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Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and genetic heterogeneity, with monogenic transmission accounting for only a minority of the cases. Here, we report a pair of monozygotic twins concordant for CVID without a family history of primary immunodeficiency. They featured a remarkably similar profile of clinical manifestations and immunological alterations at diagnosis (established at age 37) and along the subsequent 15 years of follow-up. Interestingly, whole-exome sequencing failed to identify a monogenic cause for CVID, but unraveled a combination of heterozygous variants, with a predicted deleterious impact. These variants were found in genes involved in relevant immunological pathways, such as JUN, PTPRC, TLR1, ICAM1, and JAK3. The potential for combinatorial effects translating into the observed disease phenotype is inferred from their roles in immune pathways, namely in T and B cell activation. The combination of these genetic variants is also likely to impose a significant constraint on environmental influences, resulting in a similar immunological phenotype in both twins, despite exposure to different living conditions. Overall, these cases stress the importance of integrating NGS data with clinical and immunological phenotypes at the single-cell level, as provided by multi-dimensional flow-cytometry, in order to understand the complex genetic landscape underlying the vast majority of patients with CVID, as well as those with other immunodeficiencies.
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Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/etiologia , Suscetibilidade a Doenças , Gêmeos Monozigóticos , Adulto , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Humanos , Imunofenotipagem , Masculino , Herança Multifatorial , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Avaliação de Sintomas , Linfócitos T/imunologia , Linfócitos T/metabolismo , Sequenciamento do ExomaRESUMO
Sarcoidosis involving the digestive tract is very rare and requires a strict differential diagnosis with other systemic granulomatous diseases. We present a case of multisystemic granulomatosis involving the stomach and colon, causing initial digestive symptoms. Pulmonary nodules, pleural effusion, ascites, hepatomegaly, splenomegaly, and mesenteric as well as retroperitoneal and axillary lymphadenopathy were subsequently identified. The reticulo-endothelial expression, the hypercalcemia and, above all, a rapid and complete resolution after corticosteroids supported the hypothesis of sarcoidosis involving the digestive tract. A brief review of digestive tract involvement in sarcoidosis and of the distinctive features of sarcoidosis with gastrointestinal involvement and Crohn's disease with a rare form of pleuro-pulmonary involvement is presented.
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The contribution of the decline in thymic activity for the emergence of autoimmunity is still debatable. Immune-competent adults submitted to complete thymectomy early in life provide a unique model to address this question. We applied here strict criteria to identify adults lacking thymic activity based on sjTREC levels, to exclude thymic rebound and/or ectopic thymuses. In agreement, they featured severe naïve CD4 T-cell depletion and contraction of T-cell receptor diversity. Notwithstanding this, there was neither increased incidence of autoimmune disease in comparison with age-matched controls nor significant changes in their IgG/IgA/IgM/IgE autoreactivity profiles, as assessed through extensive arrays. We reasoned that the observed relative preservation of the regulatory T-cell compartment, including maintenance of naïve regulatory CD4 T-cells, may contribute to limit the emergence of autoimmunity upon thymectomy. Our findings have implications in other clinical settings with impaired thymic activity, and are particularly relevant to studies of autoimmunity in ageing.
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Envelhecimento/imunologia , Imunocompetência , Isotipos de Imunoglobulinas/biossíntese , Linfócitos T Reguladores/imunologia , Timectomia/reabilitação , Timo/cirurgia , Adulto , Doenças Autoimunes/prevenção & controle , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Expressão Gênica , Humanos , Hipersensibilidade/prevenção & controle , Isotipos de Imunoglobulinas/genética , Lactente , Estudos Longitudinais , Masculino , Receptores de Antígenos de Linfócitos T/deficiência , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/citologia , Timo/imunologiaRESUMO
Introduction: recent literature suggests that excessive use of blood cultures could prolong length of stay and hospital costs. Moreover, low positive rates have been reported and positivity predictive scores have recently been proposed. Methods: we conducted an observational prospective study in an Internal Medicine department of a university reference hospital analysing data from all patients to whom BC was requested. Results: blood cultures were performed in 39.9% of 414 admissions. Patients with blood cultures had higher length of stay and underwent more laboratory and imaging diagnostic tests. Global positivity rate was of 7.5%. Patients fulfilling sepsis criteria had a higher positivity rate (21.7%) and there were no positive blood cultures in patients without sepsis, namely in cases of isolated creactive protein elevation, leucocytosis or fever. In addition, blood cultures results were not a determinant of antibiotic adjust or de-escalation. Conclusions: our data suggest that the use of BC should be done essentially in patients with sepsis criteria, reducing its unnecessary use, although more studies are required to validate such practice (AU)
