witness). Elie Haddad: I have relevant financial relationships with proprietary interests: CSLBehring (Advisory Board); Jasper Therapeutics (Consulting Fees (e.g., advisory boards); Leadiant Biosciences (Consulting Fees (e.g., advisory boards); Octapharma (Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); Takeda (Speaker/Honoraria (includes speakers bureau, symposia, and expert witness). Christopher C. Dvorak: I have relevant financial relationships with proprietary interests: Orchard Therapeutics (Consultant). The other authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109350 https://doi.org/10.1016/j.clim.2023.109350 (4) AIOLOS haploinsufficiency is associated with immunodeficiency, autoimmunity, and allergy Hyesun Kuehn1, Inga Sakovich2, Julie Nemela3, Agustin Gil Silva4, Jennifer Stoddard4, Ekaterina Polyakova5, Ana Esteve-Sole6, Svetlana Aleshkevich7, Jolan Walter8, Luigi Notarangelo9, Thomas Fleisher10, Xiao Peng11, Ottavia Delmonte12, Svetlana Sharapova5, Sergio Rosenzweig13 1Senior Associate Scientist/NIH/CC/DLM 2Reseacher/Belarussian Centre for Pediatric Oncology, Hematology and Immunology 3Research Biologist/NIH/CC 4Research Scientist/NIH/CC 5Leading researcher/Belarusian Research Center for Pediatric Oncology, Hematology and Immunology 6Postdoctoral fellow/Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA 7Physician/Belarusian Research Center for Pediatric Oncology, Hematology and Immunology 8Associate Professor/Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, FL, USA and Division of Allergy and Immunology, Massachusetts General Hospital for Children, Boston, MA, USA 9Chief of Laboratory of Clinical Immunology and Microbiology/NIAID, NIH 10Executive Vice President/American Academy of Allergy, Asthma and Immunology 11Director, Inborn Errors of Blood and Immunity Clinic/Johns Hopkins University SOM Department of Genetic Medicine 12Assistant Research Physician, Staff Clinician/National Institute of Allergy and Infectious Diseases, National Institutes of Health 13Chief, Immunology Service/NIH/CC, Bethesda, USA AIOLOS is a transcription factor of the IKAROS family, that is highly expressed in the lymphoid lineage and plays an important role in lymphocyte differentiation and development. Recently, two heterozygous AIOLOS germline mutations (G159R and N160S) were reported in primary immunodeficiency patients. Both variants associated distinctive and unique T and B cell differentiation defects, hematologic malignancies, and infectious disease susceptibility patterns through different dominant negative (DN) mechanisms. Here we report seven individuals from three unrelated families carrying AIOLOS variants Q402* (nonsense,1 family) and E82K (missense, 2 families), leading to AIOLOS haploinsufficiency through different mechanisms of action. Clinically, patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent respiratory tract infections, and immune dysregulation manifested by autoimmunity and allergy, with incomplete clinical penetrance. Mechanistically, while the nonsense mutant Q402* is devoid of its C-terminal zinc-finger (ZF) dimerization domain (ZF5-6), it is still able to homodimerize with wildtype (WT) AIOLOS although unable to heterodimerize with WT IKAROS or HELIOS. We introduce new insights into AIOLOS biology as we found that AIOLOS ZF1, a part of AIOLOS DNA binding domain (ZF1-4), was associated with noncanonical dimerization and negative regulation of DNA binding. Further studies revealed that the mutant Q402* displayed abnormalities of DNA binding, pericentromeric targeting, post-transcriptional modification, and transcriptome regulation by haploinsufficiency. In contrast, mutant E82K showed overall normal AIOLOS functions; however, by affecting a newly defined AIOLOS protein stability domain, it also led to AIOLOS haploinsufficiency. Unlike the previously reported AIOLOS mutations, heterozygous variants Q402* and E82K do not have a DN effect over other IKAROS family proteins. Our data extend the spectrum of pathogenic variants of AIOLOS-associated diseases and provide a novel mechanism of homodimerization and protein stability that, when disrupted, could affect human health. Abstracts / Clinical Immunology 250S (2023) 3
