RESUMO
OBJECTIVES: Rituximab (RTX), used for treatment in paediatric immune-mediated diseases, can lead to hypogammaglobulinaemia and thus to an increased risk of infection, but data on these adverse effects in children are scarce. We aimed to describe the pharmacodynamics of RTX by time to B cell repopulation in paediatric immune-mediated diseases and to assess whether low post-RTX immunoglobulin levels were associated with frequency and severity of infections. METHODS: Data of children with autoimmune diseases (AID), immune dysregulation (ID), haematological diseases (HD) and renal diseases (RD), including immunoglobulin levels pre-/post-RTX and occurrence of infections, who had received RTX at our centre were retrospectively collected. B cell depletion was defined as B cells <10 cells/µl. RESULTS: Post-RTX B cell depletion was achieved in 45/49 patients. In 30/45 patients with B cell repopulation, median time to repopulation was 166 days (IQR 140-224): AID group (n=9) (183 days (IQR 156-239), ID group (n=6) 170 days (IQR 128-184), HD group (n=7) 139 days (IQR 127-294), RD group (n=7) 160 days (IQR 121-367). Severe infections leading to hospitalisation occurred in 7/52 (13.5%) patients: ID (n=3), HD (n=1), RD (n=3). After RTX treatment, 13/52 patients (25%) had low IgG levels for their age at least once, 11/13 had an infection during low IgG but only 2/13 had a severe infection. Low IgG was not associated with severe infection (p=0.459). CONCLUSIONS: Time to B cell repopulation post-RTX ranged individually but did not significantly differ between paediatric patient groups. Severe infections were non-frequent and not associated with low (post-RTX) IgG levels.
Assuntos
Doenças Autoimunes , Linfócitos B , Humanos , Criança , Rituximab/efeitos adversos , Estudos Retrospectivos , Imunoglobulina GRESUMO
BACKGROUND: Proteasome-associated autoinflammatory syndromes (PRAASs) form a family of recently described rare autosomal recessive disorders of disturbed proteasome assembly and proteolytic activity caused by mutations in genes coding for proteasome subunits. The treatment options for these proteasome disorders consist of lifelong immunosuppressive drugs or Janus kinase inhibitors, which may have partial efficacy and noticeable side effects. Because proteasomes are ubiquitously expressed, it is unknown whether hematopoietic stem cell transplantation (HSCT) may be a sufficient treatment option. OBJECTIVE: Our aim was to report the case of a young boy with a treatment-resistant cutaneous vasculitis that was initially suspected to be associated with a gene variant in SH2D1A. METHODS: Whole-exome sequencing was performed to identify the genetic defect. Molecular and functional analyses were performed to assess the impact of variants on proteasomal function. The immune characterization led to the decision to perform HSCT on our patient and conduct follow-up over the 7-year period after the transplant. Because loss of myeloid chimerism after the first HSCT was associated with relapse of autoinflammation, a second HSCT was performed. RESULTS: After the successful second HSCT, the patient developed mild symptoms of lipodystrophy, which raised the suspicion of a PRAAS. Genetic analysis revealed 2 novel heterozygous variants in PSMB4 (encoding proteasomal subunit ß7). Retrospective analysis of patient cells stored before the first HSCT and patient cells obtained after the second HSCT demonstrated that HSCT successfully rescued proteasome function, restored protein homeostasis, and resolved the interferon-stimulated gene signature. Furthermore, successful HSCT alleviated the autoinflammatory manifestations in our patient. CONCLUSION: Patients with treatment-resistant PRAAS can be cured by HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Lipodistrofia , Criança , Humanos , Lipodistrofia/genética , Masculino , Complexo de Endopeptidases do Proteassoma/genética , Estudos Retrospectivos , SíndromeRESUMO