Introdução: o uso excessivo de hemoculturas tem sido associado a aumento do tempo de internamento e de custos hospitalares. Adicionalmente, a literatura médica reporta taxas de positividade abaixo do esperado, levando à criação de índices de predição de positividade. Métodos: estudo prospectivo observacional conduzido numa enfermaria de Medicina Interna de um hospital terciário, com recolha de dados de todos os doentes a quem foram realizadas hemoculturas. Resultados: em 414 admissões, foram colhidas hemoculturas em 39.9%. Os doentes a quem foram colhidas hemoculturas tiveram maior tempo de internamento e mais exames laboratoriais e imagiológicos pedidos. 7,5% das hemoculturas foram positivas. Nos doentes com critérios de sepsis a taxa de positividade das hemoculturas foi 21,7% e não houve nenhuma hemocultura positiva em doente sem critérios de sépsis, nomeadamente em doentes com elevação isolada de proteína c-reactiva, leucocitose ou febre. O resultado da hemocultura não foi um determinante de de-escalação antibiótica. Conclusões: este estudo sugere que as hemoculturas devem ser colhidas essencialmente em doentes com sepsis, podendo esta prática diminuir o seu sobreuso. (AU)
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Humanos , Masculino , Feminino , Hemocultura , Medicina Interna , Microbiologia , SepseRESUMO
Intratumoral or intraperitoneal hemorrhage is a recognized complication of liver adenomatosis. We report a case of multifocal massive liver adenomatosis presenting as chronic iron deficiency anemia. Clinicians' awareness about this atypical presentation not highlighted in the literature is important to allow timely diagnosis and surgical intervention to prevent fatal complications.
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Disseminated necrotizing leukoencephalopathy (DNL) is characterized by multiple microscopic foci of white matter necrosis. DNL was initially thought to be exclusively associated with immunosuppression conditions but it has been recently described in immunocompetent patients in septic shock. A 90-year-old immunocompetent woman with no previous neurological impairment presented with septic shock and drowsiness that responded well to therapy with clinical improvement and a full neurological recovery. Unexpectedly deterioration with progression to coma occurred. Investigation excluded other causes and Magnetic Resonance Imaging (MRI) was consistent with the diagnosis of DNL showing bilateral multifocal white matter lesions with a nonvascular pattern with restricted diffusion. Neurological impairment persisted with progression to death. DNL is an unexpected diagnosis in an immunocompetent patient. We compared the present case to those found in the literature of DNL complicating septic shock and discuss the antemortem diagnosis based on MRI findings.
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Chronic granulomatous disease (CGD) results from primary defects in phagocytic reactive oxygen species (ROS) production. T-cell evaluation is usually neglected during patients' follow-up, although T-cell depletion has been reported in CGD through unknown mechanisms. We describe here a 36-year-old patient with X-linked CGD with severe CD4 T-cell depletion <200 CD4 T-cells/µl, providing insights into the mechanisms that underlie T-cell loss in the context of oxidative burst defects. In addition to the typical infections, the patient featured a progressive T-cell loss associated with persistent lymphocyte activation, expansion of interleukin (IL)-17-producing CD4 T-cells, and impaired thymic activity, leading to a reduced replenishment of the T-cell pool. A relative CD4 depletion was also found at the gut mucosal level, although no bias to IL-17-production was documented. This immunological pattern of exhaustion of immune resources favors prompt, potentially curative, therapeutic interventions in CGD patients, namely, stem-cell transplantation or gene therapy. Moreover, this clinical case raises new research questions on the interplay of ROS production and T-cell homeostasis and immune senescence.
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Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31- subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31+ naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6, a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31- naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31+ naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.
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Disseminated intravascular coagulation (DIC) is the most frequent coagulation disorder associated with metastatic prostate adenocarcinoma. However, DIC with enhanced fibrinolysis as an initial presentation of prostate cancer is extremely rare. The appropriate treatment to control bleeding in these situations is challenging, controversial, and based on isolated case reports in the literature. A 66-year-old male presented at the emergency department with acute severe spontaneous ecchymoses localized to the limbs, laterocervical hematoma, and hemothorax. Prostate specific antigen level was 385 µg/L, bone scintigraphy revealed multiple bone metastases, and prostate biopsy confirmed adenocarcinoma (Gleason 9; 4 + 5). Laboratory investigation showed a pattern of enhanced fibrinolysis rather than the more common intravascular coagulation mechanism. Epsilon aminocaproic acid in monotherapy was initiated with a clear and rapid control of bleeding manifestations. This rare case of massive bleeding due to DIC with enhanced fibrinolysis as the first manifestation of prostate cancer suggests that in selected cases where the acute bleeding dyscrasia is clearly associated with a dominant fibrinolysis mechanism it is possible to use an approach of monotherapy with antifibrinolytics.
