RESUMO
Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cytokine deregulation are known to characterize the evolution of the disease, allowing immune escape and proliferation of neoplastic plasma cells. In the past decades, several studies have shown that the immune system can recognize MGUS and MM clonal cells, suggesting that anti-myeloma T cell immunity could be harnessed for therapeutic purposes. In line with this notion, chimeric antigen receptor T cell (CAR-T) therapy is emerging as a novel treatment in MM, especially in the relapsed/refractory disease setting. In this review, we focus on the pivotal contribution of T cell impairment in the immunopathogenesis of plasma cell dyscrasias and, in particular, in the disease progression from MGUS to SMM and MM, highlighting the potentials of T cell-based immunotherapeutic approaches in these settings.
Assuntos
Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Paraproteinemias , Mieloma Múltiplo Latente , Progressão da Doença , Humanos , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Paraproteinemias/terapia , Linfócitos T/patologiaRESUMO
The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.
Assuntos
Antígenos de Neoplasias/imunologia , Leucemia Mieloide Aguda/imunologia , Proteínas Nucleares/genética , Linfócitos T/imunologia , Animais , Humanos , Imunoterapia/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Proteínas Nucleares/imunologia , NucleofosminaRESUMO
The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.
Assuntos
Células-Tronco Hematopoéticas/imunologia , Imunoterapia/métodos , Inflamação/imunologia , Transtornos Mieloproliferativos/terapia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Calreticulina/genética , Calreticulina/imunologia , Calreticulina/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Inflamação/genética , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Janus Quinase 2/metabolismo , Mutação/imunologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia , Cromossomo Filadélfia , Linfócitos T/metabolismo , Microambiente Tumoral/genéticaRESUMO
Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.
Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Doenças do Complexo Imune/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Células Th2/imunologia , Vasculite/imunologia , Idoso , Anticorpos Antivirais/biossíntese , Complexo Antígeno-Anticorpo/biossíntese , Betacoronavirus/imunologia , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/virologia , COVID-19 , Complemento C3/biossíntese , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/virologia , Progressão da Doença , Células Endoteliais/imunologia , Células Endoteliais/patologia , Células Endoteliais/virologia , Humanos , Doenças do Complexo Imune/complicações , Doenças do Complexo Imune/virologia , Imunidade Humoral , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Interleucina-6/biossíntese , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/virologia , Células Th2/patologia , Células Th2/virologia , Vasculite/complicações , Vasculite/virologiaRESUMO
Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.
Assuntos
Betacoronavirus/patogenicidade , Medula Óssea/patologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Trombose/patologia , Adulto , Idoso , Autopsia , Betacoronavirus/imunologia , Medula Óssea/imunologia , Medula Óssea/virologia , COVID-19 , Núcleo Celular/imunologia , Núcleo Celular/patologia , Núcleo Celular/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Estado Terminal , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Evolução Fatal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-6/biossíntese , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Megacariócitos/imunologia , Megacariócitos/patologia , Megacariócitos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Índice de Gravidade de Doença , Trombopoese/imunologia , Trombose/complicações , Trombose/imunologia , Trombose/virologiaRESUMO
Nucleophosmin (NPM1) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico-pathologic entities. Furthermore, fit patients with NPM1-mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing NPM1-mutated MNs with blast count <20%, since NPM1-mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to NPM1-mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether NPM1 mutations may become sufficient to diagnose AML, irrespective of blast percentage.
Assuntos
Crise Blástica/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação/genética , Proteínas Nucleares/genética , Animais , Modelos Animais de Doenças , Hematopoese/genética , Humanos , NucleofosminaRESUMO
Both human immunodeficiency virus (HIV) infection and acute myeloid leukemia (AML) may be considered relatively uncommon disorders in the general population, but the precise incidence of AML in people living with HIV infection (PLWH) is uncertain. However, life expectancy of newly infected HIV-positive patients receiving anti-retroviral therapy (ART) is gradually increasing, rivaling that of age-matched HIV-negative individuals, so that the occurrence of AML is also expected to progressively increase. Even if HIV is not reported to be directly mutagenic, several indirect leukemogenic mechanisms, mainly based on bone marrow microenvironment disruption, have been proposed. Despite a well-controlled HIV infection under ART should no longer be considered per se a contraindication to intensive chemotherapeutic approaches, including allogeneic hematopoietic stem cell transplantation, in selected fit patients with AML, survival outcomes are still generally unsatisfactory. We discussed several controversial issues about pathogenesis and clinical management of AML in PLWH, but few evidence-based answers may currently be provided, due to the limited number of cases reported in the literature, mainly as case reports or small retrospective case series. Prospective multicenter clinical trials are warranted to more precisely investigate epidemiology and cytogenetic/molecular features of AML in PLWH, but also to standardize and further improve its therapeutic management.
Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Comorbidade , Tratamento Farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Análise de Sobrevida , Resultado do TratamentoAssuntos
Leucemia Mieloide Aguda , Células-Tronco de Sangue Periférico , Humanos , Adulto , Estudos de Viabilidade , Estaurosporina/uso terapêutico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoAssuntos
COVID-19/complicações , Herpes Simples/complicações , Herpesvirus Humano 1/isolamento & purificação , Necrose Hepática Massiva/complicações , Viremia/complicações , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , COVID-19/patologia , COVID-19/terapia , Gerenciamento Clínico , Herpes Simples/patologia , Herpes Simples/terapia , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Unidades de Terapia Intensiva , Masculino , Necrose Hepática Massiva/patologia , Necrose Hepática Massiva/terapia , Pessoa de Meia-Idade , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Viremia/patologia , Viremia/terapiaAssuntos
COVID-19/imunologia , Imunoglobulina G/análise , Laringoestenose/imunologia , Plasmócitos/imunologia , SARS-CoV-2 , Células Th2/imunologia , Traqueia/imunologia , Traqueostomia/efeitos adversos , Idoso , Cicatriz/etiologia , Cicatriz/imunologia , Diagnóstico Diferencial , Fibrose , Humanos , Doença Relacionada a Imunoglobulina G4/diagnóstico , Laringoestenose/etiologia , Laringoestenose/patologia , Masculino , Plasmócitos/patologia , Traqueia/patologia , Traqueia/cirurgiaAssuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Células Th2 , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/fisiopatologia , Progressão da Doença , Humanos , Imunidade Humoral , Interleucina-6/sangue , Interleucina-6/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/fisiopatologia , SARS-CoV-2 , Células Th2/imunologiaAssuntos
Betacoronavirus , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Transtornos Linfoproliferativos/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Idoso , COVID-19 , Coinfecção , Infecções por Coronavirus/complicações , Infecções por Vírus Epstein-Barr/complicações , Evolução Fatal , Humanos , Transtornos Linfoproliferativos/complicações , Masculino , Pandemias , Pneumonia Viral/complicações , SARS-CoV-2Assuntos
Anemia Aplástica/epidemiologia , Tuberculose Latente/epidemiologia , Leucemia Mieloide Aguda/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/tratamento farmacológico , Antituberculosos/uso terapêutico , Vacina BCG , Terapia Combinada , Comorbidade , Neutropenia Febril/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Testes de Liberação de Interferon-gama , Isoniazida/uso terapêutico , Tuberculose Latente/diagnóstico por imagem , Tuberculose Latente/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Adulto JovemAssuntos
Betacoronavirus , Infecções por Coronavirus , Pneumonia Viral , COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Upon infection activated plasma cells produce large quantities of antibodies which can lead to the emergence of a monoclonal component (MC), detectable by serum protein electrophoresis (SPEP). This study aims to investigate any correlation between SARS-CoV-2 infection and MC development and, if identified, whether it persists during follow-up. METHODS: SPEPs of 786 patients admitted to hospitals between March 01 2020 and March 31 2022 were evaluated. Positive (SARS-CoV-2+) and negative (SARS-CoV-2-) patients to nasopharyngeal swab for SARS-CoV-2 by RT-PCR were included. The persistence/new occurrence of MC was investigated for all patients during follow-up. Patient groups were compared by chi-square analysis. RESULTS: MC was identified in 12% of all patients admitted to hospital, of which 28.7% were SARS-CoV-2+. The most common immunoglobulin isotype in both groups was IgG-k. There was no correlation between MC development and SARS-CoV-2 infection (p = 0.173). Furthermore, the risk of MC persistence in SARS-CoV-2-negative patients was revealed to be higher than in the SARS-CoV-2+ at follow-up (HR = 0.591, p = 0.05). CONCLUSIONS: Our study suggests that the detection of MC during SARS-CoV-2 infection is most likely due to the hyperstimulation of the humoral immune system, as also occurs in other viral infections.