Objective: The aim was to investigate the association between autoantibodies (autoAbs) and neuropsychiatric (NP) involvement in patients with SLE and to evaluate whether any autoAb or a combination of these autoAbs could indicate the underlying pathogenic process. Methods: Using a multiplexed protein array for 94 antigens, we compared the serum autoAb profiles of 69 NPSLE patients, 203 SLE patients without NP involvement (non-NPSLE) and 51 healthy controls. Furthermore, we compared the profiles of NPSLE patients with clinical inflammatory (n = 38) and ischaemic (n = 31) NP involvement. Results: In total, 75 IgG and 47 IgM autoAbs were associated with SLE patients in comparison with healthy controls. Comparing NPSLE with non-NPSLE and healthy control sera, 9 IgG (amyloid, cardiolipin, glycoprotein 2, glycoprotein 210, heparin, heparan sulphate, histone H2A, prothrombin protein and vimentin) and 12 IgM (amyloid, cardiolipin, centromere protein A, collagen II, histones H2A and H2B, heparan sulphate, heparin, mitochondrial 2, nuclear Mi-2, nucleoporin 62 and vimentin) autoAbs were present at significantly different levels in NPSLE. The combination of IgG autoAbs against heparan sulphate, histone H2B and vimentin could differentiate NPSLE from non-NPSLE (area under the curve 0.845, 99.97% CI: 0.756, 0.933; P < 0.0001). Compared with non-NPSLE, four IgG and seven IgM autoAbs were significantly associated with inflammatory NPSLE. In ischaemic NPSLE, three IgG and three IgM autoAbs were significantly different from non-NPSLE patients. Conclusion: In our cohort, the presence of high levels of anti-heparan sulphate and anti-histone H2B combined with low levels of anti-vimentin IgG autoAbs is highly suggestive of NPSLE. These results need to be validated in external cohorts.
Assuntos
Autoanticorpos/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Adulto , Autoanticorpos/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Heparitina Sulfato/imunologia , Histonas/imunologia , Humanos , Imunoglobulina G/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Masculino , Pessoa de Meia-Idade , Análise Serial de Proteínas , Vimentina/imunologiaRESUMO
Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8(+) T cells and increased over time. Only the revertant CD8(+) T cells showed normal expression of CD132 and the various CD8(+) T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ(+) T cells and differentiated CD4(+)CD27(-) effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8(+) T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells.
Assuntos
Linfócitos T CD8-Positivos/fisiologia , Subunidade gama Comum de Receptores de Interleucina/genética , Mutação/genética , Imunodeficiência Combinada Severa/genética , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Criança , Humanos , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Contagem de Linfócitos , Masculino , Linhagem , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/patologiaRESUMO
INTRODUCTION: Idiopathic inflammatory myopathies (IIMs) excluding inclusion body myositis (IBM) are a group of heterogeneous autoimmune disorders characterised by subacute-onset and progressive proximal muscle weakness, which are frequently part of a multisystem autoimmune disorder. Reaching the diagnosis can be challenging, and no gold standard for the diagnosis of IIM exists. Diagnostic modalities include serum creatine kinase activity, muscle imaging (MRI or ultrasound (US)), electromyography (EMG), myositis autoantibody testing and muscle biopsy. Several diagnostic criteria have been developed for IIMs, varying in reported sensitivity and specificity. HYPOTHESIS: We hypothesise that an evidence-based diagnostic strategy, using fewer and preferably the least invasive diagnostic modalities, can achieve the accuracy of a complete panel of diagnostic tests, including MRI, US, EMG, myositis-specific autoantibody testing and muscle biopsy. METHODS AND ANALYSIS: The OptimizAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies study is a prospective diagnostic accuracy study with an over-complete study design. 100 patients suspected of an IIM excluding IBM will be included. A reference diagnosis will be assigned by an expert panel using all clinical information and all results of all ancillary tests available, including 6 months of follow-up. Several predefined diagnostic strategies will be compared against the reference diagnosis to find the optimal diagnostic strategy. ETHICS AND DISSEMINATION: Ethical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam, The Netherlands (2019-814). The results will be distributed through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: Netherlands trial register; NL8764.
