Journal of Clinical Immunology最新文献

{"title":"Quantifying the Diagnostic Odyssey Burden Among Persons with Inborn Errors of Immunity.","authors":"Sarina Nikzad, Rebekah Johnson, Christopher Scalchunes, Nicholas L Rider","doi":"10.1007/s10875-024-01855-x","DOIUrl":"10.1007/s10875-024-01855-x","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with inborn errors of immunity (IEI) have lifelong health complications including severe infections and physical impairments. Previous studies show that a patient's perception of their health is an important predictor of health outcomes. The purpose of this study was to understand factors related to patient reported health status.</p><p><strong>Methods: </strong>We used data from the Immunodeficiency Foundation (IDF) 2017 National Patient Survey and analyzed factors which correlated with the reported health status (RHS). Among a cohort of 1139 self-reported IEI patients, we identified age at the time of diagnosis, time gap between symptom onset and diagnosis, number of physicians seen, and whether the diagnosis was made in the first 5 years of life as significant. We used a two-tailed t-test, single-factor ANOVA, and Tukey-Kramer post-hoc test to assess statistical significance in the observed difference.</p><p><strong>Results: </strong>Patients who received a diagnosis before the age of 12 had a significantly better mean RHS (n = 207 pre-12a vs. n = 900 post-12a; p < 0.0001). Patients who received a diagnosis within 10 years of symptom onset showed improved mean RHS (n = 413 pre-10 vs. n = 524 post-10; p < 0.0001). Among patients who had symptom onset within the first 5 years of life, those who received a diagnosis had a significantly improved RHS (3.5 ± 0.92, n = 275 undiagnosed vs. 2.8 ± 0.94, n = 108 diagnosed; p < 0.0001). Finally, RHS was significantly impacted by number of physicians(n ≥ 4) seen prior to diagnosis (3.1 ± 0.96 vs. 3.4 ± 0.80, p < 0.0001).</p><p><strong>Conclusion: </strong>These findings shed light upon critical factors which impact IEI patient RHS. Specifically, we find that efficient, rapid and early-life IEI identification should improve patient reported health and relevant outcomes. These improvements appear to be independent of the clinician specialty ultimately making the IEI diagnosis.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"61"},"PeriodicalIF":7.2,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anifrolumab in Monogenic Lupus caused by TREX1 Mutation.","authors":"Patricia Moran-Alvarez, Virginia Messia, Valentina Matteo, Francesca Soscia, Giusi Prencipe, Fabrizio De Benedetti, Antonella Insalaco","doi":"10.1007/s10875-024-01851-1","DOIUrl":"10.1007/s10875-024-01851-1","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"60"},"PeriodicalIF":7.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes of Hematopoietic Cell Transplantation in Children with Inborn Errors of Immunity: A Single-Center Series.","authors":"Hasan Hashem, Lubna Ghatasheh, Rula Najjar, Duaa Mufarrej, Duaa Zandaki, Mayada Abu Shanap, Eman Khattab, Rawad Rihani, Iyad Sultan","doi":"10.1007/s10875-024-01853-z","DOIUrl":"https://doi.org/10.1007/s10875-024-01853-z","url":null,"abstract":"<p><p>Inborn errors of immunity (IEI) are a heterogenous group of rare monogenic disorders that affect innate or adaptive immunity, resulting in susceptibility to life-threatening infections and autoimmunity. Allogeneic hematopoietic cell transplantation (HCT) is a valuable curative option for children with IEI. We conducted a retrospective single-center study on the outcome of HCT in children with IEI. Primary outcome was overall survival (OS). We gathered data from 55 patients underwent HCT in the period 2014 to 2023. The indications for HCT were CGD (n = 14), HLH (n = 12), SCID (n = 10), and others (n = 19). Median age at HCT was 3 years (range 0.1-17). Donors were HLA-matched related (n = 27), haploidentical (n = 24), and cord (n = 4). The conditioning regimens were myeloablative (n = 34), reduced intensity (n = 18), or no conditioning (n = 3). After a median follow-up of 43 months (range 13-120), 2-year OS was 93%, 2-year EFS 79% and 2 year GvHD-free relapse-free survival (GRFS) was 69%. Univariate analysis showed that bone marrow source was significantly associated with better EFS and GRFS. Cumulative incidence of grade 2-4 acute and moderate/severe chronic GvHD were 21% and 13%, respectively. Incidence of graft failure was 13%. In conclusion, HCT is feasible and curative in children with IEI. Early diagnosis and referral in addition to timely treatment can further improve outcomes.