Assuntos
Anticorpos Bloqueadores/farmacologia , Bradicinina/sangue , Fator XII/imunologia , Angioedema/tratamento farmacológico , Animais , Anticorpos Bloqueadores/uso terapêutico , Proteína Inibidora do Complemento C1/genética , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Anafilaxia Cutânea Passiva/efeitos dos fármacosRESUMO
Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objectives: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Methods: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Results: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Conclusion: Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.
Assuntos
Anticorpos/imunologia , Síndromes de Imunodeficiência/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/mortalidade , Masculino , Pessoa de Meia-Idade , Vitória/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Chronic spontaneous urticaria (CSU) is the recurrence of urticaria without an apparent trigger. Half of the patients with CSU have IgG autoantibodies to FcεRIα on dermal mast cells and basophils, which on activation release mediators responsible for urticaria. IgG autoantibodies infer the presence of antigen/disease-specific T cells and CSU lesions are characterized by T-cell infiltration, but antigen/disease-specific T cells have not been documented in patients with CSU. OBJECTIVE: We aimed to identify autoreactive T cells to FcεRIα in patients with CSU and determine their relationship with autoantibodies to FcεRIα and their diagnostic value. METHODS: T-cell responses to FcεRIα were measured as proliferation by carboxy-fluorescein diacetate succinimidyl ester dye dilution and cytokine secretion by ELISpot. Serum autoantibodies to FcεRIα were detected by radioimmunoprecipitation. RESULTS: Blood CD4(+) T-cell proliferation to FcεRIα was detected in 27% of the subjects with CSU and 0% of controls; IFN-γ responses to FcεRIα were detected in 53%, and IL-5 or IL-13 responses in a minority of subjects with CSU. Serum FcεRIα autoantibodies were detected in 43% of subjects with CSU and 0% of controls. IFN-γ and autoantibody responses to FcεRIα were inversely related, with IFN-γ responses being detected earlier than autoantibodies in disease. Combined with autoantibody, T-cell responses to FcεRIα conferred high diagnostic sensitivity and specificity. CONCLUSIONS: Autoreactive CD4(+) T cells that target FcεRIα were detected in most subjects with CSU, with a cytokine secretion profile more typical of a TH1-cell response. The inverse relationship between IFN-γ and autoantibody responses to FcεRIα may signify different stages in the disease course. Our findings suggest that measurement of T-cell as well as autoantibody responses to FcεRIα could improve diagnostic accuracy in subjects with CSU.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Receptores de IgE/imunologia , Urticária/imunologia , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Doença Crônica , Citocinas/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Urticária/sangue , Adulto JovemRESUMO
MicroRNAs (miRNAs) regulate T cell development and function and the disruption of miRNAs in natural regulatory CD4(+) FOXP3(+) T cells (nTreg) leads to autoimmune disease in mice. To investigate miRNA expression in relation to autoimmune disease risk in humans we sequenced them in purified CD4(+) T cell subsets from individuals at high risk of type 1 diabetes (pre-T1D), as well as other healthy individuals. Differences in miRNA expression patterns were observed between specific T cell subsets and, within subsets, between pre-T1D and healthy individuals. Compared to healthy, naive CD4(+) T cells in pre-T1D displayed 32 differentially expressed miRNAs, potentially a template for altered miRNA expression in effector memory T cells in T1D. Naive nTreg in pre-T1D displayed two differentially expressed miRNAs, Let-7c and miR-15a. In contrast, nTreg activated in vivo displayed a large number of differentially expressed miRNAs, revealing a pro-inflammatory and FOXP3-repressive signature. Differential expression of specific miRNAs was also a signpost to altered T cell function. For example, in pre-T1D, increased expression of miR-26a in nTreg activated in vivo or in vitro was associated with decreased expression of its target, the histone methyltransferase EZH2. Chemical inhibition of EZH2 decreased the number of activated naïve nTreg and their expression of nTreg signature genes FOXP3 and TIGIT. Our findings demonstrate that miRNAs differentially expressed in CD4(+) T cell subsets are markers of risk and T cell dysfunction in T1D.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , MicroRNAs/genética , Biomarcadores , Análise por Conglomerados , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Biblioteca Gênica , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Insulin-dependent or type 1 diabetes (T1D) is a paradigm for prevention of autoimmune disease: Pancreatic ß-cell autoantigens are defined, at-risk individuals can be identified before the onset of symptoms, and autoimmune diabetes is preventable in rodent models. Intervention in asymptomatic individuals before or after the onset of subclinical islet autoimmunity places a premium on safety, a requirement met only by lifestyle-dietary approaches or autoantigen-based vaccination to induce protective immune tolerance. Insulin is the key driver of autoimmune ß-cell destruction in the nonobese diabetic (NOD) mouse model of T1D and is an early autoimmune target in children at risk for T1D. In the NOD mouse, mucosal administration of insulin induces regulatory T cells that protect against diabetes. The promise of autoantigen-specific vaccination in humans has yet to be realized, but recent trials of oral and nasal insulin vaccination in at-risk humans provide grounds for cautious optimism.
Assuntos
Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Vacinação , Animais , Glutamato Descarboxilase/imunologia , Humanos , Insulina/imunologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Immune restoration disease following antiretroviral therapy for human immunodeficiency virus infection can cause significant morbidity and mortality. We describe the dramatic clinical course of an human immunodeficiency virus-infected patient who developed severe immune restoration disease associated with Leishmania donovani infection in a non-endemic area of the world. It highlights the need to consider previous travel history when screening for opportunistic infections before starting antiretroviral therapy, and demonstrates the effectiveness of corticosteroid therapy for life-threatening immune restoration disease.