Journal of Clinical Immunology最新文献

{"title":"DIAPH1-Deficiency is Associated with Major T, NK and ILC Defects in Humans.","authors":"Zehra Busra Azizoglu, Royala Babayeva, Zehra Sule Haskologlu, Mustafa Burak Acar, Serife Ayaz-Guner, Fatma Zehra Okus, Mohammad Bilal Alsavaf, Salim Can, Kemal Erdem Basaran, Mehmed Fatih Canatan, Alper Ozcan, Hasret Erkmen, Can Berk Leblebici, Ebru Yilmaz, Musa Karakukcu, Mehmet Kose, Ozlem Canoz, Ahmet Özen, Elif Karakoc-Aydiner, Serdar Ceylaner, Gülsüm Gümüş, Huseyin Per, Hakan Gumus, Halit Canatan, Servet Ozcan, Figen Dogu, Aydan Ikinciogullari, Ekrem Unal, Safa Baris, Ahmet Eken","doi":"10.1007/s10875-024-01777-8","DOIUrl":"10.1007/s10875-024-01777-8","url":null,"abstract":"<p><p>Loss of function mutations in Diaphanous related formin 1 (DIAPH1) are associated with seizures, cortical blindness, and microcephaly syndrome (SCBMS) and are recently linked to combined immunodeficiency. However, the extent of defects in T and innate lymphoid cells (ILCs) remain unexplored. Herein, we characterized the primary T, natural killer (NK) and helper ILCs of six patients carrying two novel loss of function mutation in DIAPH1 and Jurkat cells after DIAPH1 knockdown. Mutations were identified by whole exome sequencing. T-cell immunophenotyping, proliferation, migration, cytokine signaling, survival, and NK cell cytotoxicity were studied via flow cytometry-based assays, confocal microscopy, and real-time qPCR. CD4⁺ T cell proteome was analyzed by mass spectrometry. p.R351* and p.R322*variants led to a significant reduction in the DIAPH1 mRNA and protein levels. DIAPH1-deficient T cells showed proliferation, activation, as well as TCR-mediated signaling defects. DIAPH1-deficient PBMCs also displayed impaired transwell migration, defective STAT5 phosphorylation in response to IL-2, IL-7 and IL-15. In vitro generation/expansion of Treg cells from naïve T cells was significantly reduced. shRNA-mediated silencing of DIAPH1 in Jurkat cells reduced DIAPH1 protein level and inhibited T cell proliferation and IL-2/STAT5 axis. Additionally, NK cells from patients had diminished cytotoxic activity, function and IL-2/STAT5 axis. Lastly, DIAPH1-deficient patients' peripheral blood contained dramatically reduced numbers of all helper ILC subsets. DIAPH1 deficiency results in major functional defects in T, NK cells and helper ILCs underlining the critical role of formin DIAPH1 in the biology of those cell subsets.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 8","pages":"175"},"PeriodicalIF":7.2,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906767","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":"Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency.","authors":"Wenjing Ying, Xin Long, Travis Vandergriff, Hemanth Karnati, Meghan Heberton, Mingyi Chen, Xiaochuan Wang, Christian Wysocki, Xiao-Fei Kong","doi":"10.1007/s10875-024-01780-z","DOIUrl":"10.1007/s10875-024-01780-z","url":null,"abstract":"<p><p>The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects. This variability is influenced by pathogen exposure, healthcare access and host-environment interactions. We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4⁺ T-cell lymphopenia. The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X). The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties. Despite his low CD4⁺ T-cell count, the patient had normal counts of CD3⁺ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2⁺ γδ T cells. γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency. The Vδ2 γδ T cells of this STK4-deficient patient are mostly CD45RA^-CD27⁺CCR7⁺ central memory γδT cells, and their ability to proliferate in response to T-cell activation was impaired, as was that of CD4⁺ T cells. In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 8","pages":"172"},"PeriodicalIF":7.2,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11306306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897570","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":"A Cross-Sectional Study of Health-Related Quality of Life in Patients with Predominantly Antibody Deficiency.","authors":"Ahmed