Invariant NKT Cell Lines Derived from the NOD·H2h4 Mouse Enhance Autoimmune Thyroiditis

To study the role of invariant Natural Killer T cell ( iNKT) cells in autoimmune thyroiditis, we derived two iNKT cell lines from the spleens of NOD· H2h4 mice, a strain that develops spontaneous autoimmune thyroiditis exacerbated by excess dietary iodine. The two lines were CD1d-restricted and expressed CD4+, DX5+, and the Vα4Jα281 gene segment, of the T-cell receptor α locus. Upon stimulation with α-galactosyl-ceramide (α-GalCer), both lines rapidly produced IL-2, IL-4, IFN-γ, IL-10, and TNF-α. Strikingly, a similar cytokine response was also induced by thyroglobulin, one of the most abundant protein in the thyroid gland and a major autoantigen in human autoimmune thyroiditis. Transfer of the iNKT cell lines to syngeneic hosts enhanced autoimmune thyroiditis. Intraperitoneal injections of α-GalCer in iodine primed mice also induced thyroid disease. This paper reports for the first time that iNKT cells respond to thyroglobulin and enhance autoimmune thyroiditis in iodine fed NOD·H2h4 mice

Immunoproteasome Overexpression Underlies the Pathogenesis of Thyroid Oncocytes and Primary Hypothyroidism: Studies in Humans and Mice

BACKGROUND:Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. METHODOLOGY/PRINCIPAL FINDINGS:Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. CONCLUSIONS/SIGNIFICANCE:In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism

Pituitary and systemic autoimmunity in a case of intrasellar germinoma

Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysitis because of similar clinical and pathological features. This differentiation, nevertheless, is critical for patient care due to different treatments of the two diseases. We report the case of an 11-year-old girl who presented with diabetes insipidus and growth retardation, and was found to have an intra- and supra-sellar mass. Initial examination of the pituitary biopsy showed diffuse lymphocytic infiltration of the adenohypophysis and absent placental alkaline phosphatase expression, leading to a diagnosis of hypophysitis and glucocorticoid treatment. Because of the lack of clinical and radiological response, the pituitary specimen was re-examined, revealing this time the presence of scattered c-kit and Oct4 positive germinoma cells. The revised diagnosis prompted the initiation of radiotherapy, which induced disappearance of the pituitary mass. Immunological studies showed that the patient’s serum recognized antigens expressed by the patient’s own germinoma cells, as well as pituitary antigens like growth hormone and systemic antigens like the Sjögren syndrome antigen B and alpha-enolase. The study first reports the presence of pituitary and systemic antibodies in a patient with intrasellar germinoma, and reminds us that diffuse lymphocytic infiltration of the pituitary gland and pituitary antibodies does not always indicate a diagnosis of autoimmune hypophysitis

Theophylline Increases the Uptake of Radioiodine by Mouse Thyroid

Diagnostic and therapeutic use of radioiodine in the management of thyroid disorders depends on the ability of thyroid cells to concentrate radioiodine, a process that is regulated by the intracellular increase in cAMP. We hypothesized that theophylline, a drug known to increase intracellular cAMP via inhibition of phosphodiesterase, could increase thyroidal radioiodine uptake. We tested this effect in vivo, using C57BL/6j mice, and in vitro, using Fisher rat thyroid (FRTL-5) cells. One mouse received 2.5mg theophylline i.p., whereas a control mouse received only saline. Twenty-hours after theophylline, mice were injected with 10 µCi Na125I in 0.1 mL saline through the tail vein. Mean thyroidal 125I activity was 3.3-fold higher in theophylline-treated mice than in their respective controls. Radioiodine uptake and intracellular cAMP production of FRTL-5 cells were increased by a relatively low concentration of theophylline (1 µM). Intracellular cAMP increased up to 30 min and then declined in response to 1 µM theophylline. Sera from theophylline-treated mice stimulated 125I uptake and intracellular cAMP production by FRTL-5 cells. These findings show that theophylline can enhance radioiodine uptake by thyrocytes in vivo and in vitro. The in vitro effects of theophylline on both radioiodine uptake and cAMP production in a dose-dependent manner are consistent with an action mediated by phosphodiesterase inhibition

