María Cecilia Poli Harlowe

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Poli Harlowe, María Cecilia

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Poli Harlowe

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María Cecilia

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María Cecilia Poli Harlowe

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Editorial: Immune response to gram-negative bacteria in the lungs
(2024) Jara-Collao, Agnes; Poli Harlowe, María Cecilia; Bain, William; Peñaloza, Hernán F.
A Third Dose of SARS-CoV-2 mRNA Vaccine Improves Immune Response in Chronic Kidney Disease Patients
(2023) Poli Harlowe, María Cecilia; Vial Cox, María Cecilia; Rey, Emma; González, Natalia; Cortés, Lina; Hormazabal, Juan; Ramírez, Carolina; De la Cruz, Javiera; Ulloa, Camilo
Chronic kidney disease (CKD) patients have an increased risk of morbidity and mortality following SARS-CoV-2 infection. Vaccination in these patients is prioritized, and monitoring of the immune response is paramount to define further vaccination strategies. This prospective study included a cohort of 100 adult CKD patients: 48 with kidney transplant (KT) and 52 on hemodialysis without prior COVID-19. The patients were assessed for humoral and cellular immune responses after four months of an anti-SARS-CoV-2 primary two-dose vaccination scheme (CoronaVac or BNT162b2) and one month after a booster third dose of BNT162b2 vaccine. We identified poor cellular and humoral immune responses in the CKD patients after a primary vaccination scheme, and these responses were improved by a booster. Robust polyfunctional CD4+ T cell responses were observed in the KT patients after a booster, and this could be attributed to a higher proportion of the patients having been vaccinated with homologous BNT162b2 schemes. However, even after the booster, the KT patients exhibited lower neutralizing antibodies, attributable to specific immunosuppressive treatments. Four patients suffered severe COVID-19 despite three-dose vaccination, and all had low polyfunctional T-cell responses, underscoring the importance of this functional subset in viral protection. In conclusion, a booster dose of SARS-CoV-2 mRNA vaccine in CKD patients improves the impaired humoral and cellular immune responses observed after a primary vaccination scheme.
Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinﬂammatory syndrome
(2024) Delafontaine, Selket; Iannuzzo, Alberto; Bigley, Tarin; Mylemans, Bram; Rana, Ruchit; Baatsen, Pieter; Poli Harlowe, María Cecilia; Rymen, Daisy; Jansen, Katrien; Mekahli, Djalila; Casteels, Ingele; Cassiman, Catherine; Demaerel, Philippe; Lepelley. Alice; Frémond, Marie; Schrijvers, Rik; Bossuyt, Xavier; Vints, Katlijn; Huybrechts, Wim; Tacine, Rachida; Willekens, Karen; Corveleyn, Anniek; Boeckx, Bram; Baggio, Marco; Ehlers, Lisa; Munck, Sebastian; Lambrechts, Diether; Voet, Arnout; Moens, Leen; Bucciol, Giorgia; Cooper, Megan; Davis, Carla; Delon, Jérôme; Meyts, Isabelle
Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinﬂammatory signaling.
Post-COVID-19 condition: a sex-based analysis of clinical and laboratory trends
(2024) Delfino, Carlos; Poli Harlowe, María Cecilia; Vial Cox, María Cecilia; Vial, Pablo; Martínez, Gonzalo; Riviotta, Amy; Arbat, Catalina; Mac-Guire, Nicole; Hoppe, Josefina; Carvajal, Cristóbal; Munoz Venturelli, Paula
Background and aim: Post-COVID-19 condition (PCC) encompasses long-lasting symptoms in individuals with COVID-19 and is estimated to affect between 31-67% of patients, with women being more commonly affected. No definitive biomarkers have emerged in the acute stage that can help predict the onset of PCC, therefore we aimed at describing sex-disaggregated data of PCC patients from a local cohort and explore potential acute predictors of PCC and neurologic PCC. Methods: A local cohort of consecutive patients admitted with COVID-19 diagnosis between June 2020 and July 2021 were registered, and clinical and laboratory data were recorded. Only those <65 years, discharged alive and followed up at 6 and 12 months after admission were considered in these analyses. Multivariable logistic regression analysis was performed to explore variables associated with PCC (STATA v 18.0). Results: From 130 patients in the cohort, 104 were contacted: 30% were women, median age of 42 years. At 6 months, 71 (68%) reported PCC symptoms. Women exhibited a higher prevalence of any PCC symptom (87 vs. 60%, p = 0.007), lower ferritin (p = 0.001) and procalcitonin (p = 0.021) and higher TNF levels (p = 0.042) in the acute phase compared to men. Being women was independently associated to 7.60 (95% CI 1.27-45.18, p = 0.026) higher risk for PCC. Moreover, women had lower return to normal activities 6 and 12 months. Conclusion: Our findings highlight the lasting impact of COVID-19, particularly in young women, emphasising the need for tailored post-COVID care. The lower ferritin levels in women are an intriguing observation, warranting further research. The study argues for comprehensive strategies that address sex-specific challenges in recovery from COVID-19.