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Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.
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Interleucina-7/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Sobrevivência Celular/imunologia , Fatores de Transcrição Forkhead/imunologia , Humanos , Adulto JovemRESUMO
Inflammatory myofibroblastic tumour (IMT) is a rare scleroinflammatory lesion, characterized by a myofibroblastic proliferation with inflammatory infiltrates, with many possible locations and diagnosis based on immunohistochemistry. Pleural IMT is uncommon and is usually an extension of a pulmonary involvement. We report on a 28-year-old woman with a new form of this rare entity, characterized by exclusive pleural involvement.
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FOXP3-expressing regulatory T cells (Treg) are essential for the prevention of autoimmunity and were shown to be reduced and/or dysfunctional in several autoimmune diseases. Although Treg-based adoptive transfer represents a promising therapy, the large cell number required to achieve clinical efficacy constitutes an important limitation. Therefore, novel strategies to generate bona fide in vitro-induced Treg (iTreg) are critical. In this study, we report that human memory CD4 T cells can be efficiently converted into iTreg, and that Delta-like 1 (DL1)-mediated Notch signaling significantly enhances this process. The iTreg generated in the presence of DL1 featured higher levels of Treg function-associated molecules and were efficient suppressors. Importantly, these iTreg displayed a stable phenotype in long-term cultures, even in the presence of proinflammatory cytokines. Additionally, DL1 potentiated FOXP3 acquisition by memory CD4 cells through the modulation of the TGF-ß signaling pathway and of Foxp3 transcription. Our data demonstrate that iTreg can be efficiently induced from memory CD4 cells, a subset enriched in relevant specificities for targeting in autoimmune diseases, and that DL1 enhances this process. DL1 also enhanced the proliferation and Treg function-associated marker expression of ex vivo-stimulated human circulating FOXP3(+) cells. Manipulation of the Notch signaling pathway constitutes a promising approach to boost the in vitro generation of iTreg and ex vivo Treg expansion, thus facilitating the establishment of effective Treg-based adoptive therapy in autoimmune diseases.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Memória Imunológica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos de Superfície/metabolismo , Proteínas de Ligação ao Cálcio , Reprogramação Celular/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , FenótipoAssuntos
Linfócitos T CD8-Positivos/imunologia , Eosinofilia/diagnóstico , Infecções por HIV/complicações , Infecções por HIV/imunologia , Interleucina-5/metabolismo , Subpopulações de Linfócitos T/imunologia , Vasculite/diagnóstico , Biópsia , Eosinofilia/patologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/imunologia , Mãos/patologia , Histocitoquímica , Humanos , Masculino , Microscopia , Pessoa de Meia-Idade , Pele/patologia , Vasculite/patologiaAssuntos
Translocação Bacteriana , Infecções por HIV/complicações , HIV-2/isolamento & purificação , Mucosa Intestinal/imunologia , Tecido Linfoide/imunologia , Carga Viral , Viremia/complicações , Adolescente , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/virologia , Histocitoquímica , Humanos , Imuno-Histoquímica , Interleucina-17/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Tecido Linfoide/patologia , Tecido Linfoide/virologia , Masculino , Microscopia , Viremia/virologiaRESUMO
Monocytes and myeloid dendritic cells (mDCs) are important orchestrators of innate and human immunodeficiency virus (HIV)-specific immune responses and of the generalized inflammation that characterizes AIDS progression. To our knowledge, we are the first to investigate monocyte and mDC imbalances in HIV type 2 (HIV-2)-positive patients, who typically feature reduced viremia and slow disease progression despite the recognized ability of HIV-2 to establish viral reservoirs and overcome host restriction factors in myeloid cells. We found a heightened state of monocyte and mDC activation throughout HIV-2 infection (characterized by CD14(bright)CD16(+) expansion, as well as increased levels of soluble CD14, HLA-DR, and CD86), together with progressive mDC depletion. Importantly, HIV-2-positive patients also featured overexpression of the inhibitory molecule PD-L1 on monocytes and mDCs, which may act by limiting the production of proinflammatory molecules. These data, from patients with a naturally occurring form of attenuated HIV disease, challenge current paradigms regarding the role of monocytes in HIV/AIDS and open new perspectives regarding potential strategies to modulate inflammatory states.