Assuntos
COVID-19 , Paraproteinemias , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/sangue , COVID-19/diagnóstico , SARS-CoV-2/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Paraproteinemias/sangue , Adulto , Idoso de 80 Anos ou mais , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Eletroforese das Proteínas SanguíneasRESUMO
OBJECTIVE: We investigated the performance of enzyme linked immunospot (ELISpot) assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematologic malignancies. METHODS: We prospectively enrolled two cohorts of patients undergoing intensive myelosuppressive or immunosuppressive treatments at high risk for IA. ELISpot was performed to detect Aspergillus-specific T cells producing Interleukin-10. RESULTS: In the discovery cohort, a derived cut-off of 40 spot forming cells (SFCs)/106 PBMCs has shown to correctly classify IA cases with a sensitivity and specificity of 89.5% and 88.6%, respectively. This cut-off is lowered to 25 SFC when considering the subset of possible IA patients, with sensitivity and specificity of 76% and 93%, respectively. The application of the 40 SFCs cut-off to the validation cohort resulted in a positivity rate of 83.3% in proven/probable cases and a negativity rate of 92.5% in possible/non-IA cases. Adopting the 25 SCFs cut-off, the assay resulted positive in 83.3% of proven/probable cases while it resulted negative in 66.7% of possible/non-IA cases. CONCLUSIONS: ELISpot shows promises in the diagnosis of IA and the possibility to use two distinct cut-offs with similar diagnostic performances according to patients' different pre-test probability of infection can widen its use in patients at risk.
Assuntos
ELISPOT , Humanos , ELISPOT/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Estudos Prospectivos , Aspergilose/diagnóstico , Aspergilose/imunologia , Interleucina-10/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/diagnóstico , Sensibilidade e Especificidade , Linfócitos T/imunologiaRESUMO
The trajectory of B cell development goes through subsequent steps governed by complex genetic programs, strictly regulated by multiple transcription factors. Interferon regulatory factor 4 (IRF4) regulates key points from pre-B cell development and receptor editing to germinal center formation, class-switch recombination and plasma cell differentiation. The pleiotropic ability of IRF4 is mediated by its "kinetic control", allowing different IRF4 expression levels to activate distinct genetic programs due to modulation of IRF4 DNA-binding affinity. IRF4 is implicated in B cell malignancies, acting both as tumor suppressor and as tumor oncogene in different types of precursors and mature B cell neoplasia. Here, we summarize the complexity of IRF4 functions related to different DNA-binding affinity, multiple IRF4-specific target DNA motif, and interactions with transcriptional partners. Moreover, we describe the unique role of IRF4 in acute leukemias and B cell mature neoplasia, focusing on pathogenetic implications and possible therapeutic strategies in multiple myeloma and chronic lymphocytic leukemia.
Assuntos
Centro Germinativo , Neoplasias , Humanos , Diferenciação Celular , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , DNA/metabolismoRESUMO
Multiple Myeloma (MM) typically originates from underlying precursor conditions, known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Validated risk factors, related to the main features of the clonal plasma cells, are employed in the current prognostic models to assess long-term probabilities of progression to MM. In addition, new prognostic immunologic parameters, measuring protective MM-specific T-cell responses, could help to identify patients with shorter time-to-progression. In this report, we described a novel Multi-antigenic Myeloma-specific (MaMs) T-cell assay, based on ELISpot technology, providing simultaneous evaluation of T-cell responses towards ten different MM-associated antigens. When performed during long-term follow-up (mean 28 months) of 33 patients with either MGUS or SMM, such deca-antigenic myeloma-specific immunoassay allowed to significantly distinguish between stable vs. progressive disease (p < 0.001), independently from the Mayo Clinic risk category. Here, we report the first clinical experience showing that a wide (multi-antigen), standardized (irrespective to patients' HLA), MM-specific T-cell assay may routinely be applied, as a promising prognostic tool, during the follow-up of MGUS/SMM patients. Larger studies are needed to improve the antigenic panel and further explore the prognostic value of MaMs test in the risk assessment of patients with monoclonal gammopathies.
RESUMO
In recent years, the introduction of new drugs targeting Bruton's tyrosine kinase (BTK) has allowed dramatic improvement in the prognosis of patients with chronic lymphocytic leukemia (CLL) and other B-cell neoplasms. Although these small molecules were initially considered less immunosuppressive than chemoimmunotherapy, an increasing number of reports have described the occurrence of unexpected opportunistic fungal infections, in particular invasive aspergillosis (IA). BTK represents a crucial molecule in several signaling pathways depending on different immune receptors. Based on a variety of specific off-target effects on innate immunity, namely on neutrophils, monocytes, pulmonary macrophages, and nurse-like cells, ibrutinib has been proposed as a new host factor for the definition of probable invasive pulmonary mold disease. The role of platelets in the control of fungal growth, through granule-dependent mechanisms, was described in vitro almost two decades ago and is, so far, neglected by experts in the field of clinical management of IA. In the present study, we confirm the antifungal role of platelets, and we show, for the first time, that the exposure to BTK inhibitors impairs several immune functions of platelets in response to Aspergillus fumigatus, i.e., the ability to adhere to conidia, activation (as indicated by reduced expression of P-selectin), and direct killing activity. In conclusion, our experimental data suggest that antiplatelet effects of BTK inhibitors may contribute to an increased risk for IA in CLL patients.