The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS
(2022) Gedik, Kader; Lamot, Lovro; Romano, Micol; Demirkaya, Erkan; Piskin, David; Torreggiani, Sofia; Adang, Laura; Armangue, Thais; Barchus, Kathe; Cordova, Devon; Crow, Yanick; Dale, Russell; Durrant, Karen; Eleftheriou, Despina; Fazz, Elisa; Gattorno, Marco; Gavazzi, Francesco; Hanson, Eric; Lee-Kirsch, Min Ae; Montealegre, Gina; Neven, Bénédicte; Orcesi, Simona; Ozen, Seza; Poli Harlowe, María Cecilia; Schumacher, Elliot; Tonduti, Davide; Uss, Katsiaryna; Aletaha, Daniel; Feldman, Brian; Vanderver, Adeline; Brogan, Paul; Goldbach, Raphaela
Objective: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. Methods: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed. Results: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. Conclusion: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.
Proteasome disorders and inborn errors of immunity
(2023) Poli Harlowe, María Cecilia
Inborn errors of immunity (IEI) or primary immune deficiencies (PIDD) are caused by variants in genes encoding for molecules that are relevant to the innate or adaptive immune response. To date, defects in more than 450 different genes have been identified as causes of IEI, causing a constellation of heterogeneous clinical manifestations ranging from increased susceptibility to infection, to autoimmunity or autoinflammation. IEI that are mainly characterized by autoinflammation are broadly classified according to the inflammatory pathway that they predominantly perturb. Among autoinflammatory IEI are those characterized by the transcriptional upregulation of type I interferon genes and are referred to as interferonopathies. Within the spectrum of interferonopathies, genetic defects that affect the proteasome have been described to cause autoinflammatory disease and represent a growing area of investigation. This review is focused on describing the clinical, genetic, and molecular aspects of IEI associated with mutations that affect the proteasome and how the study of these diseases has contributed to delineate therapeutic interventions.
Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile
(2024) Poli Harlowe, María Cecilia; Rebolledo Jaramillo, Boris; Lagos, Catalina; Orellana, Joan; Moreno, Gabriela; Martín, Luz M.; Encina, Gonzalo; Böhme, Daniela; Faundes, Víctor; Zavala, M. Jesús; Hasbún, María Trinidad; Fischer, Sara; Brito, Florencia; Araya, Diego; Lira, Manuel; Cruz, Javiera de la; Astudillo, Camila; Lay-Son, Guillermo; Cares, Carolina; Aracena, Mariana; San Martín, Esteban; Coban-Akdemir, Zeynep; Posey, Jennifer E.; Lupski, James R.; Repetto, Gabriela
Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.
The Latin American Society for Immunodeficiencies Registry
(2024) Seminario, Gisela; Gonzalez, Maria; Sanchez, Carolina; Sevciovic, Anete; Rodrigues, Gesmar; Regairaz, Lorena; Alvares, Aristoteles; LASID Registry Group; Aldave, Juan; Poli Harlowe, María Cecilia; King, Alejandra; Rodrigues, Fatima; Leiva, Lily; Franco, Jose; Espinosa, Francisco; Sorensen, Ricardo; Tavares, Beatriz; Bezrodnik, Liliana; Condino, Antonio
Purpose - The Latin American Society of Immunodeficiencies (LASID) Registry was established in 2009 to collect data on Inborn Errors of Immunity (IEI) patients in the region. Although several reports have been published regarding LASID data, this is the first report of the entire dataset. Methods - The European Society of Immunodeficiencies (ESID) donated the online platform in 2008. Data was collected from participating centers from Apr 13, 2009, to Dec 31, 2022, and included demographic, clinical, and follow-up information. Results - A total of 9307 patients were included in the database. At the end of the study period, 8,805 patients were alive or lost to follow-up, and 502 were deceased. The most common type of IEI was predominantly antibody deficiency (PAD, 60.35%), and selective IgA deficiency was the most frequent diagnosis (1627 patients, 17.48%), followed by Common Variable Immune Deficiency (CVID, 1191 patients). Most patients (78.16%) were ≤ 18 years old at inclusion, and the median age at diagnosis was 4.77 years. The median time to diagnosis was 5.04 years. Antibiotics were prescribed in 32.3% of visits, followed by immunoglobulins (29.49% ). Hematopoietic stem cell transplantation was performed in 5.03% of patients. Omenn syndrome was the most common disease in deceased patients, with a mortality rate of 52.63%. Conclusion - This study contributes to our understanding of IEIs in Latin America and highlights the importance of early diagnosis, appropriate treatments, and improved data collection to optimize patient outcome.
Clinical, immunologic, and genetic characteristics of 148 patients with natural killer cell deficiency