Keywords: AIOLOS haploinsufficiency, Immunodeficiency, Autoimmunity Disclosures: Jolan Walter: I have relevant financial relationships with proprietary interests: ADMA Biologics (Advisory Board, Consultant, Grants/ Research Support Recipient); Chiesi (Grants/Research Support Recipient); CSL Behring (Advisory Board, Consultant, Consulting Fees (e.g., advisory boards); Enzyvant (Advisory Board, Consultant); Grifols (Advisory Board, Consultant); Janssen (Grants/Research Support Recipient); MustangBio (Grants/Research Support Recipient); Octapharma (Grants/Research Support Recipient); Regeneron (Advisory Board, Consultant); Takeda group (Advisory Board, Consultant, Grants/Research Support Recipient, Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); X4-Pharmaceuticals (Advisory Board, Consultant). The other authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109351 https://doi.org/10.1016/j.clim.2023.109351 (5) Muller morphs redefined by a multimorphic IRF4 variant presenting as CID with PCP susceptibility IRF4 International Consortium1, Anselm Enders2, Sven Kracker3, Ruben Martinez Barricarte4, Stephan Mathas5, Sergio Rosenzweig6, Klaus Schwarz7, Stuart Turvey8, Ji-Yang Wang9 1-/- 2Associate Professor/Australian National University, Canberra, ACT, Australia 3Professor/Université Paris Cité, Imagine Institute 4Assistant Professor/Vanderbilt University Medical Center, Nashville, TN, USA 5Professor/Charité–Universitätsmedizin Berlin, Germany 6Chief, Immunology Service/NIH/CC, Bethesda, USA 7Professor/University of Ulm, Germany 8Canada Research Chair and Professor/UBC 9Professor/Fudan University, Shanghai, China In their last review, the IUIS reported 40 inborn errors of immunity (IEI) leading to combined immunodeficiency (CID). Yet, the genetic cause of CID in a sizeable percentage of patients remains unknown. We describe seven patients with CID from four continents with similar clinical presentations characterized by severe viral and recurrent respiratory infections, notably by Pneumocystis jirovecii. Two of the patients also suffered from mycobacterial disease. All these seven patients carry the heterozygous mutation T95R in the DNA binding domain of the interferon regulatory factor 4 (IRF4). Leveraging state-of-the-art transcriptomic, molecular, computational, and gene editing technologies, we discovered that IRF4T95R does not fit into any single category of the Muller morphs but in three of them simultaneously. In fact, we showed that IRF4-T95R causes a unique combination of (i) gain-of-function by binding DNA with higher affinity than IRF4-WT; (ii) loss-of-function since IRF4-T95R fails to induce canonical IRF4 regulated genes, and; (iii) neomorphic functions by inducing the transcription of genes that IRF4-WT does not. These alterations in the transcriptional programming caused by the mutation lead to cellular and humoral immunological abnormalities. Patients’ Bcells displayed impaired maturation, defective plasma cell differentiation, and isotype switching, all which resulted in agammaglobulinemia. Their T cells, despite proliferating normally, showed a decreased production of proinflammatory cytokines and a reduced capacity to differentiate into TH17 and TFH. Two different knock-in mouse models recapitulated the patients’ phenotypes. Overall, our data show that autosomal dominant IRF4-T95R is a new genetic cause of CID and defines a novel multimorphic molecular mechanism of a disease characterized by gain, loss, and new functions of IRF4. Keywords: Combined Immunodeficiency, PCP, IRF4, Infection, T95R, Multimorphic Disclosures: The authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109352 https://doi.org/10.1016/j.clim.2023.109352 (6) Dominant interfering CARD11 variants disrupt JNK signaling in T cells and impaired CARD11-JNK signaling increases expression of GATA3 Bradly Bauman1, Andrew Frank2, Gauthaman Sukumar3, Nermina Saucier4, Clifton Dalgard5, Alice Chan6, Joshua Milner7, Megan Cooper8, Andrew Snow9 1PhD Candidate/Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences 2Bioinformatics Scientist/Uniformed Services University of the Health Sciences 3Senior Research Associate/Henry M. Jackson Foundation for the Advancement of Military Medicine 4Research Assistant/Washington University School of Medicine 5Professor/Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences 6Associate Professor/Divisions of Pediatric AIBMT and Rheumatology, University of California, San Francisco 7Attending physician/Columbia University Irving Medical Center 8Professor of Pediatrics/Washington University St. Louis 9Professor/Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences CARD11 is a critical scaffold protein linking antigen receptor (AgR) engagement to transcriptional programs required for effector lymphocyte survival, proliferation, and differentiation. Prior work established that CARD11 mediates these effects by enabling AgR-induced signaling through NF-kB, mTORC1 and c-Jun N-terminal kinase 2 (JNK2). Although JNK influences helper CD4+ T cell differentiation, mechanisms governing JNK signal regulation and function in human lymphocytes remain incompletely understood. We therefore asked if/how dominant interfering (DI) CARD11 variants impact JNK signaling and JNK-specific transcriptomic changes in T