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1.
J Clin Immunol ; 38(7): 768-777, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30219982

RESUMO

Individuals with common variable immunodeficiency (CVID) have an increased risk of gastric cancer, and gastrointestinal lymphoma, yet screening for premalignant gastric lesions is rarely offered routinely to these patients. Proposed screening protocols are not widely accepted and are based on gastric cancer risk factors that are not applicable to all CVID patients. Fifty-two CVID patients were recruited for screening gastroscopy irrespective of symptoms or blood results and were compared to 40 controls presenting for gastroscopy for other clinical indications. Overall, 34% of CVID patients had intestinal metaplasia (IM), atrophic gastritis or moderate to severe non-atrophic gastritis, which can increase the risk of gastric cancer, compared to 7.5% of controls (p < 0.01). Focal nodular lymphoid hyperplasia, a precursor lesion for gastrointestinal lymphoma, was seen in eight CVID patients (16%), one of whom was diagnosed with gastrointestinal lymphoma on the same endoscopy. High-risk gastric pathology was associated with increased time since diagnosis of CVID, smoking, Helicobacter pylori, a low-serum pepsinogen I concentration, and diarrhea, but not pepsinogen I/II ratio, iron studies, vitamin B12 levels or upper gastrointestinal symptoms. There was a lower rate of detection of IM when fewer biopsies were taken, and IM and gastric atrophy were rarely predicted by the endoscopist macroscopically, highlighting the need for standardized biopsy protocols. The prevalence of premalignant gastric lesions in patients with CVID highlights the need for routine gastric screening. We propose a novel gastric screening protocol to detect early premalignant lesions and reduce the risk of gastric cancer and gastric lymphoma in these patients.

2.
Artigo em Inglês | MEDLINE | ID: mdl-30170123

RESUMO

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

3.
Am Heart J ; 203: 74-81, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30041066

RESUMO

Dual antiplatelet therapy, consisting of aspirin and a P2Y12 receptor antagonist, has been the cornerstone of management in those undergoing percutaneous coronary intervention, reducing stent thromboses and cardiovascular events. Given the pivotal role of aspirin in cardiovascular disease management, patients with aspirin hypersensitivity pose complex clinical challenges. Allergy to aspirin is reported in 1.5-2.6% of patients presenting with cardiac disease. Identification of the subtype of aspirin hypersensitivity will determine suitability for aspirin desensitization, dictate choice of desensitization protocol and inform risk management. Aspirin desensitization is an effective and viable clinical strategy, although it remains underutilised in clinical practice. Collaboration between cardiologists and immunologists should be strongly encouraged to facilitate optimal management of such patients. This review describes the complexity of managing patients with aspirin hypersensitivity in cardiac disease, the indications and risks of aspirin desensitization, and the approach to management of the minority of patients who are unsuitable for desensitization.

4.
Clin Med (Lond) ; 16(2): 199-200, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27037395

RESUMO

A 58-year-old man was referred for review due to the finding of splinter haemorrhages and digital infarcts. Further questioning revealed a history of unintentional weight loss and calf pain. There were no other clinical features of endocarditis, and no clear cause for the splinter haemorrhages on initial investigations. The discovery of widespread thromboembolic disease prompted a search for malignancy and an eventual diagnosis of oesophageal adenocarcinoma. Splinter haemorrhages resolved with anticoagulation and directed treatment of the underlying malignancy. This case report reminds clinicians of the potentially broad differential diagnosis associated with this clinical sign.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Hemorragia , Unhas , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Anticoagulantes/uso terapêutico , Antineoplásicos/uso terapêutico , Diagnóstico Diferencial , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/tratamento farmacológico , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Unhas/irrigação sanguínea , Unhas/patologia
7.
Blood ; 117(15): 4041-51, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21300983

RESUMO

B cells require signals delivered through B-cell activating factor of the TNF family receptor (BAFF-R) and CD40 to survive and produce antibody responses in vivo. In vitro data indicate that these signals are controlled by the homologous RING finger proteins cIAP1 and cIAP2, in collaboration with TRAF2 and TRAF3. There is also mounting evidence that all 4 of these signaling molecules can act as tumor suppressors in human B-lineage malignancies. However, it has not been possible to identify the roles of cIAP1 and cIAP2 in controlling B-cell physiology because of the absence of an appropriate in vivo model. Here we describe a unique genetically modified mouse in which the linked cIap1 and cIap2 genes can be independently inactivated. Deletion of cIAP1 plus cIAP2 (but not either protein alone) rendered primary B cells independent of BAFF-R for their survival and led to their uncontrolled accumulation in vivo. B cells deficient in cIAP1 and cIAP2 were also incapable of forming germinal centers, a key step in antibody-mediated immunity. These data define a fundamental role for cIAP1/cIAP2 in regulating B-cell survival and responsiveness, show this requires direct binding to TRAF2, and suggest how mutations of TRAF2, TRAF3, and cIAP1/cIAP2 contribute to B-lineage malignancies, such as multiple myeloma.


