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Merkel cell carcinoma is a very aggressive primary skin tumour with a high risk of local recurrences and lymphatic and distant metastases. The frequent association between this carcinoma and other skin tumour and lymphoid malignancies, its similar cellular morphology with leukocytes, and limited infiltration in bone marrow constituted a challenging diagnosis. We report an unusual case of an 82-year-old male who simultaneously presented Merkel cell carcinoma and acute myeloid lymphoma. The diagnosis was established through flow cytometry, immunohistochemical studies and next generation sequencing (NGS) analysis. Flow cytometry allowed for the differentiation of the two cell populations in bone marrow aspirate, which was crucial to the diagnosis of Merkel cell carcinoma and acute myeloid leukaemia (AML), after confirmed by immunohistochemistry. AML could be classified based on NGS results. Following diagnosis, the patient received palliative care and died 50 days later. immunophenotypic analysis by flow cytometry and Immunohistochemical study was crucial to establish the diagnosis of simultaneous affection of Merkel cell carcinoma and hematologic disorder.
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Inflammation causes a wide range of health disorders. In this process, the formation of inflammasome complexes plays a key role. Although inflammasomes have been extensively studied during kidney disease, their role in kidney transplantation has not been fully elucidated. In this study, we evaluate the gene and protein expression of several components of the inflammasome pathway before and at several time points after kidney transplantation in a cohort of patients of different ages and receiving an organ from older or younger donors. Our findings indicate the activation of the NLRP1 inflammasome in several immune cell population, monocytes and CD4+ and CD8+ cells mainly, in renal transplant, and its level increases gradually in patients who receive an older organ, whereas it has the opposite effect on older patients who receive a younger organ. Despite treatment with immunosuppressants, inflammation persists in some patients. These results lead to the hypothesis that the donor's age is a critical factor in post-transplant inflammasome activation and that specific NLRP1 inflammasome inhibitors should be considered to increase the success of kidney transplantation long-term.
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Renal transplantation is an effective treatment for severe chronic kidney diseases. However, young patients often face a scarcity of kidneys from donors of similar age, resulting in the transplantation of older organs, which increase the risk of graft rejection and several complications compared with older individuals who receive kidneys from donors of similar age or younger. This article focuses on studying different senescence biomarkers in donors and patients who received kidneys from various age ranges complying with the STROBE requirements. We studied 61 patients subjected to renal transplant isolating blood samples 24 h before, and 24 h, 3 days, 7 days, 3 months, and 6 months after transplant. The patients were divided into three groups: older donor than the patient (Old Donor), younger donor than the patient (Young Donor), and similar age (Matched). We studied different senescence markers such as p16, p21, interleukin 6 (IL-6), and senescence-associated secretory phenotype (SASP) release. Young patients who receive older organs showed increased mRNA and protein expression of the senescence makers. Hence, increased SASP release was also observed in patients from older donor. In contrast, older patients who receive younger organs showed a slow but consistent improvement in their initial senescent phenotype. In addition, macrophage cell model treated with blood-derived serum from patients 6 months after the transplant showed a pro-senescence environment in macrophages proposed by the SASP from the patients. These results lead the hypothesis that senolytics could reduce the presence of senescent cells and mitigate the complications associated with the transplantation of older organs in young patients.
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Biomarcadores , Senescência Celular , Transplante de Rim , Doadores de Tecidos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Fatores Etários , Idoso , Fenótipo Secretor Associado à Senescência , Interleucina-6/metabolismo , Interleucina-6/sangueRESUMO
The high mortality rate due to COVID-19 has necessitated the mass vaccination against SARS-CoV-2 to induce protective humoral and cellular immunity. (1) Objective: To study the dynamics of SARS-CoV-2-specific B cells after two doses of the Pfizer-BioNTech SARS-CoV-2 vaccine. (2) Methods: Immunophenotyping and cellular cultures were used to determine the kinetics of B-cell subpopulations and vaccine responses in volunteers before and seven days, three months and seven months after the second dose in Spain (n = 19). (3) Results: Seven days after immunisation, memory B cells and plasmablasts expressing receptors for factors implicated in the maturation of plasma cells were augmented in blood. Three months after vaccination, SARS-CoV-2 spike-specific plasmablasts disappeared from circulation while spike-specific memory-B cells circulated, with heterogeneous dynamics among individuals. (4) Conclusion: After vaccination, specific plasmablasts equipped with receptors for maturation factors were quickly generated and disappeared rapidly from the blood, while specific memory B cells circulated for at least seven months.