Assuntos
Doenças Autoimunes , Medicina Baseada em Evidências , Miosite , Autoanticorpos , Doenças Autoimunes/diagnóstico , Biópsia , Humanos , Miosite/diagnóstico , Estudos ProspectivosRESUMO
We present the case of a 43-year-old woman with generalised idiopathic inflammatory myopathy (IIM) with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies (Abs) that developed following recurrent focal myositis. Anti-HMGCR Abs are myositis-specific Abs that are associated with immune-mediated necrotising myopathy, a subtype of IIM that is characterised by relatively prominent and severe muscle involvement, generally necessitating multimodal immunosuppressant treatment. While earlier reports have described patients developing polymyositis following focal myositis, this is the first report to describe a patient developing IIM with anti-HMGCR Abs following focal myositis. Thus, clinicians should be aware of the possibility that focal myositis may develop into a generalised IIM and should instruct the patient and monitor the patient accordingly.
Assuntos
Autoanticorpos/imunologia , Hidroximetilglutaril-CoA Redutases/imunologia , Miosite/diagnóstico , Adulto , Anti-Inflamatórios/administração & dosagem , Progressão da Doença , Feminino , Humanos , Imunossupressores , Metotrexato/administração & dosagem , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Miosite/tratamento farmacológico , Prednisolona/administração & dosagemAssuntos
Síndrome Linfoproliferativa Autoimune/complicações , Síndrome Linfoproliferativa Autoimune/genética , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/genética , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/genética , Receptor fas/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos B/imunologia , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Feminino , Humanos , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Mutação , Linhagem , Linfócitos T/imunologiaAssuntos
Imunidade Humoral/genética , Memória Imunológica/genética , Subunidade gama Comum de Receptores de Interleucina/genética , Ativação Linfocitária/genética , Mutação , Imunodeficiência Combinada Severa/genética , Adolescente , Linfócitos B/imunologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Humanos , Imunidade Humoral/imunologia , Memória Imunológica/imunologia , Subunidade gama Comum de Receptores de Interleucina/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Linhagem , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologiaRESUMO
The expression of adhesion molecules (alpha4beta1-integrin, LFA-1, ICAM-1) on T cells, measured by flow cytometry, was compared in different subtypes of multiple sclerosis (MS) and related to future lesion development as seen as delta T1 and T2 lesion load per year on magnetic resonance imaging (MRI). LFA-1 and alpha4beta1-integrin showed higher expression on CD4 and CD8 T lymphocytes in the secondary progressive compared to the relapsing-remitting (CD4: p<0.01, p=ns, p<0.05; CD8: p<0.001, p<0.001, p<0.001, respectively) and primary progressive MS phase (CD4: p<0.001, p<0.01, p<0.05; CD8: p<0.01, p<0.01, p<0.001, respectively). The adhesion molecule expression of alpha4- (r=0.31; p<0.05) and beta1-integrin (r=0.38; p<0.01) on CD4+ cells and of LFA-1beta on both CD4+ and CD8+ (r=0.28, p<0.05) and r=0.29; p<0.05, respectively) cells was significantly related to increase in T2 lesion load. Our study provides further evidence for the involvement of integrins in lesion development, shown as T2 lesions on MRI in MS.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Moléculas de Adesão Celular/sangue , Esclerose Múltipla/patologia , Adulto , Análise de Variância , Moléculas de Adesão Celular/classificação , Demografia , Progressão da Doença , Feminino , Citometria de Fluxo/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/classificação , Esclerose Múltipla/metabolismo , Estudos Retrospectivos , Estatística como Assunto/métodosRESUMO
We here report the existence of a new cluster of adhesion-GPCRs in human immune cells. Analysis of a comprehensive immune cell transcriptome dataset indicated that expression of the closely related receptors, GPR56, GPR97, and GPR114, is associated with single lymphocyte and granulocyte subsets. Applying flow cytometric analysis with newly generated mAb, we show that expression of GPR56 is restricted to cytotoxic NK and T lymphocytes, including CD8(+), CD4(+), and γδ T cells. Primary infection with human CMV, which generates a vast population of CD8(+) T cells with an effector phenotype, induced a strong increase in GPR56 expression in virus-specific CD8(+) T cells that remained detectable during latency. In NK-92 cells, ectopic expression of GPR56 inhibited spontaneous and SDF-1-stimulated cell migration. Our data suggest that GPR56 expression is a common trait of human cytotoxic lymphocytes and might affect the migratory properties of these cells.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Movimento Celular , Regulação da Expressão Gênica , Células Matadoras Naturais/metabolismo , Receptores Acoplados a Proteínas G/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/imunologia , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Citometria de Fluxo , Humanos , Células Matadoras Naturais/imunologia , Receptores Acoplados a Proteínas G/imunologiaRESUMO
CD20 was the first B cell differentiation antigen identified, and CD20-specific mAbs are commonly used for the treatment of B cell malignancies and autoantibody-mediated autoimmune diseases. Despite this the role of CD20 in human B cell physiology has remained elusive. We describe here a juvenile patient with CD20 deficiency due to a homozygous mutation in a splice junction of the CD20 gene (also known as MS4A1) that results in "cryptic" splicing and nonfunctional mRNA species. Analysis of this patient has led us to conclude that CD20 has a central role in the generation of T cell-independent (TI) antibody responses. Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient. Consistent with this, TI antipolysaccharide B cell responses were severely impeded in CD20-deficient mice. Our study therefore identifies what we believe to be a novel type of humoral immunodeficiency caused by CD20 deficiency and characterized by normal development of antigen-independent B cells, along with a reduced capacity to mount proper antibody responses.