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"59"},"PeriodicalIF":7.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Report of the Italian Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome in the Target Therapy Era.","authors":"Federica Barzaghi, Mattia Moratti, Giuseppina Panza, Beatrice Rivalta, Giuliana Giardino, Antonio De Rosa, Lucia Augusta Baselli, Matteo Chinello, Antonio Marzollo, Davide Montin, Maddalena Marinoni, Giorgio Costagliola, Silvia Ricci, Lorenzo Lodi, Baldassarre Martire, Cinzia Milito, Antonino Trizzino, Alberto Tommasini, Marco Zecca, Raffaele Badolato, Caterina Cancrini, Vassilios Lougaris, Claudio Pignata, Francesca Conti","doi":"10.1007/s10875-024-01835-1","DOIUrl":"10.1007/s10875-024-01835-1","url":null,"abstract":"<p><strong>Background: </strong>Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity).</p><p><strong>Methods: </strong>Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers.</p><p><strong>Results: </strong>Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes. The median age at diagnosis was 15.5 years, with a median follow-up of 74 months (range 6-384). The main presenting symptoms were respiratory tract infections alone (57%) or associated with lymphoproliferation (17%). Later, non-clonal lymphoproliferation was the leading clinical sign (86%), followed by respiratory infections (79%) and gastrointestinal complications (43%). Malignant lymphoproliferative disorders, all EBV-encoding RNA (EBER)-positive at the histological analysis, occurred in 14% of patients aged 17-19 years, highlighting the role of EBV in lymphomagenesis in this disorder. Diffuse large B-cell lymphoma was the most frequent. Immunological work-up revealed combined T/B cell abnormalities in most patients. Treatment strategies included immunosuppression and PI3K/Akt/mTOR inhibitor therapy. Rapamycin, employed in 36% of patients, showed efficacy in controlling lymphoproliferation, while selective PI3Kδ inhibitor leniolisib, administered in 32% of patients, was beneficial on both infections and immune dysregulation. Additionally, three patients underwent successful HSCT due to recurrent infections despite ongoing prophylaxis or lymphoproliferation poorly responsive to Rapamycin.</p><p><strong>Conclusions: </strong>This study underscores the clinical heterogeneity and challenging diagnosis of APDS, highlighting the importance of multidisciplinary management tailored to individual needs and further supporting leniolisib efficacy.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"58"},"PeriodicalIF":7.2,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recommendations for Transitioning Young People with Primary Immunodeficiency Disorders and Autoinflammatory Diseases to Adult Care.","authors":"Muskan Israni, Eliska Alderson, Nizar Mahlaoui, Laura Obici, Linda Rossi-Semerano, Helen Lachmann, Mojca Zajc Avramovič, Aurelien Guffroy, Virgil Dalm, Rachel Rimmer, Leire Solis, Carlota Villar, Andrew R Gennery, Stephanie Skeffington, Julia Nordin, Klaus Warnatz, Anne-Sophie Korganow, Jordi Antón, Marco Cattalini, Stefan Berg, Pere Soler-Palacin, Mari Campbell, Siobhan O Burns","doi":"10.1007/s10875-024-01838-y","DOIUrl":"10.1007/s10875-024-01838-y","url":null,"abstract":"<p><strong>Purpose: </strong>Significant improvements in the prognosis for young patients with Primary Immunodeficiency Diseases (PID) and Autoinflammatory Disorders (AID), which together make up the majority of Inborn Errors of Immunity (IEI), have resulted in the need for optimisation of transition and transfer of care to adult services. Effective transition is crucial to improve health outcomes and treatment compliance among patients. Evaluations of existing transition programmes in European health centres identified the absence of disease-specific transition guidelines for PID and AID, as a challenge to the transition process. This research aimed to establish expert consensus statements for the transition of young patients with PID and AID to adult services.