The transcription factor B-lymphocyte-induced maturation protein-1 (Blimp-1) plays important roles in embryonic development and immunity. Blimp-1 is required for the differentiation of plasma cells, and mice with T-cell-specific deletion of Blimp-1 (Blimp-1 CKO mice) develop a fatal inflammatory response in the colon. Previous work demonstrated that lack of Blimp-1 in CD4+ and CD8+ T cells leads to intrinsic functional defects, but little is known about the functional role of Blimp-1 in regulating differentiation of T helper (h) cells in vivo and their contribution to the chronic intestinal inflammation observed in the Blimp1CKO mice. Here we show that Blimp-1 is required to restrain the production of the inflammatory cytokine IL17 by Th cells in vivo. Blimp-1CKO mice have greater numbers of IL17-producing TCRβ+CD4+cells in lymphoid organs and in the intestinal mucosa. The increase in IL17-producing cells was not restored to normal levels in wild type and Blimp-1CKO-mixed bone marrow chimeric mice, suggesting an intrinsic role for Blimp-1 in constraining the production of IL17 in vivo. The observation that Blimp-1-deficient CD4+ T cells are more prone to differentiate into IL17+/IFNγ+ cells and cause severe colitis when transferred to Rag1-deficient mice provides further evidence that Blimp-1 represses IL17 production. Analysis of Blimp-1 expression at the single cell level during Th differentiation reveals that Blimp-1 expression is induced in Th1 and Th2 but repressed by TGFβ in Th17 cells. Collectively, the results described here establish a new role for Blimp-1 in regulating IL17 production in vivo.
The transcriptional regulator Blimp1 plays crucial roles in controlling terminal differentiation in several lineages. In T cells, Blimp1 is expressed in both effector (Teff) and regulatory (Treg) cells, and mice with T cell-specific deletion of Blimp1 (Blimp1CKO mice) spontaneously develop severe intestinal inflammation, indicating a crucial role for Blimp1 in T cell homeostasis regulation. Blimp1 has been shown to function as a direct activator of the Il10 gene and although its requirement for IL10 expression has been demonstrated in both Treg and Teff cells under inflammatory conditions, the intrinsic requirement of Blimp1 for homeostatic maintenance of these T cell subsets had not been investigated. Using mice with Foxp3+ Treg-cell specific deletion of Blimp1 and other approaches, here we show that Foxp3+ Treg cell-intrinsic expression of Blimp1 is required to control Treg and Teff cells homeostasis but, unexpectedly, it is dispensable to prevent development of severe spontaneous intestinal inflammation. In addition, we show that Blimp1 controls common and unique aspects of Treg and Teff cell function by differentially regulating gene expression in these T cell subsets. These findings document previously unappreciated aspects of Blimp1’s role in T cell biology and shed light on the intricate mechanisms regulating Treg and Teff cell function.
SUMMARYFoxp3+ regulatory T cells (Treg) are essential modulators of immune responses, but the molecular mechanisms underlying their function are not fully understood. Here we show that the transcription factor Blimp-1 is a crucial regulator of the Foxp3+RORγt+ Treg subset. The intrinsic expression of Blimp-1 in these cells is required to prevent production of Th17-associated cytokines. Direct binding of Blimp-1 to the Il17 locus in Treg is associated with inhibitory histone modifications but unaltered binding of RORgt. In the absence of Blimp-1, the Il17 locus is activated, with increased occupancy of the co-activator p300 and abundant binding of the transcriptional regulator IRF4, which is required, along with RORγt, for IL-17 expression in the absence of Blimp-1. We also show that despite their sustained expression of Foxp3, Blimp-1−/− RORγt+IL-17-producing Treg lose suppressor function and can promote intestinal inflammation, indicating that repression of Th17-associated cytokines by Blimp-1 is a crucial requirement for RORγt+ Treg function.
Background There is still a lot unknown about the novel Coronavirus Disease 19 (COVID-19) and its effects in humans. This pandemic has posed several challenging clinical situations to healthcare providers. Objective We hope to highlight the distinctive challenges that COVID-19 presents in patients with serious mental illness and what steps primary medical teams can take to co-manage these patients with the psychiatry consultants. Methods We present a retrospective chart review of four patients who were on psychotropic polypharmacy and admitted to our hospital from the same long-term psychiatric facility with COVID-19 delirium and other associated medical complications. Results We illustrate how the primary medical teams and psychiatrists collaborated in clinical diagnosis, treatment, and management. Conclusions Patients with serious mental illness and COVID-19 infection require active collaboration between primary medical teams and psychiatrists for diagnostic clarification, reduction of psychotropic polypharmacy to avoid adverse effects and drug-drug interactions, prevention of psychiatric decompensation, and active management of agitation while balancing staff and patient safety concerns.
Peduncluar hallucinosis is a rare neurological disorder characterized by visual hallucinations, often described to be vivid and dream-like. While the exact pathophysiology has yet to be elucidated, most cases to date have suggested an etiology stemming from lesions to the thalamus or midbrain.Here presented is a case of a 54-year-old female with peduncular hallucinosis secondary to a pontine cavernoma hemorrhage in the setting of essential hypertension. The patient's vivid visual and auditory hallucinations aligned temporally with the lesion's discovery and resolved after pharmaceutical treatment. This case represents a rare form of peduncular hallucinosis secondary to a pontine cavernoma hemorrhage leading to vasospasm in the arteries feeding the brainstem.
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