Assuntos
Formação de Anticorpos , Antígenos CD20/fisiologia , Linfócitos T/imunologia , Animais , Antígenos CD20/genética , Pré-Escolar , Feminino , Humanos , Imunoglobulina D/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos B/fisiologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , VacinaçãoRESUMO
The absence of the TNF-receptor family member CD27 marks the stable acquisition of cytolytic effector functions by both CD4(+) and CD8(+) T cells. We found that the majority of circulating human NK cells was CD27(-). These cells were largely CD56(dim), contained high levels of perforin and granzyme B, and were able to exert strong cytotoxic activity. In contrast, circulating CD27(+) NK cells were mostly CD56(dim/bright), had significant lower levels of perforin and granzyme B, and had a low cytolytic potential. Primary and secondary lymphoid organs were markedly enriched for CD27(+) NK cells. When correlating the expression of CD27 to recently defined developmental stages of NK cells in tonsil, we observed that CD27 was exclusively found on mature CD94(+), stage 4 NK cells. On these cells, regulation of CD27 expression appeared to be controlled by the common gamma-chain cytokine IL-15, and down-regulation of CD27 was specifically induced by its ligand, CD70. Thus, the absence of CD27 expression allows the definition of cytotoxic effector cells within the known mature NK cell subsets in humans.
Assuntos
Citotoxicidade Imunológica , Imunofenotipagem , Células Matadoras Naturais/classificação , Células Matadoras Naturais/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Biomarcadores/sangue , Ligante CD27/fisiologia , Antígeno CD56/fisiologia , Células Cultivadas , Células Clonais , Citocinas/biossíntese , Citocinas/fisiologia , Citotoxicidade Imunológica/genética , Humanos , Células K562 , Células Matadoras Naturais/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologiaRESUMO
In humans, loss of CD27 expression is associated with the stable acquisition of effector functions by CD8+ T cells. We found that murine (CD8+)CD27- T cells were confined to the primed CD62L(dull/-)CD44(bright)CCR7- T cell population. (CD8+)CD27- T cells were absent from lymph nodes but could be found in blood, spleen and in non-lymphoid organs such as lung and liver. Late after primary influenza virus infection, low percentages of antigen-specific CD27- cells emerged in the lung and spleen. After recovery from secondary influenza virus infection, high percentages of influenza-specific CD27- T cells were found in the lung and the loss of CD27 on lung CD8+ T cells coincided with high granzyme B expression. After murine cytomegalovirus infection, loss of CD27 expression on virus-specific CD8+ T cell populations was sustained and especially marked in liver and lung. We suggest that in mice, CD27 is lost from CD8+ T cells only after repetitive antigenic stimulation. Moreover, the high expression of both granzyme B and perforin in the CD27- T cells suggests that the lack of CD27 on murine CD8+ T cells can be used to identify memory T cells with expression of cytotoxic effector molecules.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Envelhecimento/sangue , Envelhecimento/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Citomegalovirus , Infecções por Citomegalovirus/imunologia , Granzimas , Memória Imunológica , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Perforina , Proteínas Citotóxicas Formadoras de Poros , Serina Endopeptidases/metabolismo , Subpopulações de Linfócitos T/metabolismoRESUMO
The elimination of activated T cells is important to maintain homeostasis and avoid immunopathology. CD95 (Fas/APO-1) has been identified as a death mediator for activated T cells in vitro but the function of CD95 in death of mature T cells in vivo is still controversial. Here we show that triggering of the costimulatory TNF receptor family member CD27 sensitized T cells for CD95-induced apoptosis. CD95-deficient (lpr/lpr) T cells massively expanded and differentiated into IFN-gamma-secreting effector cells in transgenic mice that constitutively express the CD27 ligand, CD70. Concomitantly, CD95-deficient CD70 transgenic mice became moribund by 4 wk of age with severe liver pathology and bone marrow failure. These findings establish that CD95 is a critical regulator of effector T cell homeostasis in chronic immune activation.