</p><p><strong>Methods: </strong>This project used the Delphi method to establish mutual agreement for the proposed recommendations. A draft set of statements was developed following a literature review of existing transition programmes. Then the ERN RITA Transition Working Group convened to review the drafted recommendations and develop them into a survey. This survey was circulated among healthcare professionals to determine consensus using a five-point Likert scale, with the level of agreement set to 80% or greater. Statements that did not reach consensus were revised by the Working Group and recirculated among respondents.</p><p><strong>Results: </strong>The initial survey received 93 responses from 68 centres across 23 countries, while the following survey outlining revised recommendations received 66 responses. The respondents agreed upon recommendations detailing the structure and administration of transition programmes, collaborative working with social systems, and contraindications to transfer of care.</p><p><strong>Conclusion: </strong>This paper sets out a comprehensive set of recommendations to optimise transitional care for PID and AID.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"57"},"PeriodicalIF":7.2,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutational Landscape of Patients with Wiskott Aldrich Syndrome: Update from India.","authors":"Pallavi Gaikwad, Umair A Bargir, Neha Jodhawat, Aparna Dalvi, Shweta Shinde, Parag Tamhankar, Priyanka Setia, Priyanka Kambli, Amruta Dhawale, Lavina Temkar, Disha Vedpathak, Amrutha Jose, Maya Gupta, Reetika Yadav-Malik, Shubhankar Dutta, Kokoli Bose, Prasad Taur, Vijaya Gowri, Vaishnavi Iyengar, Akshaya Chougule, Mukesh Desai, Meena Sivasankaran, Sagar Bhattad, Sarath Balaji, Sangeeta Mudaliar, Ashruti Kacha, Girish Subramanian, Swati Patel, Sujata Sharma, Abhilasha Sampagar, Manisha Madkaikar","doi":"10.1007/s10875-024-01848-w","DOIUrl":"https://doi.org/10.1007/s10875-024-01848-w","url":null,"abstract":"<p><strong>Purpose: </strong>Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder characterized by distinctive features including microthrombocytopenia, eczema and recurrent infections. In the present study we report clinical, immunological and molecular spectrum of 41 WAS patients diagnosed over last five years.</p><p><strong>Methods: </strong>Clinical and family history was collected from case records. Comprehensive immunological assessments including lymphocyte subset analysis, and flow cytometry based evaluation of WAS protein (WASP) expressions were performed in patients along with evaluation of carrier status in mothers. Genetic analysis was carried out with either Sanger sequencing or targeted exome sequencing.</p><p><strong>Results: </strong>The patients included in this study presented at a median age of 9.5 months, with two adult cases. Clinical manifestations encompassed thrombocytopenia, eczema, bleeding, diarrhea, respiratory tract infections, CMV infection, and malignancy. Immunological phenotype revealed T cell lymphopenia, B cell lymphopenia, and elevated IgE levels. Flow cytometry analysis of WASP was performed in 36 cases out of which 68.42% demonstrated complete absent expression while others showed reduced expression. Genetic analysis highlighted that the majority of mutations affect the WH1 domain of WASP while both adult patients showed intronic mutations. Molecular Dynamics analysis conducted for the novel variants P398R and G33R showed an average RMSD (Å) higher than that of the wild type, indicating greater structural perturbations in WASP.</p><p><strong>Conclusion: </strong>In the present study we have documented 56.09% novel WAS mutations in Indian cohort. Notably, the application of flow cytometry has emerged as a valuable and efficient diagnostic tool for identifying these WAS patients.