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1.
Clin Infect Dis ; 72(12): 2206-2208, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32745179

RESUMO

Patients with autoantibodies to interferon-γ (IFN-γ) may develop severe nontuberculous mycobacterial infections. We describe the novel use of daratumumab in a patient with autoantibodies to IFN-γ who had progressive infection, resulting in clinical and radiographic improvement.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Micobactérias não Tuberculosas , Anticorpos Monoclonais/uso terapêutico , Autoanticorpos , Humanos , Interferon gama , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico
2.
J Clin Immunol ; 40(7): 1045-1047, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32696284

RESUMO

This is a report of a successful bone marrow transplant in an IFN-γR1 patient with progressive mycobacterial infection. PURPOSE: Hematopoietic cell transplant in patients with interferon gamma receptor deficiencies has been fraught with challenges, not the least of which is failure of engraftment and infectious complications. METHODS: This is a report of a successful hematopoietic cell transplant in an actively infected patient of advanced age. RESULTS: This case report shows successful engraftment and resolution of infection posttransplant using a matched related donor in a single institution. CONCLUSION: A successful curative HCT despite persistent, disseminated, nontuberculous mycobacterial infection in a patient with AD-IFNγR1 suggests that this approach, while difficult, may be useful in other patients with otherwise refractory disease.


Assuntos
Transplante de Medula Óssea , Genes Dominantes , Estudos de Associação Genética , Predisposição Genética para Doença , Receptores de Interferon/deficiência , Transplante de Células-Tronco Hematopoéticas , Humanos , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Infecções por Mycobacterium/terapia , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/etiologia , Infecções por Mycobacterium não Tuberculosas/terapia , Índice de Gravidade de Doença , Transplante Homólogo , Resultado do Tratamento , Receptor de Interferon gama
3.
J Allergy Clin Immunol ; 141(1): 365-371, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28528201

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is characterized by recurrent life-threatening bacterial and fungal infections and aberrant inflammation. Mutations in CYBB cause X-linked CGD and account for 65% to 70% of cases in Western countries. OBJECTIVE: We sought to understand the clinical manifestations associated with the X-linked CGD carrier state. METHODS: We undertook a comprehensive retrospective study of 162 affected female subjects. We examined dihydrorhodamine 123 (DHR) oxidation data for percentage of X-chromosome inactivation. We correlated lyonization (%DHR+) with clinical features. Where possible, we followed %DHR+ values over time. RESULTS: Clinical data were available for 93 female subjects: %DHR+ values were 46% (mean) and 47% (median; SD, 24). Using the %DHR+ value as the criterion for X inactivation, 78% of patients had levels of inactivation of 20% to 80%, suggesting random inactivation that was independent of age. In contrast, carriers with CGD-type infections had median %DHR+ values of 8% (n = 14; range, 0.06% to 48%), and those with only autoimmune or inflammatory manifestations had median %DHR+ values of 39% (n = 31; range, 7.4% to 74%). Those with both infections and autoimmunity had low %DHR+ values (n = 6; range, 3% to 14%). A %DHR+ value of less than 10% was strongly associated with infections (odds ratio, 99). Strong association persisted when %DHR+ values were less than 20% (odds ratio, 12). Autoimmunity was not associated with %DHR+ values. In 2 sets of identical twins, the %DHR+ populations tracked closely over time. Although the %DHR+ populations were very similar between sisters, those between mothers and daughters were unrelated. CONCLUSIONS: A low %DHR+ value strongly predicts infection risk in X-linked CGD carriers, and the carrier state itself is associated with autoimmunity.


Assuntos
Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Heterozigoto , Fenótipo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Lactente , Infecções/etiologia , Pessoa de Meia-Idade , Mutação , Razão de Chances , Avaliação de Sintomas , Inativação do Cromossomo X , Adulto Jovem
4.
Nat Med ; 30(9): 2461-2472, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38961223

RESUMO

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.


Assuntos
Biomarcadores , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Biomarcadores/sangue , Idoso , Adulto Jovem , Envelhecimento/imunologia , Envelhecimento/genética , Aprendizado de Máquina , Adolescente , Estudos de Casos e Controles , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/genética , Transcriptoma
5.
Sci Adv ; 9(41): eadh3150, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37824621

RESUMO

Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.


