Review
Immunology
Aurora Chinnici, Linda Beneforti, Francesco Pegoraro, Irene Trambusti, Annalisa Tondo, Claudio Favre, Maria Luisa Coniglio, Elena Sieni
Summary: Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical condition characterized by sustained but ineffective immune system activation, leading to severe and systemic hyperinflammation. Prompt diagnosis and treatment are crucial for survival, as a considerable proportion of patients with HLH still die from progressive disease. Expert consultation and genetic analysis are recommended for accurate interpretation and therapeutic decisions.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Immunology
Snehal Shabrish, Madhura Kelkar, Reetika Malik Yadav, Umair Ahmed Bargir, Maya Gupta, Aparna Dalvi, Jahnavi Aluri, Manasi Kulkarni, Shweta Shinde, Sneha Sawant-Desai, Priyanka Kambli, Gouri Hule, Priyanka Setia, Neha Jodhawat, Pallavi Gaikwad, Amruta Dhawale, Nayana Nambiar, Vijaya Gowri, Ambreen Pandrowala, Prasad Taur, Revathi Raj, Ramya Uppuluri, Ratna Sharma, Pranoti Kini, Meena Sivasankaran, Deenadayalan Munirathnam, Ramprasad Vedam, Pandiarajan Vignesh, Aaqib Banday, Amit Rawat, Amita Aggarwal, Ujjal Poddar, Meenakshi Girish, Abhijit Chaudhary, Abhilasha Sampagar, Dharani Jayaraman, Narendra Chaudhary, Nitin Shah, Farah Jijina, S. Chandrakla, Swati Kanakia, Brijesh Arora, Santanu Sen, Madhukar Lokeshwar, Mukesh Desai, Manisha Madkaikar
Summary: Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation and systemic inflammation. In India, FHL2 and FHL3 are the most common subtypes. Genetic heterogeneity in the Indian population and poor prognosis of FHL were confirmed in this study, emphasizing the importance of flow cytometry-based assays in rapid diagnosis and validation of novel variants.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Medicine, General & Internal
Ayse Gonca Kacer, Tiraje Tulin Celkan
Summary: Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing and life-threatening disease characterized by activated lymphocytes and macrophages that secrete excessive cytokines. The diverse underlying conditions in HLH and the nonspecific clinical findings make diagnosis challenging. Urgent immunosuppressive therapy and hematopoietic stem cell transplantation are key treatment methods for HLH.
BALKAN MEDICAL JOURNAL
(2022)
Article
Medicine, Research & Experimental
Kristoffer Weissert, Sandra Ammann, Tamara Koegl, Viviane Dettmer-Monaco, Christoph Schell, Toni Cathomen, Stephan Ehl, Peter Aichele
Summary: Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by impaired lymphocyte cytotoxicity. Current therapeutic regimens have limited efficacy in treating HLH. Adoptive T cell therapy (ATCT) using gene-corrected autologous T cells has shown promising results in a mouse model of HLH. This study provides a proof-of-concept for the use of ATCT in treating active HLH.
EMBO MOLECULAR MEDICINE
(2022)
Article
Immunology
Deli Song, Jingshi Wang, Jia Zhang, Junxia Hu, Chaofan Wu, Zhao Wang
Summary: In this article, five cases of HAVCR2 mutation-associated HLH were reported. The study found an elevated level of IL-1RA in the serum of these patients. The potential mechanisms underlying HLH associated with HAVCR2 mutation were also investigated.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Hematology
Vandana Chaturvedi, Rebecca A. Marsh, Adi Zoref-Lorenz, Erika Owsley, Vijaya Chaturvedi, Trung C. Nguyen, Jordana R. Goldman, Michael M. Henry, Jay N. Greenberg, Stephan Ladisch, Michelle L. Hermiston, Michael Jeng, Ahmed Naqvi, Carl E. Allen, Hector R. Wong, Michael B. Jordan
Summary: Hemophagocytic lymphohistiocytosis (HLH) is characterized by acute T-cell activation, with CD38(high)/HLA-DR+ effector cells being most pronounced. In contrast, sepsis does not show this distinctive T-cell activation. CD38(high)/HLA-DR+ cells concentration above 7% has strong predictive value for distinguishing HLH from early sepsis or healthy controls.
