Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-γ Immunity

Schimke, Lena F.; Hibbard, James; Martı́nez-Barricarte, Rubén; Khan, Taj Ali; Cavalcante, Ricardo de Souza; Oliveira, Edgar Borges de; França, Tábata Takahashi; Iqbal, Asif; Yamamoto, Guilherme Lopes; Arslanian, Christina; Feriotti, Cláudia; Costa, Tânia Alves da; Bustamante, Jacinta; Boisson–Dupuis, Stéphanie; Casanova, Jean‐Laurent; Barbuto, José Alexandre Marzagão; Zatz, Mayana; Mendes, Rinaldo Pôncio; Calich, Vera Lúcia Garcia; Ochs, Hans D.; Torgerson, Troy R.; Cabral-Marques, Otávio; Condino‐Neto, Antônio

doi:10.1093/infdis/jix522

Cited by 29 publications

(16 citation statements)

References 49 publications

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“…STAT4 and T-BET are also necessary for the generation and maintenance of MCMV-specific memory NK cells (135, 136). In line with the lessons learnt from mice, a heterozygous missense mutation in STAT4 leading to a defect in IL-12-dependent IFN-γ immunity was identified in two patients suffering from acute chronic fungal infections (137).…”

Section: Jak/stat Signalingmentioning

confidence: 87%

JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

et al. 2019

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Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) that differentiate through common lymphoid progenitors (CLPs) to NK lineage-restricted progenitors (NKPs). The orchestrated action of multiple cytokines is crucial for NK cell development and maturation. Many of these cytokines such as IL-2, IL-7, IL-12, IL-15, IL-21, IL-27, and interferons (IFNs) signal via the Janus Kinase / Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We here review the current knowledge about these cytokines and the downstream signaling involved in the development and maturation of conventional NK cells and their close relatives, innate lymphoid cells type 1 (ILC1). We further discuss the role of suppressor of cytokine signaling (SOCS) proteins in NK cells and highlight their potential for therapeutic application.

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Section: Jak/stat Signalingmentioning

confidence: 87%

JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

et al. 2019

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“…Interestingly, STAT5B LOF mutations may also provoke autoimmune phenotypes due to non-functional T regulatory cells (Tregs) [ 111 ]. LOF mutations in STAT1 and TYK2 enhance the susceptibility to bacterial and viral infections [ 110 , 112 ], while LOF in STAT2 and STAT4 increase the incidence of viral and fungal infections, respectively [ 113 , 114 , 115 , 116 ]. Similarly, GOF mutations of STAT1 and STAT3 may suppress the immune system and manifest with impaired anti-viral, anti-bacterial, and for STAT1, also anti-fungal responses [ 110 , 117 ].…”

Section: Jak-stat Signaling In the Immune Systemmentioning

confidence: 99%

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

Klein

Stoiber

Sexl

et al. 2021

Cancers

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The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.

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“…However, no comparative evaluation was not undertaken by these authors. A report of a case of fatal fungemia caused by P. lutzii in a patient who did not exhibit any immunosuppressive co-morbidity led to the hypothesis that this species is more pathogenic than the P. brasiliensis complex [31], yet, a possible primary immunodeficiency was not investigated, as it was confirmed by Schimke et al [32].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Comparison of clinico-epidemiological and radiological features in paracoccidioidomycosis patients regarding serological classification using antigens from Paracoccidioides brasiliensis complex and Paracoccidioides lutzii

et al. 2020

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Genotyping of the genus Paracoccidioides showed its diversity and geographical distribution. Four species constituting the Paracoccidioides brasiliensis complex and Paracoccidioides lutzii are etiological agents of paracoccidioidomycosis (PCM). However, there are no studies comparing the clinical and epidemiological aspects between PCM caused by the P. brasiliensis complex and by P. lutzii. Demographic and clinical data from 81 patients with PCM-confirmed by mycological and/or histopathological examination-from Mato Grosso do Sul state (Brazil) were studied. All patients underwent serology by immunodiffusion with antigens obtained from the P. brasiliensis complex (ExoPb and gp43) and Cell Free Antigens obtained from P.lutzii (CFAPl).The cases were classified regarding their serological profile into three groups: G1: PCM patients seropositive to ExoPb and/or gp43 and seronegative to CFAPl (n = 51), assumed to have PCM caused by P. brasiliensis complex; G2: PCM patients seronegative to gp43 and seropositive to CFAPl (n = 16), with PCM caused by P. lutzii; and G3: PCM patients seropositive to ExoPb or gp43 and seropositive to CFAPl (n = 14), with undetermined serological profile, was excluded from the analyses. The Fisher's exact test or the Mann-Whitney U test, and cluster analysis according to Ward's method and Euclidean distance were used to analyze the results. Patients with serological profile suggestive of P. lutzii lived predominantly in municipalities in the Central and Southern regions of the state, while those with serological profile indicative of the P. brasiliensis complex were distributed throughout the state. No differences were found between the two groups regarding gender, age, schooling, rural work, clinical form, severity, organs involved, intensity of pulmonary involvement, degree of anemia, erythrocyte sedimentation rate values, and therapeutic response. PCM patients with serological profile suggestive of P.

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Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-γ Immunity

Abstract: Our data suggest autosomal dominant STAT4 deficiency as a novel inborn error of IL-12-dependent IFN-γ immunity associated with susceptibility to paracoccidioidomycosis.

Cited by 29 publications

References 49 publications

JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

Comparison of clinico-epidemiological and radiological features in paracoccidioidomycosis patients regarding serological classification using antigens from Paracoccidioides brasiliensis complex and Paracoccidioides lutzii

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