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Homeostase/imunologia , Ativação Linfocitária/imunologia , Receptor fas/fisiologia , Transferência Adotiva , Animais , Animais Recém-Nascidos , Antígenos CD/genética , Antígenos CD/fisiologia , Apoptose/genética , Apoptose/imunologia , Ligante CD27 , Linfócitos T CD8-Positivos/metabolismo , Morte Celular/genética , Morte Celular/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Deleção de Genes , Homeostase/genética , Interferon gama/metabolismo , Interferon gama/farmacologia , Ativação Linfocitária/genética , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Camundongos Transgênicos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/farmacologia , Receptor fas/genéticaRESUMO
Five pediatric patients with no history of immunodeficiency had a life-threatening course of varicella. Strikingly, natural killer (NK) cells were absent from the circulation in all children, and, despite active viral infection, up to 98% of the CD8(+) cells were naive. Primary immunodeficiencies were excluded--NK cells and primed CD8(+) cells reappeared in the circulation, granzymes were detectable in plasma early during infection, and no abnormalities could be detected in interleukin-15 receptor function. Our data indicate that varicella-zoster virus (VZV) has a unique capability to seclude primed CD8(+) cells and NK cells from the circulating lymphocyte pool. This may be the consequence of an overwhelming immune response to VZV that is influenced by factors such as infectious dose, age, and the presence of maternal antibodies during infancy. Because both homozygous twin sisters in the study had a severe course of varicella, particular genetic factors may contribute to severe varicella.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Varicela/imunologia , Herpesvirus Humano 3/patogenicidade , Imunocompetência/imunologia , Células Matadoras Naturais/imunologia , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Two prototypic types of virus-specific CD8(+) T cells can be found in latently infected individuals: CD45R0(+)CD27(+)CCR7(-) effector-memory, and CD45RA(+)CD27(-)CCR7(-) effector-type cells. It has recently been implied that CD45RA(+)CD27(-)CCR7(-) T cells are terminally differentiated effector cells and as such have lost all proliferative capacity. We show in this study, however, that stimulation of CMV-specific CD45RA(+)CD27(-)CCR7(-) T cells with their cognate peptide in concert with either CD4(+) help or IL-2, IL-15, or IL-21 in fact induces massive clonal expansion. Concurrently, these stimulated effector T cells change cell surface phenotype from CD45RA to CD45R0 and regain CCR7, while effector functions are maintained. Our data imply that CD45RA(+)CD27(-)CCR7(-) effector-type T cells contribute to immunity not only by direct execution of effector functions, but also by yielding progeny in situations of viral reinfection or reactivation.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Citomegalovirus/imunologia , Epitopos de Linfócito T/fisiologia , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Divisão Celular/imunologia , Células Cultivadas , Testes Imunológicos de Citotoxicidade , Humanos , Epitopos Imunodominantes/fisiologia , Imunofenotipagem , Interleucina-15/fisiologia , Interleucina-2/fisiologia , Interleucinas/fisiologia , Fosfoproteínas/fisiologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Tuberculina/fisiologia , Proteínas da Matriz Viral/fisiologiaRESUMO
It has been proposed that HIV-1, in addition to directly infecting and killing CD4+ T cells, causes T cell dysfunction and T cell loss by chronic immune activation. We analyzed the effects of chronic immune activation in mice that constitutively expressed CD70, the ligand for the tumor necrosis factor receptor family member CD27, on B cells. CD70 transgenic (CD70 Tg) mice showed a progressive conversion of naive T cells into effector-memory cells, which culminated in the depletion of naive T cells from lymph nodes and spleen. T cell changes depended on continuous CD27-CD70 interactions and T cell antigen receptor stimulation. Despite this hyperactive immune system, CD70 Tg mice died aged 6-8 months from Pneumocystis carinii infection, a hallmark of T cell immunodeficiency. Thus, persistent delivery of costimulatory signals via CD27-CD70 interactions, as may occur during chronic active viral infections, can exhaust the T cell pool and is sufficient to induce lethal immunodeficiency.