Article
Immunology
Madhura G. Kelkar, Umair Ahmad Bargir, Reetika Malik-Yadav, Maya Gupta, Aparna Dalvi, Neha Jodhawat, Shweta Shinde, Manisha R. Madkaikar
Summary: The study found that CD8+ cytotoxic T lymphocytes from HLH patients exhibited high expression of exhaustion markers with overall impaired function. This is the first report suggesting functional exhaustion of CD8 T cells in both primary and secondary HLH. Further research is needed to understand the association between exhaustion and disease outcome for potential therapeutic implementation.
JOURNAL OF CLINICAL IMMUNOLOGY
(2021)
Article
Immunology
Julia E. Segal, Jessica D. Daley, Jessie L. Barnum, Claudia M. Salgado, Miguel Reyes-Mugica, Corinne Schneider, Serter Gumus, Darshit Thakrar, Steven W. Allen, Scott W. Canna
Summary: This case report illustrates HLH foci presenting as pulmonary/renal nodules, demonstrates the importance of monitoring a range of HLH biomarkers, and suggests the potential benefit of earlier initiation of salvage therapy.
JOURNAL OF CLINICAL IMMUNOLOGY
(2021)
Editorial Material
Clinical Neurology
Lauren Lu, Agnes Zhu, Christopher Y. Itoh, Ryan P. Coburn, Rafid Mustafa
Summary: A 26-year-old man presented with progressive encephalopathy, right inferior quadrantanopia, right hemiparesis, and facial swelling for 2 months. Imaging studies revealed an enhancing left parietal lesion and PET scan showed hypermetabolism in the lesion, face, and abdominal musculature. Biopsies confirmed CD8(+), CD30(-) T-cell lymphoma and the patient responded well to methotrexate and temozolomide treatment.
Article
Immunology
Yue Song, Xiaoli Li, Xuefeng He, Fei Zhou, Feng Du, Ziyan Wang, Suning Chen, Depei Wu
Summary: This study investigates the use of dose-escalating ruxolitinib in HLH patients who did not respond to the general dose. The results show that half of the patients achieved better remission after dose escalation, and sCD25 levels can serve as an early indicator for considering chemotherapy during treatment.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Medical Laboratory Technology
Tanya Sajan Ponnatt, Cullen M. Lilley, Kamran M. Mirza
Summary: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder of immune regulation that requires rapid diagnosis and aggressive management. Understanding the pathogenesis and early diagnosis of HLH plays a crucial role in determining patient outcome. HLH can be caused by genetic mutations or acquired factors, and proper management is essential for improving prognosis.
ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE
(2022)
Article
Hematology
Melissa R. Hines, Camille Keenan, Gabriela Maron Alfaro, Cheng Cheng, Yinmei Zhou, Akshay Sharma, Caitlin Hurley, Kim E. Nichols, Stephen Gottschalk, Brandon M. Triplett, Aimee C. Talleur
Summary: CAR T-cell therapy can lead to severe toxicity resembling carHLH, occurring in 14.8% of pediatric and young adult patients. Diagnosis and treatment of carHLH require suspicion and immunomodulation therapy, showing variable responses. Patients with carHLH have reduced response to therapy and overall survival compared to those without carHLH.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Allergy
Josee-Anne Joly, Alexis Vallee, Benoite Bourdin, Sara Bourbonnais, Natalie Patey, Louis Gaboury, Yves Theoret, Helene Decaluwe
Summary: This study found that the combination of IFN-y blockade and JAK 1/2 inhibitor ruxolitinib can effectively suppress disease progression in familial hemophagocytic lymphohistiocytosis (HLH).
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Article
Immunology
Xiang Liu, Xueling Zhu, Xiaotang Zhou, Yirui Xie, Dairong Xiang, Zhikai Wan, Ying Huang, Biao Zhu
Summary: This study describes two cases of AIDS-related secondary HLH treated with ruxolitinib. The results highlight the feasibility of using ruxolitinib as a first-line therapy in patients with HIV infection and secondary HLH. However, the safety and efficacy of this novel treatment need to be evaluated in large clinical trials in the future.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Tamir Diamond, Thomas N. Burn, Mailyn A. Nishiguchi, Danielle Minichino, Julie Chase, Niansheng Chu, Portia A. Kreiger, Edward M. Behrens
Summary: This study demonstrates the critical role of hepatic response to IFN-gamma in the development of FHL hepatitis in mice and highlights the importance of non-hematopoietic IFN-gamma response in activating lymphocytes and recruiting immune cells.