Elmoursi, Baijun Zhou, Mei-Sing Ong, Joseph S Hong, Andrew Pak, Megha Tandon, Natalia Sutherland, Daniel V DiGiacomo, Jocelyn R Farmer, Sara Barmettler","doi":"10.1007/s10875-024-01781-y","DOIUrl":"10.1007/s10875-024-01781-y","url":null,"abstract":"<p><p>Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. \"Fair or poor\" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoimmune and inflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported \"fair or poor\" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 8","pages":"173"},"PeriodicalIF":7.2,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897569","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":"Description of BCG and Tuberculosis Disease in a Cohort of 79 Patients with Chronic Granulomatous Disease.","authors":"Ximena León-Lara, Uriel Pérez-Blanco, Marco A Yamazaki-Nakashimada, Juan Carlos Bustamante-Ogando, Nancy Aguilar-Gómez, Hernán Cristerna-Tarrasa, Aidé-Tamara Staines-Boone, Omar J Saucedo-Ramírez, Eunice Fregoso-Zuñiga, Ana-Paola Macías-Robles, María R Canseco-Raymundo, Marco Venancio-Hernández, Cristina Moctezuma-Trejo, Berenise Gámez-González, Carmen Zarate-Hernández, Roselia Ramírez-Rivera, Selma Scheffler-Mendoza, Nancy Jiménez-Polvo, Leticia Hernández-Nieto, Jocelyn Carmona-Vargas, María L García-Cruz, Óscar Zavaleta-Martínez, Carla M Román-Montes, Victoria Cervantes-Parra, Anelena González-Reynoso, Rogelio Guzmán-Cotaya, Francisco Espinosa-Rosales, Patricia Saltigeral-Simental, Sara Espinosa-Padilla, Lizbeth Blancas Galicia","doi":"10.1007/s10875-024-01778-7","DOIUrl":"10.1007/s10875-024-01778-7","url":null,"abstract":"<p><strong>Purpose: </strong>Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by pathogenic variants of genes encoding the enzyme complex NADPH oxidase. In countries where tuberculosis (TB) is endemic and the Bacillus Calmette-Guérin (BCG) vaccine is routinely administered, mycobacteria are major disease-causing pathogens in CGD. However, information on the clinical evolution and treatment of mycobacterial diseases in patients with CGD is limited. The present study describes the adverse reactions to BCG and TB in Mexican patients with CGD.</p><p><strong>Methods: </strong>Patients with CGD who were evaluated at the Immunodeficiency Laboratory of the National Institute of Pediatrics between 2013 and 2024 were included. Medical records were reviewed to determine the clinical course and treatment of adverse reactions to BCG and TB disease.</p><p><strong>Results: </strong>A total of 79 patients with CGD were included in this study. Adverse reactions to BCG were reported in 55 (72%) of 76 patients who received the vaccine. Tuberculosis was diagnosed in 19 (24%) patients. Relapse was documented in three (10%) of 31 patients with BGC-osis and six (32%) of 19 patients with TB, despite antituberculosis treatment. There was no difference in the frequency of BCG and TB disease between patients with pathogenic variants of the X-linked CYBB gene versus recessive variants.</p><p><strong>Conclusions: </strong>This report highlights the importance of considering TB in endemic areas and BCG complications in children with CGD to enable appropriate diagnostic and therapeutic approaches to improve prognosis and reduce the risk of relapse.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 8","pages":"171"},"PeriodicalIF":7.2,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889395","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":"Insights into Patient Experiences with Facilitated Subcutaneous Immunoglobulin Therapy in Primary Immune Deficiency: A Prospective Observational Cohort.","authors":"Ezgi Yalcin Gungoren, Melek Yorgun Altunbas, Ummugulsum Dikici, Zeynep Meric, Isil Eser Simsek, Ayca Kiykim, Salim Can, Esra Karabiber, Nalan Yakici, Fazil Orhan, Haluk Cokugras, Metin Aydogan, Oner Ozdemir, Sevgi Bilgic Eltan, Safa Baris, Ahmet Ozen, Elif Karakoc-Aydiner","doi":"10.1007/s10875-024-01771-0","DOIUrl":"10.1007/s10875-024-01771-0","url":null,"abstract":"<p><strong>Background: </strong>Immunoglobulin G replacement therapy (IgRT), intravenous (IV) and subcutaneous (SC) routes, is pivotal in treatment of primary immunodeficiencies (PID). In recent years, facilitated subcutaneous immunoglobulin (fSCIG), a combination of rHuPH20 and 10% IgG has emerged as a delivery method to combine advantages of both IV and SC.