Assuntos
Antígenos CD , Síndromes de Imunodeficiência/etiologia , Proteínas de Membrana/metabolismo , Linfócitos T/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Ligante CD27 , Efeito Citopatogênico Viral , Infecções por HIV/etiologia , Infecções por HIV/imunologia , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Memória Imunológica , Ativação Linfocitária , Contagem de Linfócitos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pneumonia por Pneumocystis/etiologia , Pneumonia por Pneumocystis/imunologia , Linfócitos T/patologiaRESUMO
Viral infections may cause serious disease unless the adaptive immune system is able to clear the viral agents through its effector arms. Recent identification and functional characterization of subpopulations of human CD8(+) T cells has set the stage to study the correlation between the appearance of particular subsets and common viral infections during childhood, i.e., EBV, CMV, varicella-zoster virus (VZV), and the attenuated measles-mumps-rubella (MMR) vaccine strains. In a cohort of 220 healthy children we analyzed lymphocytes and subpopulations of CD4(+) and CD8(+) T cells. The presence of the cytolytic CD45RA(+)CD27(-) subset of CD8(+) T cells correlated with prior CMV infection as defined by seroconversion (p < 0.0001). The number of this CD8(+) T cell subset remained stable during follow-up over 3 years in 40 children. The CD45RA(+)CD27(-) subset of CD8(+) T cells first appeared during acute CMV infection and subsequently stabilized at an individual set-point defined by age and immunocompetence. The functional importance of these cells in CMV surveillance was reflected by their increased numbers in immunosuppressed pediatric kidney transplant patients. Preferential expansion of CD8(+)CD45RA(+)CD27(-) cytolytic T cells seems unique for CMV.
Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Citotoxicidade Imunológica , Antígenos Comuns de Leucócito/biossíntese , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Doença Aguda , Adolescente , Envelhecimento/imunologia , Anticorpos Antivirais/sangue , Divisão Celular/imunologia , Criança , Pré-Escolar , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Humanos , Imunocompetência/imunologia , Imunofenotipagem , Lactente , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Linhagem , Recidiva , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos T/virologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologia , Linfócitos T Citotóxicos/virologiaRESUMO
During immunosuppressive medication, Epstein-Barr virus (EBV) infection is associated with a risk of developing posttransplant lymphoproliferative disease (PTLD). The appropriateness of a spontaneous EBV B-cell transformation (SET) assay as a monitor of EBV-specific immunity was evaluated to investigate if it safely allows reducing immunosuppressive medication, thereby decreasing the risk of developing PTLD. PBMC were isolated longitudinally from 20 pediatric renal allograft recipients treated with prednisone and cyclosporine combined with either azathioprine or mycophenolate mofetil. Most significantly, EBV-peptide-specific CD8+ T cells were detectable in the blood of patients with negative SET assays, coinciding with significantly lower EBV loads, whereas these cells were less frequent in the blood of patients with positive SET assays. Reducing the levels of immunosuppression resulted in normalization of the SET assays. Therefore, the SET assay is a reflection of the interaction between viral replication, transformation of B cells, and EBV-specific immunity in vivo and hence a valuable screening test for EBV-driven lymphoproliferative phenomena in allograft recipients.