Toll-like receptor 7 (TLR7) is critical to the induction of antiviral immunity, but TLR7 dosage is also a key pathogenic factor in systemic lupus erythematosus (SLE), an autoimmune disease with strong female bias. SLE prevalence is also elevated in individuals with Klinefelter syndrome, who carry one or more supernumerary X chromosomes, suggesting that the X chromosome complement contributes to SLE susceptibility. TLR7 is encoded by an X chromosome locus, and we examined here whether the gene evades silencing by X chromosome inactivation in immune cells from women and Klinefelter syndrome males. Single-cell analyses of allelic expression demonstrated that substantial fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells not only in women but also in Klinefelter syndrome males express on both X chromosomes. Biallelic B lymphocytes from women displayed greater transcriptional expression than the monoallelic cells, correlated with higher TLR7 protein expression in female than in male leukocyte populations. Biallelic B cells were preferentially enriched during the TLR7-driven proliferation of CD27 plasma cells. In addition, biallelic cells showed a greater than twofold increase over monoallelic cells in the propensity to immunoglobulin G class switch during the TLR7-driven, T cell-dependent differentiation of naive B lymphocytes into immunoglobulin-secreting cells. escape from X inactivation endows the B cell compartment with added responsiveness to TLR7 ligands. This finding supports the hypothesis that enhanced TLR7 expression owing to biallelism contributes to the higher risk of developing SLE and other autoimmune disorders in women and in men with Klinefelter syndrome.
In women with normal somatotroph function, IGF-1 levels decrease in the first trimester of pregnancy without changes in GH or IGF-BP3 levels. These results confirm liver resistance to GH as a consequence of the physiological increase of estrogens during the first trimester.
Context: Sight-threatening Graves' orbitopathy affects 3% to 5% of patients with Graves' orbitopathy.Objectives: To describe the management of patients with sight-threatening Graves' orbitopathy seen in a multidisciplinary thyroid-eye outpatient clinic dedicated to Graves' orbitopathy (GO). Patients and methods:We enrolled all patients with sight-threatening GO (dysthyroid optic neuropathy and corneal ulcer as defined in the EUGOGO statement) seen and treated in our GO multidisciplinary thyroid-eye outpatient clinic over the last two decades.Results: A total of 31 patients (median age 51 years old) including 24 women (77%) and 58% active smokers. This population represented 47 cases (case = eye) of sightthreatening GO. Dysthyroid optic neuropathy (DON) occurred in 40 eyes, corneal ulcer in 15 eyes and both in 8. At presentation, the clinical features of DON were reduced visual acuity (85%), visual field defects (80%), optic disc swelling (42%) and reduced colour vision (100%). At one year, surgical orbital decompression (OD) was performed in 82.5% of DON cases. Only seven eyes with DON were treated with pulses of intra-venous glucocorticoids. For 10 patients, several therapeutic strategies (OD n = 4, punctal plug n = 1, amniotic membrane graft n = 2, tarsorrhaphy n = 2, botulinum toxin injection = 3 and eyelid surgery n = 2) were used to treat corneal ulcer. For each ophthalmological parameter, more than 85% of DON cases had recovery or improvement after treatment. For visual acuity in corneal ulcer, it was 71.4%. Conclusion:We report 47 cases of sight-threatening GO. Orbital decompression was performed in the majority of DON cases and several therapeutic strategies were necessary to treat corneal ulcer. The results are satisfactory in sight-threatening Graves' orbitopathy due to multidisciplinary management. K E Y W O R D Scornea, dysthyroid optic neuropathy, orbital decompression, sight-threatening Graves' orbitopathy | 209TramunT eT al.
Central hypothyroidism (CH) is a rare cause of hypothyroidism generally related to a hypothalamic-pituitary disorder or arising as an iatrogenic complication. In adults, CH may be secondary to quantitative and/or qualitative alterations in thyroid-stimulating hormone (TSH) secretion. The disease is difficult to diagnose clinically because it lacks specific clinical signs and these may be masked by other anterior pituitary hormone secretion deficiencies. In patients with long-standing and marked CH, a diagnosis may be made based on low free T4 levels and normal, low or moderately increased TSH levels. In patients with early-stage or moderate CH, exploration of the circadian TSH cycle, determination of TSH response after a TRH test or recombinant TSH injection, estimation of TSH index, or evaluation of peripheral indexes of thyroid hormone metabolism may be required to establish a diagnosis. Regarding treatment, patients should receive levothyroxine replacement therapy, but hormone objectives during follow-up need to be precisely determined in order to reduce cardiovascular risks and to improve the quality of life of patients.
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