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Gestational diabetes mellitus (GDM) increases the risk of hypertensive disorders of pregnancy (HDP). We aimed to analyze the altered inflammatory markers and angiogenic factors among women with GDM to identify pregnant women at higher risk of developing HDP. Methods: This was a prospective study of 149 women without hypertension diagnosed in the third trimester with GDM. Inflammatory markers and angiogenic factors were measured at 28−32 weeks of pregnancy. Obstetric and perinatal outcomes were evaluated. Results: More than eight percent of the women developed HDP. Higher levels of the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PIGF) ratio (4.9 ± 2.6 versus 2.3 ± 1.3, respectively; p < 0.001) and leptin (10.9 ± 0.8 versus 10.08 ± 1.1, respectively; p = 0.038), as well as lower levels of adiponectin (10.5 ± 1.3 versus 12.9 ± 2.7, respectively; p = 0.031), were seen in women who developed HDP versus normotensive women with GDM. A multivariable logistic regression analysis showed that adiponectin had a protective effect with 0.45-fold odds (0.23−0.83; p = 0.012), and that the sFlt-1/PIGF ratio was associated with 2.70-fold odds of developing HDP (CI 95%: 1.24−5.86; p = 0.012). Conclusion: An increase in angiogenic imbalance in the sFlt-1/PIGF ratio in women with GDM was detected and may be an indicator of developing HDP in addition to any subsequent obstetric and perinatal complications.
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Systemic lupus erythematosus and rheumatoid arthritis are autoimmune diseases characterised by B-cell hyperactivation and production of autoantibodies (AutoAbs) against various self-antigens, including extractable nuclear antigens and citrullinated peptides. Therefore, B lymphocytes and antibody-secreting cells are considered relevant targets for therapies. However, isolation and characterisation of auto-reactive specific B lymphocytes are limited, primarily due to technical issues. In this work, we purified extractable nuclear antigen-specific and citrullinated peptide-specific auto-reactive B lymphocytes by magnetic selection with ENA- and citrullinated peptide-bound immunobeads. We obtained blood auto-reactive B lymphocytes from most patients. Their nature was primarily naïve B cells, some of them in an active status, with low levels of somatic hypermutations in the immunoglobulin heavy-chain variable regions. Their presence correlated with serum levels of autoAb. Auto-reactive B lymphocytes were able to differentiate into auto-reactive antibody-secreting cells under conditions of stimulation. In addition, based on the presence of circulating auto-reactive B cells and/or antibody-secreting cells, four different profiles were described in lupus patients. Thus, tracking auto-reactive B cells and/or antibody-secreting cells in patient blood could represent a biomarker for deciding whether to use therapies blocking either B cells, plasma cells or both, as well as a new tool for monitoring minimal residual autoimmune disease in patients.
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Antígenos Nucleares/metabolismo , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Separação Imunomagnética/métodos , Lúpus Eritematoso Sistêmico/imunologia , Adolescente , Adulto , Idoso , Autoantígenos/imunologia , Biomarcadores , Células Cultivadas , Citrulinação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Adulto JovemRESUMO
We describe a successful desensitization to alemtuzumab in one patient diagnosed with T-cell prolymphocytic leukaemia. Alemtuzumab treatment was initiated during infusion number 18, the patient showed cutaneous eruption with a miliary pattern, despite premedication with corticosteroids and antihistamines. The eruption returned with successive alemtuzumab infusions (infusions 19, 20 and 21), remained present for longer and was more severe with each infusion. The patient was referred to our Allergy Unit as it was necessary to maintain alemtuzumab treatment. Total immunoglobulin E level was 3 UI/ml and specific immunoglobulin E against more common pneumo-allergens, food, latex and hamster were inferior to 0.35 UI/ml. Prick test using the undiluted drug (30 mg/ml) and intradermal tests using serial dilutions (1/10, 1/100) were performed. The result of alemtuzumab skin prick test was 4 mm. The intradermal skin test result was positive at 1/100 dilution (papule: 8 mm; erythema: 12 mm). The basophil activation test with alemtuzumab was performed concluding that 10% of the basophils were activated by alemtuzumab. The patient underwent alemtuzumab desensitization according to a 12-step protocol that resolved to be safe and efficacious. Our experience may be helpful for similar clinical cases where the therapeutic options are very limited and a life-threatening condition such T-cell prolymphocytic leukaemia is present. In addition, a careful risk/benefit ratio should be considered and accurate informed consent is mandatory.
