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2.
Infez Med ; 27(1): 73-76, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30882382

RESUMO

Agammaglobulinemia is a congenital deficit of humoral immunity characterized by a decreased level or complete absence of immunoglobulins and profound reduction of B-lymphocytes associated with an increased risk of life-threatening bacterial infection. We report a case of invasive Pseudomonas aeruginosa severe skin and soft tissue infection treated with vacuum-assisted closure and antibiotics in a toddler with a previously unreported mutation of the Bruton tyrosin kinase gene.

3.
J Allergy Clin Immunol Pract ; 7(5): 1568-1577, 2019 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30716504

RESUMO

BACKGROUND: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. OBJECTIVE: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. METHODS: Data were collected from an international cohort of 18 patients with CXCR4 mutations. RESULTS: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. CONCLUSIONS: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.

5.
Clin Immunol ; 200: 31-34, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639166

RESUMO

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.

6.
Clin Immunol ; 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30500415

RESUMO

This study provides evidence for a novel role for NFKB2 in human B cell development in the bone marrow and in the periphery, leading to progressive peripheral B cell deficiency not always combined with autoimmune phenomena, broadening thus the clinical spectrum of NFKB2 mutated CVID disease and implying an essential role for NFKB2 in early human B cell development.

7.
Cancer Immunol Res ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30401679

RESUMO

Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in loco-regional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared to what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma (MM) patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR-agonist based trials.

10.
Clin Immunol ; 191: 75-80, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29548898

RESUMO

Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common ß-chain of the ß2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.

14.
Front Immunol ; 8: 798, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769923

RESUMO

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

17.
Immunol Lett ; 177: 22-4, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27378136

RESUMO

Herein we describe the case of a 8-years-old boy with diagnosis of atypical autoimmune lymphoproliferative syndrome (ALPS), carrying heterozygous mutation of CASP10 gene (I406L). He presented with multiple non-invasive infections of the skin, that were associated to chronic non-malignant non-infectious lymphadenopathy, failure to thrive, weakness, arthralgia, relapsing oral aftosis, and expansion of TCRαß(+) CD4(-)/CD8(-) T cells. This observation suggests that cutaneous infections can be observed in ALPS patients carrying CASP10 mutations.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Caspase 10/genética , Infecção/imunologia , Pele/imunologia , Linfócitos T/imunologia , Síndrome Linfoproliferativa Autoimune/genética , Proliferação de Células , Criança , Humanos , Linfadenopatia , Masculino , Penetrância , Característica Quantitativa Herdável , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Pele/microbiologia , Pele/patologia , Estomatite Aftosa
18.
Blood ; 127(26): 3382-6, 2016 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-27207797

RESUMO

Hermansky-Pudlak syndrome type 2 (HPS2) is a primary immunodeficiency due to adaptor protein-3 (AP-3) complex deficiency. HPS2 patients present neutropenia, partial albinism, and impaired lysosomal vesicles formation in hematopoietic cells. Given the role of dendritic cells (DCs) in the immune response, we studied monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) in two HPS2 siblings. Mature HPS2 moDCs showed impaired expression of CD83 and DC-lysosome-associated membrane protein (LAMP), low levels of MIP1-ß/CCL4, MIG/CXCL9, and severe defect of interleukin-12 (IL-12) secretion. DCs in lymph-node biopsies from the same patients showed a diffuse cytoplasm reactivity in a large fraction of DC-LAMP(+) cells, instead of the classical dot-like stain. In addition, analysis of pDC-related functions of blood-circulating mononuclear cells revealed reduced interferon-α secretion in response to herpes simplex virus-1 (HSV-1), whereas granzyme-B induction upon IL-3/IL-10 stimulation was normal. Finally, T-cell costimulatory activity, as measured by mixed lymphocyte reaction assay, was lower in patients, suggesting that function and maturation of DCs is abnormal in patients with HPS2.


Assuntos
Complexo 3 de Proteínas Adaptadoras/deficiência , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Síndrome de Hermanski-Pudlak/imunologia , Monócitos/imunologia , Complexo 3 de Proteínas Adaptadoras/imunologia , Antígenos CD/genética , Antígenos CD/imunologia , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/imunologia , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/patologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Granzimas/genética , Granzimas/imunologia , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/patologia , Herpesvirus Humano 1/imunologia , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Monócitos/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
19.
J Allergy Clin Immunol ; 138(1): 229-240.e3, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26875746

RESUMO

BACKGROUND: Partial DiGeorge syndrome (pDGS) is caused by deletion of the 22q11.2 region. Within this region lies CrK-like (CRKL), a gene encoding an adapter protein belonging to the Crk family that is involved in the signaling cascade of IL-2, stromal cell-derived factor 1α, and type I interferon. Although recurrent infections can be observed in patients with deletion of chromosome 22 syndrome, the immune pathogenesis of this condition is yet not fully understood. OBJECTIVE: We aimed to investigate the role of CRKL in T-cell functional responses in patients affected with pDGS. METHODS: Protein expression levels and phosphorylation of CRKL were evaluated in patients with pDGS. T-cell functional assays in vitro and gene-silencing experiments were also performed. RESULTS: CRKL protein expression, as well as its phosphorylation, were reduced in all patients with pDGS, especially on IL-2 stimulation. Moreover, T cells presented impaired proliferation and reduced IL-2 production on anti-CD3/CD28 stimulation and decreased c-Fos expression. Finally, CRKL silencing in Jurkat T cells resulted in impaired T-cell proliferation and reduced c-Fos expression. CONCLUSIONS: The impaired T-cell proliferation and reduction of CRKL, phosphorylated CRKL, and c-Fos levels suggest a possible role of CRKL in functional deficiencies of T cells in patients with pDGS.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Síndrome de DiGeorge/etiologia , Síndrome de DiGeorge/metabolismo , Regulação da Expressão Gênica , Proteínas Nucleares/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Biomarcadores , Estudos de Casos e Controles , Linhagem Celular , Criança , Pré-Escolar , Citocinas/biossíntese , Síndrome de DiGeorge/diagnóstico , Inativação Gênica , Humanos , Isotipos de Imunoglobulinas/sangue , Isotipos de Imunoglobulinas/imunologia , Lactente , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Fenótipo , Fosforilação , Interferência de RNA , Fator de Transcrição STAT5/metabolismo , Adulto Jovem
20.
Orphanet J Rare Dis ; 11: 3, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26758562

RESUMO

Proteus syndrome (PS) is an extremely rare and complex disease characterized by malformations and overgrowth of different tissues. Prognosis of affected patients may be complicated by premature death, mostly due to pulmonary embolism and respiratory failure. To date, immunological data in Proteus syndrome are scarse.We report on the novel immunologic findings of a 15 years old girl affected with PS. Detailed T and B cell evaluation revealed maturational alterations for both subsets and functional hyperactivation for the latter. Such findings have not been reported previously in PS and may be the spy of more complex immune abnormalities in this syndrome.


Assuntos
Síndrome de Proteu/diagnóstico , Síndrome de Proteu/imunologia , Adolescente , Linfócitos B/imunologia , Feminino , Humanos , Síndrome de Proteu/complicações , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiologia , Embolia Pulmonar/imunologia , Linfócitos T/imunologia
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