Assuntos
Linfócitos B/citologia , Linfócitos B/fisiologia , Centro Germinativo/citologia , Proteínas Inibidoras de Apoptose/genética , Animais , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Proteína 3 com Repetições IAP de Baculovírus , Antígenos CD40/metabolismo , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Sobrevivência Celular/imunologia , Deleção de Genes , Centro Germinativo/fisiologia , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligases
8.
Transplantation ; 87(7): 1052-6, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19352127

RESUMO

BACKGROUND: Flow cytometric techniques are increasingly used in pretransplant crossmatching, although there remains debate regarding the clinical significance and predictive value of donor-specific antibodies detected by flow cytometry. At least some of the discrepancies between published studies may arise from differences in cutoffs used and lack of standardization of the test. METHODS: We selected cut-off values for pretransplant flow cytometric crossmatching (FCXM) based on the correlation of retrospective results with the occurrence of antibody-mediated rejection. The impact on long-term renal graft survival of prospective FCXM was determined by comparing graft survival between patients crossmatched with complement-dependent cytotoxicity (CDC) only with those prospectively crossmatched with both CDC and FCXM. RESULTS: Chosen cut-off values gave a positive predictive value of FCXM for antibody-mediated rejection of 83%, and a negative predictive value of 90%. After the introduction of prospective B- and T-cell crossmatching by flow cytometry in addition to CDC in our center, there was a significant improvement in renal graft survival in highly sensitized patients (P=0.017). Four-year graft survival in highly sensitized patients after the introduction of FCXM was 89%, which did not differ significantly from that seen in nonsensitized patients (93%; P=0.638). CONCLUSIONS: Our data demonstrate that prospective FCXM improves renal transplant outcome in highly sensitized patients, provided that cut-off values are carefully validated and results interpreted in the context of sensitization history and antibody screening results.


Assuntos
Sobrevivência de Enxerto/imunologia , Teste de Histocompatibilidade , Imunização , Transplante de Rim/imunologia , Linfócitos B/imunologia , Citometria de Fluxo/métodos , Humanos , Isoanticorpos/imunologia , Transplante de Rim/mortalidade , Valor Preditivo dos Testes , Análise de Sobrevida , Sobreviventes , Linfócitos T/imunologia
9.
J Clin Rheumatol ; 11(3): 150-2, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16357734

RESUMO

BACKGROUND: Early diagnosis of rheumatoid arthritis allows prompt initiation of antirheumatic therapy, which is associated with improved outcome. The use of IgM rheumatoid factor, the most widely used serologic test in assisting the diagnosis of rheumatoid arthritis, is limited by low specificity. An enzyme-linked immunosorbent assay test detecting antibodies to cyclic citrullinated peptide (CCP) has been developed with apparently higher specificity for rheumatoid arthritis. AIM: We aimed to evaluate an assay for anti-CCP antibodies by determining the prevalence and titer of antibodies to CCP in a group of patients with chronic arthritis. METHOD: Thirty-four sera were collected from outpatients attending an arthritis-monitoring clinic and tested for anti-CCP and IgM rheumatoid factor. RESULTS: Anti-CCP and rheumatoid factor were detected in 86% and 72% of patients with rheumatoid arthritis, respectively. Six patients negative for rheumatoid factor were positive for anti-CCP. CONCLUSION: Anti-CCP antibodies are frequently detectable in high titer in patients with longstanding rheumatoid arthritis. This assay may be especially helpful in such cases when positive in rheumatoid factor-negative patients.


Assuntos
Anticorpos/sangue , Artrite/imunologia , Peptídeos Cíclicos/imunologia , Artrite/diagnóstico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina M/sangue , Masculino , Ambulatório Hospitalar , Fator Reumatoide/sangue
10.
Nephrology (Carlton) ; 10(3): 317-20, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15958049

RESUMO

The following case reports are of two patients who have developed hypersensitivity reactions to the red cell growth hormones, darbepoietin and erythropoietin. The subsequent skin testing and clinical course suggested that the cause of these reactions was due to the excipient polysorbate 80. This finding might have implications in the recent increase in the incidence of pure red cell aplasia.


Assuntos
Anemia/tratamento farmacológico , Hipersensibilidade a Drogas/etiologia , Eritropoetina/análogos & derivados , Eritropoetina/administração & dosagem , Excipientes/efeitos adversos , Polissorbatos/efeitos adversos , Adulto , Idoso , Anemia/etiologia , Darbepoetina alfa , Eritropoetina/efeitos adversos , Feminino , Humanos , Falência Renal Crônica/complicações , Proteínas Recombinantes
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