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1.
BMC Med Genet ; 21(1): 131, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32552675

RESUMO

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder. METHODS: We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR . RESULTS: We evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G > T and c.112 T > C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631 + 2 T > C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631 + 1G > T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931 T > C mutation; the female fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C > T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy. CONCLUSION: We confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Diagnóstico Pré-Natal , Agamaglobulinemia/diagnóstico , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Família , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem
3.
Iran J Allergy Asthma Immunol ; 19(1): 94-101, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32245326

RESUMO

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders caused by early defects in the development and function of T cells. Other lymphocyte lineages (B and/or natural killer cells) are variably affected. With a worldwide frequency of approximately 1:50,000 live births, SCID may result from diverse mutations in over 16 genes. Whole-exome sequencing (WES) provides an opportunity for parallel screening of all those genes. This approach is also useful for genetic diagnosis in parents whose infant expired before genetic testing. Here, we describe a heterozygous novel non-frameshift deletion (c.587_598del p.196_199del) in the adenosine deaminase (ADA) gene identified by WES in healthy parents of an expired child with SCID. The mutation was subsequently confirmed to be homozygous in the deceased baby whose left-over blood sample volume was insufficient for direct WES analysis. In conclusion, we here describe a novel mutation in ADA, a well-known SCID gene.


Assuntos
Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Agamaglobulinemia/genética , Imunodeficiência Combinada Severa/genética , Feminino , Humanos , Lactente , Irã (Geográfico) , Masculino , Mutação , Linhagem , Sequenciamento Completo do Exoma
4.
Clin Immunol ; 214: 108387, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32194234

RESUMO

Biallelic variants in BLNK cause primary B-cell immunodeficiency that usually results in absence of B cells and immunoglobulin. Here, we identified disease-causing variant(s) in two unrelated Chinese patients with agammaglobulinemia. Patient 1 showed a moderate reduction in total B-cell count but demonstrated both extremely low levels of memory B-cells and lower levels of memory T cells relative to those in healthy controls. Whole-exome sequencing (WES) revealed a novel heterozygous splice variant (c.676+1G>A), and suggested exon 9 deletion from BLNK, which was subsequently validated by quantitative polymerase chain reaction. For Patient 2, WES revealed novel compound heterozygous of a frameshift variant (p.T152Pfs*6) and a synonymous variant (c.525G>A) that resulted in exon 6 skipping, according to cDNA sequencing. These findings represent the first report of a BLNK-deficient patient presenting with impaired memory B-cell and memory T-cell development. Furthermore, this study is the first reporting a pathogenic synonymous splice variant in BLNK.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Agamaglobulinemia/genética , Linfócitos B/patologia , Agamaglobulinemia/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Epilepsia/complicações , Éxons/genética , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Memória Imunológica , Contagem de Linfócitos , Masculino , Linhagem , Isoformas de Proteínas/genética , Recidiva , Infecções Respiratórias/complicações , Deleção de Sequência , Subpopulações de Linfócitos T/patologia , Sequenciamento Completo do Exoma
5.
Pediatr Allergy Immunol ; 31 Suppl 24: 11-12, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32017208

RESUMO

Primary B-cell immunodeficiency is the most frequent immune defect in infancy. Selective absence of serum and secretory immunoglobulin IgA is the most common, with rates ranging from 1/333 persons to 1/16 000, among different races. By contrast, it has been estimated that hypo/agammaglobulinemia occurs with a frequency of 1/50 000 persons. Patients with antibody deficiency are usually recognized because they have recurrent infections with encapsulated bacteria or a history of failure to respond adequately to antibiotic treatment. However, some individuals, mainly those affected by IgA deficiency (SIgAD) or transient hypogammaglobulinemia of infancy , may have few or no infections.


Assuntos
Agamaglobulinemia/diagnóstico , Linfócitos B/imunologia , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Deficiência de IgA/diagnóstico , Imunoglobulina A/genética , Infecções/diagnóstico , Agamaglobulinemia/genética , Ligante de CD40/genética , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/genética , Deficiência de IgA/genética , Lactente , Recém-Nascido , Infecções/genética , Ativação Linfocitária , Recidiva
6.
J Clin Invest ; 130(4): 1793-1807, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31895698

RESUMO

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A-mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti-IL-ß or anakinra, an inhibitor of IL-1ß signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn's disease.