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Alemtuzumab/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/terapia , Adulto , Humanos , Masculino , Testes CutâneosRESUMO
Hemophagocytic lymphohistiocytosis is characterized by uncontrolled activation of the immune system that leads to systemic hyperinflammation. Lymphoproliferative syndrome linked to the X chromosome is a hereditary immunodeficiency characterized by an inability to mount an adequate immune response to an Epstein-Barr virus infection. Hemophagocytic lymphohistiocytosis is one of the main clinical features of X-linked lymphoproliferative syndrome. We report the case of a patient who presented with primary hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection without a familial history of immunodeficiency. A mutation in the SH2D1A gene was identified, which confirmed the diagnosis of type 1 X-linked lymphoproliferative syndrome.
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Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Mutação , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Substituição de Aminoácidos , Biomarcadores , Biópsia , Criança , Códon , Análise Mutacional de DNA , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Humanos , Imunofenotipagem , Masculino , Imagem Multimodal , FenótipoAssuntos
Teste de Degranulação de Basófilos/métodos , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/prevenção & controle , Imunoconjugados/efeitos adversos , Adulto , Brentuximab Vedotin , Feminino , Doença de Hodgkin/tratamento farmacológico , Humanos , Imunoconjugados/imunologia , Masculino , Pessoa de Meia-IdadeAssuntos
Ciclosporina/uso terapêutico , Glucagonoma/complicações , Eritema Migratório Necrolítico/tratamento farmacológico , Neoplasias Pancreáticas/complicações , Fármacos Dermatológicos/uso terapêutico , Glucagonoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Eritema Migratório Necrolítico/diagnóstico , Eritema Migratório Necrolítico/etiologia , Neoplasias Pancreáticas/diagnóstico , Síndromes Paraneoplásicas/complicações , Síndromes Paraneoplásicas/diagnósticoRESUMO
Disturbances of plasma cell homeostasis and auto-antibody production are hallmarks of systemic lupus erythematosus. The aim of this study was to explore the presence of circulating anti-ENA and anti-dsDNA antibody-secreting cells, to determine their dependence on plasma cell-niche cytokines and to analyze their clinical value. The study was performed in SLE patients with serum anti-ENA and/or anti-dsDNA antibodies (n = 57). Enriched B-cell fractions and sorted antibody-secreting cells (CD19low CD38high ) were obtained from blood. dsDNA- and ENA-specific antibody-secreting cells were identified as cells capable of active auto-antibody production in culture. The addition of a combination of IL-6, IL-21, BAFF, APRIL, and CXCL12 to the cultures significantly augmented auto-antibody production and antibody-secreting cell proliferation, whereas it diminished apoptosis. The effect on auto-antibody production was dependent on STAT-3 activation as it was abrogated in the presence of the JAK/STAT-3 pathway inhibitors ruxolitinib and stattic. Among patients with serum anti-dsDNA antibodies, the detection of circulating anti-dsDNA-antibody-secreting cells was associated with higher disease activity markers. In conclusion, auto-antibody production in response to plasma cell-niche cytokines that are usually at high levels in SLE patients is dependent on JAK/STAT-3 activation. Thus, patients with circulating anti-dsDNA antibody-secreting cells and active disease could potentially benefit from therapies targeting the JAK/STAT3 pathway.