cells. Wild-type (WT) and CARD11 knockout (KO) Jurkat T cells were transfected with plasmids expressing WT or DI CARD11 variants to assess effects on CARD11-dependent JNK signaling. Additionally, RNA sequencing was performed on mitogen-activated WT and CARD11 KO Jurkat T cells +/− JNK inhibition. Our results revealed that CARD11 is required for AgRdependent activation of JNK1 and JNK2. Furthermore, heterozygous DI CARD11 mutations found in patients with CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS) disease disrupted AgRdependent JNK1/2 phosphorylation, c-Jun accumulation, and AP-1 transcriptional activity with variable potency, similar to the degree of impaired NF-kB activation. Intriguingly, JNK inhibition in Jurkat and primary CD4+ T cells enhanced AgR-induced expression of GATA3, the master transcriptional regulator of Th2 cell differentiation. These results were recapitulated in effector T cells generated from CADINS patient PBMC, with greater GATA3 induction observed after mitogen activation relative to healthy controls. Abstracts / Clinical Immunology 250S (2023) 4
Intriguingly, simultaneous reactivation of JNK signaling through a CARD11independent mechanism blunted AgR-induced GATA3 induction, suggesting JNK activity can directly modulate GATA3 expression. In summation, our novel findings imply that defective CARD11-dependent JNK signaling in CD4+ T cells contributes to enhanced Th2 differentiation and the atopic diathesis observed in CADINS patients, unveiling a new potential therapeutic target for ameliorating severe allergic disease manifestations. Keywords: CARD11, CADINS, JNK, NF-kB, AP-1, T cells Disclosures: Megan Cooper: I have relevant financial relationships with proprietary interests: Pharming (Consultant); Sobi (Consultant). The other authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109353 https://doi.org/10.1016/j.clim.2023.109353 Abstracts / Clinical Immunology 250S (2023) 5
Oral Presentation Abstracts (7) Severe Leukocyte Adhesion Deficiency-I (LAD-I) Lentiviral-Mediated Ex-Vivo Gene Therapy: Ongoing Phase 1/2 Study Results Claire Booth1, Julian Sevilla2, Maria Chitty Lopez3, Elena Almarza4, Josune Zubicaray2, Kritika Chetty5, Theodore Moore6, Juan Bueren7, Jonathan Schwartz8, Donald Kohn9 1Professor of Gene Therapy and Paediatric Immunology/UCL Great Ormond Street Institute of Child Health, London, UK 2Hematology/Oncology/Fundación para la investigación Biomédica, Hospital Infantil Universitario Niño Jesús (HIUNJ) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII), Madrid, Spain 3Medical Director of LAD-I Program/Rocket Pharmaceuticals, Inc., Cranbury, NJ 4Principal Scientist and Director, Process Development LVV/Rocket Pharmaceuticals, Inc., Cranbury, NJ 5Senior Clinical Research Fellow/UCL Great Ormond Street Institute of Child Health, London, UK 6Chief of Pediatric Hematology/Oncology and Director of Pediatric Blood and Marrow Transplant Prgm./University of California, Los Angeles, CA 7Head of the Hematopoietic Innovative Therapies Division/Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERERISCIII), Madrid, Spain 8Chief Medical Officer/Rocket Pharmaceuticals, Inc., Cranbury, NJ 9Prof. MIMG, Pediatrics and Molecular & Medical Pharmacology/Director UCLA Gene and Cell Therapy/University of California, Los Angeles, CA Background: Severe leukocyte adhesion deficiency-I (LAD-I) is an autosomal recessive inborn error of immunity due to mutations in the ITGB2 gene that encodes the common CD18 subunit of β2-integrins, essential for neutrophil adhesion to the inflamed endothelium and transmigration into tissues. Severe LAD-I, defined as <2% of normal CD18 polymorphonucleocyte [PMN] expression, is characterized by frequent and often refractory bacterial and fungal infections, impaired wound healing, and significant pediatric mortality in the absence of allogeneic hematopoietic stem cell transplant (HSCT). HSCT is potentially curative but limited by donor availability, graft-versus-host disease, and graft failure. The gene therapy RP-L201-0318 (NCT03812263) employs autologous CD34+ cells transduced with a lentiviral vector carrying ITGB2 to restore CD18 expression. Methods: Patients ≥3 months old with severe LAD-I were enrolled. Hematopoietic stem cells (HSCs) were collected via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor and transduced ex-vivo with Chim-CD18-WPRE-LV. Myeloablative therapeutic drug monitoring (TDM) busulfan conditioning preceded RP-L201 infusion. Patients were followed for safety and efficacy measures, including survival to age two and≥1-year post-infusion, peripheral blood [PB] PMN CD18 expression, PB vector copy number [VCN], neutrophilia improvement, decrease in infections/hospitalizations, and resolution of skin/periodontal