</p><p><strong>Method: </strong>In an observational prospective cohort, we investigated patient experience with fSCIG in PID patients from 5 PID centers for up to 12 months. We assessed the efficacy and safety of this treatment with patient/caregiver- and physician-reported indicators. Additionally, we analyzed patient treatment satisfaction (TSQM-9) and quality of life (QoL).</p><p><strong>Results: </strong>We enrolled 29 patients (22 pediatric and 7 adults; 14 females and 15 males; (median: 15, min-max: 2-40.9 years) who initiated fSCIG as IgRT-naive (n = 1), switched from conventional rapid-push 10% SCIG (n = 6) or IVIG (n = 22). Among the participants, 19 (65%) exhibited antibody deficiencies, 8 (27%) combined immunodeficiencies, and 2 (7%) immune dysregulations. Remarkably, targeted trough immunoglobulin G levels were achieved under all previous IgRTs as well as fSCIG. No severe systemic adverse drug reactions were documented, despite prevalent local (%86.45) and mild systemic (%26.45) adverse reactions were noted with fSCIG. Due to mild systemic symptoms, 2 patients switched from fSCIG to 10% SCIG. The patient satisfaction survey revealed a notable increase at 2-4th (p = 0.102); 5-8th (p = 0.006) and 9-12th (p < 0.001) months compared to the baseline. No significant trends were observed in QoL surveys.</p><p><strong>Conclusion: </strong>fSCIG demonstrates admissable tolerability and efficacy in managing PIDs in addition to notable increase of patients' drug satisfaction with IgRT. The identified benefits support the continuation of this therapy despite the local reactions.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 8","pages":"169"},"PeriodicalIF":7.2,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11298503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889396","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":"A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.","authors":"Aimee Huynh, Paul E Gray, Anna Sullivan, Joseph Mackie, Antoine Guerin, Geetha Rao, Karrnan Pathmanandavel, Erika Della Mina, Georgina Hollway, Matthew Hobbs, Karen Enthoven, Patrick O'Young, Sam McManus, Luke H Wainwright, Megan Higgins, Fallon Noon, Melanie Wong, Paul Bastard, Qian Zhang, Jean-Laurent Casanova, Kuang-Chih Hsiao, Alberto Pinzon-Charry, Cindy S Ma, Stuart G Tangye","doi":"10.1007/s10875-024-01774-x","DOIUrl":"10.1007/s10875-024-01774-x","url":null,"abstract":"<p><p>Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 8","pages":"170"},"PeriodicalIF":7.2,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11298505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889394","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":"Inheritance of STING mosaicism in two half-siblings.","authors":"Alix de Becdelièvre, Laurye-Anne Eveillard, Beata Wolska-Kuśnierz, Marie-Louise Frémond","doi":"10.1007/s10875-024-01768-9","DOIUrl":"10.1007/s10875-024-01768-9","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"168"},"PeriodicalIF":7.2,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792621","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":"Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.","authors":"Takanori Utsumi, Miyuki Tsumura, Masato Yashiro, Zenichiro Kato, Kosuke Noma, Fumiaki Sakura, Reiko Kagawa, Yoko Mizoguchi, Shuhei Karakawa, Hidenori Ohnishi, Charlotte Cunningham-Rundles, Peter D Arkwright, Masao Kobayashi, Hirokazu Kanegane, Dusan Bogunovic, Bertrand Boisson, Jean-Laurent Casanova, Takaki Asano, Satoshi Okada","doi":"10.1007/s10875-024-01758-x","DOIUrl":"10.1007/s10875-024-01758-x","url":null,"abstract":"<p><strong>Purpose: </strong>Transcription factor 3 (TCF3) encodes 2 transcription factors generated by alternative splicing, E12 and E47, which contribute to early lymphocyte differentiation. In humans, autosomal dominant (AD) E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the recurrent de novo p.E555K pathogenic variant has been associated with this disease and acts via a dominant-negative (DN) mechanism. In this study, we describe the first Asian patient with agammaglobulinemia caused by the TCF3 p.E555K variant and provide insights into the structure and function of this variant.