Article
Hematology
Francesco Saettini, Cecilia Poli, Jaime Vengoechea, Sonia Bonanomi, Julio C. Orellana, Grazia Fazio, Fred H. Rodriguez, Loreani P. Noguera, Claire Booth, Valentina Jarur-Chamy, Marissa Shams, Maria Iascone, Maja Vukic, Serena Gasperini, Manuel Quadri, Amairelys Barroeta Seijas, Elizabeth Rivers, Mario Mauri, Raffaele Badolato, Giovanni Cazzaniga, Cristina Bugarin, Giuseppe Gaipa, Wilma G. M. Kroes, Daniele Moratto, Monique M. van Ostaijen-ten Dam, Frank Baas, Silvere van der Maarel, Rocco Piazza, Zeynep H. Coban-Akdemir, James R. Lupski, Bo Yuan, Ivan K. Chinn, Lucia Daxinger, Andrea Biondi
Summary: Agammaglobulinemia, recurrent infections, hypertrophic cardiomyopathy and neutropenia were found in three novel patients in this study. Variants in the gene for folliculin interacting protein 1 (FNIP1) were identified, leading to impaired B-cell metabolism and development. This study highlights the importance of FNIP1 in B-cell development and metabolism.
Review
Hematology
Neelam Panchal, Sujal Ghosh, Claire Booth
Summary: Therapeutic T cells have been utilized in the treatment of various diseases, with successes in donor lymphocyte infusions, virus-specific T cells, and CAR-T cell therapy. Primary immunodeficiencies are monogenetic disorders, with hematopoietic stem cell transplantation and gene therapy being the main treatment options. Autologous gene-modified T cell therapy shows promise in conditions primarily affecting the lymphoid compartment.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Review
Biotechnology & Applied Microbiology
Kritika Chetty, Claire Booth
Summary: Gene therapy is a targeted treatment that reduces infection risk in PID patients by utilizing autologous hematopoietic stem cells. The field of gene therapy has rapidly developed over the last three decades, with significant improvements in vector design making the treatment a viable curative therapy after initial clinical trials discovered serious adverse events. Cryopreservation has expanded the scope of gene therapy by increasing accessibility to wider geographic locations. Targeted gene editing using engineered nucleases is in early stages of development and will add to the potential treatments available for PIDs.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2021)
Letter
Dermatology
Bustamante-Ogando Juan Carlos, Scheffler-Mendoza Selma, Yamazaki-Nakashimada Marco Antonio, Saez-de-Ocariz Marimar
INTERNATIONAL JOURNAL OF DERMATOLOGY
(2021)
Letter
Immunology
Julian Thalhammer, Maria Elena Maccari, Oliver Wegehaupt, Stephan Ehl, Carsten Speckmann
JOURNAL OF CLINICAL IMMUNOLOGY
(2021)
Letter
Hematology
Matthias Lange, Tobias Linden, Hermann L. Muller, Meera A. Flasskuehler, Holger Koester, Kai Lehmberg, Svea Ledig, Stephan Ehl, Axel Heep, Florian Beske
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Review
Immunology
Peter Aichele, Christoph Neumann-Haefelin, Stephan Ehl, Robert Thimme, Toni Cathomen, Melanie Boerries, Maike Hofmann
Summary: The root cause of immunopathologies lies in impaired immune responses, rather than exaggerated immune responses; The focus of research is on impaired immune reactions mediated by CD8(+) T cells.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Immunology
Alexandra Y. Kreins, Helena F. Velasco, Kai-Ning Cheong, Kanchan Rao, Paul Veys, Austen Worth, H. Bobby Gaspar, Claire Booth
Summary: Unconditioned HSCT is recommended for ADA-deficient patients with an HLA-matched donor, showing improved survival rates compared to unrelated donors. However, unconditioned procedures may lead to decreased engraftment and metabolic correction, while the use of RIC prior to transplantation can improve long-term outcomes.
