FABIO FERNANDES MORATO CASTRO
Projetos de Pesquisa
Unidades Organizacionais
FM, Faculdade de Medicina
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/60 - Laboratório de Imunologia Clínica e Alergia, Hospital das Clínicas, Faculdade de Medicina - Líder
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/60 - Laboratório de Imunologia Clínica e Alergia, Hospital das Clínicas, Faculdade de Medicina - Líder
9 resultados
Resultados de Busca
Agora exibindo 1 - 9 de 9
- Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus(2022) STEINER, Annemarie; REYGAERTS, Thomas; PONTILLO, Alessandra; CECCHERINI, Isabella; MOECKING, Jonas; MOGHADDAS, Fiona; DAVIDSON, Sophia; CAROLI, Francesco; GROSSI, Alice; CASTRO, Fabio Fernandes Morato; KALIL, Jorge; GOHR, Florian N.; I, Florian Schmidt; BARTOK, Eva; ZILLINGER, Thomas; HARTMANN, Gunther; GEYER, Matthias; GATTORNO, Marco; MENDONCA, Leonardo Oliveira; MASTERS, Seth L.Purpose NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis. Methods Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1 beta/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal. Results A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1 beta therapy partially controlled symptoms. While on treatment, serum IL-1 beta and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1 beta/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778-3.644), P = 0.01305. Conclusion NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.
conferenceObject Systemic inflammatory syndromes with immunodysregulatory phenotype: clinical characteristics, genetic findings and therapeutic response(2021) PEREIRA, Grazielly Pereira; PRADO, Alex; BRANDAO, Jaqueline Brandao; ZANETTI, Francine Zanetti; ALBERTO, Nazoneth; ALBERTO, Samucanda; KALIL, Jorge; FONSECA, Luiz; CASTRO, Fabio Castro; TOLEDO-BARROS, Myrthes; MENDONCA, Leonardo MendoncaconferenceObject In vitro NLRP3 inflammasome activation assay assists diagnosis of genetically negative CAPS patients and guides anti-IL1 therapy(2020) MENDONCA, L. O.; TOLEDO-BARROS, M. A. M.; FRANCO, P. A.; GIAVINA-BIANCHI JUNIOR, P. F.; KALIL, J. E.; CASTRO, F. F. Morato; CAROLI, F.; GROSSI, A.; CECCHERINI, I; ROBAZZI, T.; PILEGGI, G. S.; RIVITTI, M. C.; SANCHES JUNIOR, J. A.; GRUMACH, A. S.; GATTORNO, M.; PONTILLO, A.- In-vitro NLRP3 functional test assists the diagnosis of cryopyrin-associated periodic syndrome (CAPS) patients: A Brazilian cooperation(2022) MENDONCA, Leonardo Oliveira; TOLEDO-BARROS, Myrthes Anna Maragna; LEAL, Vinicius Nunes Cordeiro; ROA, Mariela Estefany Gislene Vera; CAMBUI, Raylane Adrielle Goncalves; TOLEDO, Eliana; BARROS, Samar Freschi; OLIVEIRA, Amanda Melato de; RIVITTI-MACHADO, Maria Cecilia; FRANCESCANTONIO, Isadora Carvalho Medeiros; GRUMACH, Anete Sevciovic; PENIDO, Norma de Oliveira; CASTRO, Fabio Fernandes Morato; KALIL, Jorge; PONTILLO, AlessandraObjective: To report our five-years experience on the use of NLRP3 inflammasome functional assays in the differential diagnosis of Brazilian patients with a clinical suspicion of CAPS. Patients and methods: The study included 9 patients belonging to 2 families (I, II) and 7 unrelated patients with a clinical suspicion of AID according to Eurofever/PRINTO classification, recruited between 2017 and 2022. The control group for the NLRP3 functional assay consisted of 10 healthy donors and for the CBA cytokines measurement of 19 healthy controls. Patients underwent clinical evaluation, genetic and functional analysis. Results: All members of the family I received the diagnosis of Muckle-Wells Syndrome (MWS), carried the NLRP3 Thr348Met variant and resulted positive for the functional assay. The 2 patients of the family II resulted negative for the mutational screening but positive for the functional assay compatible with a MWS clinical phenotype. In 2 unrelated patients with NLRP3 mutations, including a novel mutation (Gly309Val, Asp303His), a positive functional test confirmed the clinical diagnosis of NOMID. 3 unrelated MWS and 1 FCAS patients resulted negative to the genetic screening and positive for the functional test. One patient with a FCAS-like phenotype harbored the NLRP12 His304Tyr variant confirming the diagnosis of FCAS2. Conclusion: The NLRP3 inflammasome functional assay can assist the clinical diagnosis of CAPS even in patients with unknown genetic defects.