Assuntos
Tirosina Quinase da Agamaglobulinemia/deficiência , Doença de Crohn , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia/metabolismo , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Doença de Crohn/enzimologia , Doença de Crohn/genética , Doença de Crohn/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Masculino , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
9.
J Dermatol ; 47(1): 58-60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31773767

RESUMO

A case of atopic dermatitis (AD) with X-linked agammaglobulinemia (XLA), which is one of the primary immunodeficiency diseases, is reported. A 12-year-old boy had suffered from dry skin and recurrent itchy eruptions since he was 2 years old, and he was diagnosed as having XLA at the age of 4 years. His total immunoglobulin (Ig)E level was 7 IU/mL, even with regular Ig replacement therapy. Furthermore, filaggrin (FLG) mutations known in the Japanese population were not found. His skin lesions were well controlled by the application of a mild-class topical steroid and a moisturizer, though he developed folliculitis due to Staphylococcus aureus infection during treatment with a strong-class topical steroid. This case suggests that the FLG mutation and IgE-mediated sensitization are not necessary to induce AD skin manifestation.


Assuntos
Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Imunoglobulina E/imunologia , Proteínas S100/genética , Agamaglobulinemia/sangue , Agamaglobulinemia/complicações , Criança , Dermatite Atópica/sangue , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Humanos , Imunoglobulina E/sangue , Mutação com Perda de Função , Masculino
10.
Curr Opin Hematol ; 27(1): 11-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31652152

RESUMO

PURPOSE OF REVIEW: WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. We reviewed clinical manifestations in 24 patients in 9 families to expand understanding of this syndrome. RECENT FINDINGS: Warts, cellulitis and respiratory infections are common in patients with WHIMs. Less commonly these patients have congenital heart disease, human papilloma virus-associated malignancies (cervical and vulvular) and lymphomas. Hearing loss because of recurrent otitis media is another important complication. Treatment with granulocyte colony-stimulating factor is controversial; this review indicates that it is effective to prevent and treat infections based upon long-term observations of patients enrolled in the Severe Chronic Neutropenia International Registry. Understanding the natural history and diversity of this syndrome are important for ongoing clinical trials of novel agents to treat WHIMs. SUMMARY: WHIM syndrome has diverse manifestations; some features occur consistently in almost all patients, for example, neutropenia, lymphocytopenia and mild hypogammaglobulinemia. However, the clinical consequences are quite variable across patient cohorts and within families. Each complication is important as a cause for morbidity and a source for patient and family concerns.


Assuntos
Agamaglobulinemia , Família , Mutação , Doenças da Imunodeficiência Primária , Receptores CXCR4/genética , Sistema de Registros , Verrugas , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Agamaglobulinemia/terapia , Feminino , Humanos , Masculino , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/patologia , Doenças da Imunodeficiência Primária/terapia , Fatores de Risco , Verrugas/diagnóstico , Verrugas/genética , Verrugas/patologia , Verrugas/terapia
12.
BMC Neurol ; 19(1): 320, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830942

RESUMO

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years. CASE REPORT: An 8-year-old Chinese boy presented with fever, dizziness and recurrent vomiting for 3 days. The cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) results were suggestive of bacterial meningoencephalitis, despite the negative gram staining and cultures of the CSF. The patient was treated with broad-spectrum antibiotics and responded well to the treatment. He had history of another episode of acute pneumococci meningitis 4 years before. The respective level of Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM) was 4.85 g/L, 0.93 g/L and 0.1 g/L at 1st episode, whereas 1.9 g/L, 0.27 g/L and 0 g/L at second episode. The B lymphocytes were 0.21 and 0.06% of peripheral blood lymphocytes at first and second episode respectively. Sequencing of the BTK coding regions showed that the patient had a point mutation in the intron 14, hemizyous c.1349 + 5G > A, while his mother had a heterozygous mutation. It was a splice site mutation predicted to lead to exon skipping and cause a truncated BTK protein. CONCLUSION: Immunity function should be routinely checked in patients with severe intracranial bacterial infection. Absence of B cells even with normal level of serum immunoglobulin suggests the possibility of XLA, although this happens only in rare instances. Mutational analysis of BTK gene is crucial for accurate diagnosis to atypical patients with XLA.


Assuntos
Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Encefalite Infecciosa/genética , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Criança , Análise Mutacional de DNA , Diagnóstico Tardio , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Mutação
14.
Am J Med Genet A ; 179(12): 2474-2480, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31584751

RESUMO

Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Síndrome dos Cabelos Anágenos Frouxos/diagnóstico , Síndrome dos Cabelos Anágenos Frouxos/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/genética , Alelos , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Humanos , Mutação , Radiografia , Avaliação de Sintomas
15.
Front Immunol ; 10: 1871, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474980