Assuntos
COVID-19 , Imunoglobulina G , Humanos , Vacinas contra COVID-19 , Estudos Prospectivos , COVID-19/prevenção & controle , Imunidade
6.
Res Sq ; 2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-36993430

RESUMO

Monogenic diseases are often studied in isolation due to their rarity. Here we utilize multiomics to assess 22 monogenic immune-mediated conditions with age- and sex-matched healthy controls. Despite clearly detectable disease-specific and "pan-disease" signatures, individuals possess stable personal immune states over time. Temporally stable differences among subjects tend to dominate over differences attributable to disease conditions or medication use. Unsupervised principal variation analysis of personal immune states and machine learning classification distinguishing between healthy controls and patients converge to a metric of immune health (IHM). The IHM discriminates healthy from multiple polygenic autoimmune and inflammatory disease states in independent cohorts, marks healthy aging, and is a pre-vaccination predictor of antibody responses to influenza vaccination in the elderly. We identified easy-to-measure circulating protein biomarker surrogates of the IHM that capture immune health variations beyond age. Our work provides a conceptual framework and biomarkers for defining and measuring human immune health.

7.
J Transl Autoimmun ; 4: 100102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34041472

RESUMO

Interferon-γ autoantibodies increase the risk of disseminated nontuberculous mycobacterial infections. Addition of rituximab to antibiotics accelerates and improves outcomes, but refractory infections can occur due to persistent production of autoantibodies. We combined bortezomib with rituximab to reduce autoantibodies leading to clinical and radiographic improvement in infection.

8.
Nat Commun ; 11(1): 2031, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341348

RESUMO

Neutrophils employ several mechanisms to restrict fungi, including the action of enzymes such as myeloperoxidase (MPO) or NADPH oxidase, and the release of neutrophil extracellular traps (NETs). Moreover, they cooperate, forming "swarms" to attack fungi that are larger than individual neutrophils. Here, we designed an assay for studying how these mechanisms work together and contribute to neutrophil's ability to contain clusters of live Candida. We find that neutrophil swarming over Candida clusters delays germination through the action of MPO and NADPH oxidase, and restricts fungal growth through NET release within the swarm. In comparison with neutrophils from healthy subjects, those from patients with chronic granulomatous disease produce larger swarms against Candida, but their release of NETs is delayed, resulting in impaired control of fungal growth. We also show that granulocyte colony-stimulating factors (GCSF and GM-CSF) enhance swarming and neutrophil ability to restrict fungal growth, even during treatment with chemical inhibitors that disrupt neutrophil function.


Assuntos
Candida albicans/crescimento & desenvolvimento , Neutrófilos/citologia , Neutrófilos/microbiologia , Sistemas CRISPR-Cas , Candidíase/microbiologia , Linhagem Celular , Armadilhas Extracelulares/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Doença Granulomatosa Crônica/microbiologia , Humanos , Processamento de Imagem Assistida por Computador , Análise em Microsséries , NADPH Oxidases/metabolismo , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Nat Commun ; 11(1): 2492, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409681

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

10.
Blood Adv ; 3(2): 136-147, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30651282

RESUMO

Mutations in NCF1 (p47phox) cause autosomal recessive chronic granulomatous disease (CGD) with abnormal dihydrorhodamine (DHR) assay and absent p47phox protein. Genetic identification of NCF1 mutations is complicated by adjacent highly conserved (>98%) pseudogenes (NCF1B and NCF1C). NCF1 has GTGT at the start of exon 2, whereas the pseudogenes each delete 1 GT (ΔGT). In p47phox CGD, the most common mutation is ΔGT in NCF1 (c.75_76delGT; p.Tyr26fsX26). Sequence homology between NCF1 and its pseudogenes precludes reliable use of standard Sanger sequencing for NCF1 mutations and for confirming carrier status. We first established by flow cytometry that neutrophils from p47phox CGD patients had negligible p47phox expression, whereas those from p47phox CGD carriers had ∼60% of normal p47phox expression, independent of the specific mutation in NCF1 We developed a droplet digital polymerase chain reaction (ddPCR) with 2 distinct probes, recognizing either the wild-type GTGT sequence or the ΔGT sequence. A second ddPCR established copy number by comparison with the single-copy telomerase reverse transcriptase gene, TERT We showed that 84% of p47phox CGD patients were homozygous for ΔGT NCF1 The ddPCR assay also enabled determination of carrier status of relatives. Furthermore, only 79.2% of normal volunteers had 2 copies of GTGT per 6 total (NCF1/NCF1B/NCF1C) copies, designated 2/6; 14.7% had 3/6, and 1.6% had 4/6 GTGT copies. In summary, flow cytometry for p47phox expression quickly identifies patients and carriers of p47phox CGD, and genomic ddPCR identifies patients and carriers of ΔGT NCF1, the most common mutation in p47phox CGD.


Assuntos
Predisposição Genética para Doença , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , NADPH Oxidases/deficiência , Biomarcadores , Mapeamento Cromossômico , Variações do Número de Cópias de DNA , Feminino , Citometria de Fluxo , Expressão Gênica , Estudos de Associação Genética , Loci Gênicos , Genótipo , Doença Granulomatosa Crônica/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Linhagem , Espécies Reativas de Oxigênio/metabolismo
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