</p><p><strong>Methods: </strong>TCF3 variant was identified by inborn errors of immunity-related gene panel sequencing. The variant E555K was characterized by alanine scanning of the E47 basic region and comprehensive mutational analysis focused on position 555.</p><p><strong>Results: </strong>The patient was a 25-year-old male with B-cell deficiency, agammaglobulinemia, and mild facial dysmorphic features. We confirmed the diagnosis of AD E47 transcription factor deficiency by identifying a heterozygous missense variant, c.1663 G>A; p.E555K, in TCF3. Alanine scanning of the E47 basic region revealed the structural importance of position 555. Comprehensive mutational analysis focused on position 555 showed that only the glutamate-to-lysine substitution had a strong DN effect. 3D modeling demonstrated that this variant not only abolished hydrogen bonds involved in protein‒DNA interactions, but also inverted the charge on the surface of the E47 protein.</p><p><strong>Conclusions: </strong>Our study reveals the causative mutation hotspot in the TCF3 DN variant and highlights the weak negative selection associated with the TCF3 gene.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"167"},"PeriodicalIF":7.2,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788236","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":"Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children's Hospital Medical Center.","authors":"Xinxiu Xu, James Denton, Yaning Wu, Jie Liu, Qiaoning Guan, D Brian Dawson, Jack Bleesing, Wenying Zhang","doi":"10.1007/s10875-024-01772-z","DOIUrl":"10.1007/s10875-024-01772-z","url":null,"abstract":"<p><p>Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children's Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"166"},"PeriodicalIF":7.2,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766192","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":"Discordant Phenotypes of Nephritis in Patients with X-linked Agammaglobulinemia.","authors":"Toru Kanamori, Tomohiro Udagawa, Takayuki Fujii, Hiroyoshi Matsukura, Yuka Iwaya, Motoshi Sonoda, Keisuke Sugimoto, Masahiro Takeguchi, Atsunori Yoshino, I-Feng Wang, Daw-Yang Hwang, Harry W Schroeder, Masaki Shimizu, Hans D Ochs, Tomohiro Morio, Hirokazu Kanegane","doi":"10.1007/s10875-024-01766-x","DOIUrl":"10.1007/s10875-024-01766-x","url":null,"abstract":"<p><strong>Purpose: </strong>To define the clinical and histological characteristics of nephritis in patients with X-linked agammaglobulinemia (XLA) and their immunological profiles.</p><p><strong>Methods: </strong>The clinical, immunological, and histological findings of nine patients with XLA and nephritis were retrospectively analyzed.</p><p><strong>Results: </strong>Based on kidney histological findings, patients with XLA and nephritis could be divided into two groups, viz., chronic glomerulonephritis (CGN) and tubulointerstitial nephritis (TIN). The two groups showed different immunological profiles. Patients in the CGN group exhibited an atypical immunological profile of XLA, with pathogenic leaky B cells producing immunoglobulins that may play a role in forming immune complexes and causing immune-mediated glomerulonephritis. In contrast, patients in the TIN group exhibited a typical immunological profile of XLA, suggesting that antibody-independent/other BTK-dependent mechanisms, or immunoglobulin replacement therapy (IgRT)-related immune/nonimmune-mediated nephrotoxicity causes TIN.</p><p><strong>Conclusion: </strong>Nephritis occurring in patients with XLA could have links between their renal pathology and immunological status. Careful observation is recommended to detect kidney pathology in patients with XLA on IgRT.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"164"},"PeriodicalIF":7.2,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759028","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}