Thyroid Autoantibodies Are Associated with a Reduced Prevalence of Frailty in Community-Dwelling Older Women

Context: The contribution of autoimmunity to the multisystem dysregulation that characterizes the frailty syndrome in older adults is unknown. Objective: The aim of the study was to investigate the relationship between thyroid antibodies and frailty in older women. Design, Setting, and Participants: We conducted a cross-sectional study nested within the Women’s Health and Aging Studies I and II. Thyroglobulin antibodies (TgAbs), thyroid peroxidase antibodies (TPOAbs), and antinuclear antibodies were measured in the baseline sera of 641 community-dwelling older women. Main Outcome Measure: Frailty was defined using a validated five-component measure. Results: The prevalence of prefrailty and frailty was lower in TgAb-positive than negative older women (37.1 vs. 47.8% and 6.7 vs.11.9%, respectively; P = 0.01 and 0.03). The prevalence of prefrailty, but not frailty, was lower in TPOAb-positive than negative women (38.9 vs. 48.0% and 10.1 vs. 11.3%; P = 0.04 and 0.34). After adjustment for covariates including serum thyroid stimulation hormone concentration and thyroid medication usage in multinomial regression models, TgAb-positive older women had lower odds of prefrailty and frailty compared with TgAb-negative women (odds ratio 0.57 and 0.30; 95% confidence interval 0.34–0.98 and 0.10–0.85, respectively). Similarly, TPOAb-positive older women had lower odds of frailty compared with TPOAb-negative women (odds ratio 0.44; 95% confidence interval 0.20–0.96). These trends were not observed with antinuclear antibodies. Conclusion: Independent of thyroid function status, community-dwelling older women who are seropositive for TgAbs and TPOAbs are less likely to be frail than seronegative women

New Insights into the Function of the Immunoproteasome in Immune and Nonimmune Cells

The immunoproteasome is a highly efficient proteolytic machinery derived from the constitutive proteasome and is abundantly expressed in immune cells. The immunoproteasome plays a critical role in the immune system because it degrades intracellular proteins, for example, those of viral origin, into small proteins. They are further digested into short peptides to be presented by major histocompatibility complex (MHC) class I molecules. In addition, the immunoproteasome influences inflammatory disease pathogenesis through its ability to regulate T cell polarization. The immunoproteasome is also expressed in nonimmune cell types during inflammation or neoplastic transformation, supporting a role in the pathogenesis of autoimmune diseases and neoplasms. Following the success of inhibitors of the constitutive proteasome, which is now an established treatment modality for multiple myeloma, compounds that selectively inhibit the immunoproteasome are currently under active investigation. This paper will review the functions of the immunoproteasome, highlighting areas where novel pharmacological treatments that regulate immunoproteasome activity could be developed

Johns Hopkins hospital notables portrayed on philatelic material

The philatelic medium is an extensive repository of the portraits of doctors of many nations. Using an electronic matching system to identify links between the lists of alumni and faculties register of Johns Hopkins Hospital in Baltimore and that of three stamp catalogues, 14 notable persons have been identified in the philatelic record. The Johns Hopkins Hospital was established in Baltimore in 1889 and instituted the revolutionary concept of combining patient care with research and teaching. Its founder Johns Hopkins (1795-1873) and 13 among alumni and faculties have been portrayed on postage stamps and first day covers of USA, Canada, Antigua, Barbuda, Palau, Maldives, Canada and Sweden. Five of them - du Vigneaud (1901-78), Smith (b. 1931), Nathans (1928-99), Hubel (b. 1926) and Wiesel (b. 1924) - were awarded the Nobel Prize for Medicine or Physiology. By means of the philatelic medium, portraits of Hopkins scientists and doctors, including Sir William Osler (1849-1919) and Dr Virgina Apgar (1909-74), are distributed in their many tens of thousands on envelopes sent not only to recipients in the USA but to the wider world