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Células Dendríticas/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-2/imunologia , HIV-2/patogenicidade , Monócitos/imunologia , Adulto , Idoso , Antígenos CD/análise , Antígeno B7-H1/análise , Células Dendríticas/química , Feminino , Antígenos HLA-DR/análise , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Monócitos/química , Adulto JovemRESUMO
Haploidentical hematopoietic stem cell transplantation (HSCT) constitutes an important alternative for patients lacking a human leukocyte antigen (HLA)-matched donor. Although the use of haploidentical donors is increasingly common, the long-term impact of generating a donor-derived immune system in the context of an HLA-mismatched thymic environment remains poorly characterized. We performed an in-depth assessment of immune reconstitution in a group of haploidentical HSCT recipients 4 to 6 years posttransplantation, in parallel with the respective parental donors and age-matched healthy control subjects. Our data show that the proportion of naive and memory subsets in the recipients, both within CD8(+) and CD4(+) T cells, more closely resembled that observed in age-matched control subjects than in the donors. HSCT recipients displayed relatively high signal-joint T cell-receptor excision circle levels and a high frequency of the recent thymic emigrant-enriched CD31(+) subset within naive CD4(+) and naive regulatory T cells. Moreover, CD8(+), CD4(+), and regulatory T cells from HSCT recipients displayed a diverse T cell repertoire. These results support a key role for thymic output in T cell reconstitution. Nevertheless, HSCT recipients had significantly shorter telomeres within a naive-enriched CD4(+) T cell population than age-matched control subjects, despite the similar telomere length observed within the most differentiated CD8(+) and CD4(+) T cell subsets. Overall, our data suggest that long-term immune reconstitution was successfully achieved after haploidentical HSCT, a process that appears to have largely relied on de novo T cell production.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Subpopulações de Linfócitos T/imunologia , Adulto , Anemia Aplástica/imunologia , Anemia Aplástica/cirurgia , Estudos Transversais , Feminino , Haploidia , Humanos , Memória Imunológica , Leucemia/imunologia , Leucemia/cirurgia , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos , Imunologia de Transplantes , Transplante Homólogo , Adulto JovemRESUMO
OBJECTIVE: Memory B-cell loss has long been recognized as an important contributor to HIV immunodeficiency. HIV-2 infection, which is characterized by a slow rate of progression to AIDS and reduced to undetectable viremia, provides a unique model to investigate B-cell disturbances. DESIGN AND METHODS: B-cell subsets were evaluated in 38 HIV-2-infected individuals, along with markers of T-cell activation and serum levels of immunoglobulins and a major B-cell homeostatic cytokine, B-cell activating factor (BAFF). Untreated HIV-1-infected and seronegative control individuals were studied in parallel. Statistical analysis was performed using Mann-Whitney tests and Spearman's correlations. RESULTS: We found that HIV-2 was associated with significant depletion of both unswitched (CD27(+)IgD(+)) and switched (CD27(+)IgD(neg)) memory B-cells that directly correlated with T-cell activation, even in individuals with undetectable plasma viral load. Nevertheless, the presence of detectable viremia, even at low levels, was associated with significant memory B-cell loss and higher BAFF levels. Moreover, these alterations were not recovered by antiretroviral-therapy, as treated HIV-2-infected patients showed more pronounced B-cell disturbances, possibly related to their extended length of infection. CONCLUSION: These first data regarding B-cell imbalances during HIV-2 infection show that, irrespective of viremia, prolonged HIV infection leads to irreversible damage of memory B-cell homeostasis.
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Síndrome da Imunodeficiência Adquirida/imunologia , Linfócitos B/imunologia , Progressão da Doença , Soropositividade para HIV/imunologia , HIV-2/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/genética , Adulto , Fármacos Anti-HIV/farmacologia , Fator Ativador de Células B/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/virologia , Feminino , Citometria de Fluxo , Soronegatividade para HIV/imunologia , Soropositividade para HIV/tratamento farmacológico , HIV-1/imunologia , HIV-2/imunologia , Humanos , Memória Imunológica , Imunofenotipagem , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga Viral , Viremia/diagnóstico , Viremia/virologiaRESUMO
Forkhead box N1 (FOXN1) is a transcription factor crucial for thymic epithelium development and prevention of its involution. Investigation of a patient with a rare homozygous FOXN1 mutation (R255X), leading to alopecia universalis and thymus aplasia, unexpectedly revealed non-maternal circulating T-cells, and, strikingly, large numbers of aberrant double-negative αß T-cells (CD4negCD8neg, DN) and regulatory-like T-cells. These data raise the possibility that a thymic rudiment persisted, allowing T-cell development, albeit with disturbances in positive/negative selection, as suggested by DN and FoxP3+ cell expansions. Although regulatory-like T-cell numbers normalized following HLA-mismatched thymic transplantation, the αßDN subset persisted 5 years post-transplantation. Involution of thymus allograft likely occurred 3 years post-transplantation based on sj/ßTREC ratio, which estimates intrathymic precursor T-cell divisions and, consequently, thymic explant output. Nevertheless, functional immune-competence was sustained, providing new insights for the design of immunological reconstitution strategies based on thymic transplantation, with potential applications in other clinical settings.