RESUMO

Background: We report here two new familial cases of associated del15q11 and del7p22, with the latter underlining the clinical variability of this deletion. Two siblings patients presented a similar familial imbalanced translocation, originating from a balanced maternal translocation, with deletions of 7p22 and of 15q11 [arr[GRCh37] 7p22.3-p22.2(42976-3736851)x1, 15q11.1-q11.2(20172544-24979427)x1]. Methods: We used aCGH array, FISH, and karyotype for studying the phenotype of the two patients. Results: The 7p22 deletion (3.5 Mb) contained 58 genes, including several OMIM genes. Patients 1 and 2 exhibited acquisition delays, morphological particularities, and hypogammaglobulinemia, which was more severe in patient 1. Patient 1 presented also with cerebral vasculitis. Conclusion: We discuss here how the PDGFa, CARD11, LFNG, GPER1, and MAFK genes, included in the deletion 7p22, could be involved in the clinical and biological features of the two patients.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 7/genética , Síndromes de Imunodeficiência/genética , Agamaglobulinemia/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Criança , Feminino , Glicosiltransferases/genética , Guanilato Ciclase/genética , Humanos , Síndromes de Imunodeficiência/imunologia , Deficiência Intelectual/genética , Fator de Transcrição MafK/genética , Masculino , Fator de Crescimento Derivado de Plaquetas/genética , Receptores Estrogênicos/genética , Receptores Acoplados a Proteínas-G/genética
16.
Front Immunol ; 10: 1953, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31481959

RESUMO

X-linked agammaglobulinemia (XLA), caused by a mutation in the Bruton's tyrosine kinase (BTK) gene, is rarely reported in patients with recurrent hemophagocytic lymphohistiocytosis (HLH). This mutation leads to significantly reduced numbers of circulatory B cells and serum immunoglobulins in patients. Therefore, they exhibit repetitive bacterial infections since infancy, and immunoglobulin (Ig) replacement therapy is the primary treatment. HLH is a life-threatening condition with manifestations of non-remitting fever, hepatosplenomegaly, cytopenias, coagulopathy, lipid disorder, and multiple organ failure. It is caused by the immune dysregulation between cytotoxic T cells, NK cells, and histiocytes. The treatment is based on HLH-2004 protocol including immunotherapy, chemotherapy, supportive therapy, and stem cell transplantation. However, as we know more about the classification and pathophysiology of HLH, the treatment is modified. T-cell-directed immunotherapy is effective in patients with primary HLH, and strong immunosuppression is contraindicated in patients with severe ongoing infections or some primary immunodeficiency diseases (PIDs). Here, we report the case of a 7-year-old boy who presented with ecthyma gangrenosum and several episodes of pyogenic infections during childhood. At the age of 5 years, he exhibited cyclic HLH every 2-3 months. The remission of HLH episodes finally achieved after he received monthly Ig replacement therapy (400 mg/kg) at the 4th HLH. However, transient elevation of IgM was incidentally discovered after 6 cycles of monthly Ig replacement therapy. IgM-secreting multiple myeloma, Waldenström's macroglobulinemia, and lymphoma were excluded. The IgM levels then declined and returned to the normal range within a year. The patient and his parents received whole-genome sequencing analysis. It revealed a novel hemizygous c.1632-1G>A mutation in the BTK gene and XLA was diagnosed. XLA exhibits a spectrum of clinical and immunological presentations in patients. The identification of the mutation in the BTK gene contribute to an accurate diagnosis. Ig replacement therapy is the primary treatment for HLH in patients with XLA.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Linfo-Histiocitose Hemofagocítica/genética , Criança , Humanos , Masculino , Mutação
17.
BMC Med Genet ; 20(1): 157, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31510946

RESUMO

BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Therefore, gene sequencing, therapeutic drug monitoring and any possible measurement to predict DRT should be considered before determining the course of chemotherapy for XLA patients with CRC. CASE PRESENTATION: In this study, we reported a 21-year-old male who developed metastatic CRC in the context of XLA. Since the whole exome sequencing and therapeutic drug monitoring did not reveal any predictive markers of DRT, we applied standard first-line chemotherapy to the patient. However, progressive disease occurred after the fifth treatment cycle. Therefore, the administration of oxaliplatin was changed to irinotecan as second-line therapy. After that, the patient firstly suffered from severe hypocalcemia and eventually died due to metastatic CRC after the eighth treatment cycle. The overall survival time was 7.5 months. CONCLUSIONS: This study reported the first written record of a Chinese XLA patient with metastatic CRC and severe hypocalcemia. Whole exome sequencing and bioinformatic analysis indicated the somatic mutations in ABCA6, C6 and PAX3 genes might contribute to the early-onset and metastasis CRC. Besides, a number of germline mutations in genes related to calcium metabolism (CACNA2D4, CD36, etc.) and the administration of irinotecan were speculated to be the causes of severe hypocalcemia. We therefore suggested that in order to avoid severe DRT, clinicians should take genetic background and therapeutic drug monitoring into consideration while planning chemotherapy treatment for XLA patients with CRC.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Neoplasias Colorretais/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença/genética , Hipocalcemia/complicações , Irinotecano/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Agamaglobulinemia/diagnóstico por imagem , Grupo com Ancestrais do Continente Asiático , Linfócitos B , Canais de Cálcio Tipo L/genética , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Complemento C6/genética , Monitoramento de Medicamentos , Tratamento Farmacológico , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Humanos , Hipocalcemia/induzido quimicamente , Imunoglobulinas , Irinotecano/uso terapêutico , Masculino , Mutação , Oxaliplatina/uso terapêutico , Fator de Transcrição PAX3/genética , Sequenciamento Completo do Exoma , Adulto Jovem
18.
Immunol Invest ; 48(8): 860-874, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31185757