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"56"},"PeriodicalIF":7.2,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel AGR2 Variant Causing Aberrant Monomer-Dimer Equilibrium Leading to Severe Respiratory and Digestive Symptoms.","authors":"Sanami Takada, Silvanna Gallo, Sebastian Silva, Hiroki Tanaka, Oscar Pincheira, Juan Zúñiga, Marcela Villarroel, Ximena Hidalgo, Joel Melo-Tanner, Hidefumi Suzuki, Shinichi Machida, Hidehisa Takahashi, Noriko Miyake","doi":"10.1007/s10875-024-01847-x","DOIUrl":"10.1007/s10875-024-01847-x","url":null,"abstract":"<p><p>Anterior gradient 2 (AGR2) is a protein disulfide isomerase that is important for protein processing in the endoplasmic reticulum and is essential for mucin production in the digestive and respiratory tracts. Bi-allelic AGR2 variants were recently found to cause recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD; MIM # 620233), although the mechanisms behind this condition remain unclear. To date, at least 15 patients with homozygous AGR2 variants have been reported. Here, we report two affected siblings in a consanguineous family who had recurrent respiratory infections and digestive symptoms, one of whom needed lung transplantation. To identify the genetic cause of their symptoms, we performed exome sequencing and identified a novel homozygous missense variant in AGR2 (NM_006408.4, c.250A>C, p.(Ser84Arg)) in both affected siblings. Both parents had the identical variant in a heterozygous state. This variant is quite rare in the general population and is clinically compatible with RIFTD, substituting a highly conserved CXXS motif with CXXR. We performed structural modeling and functional studies to investigate the effect of this variant. Through transient overexpression, Ser84Arg AGR2 decreased protein stability, and promoted aberrant dimerization under non-reducing conditions. AGR2 functions in a monomer-dimer equilibrium. Size-exclusion chromatography showed that the Ser84Arg mutant had a larger molecular size than the wild-type protein under non-reducing, but not reducing conditions, indicating that Ser84Arg enhanced intermolecular disulfide bonds. In conclusion, we identified a novel pathogenic AGR2 variant and indicated its abnormal monomer-dimer equilibrium as a possible mechanism involved in the pathogenesis of RIFTD.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"55"},"PeriodicalIF":7.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prime Editor Gene Therapy and TREX1 Mosaicism in Retinal Vasculopathy with Cerebral Leukoencephalopathy.","authors":"Samuel D Chauvin, Joe A Holley, Subhajit Poddar, Cathrine A Miner, Lindsay Kumble, Jiayuan Fu, Hanka Laue-Gizzi, Todd A Hardy, Jonathan J Miner","doi":"10.1007/s10875-024-01846-y","DOIUrl":"10.1007/s10875-024-01846-y","url":null,"abstract":"<p><p>TREX1 mutations underlie a variety of human diseases, including retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S), a catastrophic adult-onset vasculopathy that is often confused with multiple sclerosis, systemic vasculitis, or systemic lupus erythematosus. Patients with RVCL develop brain, retinal, liver, and kidney disease around age 35-55, leading to premature death in 100% of patients expressing an autosomal dominant C-terminally truncated form of TREX1. We previously demonstrated that RVCL is characterized by high levels of DNA damage, premature cellular senescence, and risk of early-onset breast cancer before age 45. Here, we report human TREX1 mosaicism causing organ-limited RVCL in the retina, as well as a gene therapy to synthetically create TREX1 mosaicism as a potential treatment for RVCL. In our patient with organ-limited disease, the mosaic TREX1 mutant allele underwent germline transmission to 3 children, who developed severe multi-organ disease at ~ age 40, unlike their mosaic parent, who has organ-limited disease at age 74. Additionally, we describe our TREX1 prime editor gene therapy that corrects the most common RVCL-causing TREX1 variant in cell culture and in mice. Thus, TREX1 mosaicism causes organ-limited RVCL with a normal lifespan, suggesting that a gene therapy to create TREX1 mosaicism in adults may someday become useful as a treatment for patients with RVCL.