abnormalities. Results: Nine patients (age five months to nine years) received RP-L201; follow-up was 3 to 24 months. RP-L201 cell doses ranged from 2.8 × 106 to 10 × 106 CD34+ cells/kg with a drug product VCN of 1.8 to 3.8. All nine patients demonstrated PMN CD18 restoration (median expression of 56.3%) with sustained, stable genetic markings (median PB mononuclear cell VCN of 1.53). At one year, the overall survival (OS) rate was 100% per KaplanMeier estimate. Pre-treatment leukocytosis improved uniformly. Hospitalizations and severe infections were significantly reduced following therapy. No RP-L201-related serious adverse events (SAEs) were reported. Insertion site analyses indicate highly polyclonal integration patterns across the entire cohort. Conclusion: RP-L201 has a favorable safety profile and confers durable correction of the severe LAD-I phenotype with improved clinical course in all nine pediatric patients treated as demonstrated via all laboratory and clinical parameters. Keywords: Gene Therapy, Primary Immundodeficiencies, Leukocyte Adhesion Deficiency-I Disclosures: Claire Booth: I have relevant financial relationships with proprietary interests: GSK (Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); Orchard (Consultant, Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); Rocket Pharmaceuticals, Inc. (Consultant); SOBI (Consultant, Speaker/Honoraria (includes speakers bureau, symposia, and expert witness); Takeda (Speaker/Honoraria (includes speakers bureau, symposia, and expert witness). Julian Sevilla: I have relevant financial relationships with proprietary interests: Rocket Pharmaceuticals, Inc. (Consultant, Royalties). Maria Chitty Lopez: I have relevant financial relationships with proprietary interests: Rocket Pharmaceuticals, Inc. (Employee). Elena Almarza: I have relevant financial relationships with proprietary interests: Rocket Pharmaceuticals, Inc. (Employee). Josune Zubicaray: I have relevant financial relationships with proprietary interests: Novartis (Consultant). Juan Bueren: I have relevant financial relationships with proprietary interests: Rocket Pharmaceuticals, Inc. (Consultant, Grants/Research Support Recipient). Jonathan Schwartz: I have relevant financial relationships with proprietary interests: Rocket Pharmaceuticals, Inc. (Employee, Owner/Co-Owner Founder/Co-Founder). Donald Kohn: I have relevant financial relationships with proprietary interests: Allogene Therapeutics (Scientific Advisory Board); ImmunoVec (Scientific Advisory Board); MyoGeneBio (Scientific Advisory Board); Pluto Therapeutics (Scientific Advisory Board). The other authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109354 https://doi.org/10.1016/j.clim.2023.109354 Clinical Immunology 250S (2023) Abstracts CIS 2023 Contents lists available at ScienceDirect Clinical Immunology journal homepage: https://www.elsevier.com/locate/yclim 1521-6616/© 2023 All rights reserved.
(8) Use of single cell DNA sequencing to characterize somatic mosaicism in a patient with two signal transduction and activator of transcription 1 (STAT1) gain-of-function variants Craig Platt1, Tina Banzon2, Sandra Burchett3, Wehrman Andrew4, Pui Lee5 1Assistant Professor/Division of Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 2Instructor/Boston Childrens Hospital 3Associate Professor/Boston Children’s Hospital 4Instructor/Boston Children’s Hospital 5Assistant Professor/Boston Childrens Hospital There is increasing recognition that immune defects caused by somatic mosaicism are often clinically indistinguishable from classical germline inborn errors of immunity. Here we demonstrate the utility of single cell DNA sequencing in defining the cellular genotypes and specific cellular populations involved in the pathogenesis of immune dysregulation in a patient with two novel STAT1 variants and a clinical presentation consistent with STAT1 gain-of-function. A 5-month-old male presented with Pneumocystis jiroveci pneumonia, CMV viremia, and immune-mediated hepatitis. Lymphocyte subset analysis was not consistent with a combined immunodeficiency. Sequencing of genomic DNA using targeted panel of 407 inborn error of immunity genes revealed two heterozygous variants in the coiled-coil region of STAT1 (c.496_504del, p.Leu166_Asp168del; c.489_497del, p. Glu164_Leu166del). Functional analysis was consistent with STAT1 gain-offunction–patient peripheral blood mononuclear cells displayed increased IFN-alpha and IFN-beta-mediated STAT1 phosphorylation, and increased expression of downstream IFN-stimulated genes including IFI44, ISG15, and Ly6E. Further examination of the patient’s STAT1 sequencing data revealed that the two in-frame deletion variants were present on distinct alleles, and surprisingly, that a WT