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Alopecia/genética , Alopecia/terapia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Mutação de Sentido Incorreto , Timócitos/metabolismo , Timo/transplante , Alopecia/metabolismo , Feminino , Humanos , Lactente , Timo/metabolismo , Transplante HomólogoRESUMO
OBJECTIVE: Hyper-immune activation is a main determinant of HIV disease progression, potentially counter-acted by T-cell inhibitory pathways. Here we investigated, for the first time, inhibitory molecules in HIV-2 infection, a naturally occurring attenuated form of HIV disease, associated with reduced viremia and very slow rates of CD4 T-cell decline. DESIGN: Programmed death (PD)-1/PD-L1, an important pathway in limiting immunopathology, and its possible relationship with T-cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a recently identified inhibitory molecule, were studied in untreated HIV-2 and HIV-1 cohorts, matched for degree of CD4 T-cell depletion, and noninfected individuals. METHODS: Flow cytometric analysis of T-cell expression of PD-1, PD-L1 and TIM-3, combined with markers of cell differentiation, activation, cycling and survival. Statistical analysis was performed using ANOVA, Mann-Whitney/Wilcoxon tests, Spearman's correlations, multiple linear regressions and canonical correlation analysis. RESULTS: T-cell expression of PD-1 and PD-L1 was tightly associated and directly correlated with CD4 T-cell depletion and immune activation in HIV-2 infection. No such correlation was found for PD-L1 expression in HIV-1-positive patients. Central memory and intermediate memory cells, rather than terminally differentiated T-cells, expressed the highest levels of both PD-1 and PD-L1 molecules. Conversely, TIM-3 expression was independent of T-cell differentiation and dissociated from cell cycling, suggesting distinct induction mechanisms. Importantly, in contrast with HIV-1, no significant increases in TIM-3 expression were found in the HIV-2 cohort. CONCLUSIONS: Our data suggest that PD-1/PD-L1 molecules, rather than markers of T-cell exhaustion, may act as modulators of T-cell immune activation, contributing to the slower course of HIV-2 infection. These data have implications for the design of antiretroviral therapy-complementary immune-based strategies.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , HIV-2/imunologia , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Infecções por HIV/metabolismo , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Proteínas de Membrana/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: The dynamics of CD4(+) regulatory T cells (Treg) during HIV-1 infection remains unclear. To further investigate Treg in this context, we characterized, for the first time, this population in HIV-2-positive individuals. Although both HIV infections are associated with hyperimmune activation and CD4(+) T-cell lymphopenia, most HIV-2-positive individuals display slower disease progression and low-to-undetectable viremia. DESIGN/METHODS: Samples were obtained from cohorts of untreated HIV-2-positive and HIV-1-positive, treated HIV-1-positive and seronegative individuals. The proportion of CD4(+) T cells bearing a Treg phenotype, defined in terms of high-level CD25 or Foxp3 expression, was assessed by flow cytometry and correlated with markers of disease progression. The proportions of naive and memory-like subsets as well as cycling cells were determined. RESULTS: We observed an increased proportion of Treg, associated with disease progression, as well as increased proportions of cycling (Ki67(+)) memory Treg, in untreated HIV-2-positive and HIV-1-positive individuals. We also noted an expansion of Treg that persisted over time in treated, immunologically discordant HIV-1-positive individuals, who, similarly to HIV-2-positive patients, present undetectable viremia and low CD4 T-cell count. CONCLUSION: Overall, we demonstrated that Treg frequency was increased in all lymphopenic HIV-2-positive and HIV-1-positive individuals irrespective of the presence or absence of viremia or antiretroviral treatment. This, in turn, suggests that the observed alterations in Treg frequency in HIV/AIDS are more directly related to the degree of CD4 depletion than to viremia.