- Immunological repertoire linked to PSTPIP1-associated myeloid-related inflammatory (PAMI) syndrome(2021) MENDONCA, Leonardo Oliveira; TERRERI, Maria Teresa; OSAKU, Fabiane Mitie; BARROS, Samar Freschi; KOHLER, Karen Francine; PRADO, Alex Isidoro; BARROS, Myrthes Toledo; KALIL, Jorge; CASTRO, Fabio Fernandes MoratoBackground Mutations along PSTPIP1 gene are associated to two specific conditions, PAPA syndrome and PAMI syndrome, both autoinflammatory disorders associated to disturbances in cytoskeleton formation. Immunological aspects of PAMI syndrome has not yet been reported neither the clinical impact on therapeutical decisions. Methods Clinical data of patients records were retrospectively accessed. Genomic DNA were extracted and sequenced following standard procedures. Peripheral lymphocytes were quantified in T, B e FOXP3 phenotypes. Results We describe two related patients with PAMI syndrome harboring the usual E250K mutation. Anti-IL1 therapy could partially control the disease in the index patient. A broad spectrum of immunological effects as well as an aberrant expression of FOXP3 could be observed. Conclusions Here we report two related brazilian patients with PAMI syndromes harboring the E250K mutation in PSTPIP1, their immunological aspects and the therapeutical response to canakinumab.
conferenceObject Clinical, genetic and therapeutical findings of two Brazilian patients with cutaneous mastocytosis associated with systemic autoinflammation(2020) MENDONCA, L. O.; PEREIRA, G. D. F.; FRANCO, P. A.; TOLEDO-BARROS, M. A. M.; AGONDI, R. C.; MORATO-CASTRO, F. F.; CAROLI, F.; GROSSI, A.; CECCHERINI, I; PONTILLO, A.; KALIL, J. E.; GATTORNO, M.; GIAVINA-BIANCHI JUNIOR, P. F.conferenceObject A Case Report of a Novel Compound Heterozygous Mutation in a Brazilian Patient with Deficiency of IL1RA (DIRA)(2017) MENDONCA, L. O.; GROSSI, A.; CORDOVA, P. Torres; AMORIM, L. C.; KALIL, J.; CASTRO, F. M.; PONTILLO, A.; CECCHERINI, I.; GATTORNO, M.; BARROS, M. T. Toledo- Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome(2021) MENDONCA, Leonardo Oliveira; PRADO, Alex Isidoro; COSTA, Izelda Maria Carvalho; BANDEIRA, Marcia; DYER, Rafael; BARROS, Samar Freschi; KHOLER, Karen Francine; FONSECA, Luiz Augusto Marcondes; KALIL, Jorge; CASTRO, Fabio Morato; TOLEDO-BARROS, Myrthes Anna MaragnaSince the first description of the syndrome of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD), clinical pictures lacking both neurological and hematological manifestations have been reported. Moreover, prominent skin involvement, such as with relapsing erythema nodosum, is not a common finding. Up to this moment, no genotype and phenotype correlation could be done, but mild phenotypes seem to be located in the N or C part. B-cell deficiency is a hallmark of SIFD syndrome, and multiple others immunological defects have been reported, but not high levels of double negative T cells. Here we report a Brazilian patient with a novel phenotype of SFID syndrome, carrying multiple immune defects and harboring a novel mutation on TRNT1 gene.
- A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)(2020) MENDONCA, Leonardo Oliveira; GROSSI, Alice; CAROLI, Francesco; OLIVEIRA, Robson Aguiar de; KALIL, Jorge; CASTRO, Fabio Fernandes Morato; PONTILLO, Alessandra; CECCHERINI, Isabella; BARROS, Myrthes Anna Maragna Toledo; GATTORNO, MarcoBackground Deficiency of the natural antagonist of interleukin-1 was first described in 2009 and so far 20 patients has been reported. In Brazil just two cases have been reported both carrying the same homozygous 15 bp deletion. Blocking interleukin-1 has changed rate survival for DIRA patients. The use of anakinra and rilonacept has been reported safe and efficient, whereas the selective blockade of interleukin-1 beta, using the monoclonal antibody canakinumab has been reported in a single case only. Case presentation Here we report a case of a 7 years old Brazilian boy that presented with recurrent episodes of systemic inflammation with severe disabling osteomyelitis with mild pustular skin rash. A Next Generation Sequencing gene panel allowed to detect two pathogenic mutations in the IL1RN gene, described in compound heterozygosity. Corticosteroids was effective in controlling inflammation and anti-IL1 beta blocker triggered disease flare. Complete clinical control could be achieved using IL-1 receptor antagonist. Conclusions DIRA is a severe, life threatening autoinflammatory condition with low numbers of patients described all over the world. The mutation p.Asp72_Ile76del in IL1RN is presented in all Brazilian DIRA patients already described and p.Q45* (rs1019766125) is a new mutation affecting the IL1RN gene. Following the pathogenesis of DIRA, blocking both subunits of interleukin one as well as antagonizing the receptor using anakinra or rilonacept seems to be effective. There is just one report using canakinumab for the treatment of DIRA and this is the first report of disease flare using this drug.