Correlations of TNF-α gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis in a northern Chinese Han population

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Follow-up study of thymomas with special reference to their clinical stages

Akira Masaoka, Yasumasa Monden, Kazuya Nakahara … (1981)

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TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms.

Marianne Silver, Dorian LaTocha, A Fleischman … (2011)

Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2(V617F) expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2(V617F)-positive MPN. Altogether our data are consistent with a model where JAK2(V617F) promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.

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Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals.

A Alshekhlee, B Katirji, Simon Miles … (2009)

To determine the incidence and mortality rates and predictors of death in myasthenia gravis (MG) and MG crisis in a large US cohort. Our cohort was identified from the Nationwide Inpatient Sample database for the years 2000 through 2005 using ICD-9-CM codes. MG crisis was identified by the principal diagnosis code or by the presence of respiratory failure. The incidence of MG was stratified by age, ethnicity, and gender. Multivariate logistic regression analysis was used to identify predictors of mortality in MG. For trend analyses of immune intervention, we used the Cochrane-Armitage test. After data cleansing, 5,502 patients with MG were included. In women, the incidence of admission was two to three times higher during the first 5 decades. In men, the incidence of admission was higher during the sixth, seventh, and eighth decades. The annual incidence rate of MG was higher in black women (0.01 per 1,000 persons/year) compared to white women and white and black men (0.009, 0.008, and 0.007 per 1,000 persons/year). The overall in-hospital mortality rate was 2.2%, being higher in MG crisis (4.47%). Older age and respiratory failure were the predictors of death, with adjusted odds ratios of 9.28 (95% confidence interval [CI], 3.31, 26.0) and 3.58 (95% CI, 2.01, 6.38). The trend of i.v. immunoglobulin utilization has increased compared to plasma exchange and thymectomy (p < 0.0001). Myasthenia gravis (MG) is still a disease of young women and old men, as reflected by the hospital admission rates. In-hospital mortality of MG is low. Hospital utilization of i.v. immunoglobulin has significantly increased compared to plasma exchange and thymectomy.