RESUMO

Toll-like receptors (TLRs) are inevitable elements for immunity development and antibody production. TLRs are in close interaction with Bruton's tyrosine kinase which has been found mutated and malfunctioned in the prototype antibody deficiency disease named X-linked agammaglobulinemia (XLA). TLRs' ability was evaluated to induce transcription of TLR-negative regulators, including suppressor of cytokine signaling 1 (SOCS1), interleukin-1 receptor-associated kinase 3 (IRAK-M), tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20), and Ring finger protein 216 (RNF216), and Tumor necrosis factor-α (TNF-α) and Interferon-α (IFN-α) production via Lipopolysaccharides (LPS) and CpG-A oligodeoxynucleotides (CpG-A ODN). Measured by TaqMan real-time polymerase chain reaction (PCR), meaningfully increased transcripts of SOCS1 and RNF216 were found in XLA peripheral blood mononuclear cells (PBMCs). Also, TLR inductions of XLA have led to similar downregulations in the regulator's transcription which was different from that in healthy donors. Cytokine measurement by enzyme-linked immunosorbent assay (ELISA) revealed a significant lower TNF-α production both before and after LPS. By selected molecules in this study, TLRs' potential defectiveness range expands TLRs expression, downstream signaling, and cytokine production. The results show new potential elements that could play a part in TLRs defect and pathogenesis of agammaglobulinemia as well.


Assuntos
Agamaglobulinemia/metabolismo , Citocinas/metabolismo , Leucócitos Mononucleares/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/metabolismo , Adolescente , Agamaglobulinemia/sangue , Agamaglobulinemia/genética , Células Cultivadas , Criança , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Oligodesoxirribonucleotídeos/farmacologia , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genética , Receptores Toll-Like/genética , Transcrição Genética/efeitos dos fármacos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Adulto Jovem
19.
Proc Natl Acad Sci U S A ; 116(26): 12952-12957, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31189594

RESUMO

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton's tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+ plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Agamaglobulinemia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Imunidade Humoral , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ácido Fítico/imunologia , Tirosina Quinase da Agamaglobulinemia/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Modelos Animais de Doenças , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Camundongos , Camundongos Transgênicos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ácido Fítico/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/imunologia
20.
Transfus Med ; 29(5): 364-368, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31115091

RESUMO

AIMS/OBJECTIVES: To investigate the underlying molecular mechanism of the patient's ABO typing discrepancy. BACKGROUND: ABO typing discrepancy was frequently seen in patients due to different causes. In this study, ABO typing discrepancy was found in a 24-year-old man with arthralgia, whose forward ABO grouping was O and reverse ABO grouping was AB. Primary immunodeficiency disease was speculated in this patient, especially X-linked agammaglobulinemia (XLA). METHODS: Immunoglobulins of all isotypes were detected using a specific protein analyser. Lymphocyte subgroups were analysed by flow cytometry. All 19 exons and boundaries of BTK gene were amplified by polymerase chain reaction (PCR), and all PCR products were sequenced by a DNA analyser. BTK protein in the leukocytes and platelets was detected by Western blot. RESULTS: No B lymphocytes could be detected in the peripheral blood of the patient. A novel BTK gene variation, c.817G>T, in the exon 9 of BTK gene was discovered. No BTK protein expression could be detected in the leukocytes and platelets of the patient. CONCLUSIONS: XLA could be occasionally discovered by ABO typing discrepancy in some cases because of the deficiency of reciprocal IgM anti-A and/or anti-B antibodies in the serum of the patient. Humoral immunodeficiency is one of the causes of ABO typing discrepancy.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia , Éxons , Doenças Genéticas Ligadas ao Cromossomo X , Variação Genética , Adulto , Tirosina Quinase da Agamaglobulinemia/biossíntese , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Tipagem e Reações Cruzadas Sanguíneas , Procedimentos Cirúrgicos Eletivos , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino
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