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"54"},"PeriodicalIF":7.2,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and Clinical Characterization of a Founder Mutation Causing G6PC3 Deficiency.","authors":"Xin Zhen, Michael J Betti, Meltem Ece Kars, Andrew R Patterson, Edgar Alejandro Medina-Torres, Selma Cecilia Scheffler Mendoza, Diana Andrea Herrera Sánchez, Gabriela Lopez-Herrera, Yevgeniya Svyryd, Osvaldo M Mutchinick, Eric R Gamazon, Jeffrey C Rathmell, Yuval Itan, Janet Markle, Patricia O'Farrill Romanillos, Saul Oswaldo Lugo-Reyes, Ruben Martinez-Barricarte","doi":"10.1007/s10875-024-01836-0","DOIUrl":"10.1007/s10875-024-01836-0","url":null,"abstract":"<p><p>G6PC3 deficiency is a monogenic immunometabolic disorder that causes severe congenital neutropenia type 4. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican descent. Based on the shared haplotypes amongst mutation carriers, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it appeared in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived Epstein-Barr Virus-immortalized B (EBV-B) cells. The neutropenia observed in G6PC3-deficient patients is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the c.210delC variant impacts glycolysis by performing extracellular flux assays on patient-derived EBV-B cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3-deficient patients reported in the literature, and we found that the c.210delC carriers display all prominent clinical features observed in prior patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"53"},"PeriodicalIF":7.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11618172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restitutio ad integrum: Rescuing the Alveolar Macrophage Function with HSCT in Pulmonary Alveolar Proteinosis Due to CSF2Rα Deficiency.","authors":"Varsha Mishra-Sopori, Indu Khosla, Sanaa Khan, Darshan Kataria, Pralhad Prabhudesai, Parmarth Chandane, Kunal Sehgal, Minnie Bodhanwala, Ambreen Pandrowala, Prashant Hiwarkar","doi":"10.1007/s10875-024-01844-0","DOIUrl":"10.1007/s10875-024-01844-0","url":null,"abstract":"<p><p>Hereditary pulmonary alveolar proteinosis (hPAP) is a rare lung-related primary immunodeficiency. In hPAP, variants of genes encoding the heterodimeric GM-CSF receptor alpha or beta-chains (CSF2Rα, CSF2Rβ) lead to perturbations in GM-CSF signalling. These perturbations impair the scavenging function of pulmonary alveolar macrophages leading to accumulation of surfactant proteins and lipids within the alveoli. The replacement of defective pulmonary alveolar macrophages can be achieved with allogeneic hematopoietic stem cell transplantation. However, previous reports highlight undesirable pulmonary outcomes associated with this therapeutic approach. We report a 4-year-old developmentally normal girl born of second-degree consanguineous marriage diagnosed with severe form of CSFRα-deficient PAP. She required recurrent whole lung lavage and hence was treated with allogeneic hematopoietic stem cell transplantation. A reduced toxicity treosulfan-based myeloablative regimen with alemtuzumab serotherapy was used for conditioning. Ciclosporin, mycophenolate mofetil and FAM (fluticasone inhaler, azithromycin, montelukast) were used to prevent graft-versus-host disease and immune-related complications of lung. Her post-transplant course was uneventful with full donor chimerism and complete resolution of symptoms. We demonstrate for the first time in a case of severe CSF2Rα-deficient PAP, the successful use of hematopoietic stem cell transplantation as a primary curative treatment, restoring normal lungs both anatomically and functionally. The case report provides evidence for considering allogeneic hematopoietic stem cell transplant in severe forms of CSF2R-deficient PAP.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"52"},"PeriodicalIF":7.2,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}