(2025) Abdalgani, Manar; Hernandez , Evelyn; Pedroza, Luis; Chinn, Ivan; Forbes, Lisa; Rider, Nicholas; Banerjee, Pinaki; Poli Harlowe, María Cecilia; Mahapatra, Sanjana; Canter, Debra; Cao, Tram; Shawver, Linda; Nandiwada, Sarada; Lupski, James; Posey, Jennifer; Ramakrishnan, Rajasekhar; Mace, Emily; Orange, Jordan
Background: Natural killer (NK) cell deficiency (NKD) is an immunodeficiency phenotype in which abnormality of NK cells is the major clinically relevant immune defect. Objective: We sought to define the clinical, immunologic, and genetic characteristics of patients with NKD to aid in the understanding of these individuals and this cell type and guide future research and clinical practice. Methods: During 2006-2022, 168 individuals with a suspected diagnosis of NKD were enrolled, with comprehensive clinical, immunologic, and genetic data collected and analyzed. Research exome sequencing was performed to identify both known and novel genetic associations. Results: NK cell abnormalities consistent with NKD were confirmed in 148 participants. Most presented during childhood (median age 13 years, range 0-76 years), though 34% were adults. All tested individuals exhibited reduced NK cell cytotoxic function; 44% also had decreased NK cell numbers and/or mature NK cells. Herpesvirus and/or papillomavirus infections were observed in 71%, malignancies were observed in 7%, and a 5% case-fatality rate was noted. Among the 99 participants who underwent research exome sequencing, 29% were considered solved for a likely contributing variant allele, with 52% of these cases involving known genes and 48% involving novel genes. Conclusions: NKD is a phenotypic immunodeficiency associated with increased susceptibility to certain viral infections and cancer with multiple genetic etiologies, revealing key biological pathways for NK cell development and function. This research underscores the role of NK cells in human immune defenses and helps advance the identification of at-risk populations, precise genetic diagnoses, and informed clinical management for patients with NKD.
Multiomics dissection of human RAG deficiency revealsdistinctive patterns of immune dysregulation but acommon inflammatory signature
(2025) Bosticardo, Marita; Dobbs, Kerry; Delmonte, Ottavia; Martins, Andrew; Pala, Francesca; Kawai, Tomoki; Kenney, Heather; Magro, Gloria; Rosen, Lindsey; Yamazaki, Yasuhiro; Yu, Hsin-Hui; Calzoni, Enrica; Lee, Yu Nee; Liu, Can; Stoddard, Jennifer; Niemela, Julie; Fink, Danielle; Castagnoli, Riccardo; Ramba, Meredith; Cheng, Aristine; Riley, Deanna; Oikonomou, Vasileios; Shaw, Elana; Belaid, Brahim; Keles, Sevgi; Al- Herz, Waleed; Cancrin, Caterina; Cifald, Cristina; Baris, Safa; Sharapova, Svetlana; Schuetz, Catharina; Gennery, Andrew; Freeman, Alexandra; Somech, Raz; Choo, Sharon; Giliani, Silvia; Güngör, Tayfun; Drozdov, Daniel; Meyt, Isabelle; Moshous, Despina; Neven, Benedicte; Abraham, Roshini; El- Marsafy, Aisha; Kanariou, Maria; King, Alejandra; Licciardi, Francesco; Cruz, Mario; Palma, Paolo; Poli Harlowe, María Cecilia; Adelo, Mehdi; Algeri, Mattia; Alroqi, Fayhan; Bastard, Paul; Bergerson, Jenna; Booth, Claire; Brett, Ana; Burns, Siobhan; Butt, Manish; Padem, Nurcicek; de la Morena, M. Teresa
Competing interests: M.J.B. is a speaker for Grifols; consults for Pharming, Horizon/Amgen, and Grifols; receives sponsored research funding from the NIH, the Bill and Melinda Gates Foundation, and Pharming; and serves on the scientific advisory board for ADMA Biologics. H.C.S. has stock holdings in Amgen and Eli Lily. R.S.A. receives royalties from Elsevier for book publications, serves as deputy editor for the Journal of Immunology, is Committee Chair of Newborn Screening for SCID for the Clinical and Laboratory Standards Institute, and is a member of the Immunology Clinical Domain Working Group for ClinGen. B.J.D.S. is an ad hoc consultant for Sobi and a member of the Data Safety Monitoring Board for Orchard Therapeutics. I.M. is a senior Clinical Researcher at the FWO Flanders. R.L.F. has consulted for Takeda, Griffons, Horizon, and Pharming. B.W. serves as consultant for the Immunology Speakers Bureau, Takeda Pharmaceutocals. S. Prockop receives support for the conduct of clinical trials through Boston Children’s Hospital from AlloVir, Atara, and Jasper. She is an inventor of intellectual property related to development of third-party virus-specific T cells program with all rights assigned to Memorial Sloan Kettering Cancer Center; receives honoraria from Pierre Fabre, Regeneron; serves on the data safety monitoring board at Stanford University and New York Blood Center; and is consulting for Atara, Ensoma, Pierre Fabre, HEOR and VOR. J.S.T. serves on the scientific advisory board of CytoReason Inc. and Immunoscape Inc. and as the co–chief science officer (unpaid) of the Human Immunome Project (nonprofit). All other authors declare that they have no competing interests.