JOURNAL OF CLINICAL IMMUNOLOGY
(2022)
Article
Cell Biology
Ina Harder, Matthias Muenchhalfen, Geoffroy Andrieux, Melanie Boerries, Bodo Grimbacher, Hermann Eibel, Maria Elena Maccari, Stephan Ehl, Juergen Wienands, Julia Jellusova, Klaus Warnatz, Baerbel Keller
Summary: Alterations in signaling pathways downstream of antigen receptors in T and B cells contribute to dysregulation of the adaptive immune system, potentially leading to immunodeficiency and autoimmunity. Investigating patients with genetically defined primary immunodeficiencies provides insights into these complex systems. Disturbed B-cell receptor signaling was observed in a subgroup of CVID patients, while a gain-of-function mutation in PIK3CD did not impair BCR-induced AKT-mTOR-S6 phosphorylation in APDS patients. This highlights the fundamental differences in B-cell signaling defects between CVID and APDS, and suggests that assessing BCR stimulation responses is a suitable diagnostic test for APDS.
Article
Cell Biology
Marc Descatoire, Remi Fritzen, Samuel Rotman, Genevieve Kuntzelman, Xavier Charles Leber, Stephanie Droz-Georget, Adrian J. Thrasher, Elisabetta Traggiai, Fabio Candotti
Summary: A main feature of Wiskott-Aldrich syndrome is increased susceptibility to autoimmunity, with WAS protein playing a key role in controlling peripheral tolerance in germinal center B cells, leading to the development of self-reactive antibodies and kidney pathology.
Editorial Material
Immunology
Stephan Ehl, Robert Thimme
Summary: Traditionally, immune-mediated pathology was believed to be a result of immune system hyperactivity. However, it has now been realized that immunopathology can also occur due to impaired immune reactions. This understanding has important implications for therapy, with immune suppression being ideal for hyperactivity-related pathology and immune stimulation or immune reconstitution beneficial for immunopathology caused by impaired immune reactions. The IMPATH paradox, as this concept is called, is the focus of the CRC1160 research center, funded by the German Research Foundation, researching the causal relationship between impaired immune reactions and immunopathology in human and murine models.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Medicine, Research & Experimental
Kristoffer Weissert, Sandra Ammann, Tamara Koegl, Viviane Dettmer-Monaco, Christoph Schell, Toni Cathomen, Stephan Ehl, Peter Aichele
Summary: Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by impaired lymphocyte cytotoxicity. Current therapeutic regimens have limited efficacy in treating HLH. Adoptive T cell therapy (ATCT) using gene-corrected autologous T cells has shown promising results in a mouse model of HLH. This study provides a proof-of-concept for the use of ATCT in treating active HLH.
EMBO MOLECULAR MEDICINE
(2022)
Article
Immunology
Joseph Topal, Neelam Panchal, Amairelys Barroeta, Anna Roppelt, Annelotte Mudde, H. Bobby Gaspar, Adrian J. Thrasher, Benjamin C. Houghton, Claire Booth
Summary: This study successfully restored immune function in XIAP-deficient mice by transducing human XIAP cDNA into their hematopoietic progenitor cells, and achieved comparable toxin resistance to wild-type mice. The same method was also validated in monocytes from XIAP-deficient patients.
JOURNAL OF CLINICAL IMMUNOLOGY
(2023)
Review
Biotechnology & Applied Microbiology
Claire Booth, Alessandro Aiuti
Summary: Gene therapies face challenges in rare diseases, but innovative solutions are being explored.
HUMAN GENE THERAPY
(2023)
Article
Biotechnology & Applied Microbiology
Benjamin C. Houghton, Neelam Panchal, Simone A. Haas, Kay O. Chmielewski, Markus Hildenbeutel, Thomas Whittaker, Claudio Mussolino, Toni Cathomen, Adrian J. Thrasher, Claire Booth
Summary: X-linked lymphoproliferative disease is a rare inherited immune disorder. This study assessed the ability of TALEN, CRISPR-Cas9, and CRISPR-Cas12a nucleases to drive targeted insertion of a specific gene, showing their potential in correcting the immune functions of XLP patients and providing new therapeutic opportunities.
FRONTIERS IN GENOME EDITING
(2022)