allele was also detected. Based on the presence of three distinct alleles, somatic mosaicism was suspected. Parental testing failed to detect either variant, suggesting that the variants were de novo. Sequencing of DNA extracted from a buccal swab of the patient revealed only wild type STAT1 sequence. Single cell DNA sequencing analysis demonstrated that the two in-frame deletions comprised three different genotypes –a compound heterozygous population comprising 9% of leukocytes, a heterozygous p. Leu166_Asp168del/wild type population comprising of 82% of leukocytes, and a WT population comprising 9% of leukocytes. This analysis additionally revealed that all three genotypes were uniformly distributed among both myeloid and lymphoid populations. Functional analysis of the two in-frame deletions demonstrated that both promote increased STAT1 activity. That both STAT1 variants occur at nearly identical locations, and the uniform distribution among leukocytes, suggests a still undefined genetic event occurring prior to the divergence of common myeloid and lymphoid progenitor cells in hematopoietic stem cell ontogeny. This case demonstrates the power of single cell DNA sequencing in precisely defining disease pathogenesis in patients with somatic mosaicism. Keywords: STAT1 gain-of-function, Somatic mosaicism, Single cell DNA sequencing Disclosures: Craig Platt: I have relevant financial relationships with proprietary interests: LogicBio (Consultant); Qiagen (Advisory Board); Quest Diagnostics (Employee); X-4 Pharmaceuticals (Consultant). Wehrman Andrew: I have relevant financial relationships with proprietary interests: Albireo (Clinical Trial Investigator). The other authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109355 https://doi.org/10.1016/j.clim.2023.109355 (9) CDC45 haploinsufficiency as a novel cause of natural killer cell deficiency Nicole C. Guilz1, Matilde I Conte1, S. Andrea Salinas2, Ivan K. Chinn2, James R. Lupski2, Emily M Mace1 1Department of Pediatrics, Columbia University Irving Medical Center 2Department of Pediatrics, Baylor College of Medicine Natural killer cell deficiency (NKD) is a primary immunodeficiency where natural killer cells are the primary lineage affected. Individuals with NKD present with malignancies and susceptibility to viral infection, especially from the Herpesviridae family. Though NKD is rare, four genes that are involved in the CDC45-MCM-GINS (CMG) helicase have been described to result in NKD, including MCM4, GINS1, MCM10, and GINS4. The CMG helicase is critical for eukaryotic replication and plays a critical role in maintaining genomic stability. To our knowledge, CDC45 has never been described as a monogenic cause of NKD. However, here we describe a single damaging heterozygous variant in CDC45 in an individual with consistent defects in the NK cell compartment. This individual has a disruption in the ratio of CD56bright to CD56dim cells, severely decreased frequency of adaptive NK cells, and decreased NK cell cytotoxic function. As previously reported for other helicase variants that cause NKD, we found cell cycle defects, increased DNA damage, and impaired DNA damage repair signaling in patient lymphocytes. The description of CDC45 as a cause of NKD contributes to our understanding of the role of the CMG helicase in NK cell maturation, function, and biology. Keywords: Natural killer cell deficiency, CDC45, Natural killer cell development, Helicase Disclosures: The authors have no financial relationships or conflicts of interest to report. Clinical Immunology 250S (2023) 109356 https://doi.org/10.1016/j.clim.2023.109356 (10) Resolving Incomplete Penetrance in Primary Immunodeficiencies O’Jay Stewart 1, Roosheel Patel2, Conor Gruber3, Dusan Bogunovic4 1MD-PhD Student/Icahn School of Medicine at Mount Sinai 2Postdoctoral Associate/Icahn School of Medicine at Mount Sinai 3Resident Physician/Kravitz Children’s Hospital - Mount Sinai 4Professor/Icahn School of Medicine at Mount Sinai Introduction: Primary Immunodeficiencies (PIDs) are monogenic disorders of the immune system. Phenotypic variability of PIDs provide clinical challenges in these inborn errors. Recent studies indicate that 10% of autosomal genes randomly commit to expression of a single allele, termed monoallelic expression (MAE). Unlike X-inactivation or imprinting, MAE is not specific to gene clusters or a single chromosome and leads to a diverse population of cells at the transcript level. Despite an increase in the understanding of MAE, both the functional and mechanistic impact in disease is unknown. Hypothesis: MAE contributes to the phenotypic variability in individuals withPIDs. Abstracts / Clinical Immunology 250S (2023) 2
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