CD40 Ligand Expression is Defective in a Subset of Patients with Common Variable Immunodeficiency.

Common variable immunodeficiency (CVI) is characterized by hypogammaglobulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma cells. We hypothesized that T-cell dysfunction resulting in abnormal contact-mediated B-cell activation may play a prominent role in the failure of CVI B cells to produce specific antibody. We have previously shown that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evaluated, indicating that CVI B cells respond to signals delivered via CD40. Here we report that CD40 ligand (gp39) mRNA expression by activated lymphocytes from CVI patients (n = 31) as a group was significantly depressed (P \u3c 0.0001) compared with normal controls (n = 32). gp39 mRNA expression by activated lymphocytes from 13 CVI patients fell below the normal control range. T-cell surface expression of functional gp39 protein was correspondingly low in those patients with gp39 mRNA levels below normal control range and normal in patients with gp39 mRNA levels within normal control range. In CVI patients as a group, gp39 mRNA levels correlated with IL-2 mRNA levels (P \u3c 0.002, r = 0.6) and production (P \u3c 0.001, r = 0.7) but not with gene expression or production of other lymphokines evaluated, suggesting an as-yet-undetermined association between gp39 and IL-2 gene regulation. Of the 13 patients whose activated T cells exhibited gp39 mRNA expression below the normal control range, 2 had normal T-cell-derived lymphokine production, whereas the remaining 11 exhibited broader T-cell dysfunction, resulting in IL-2 deficiency, and in some patients deficient production of other lymphokines as well, reflecting a heterogeneity in the underlying mechanisms leading to depressed gp39 expression in these patients. The observation that both gene and surface expression of gp39 by activated T cells is depressed in a subgroup of CVI patients suggests that inefficient signaling via CD40 may be responsible, in part, for failure of B-cell differentiation in these patients

Two distinct mechanisms of interleukin-2 gene expression in human T lymphocytes

Interleukin-2 (IL-2) gene regulation was investigated in primary cultures of highly purified human peripheral blood CD28+T cells. Two discrete mechanisms for induction of T-cell proliferation could be distinguished by examining cell cycle progression and the expression of the IL-2 gene. Stimulation of cells by CD3 MoAb induced only transiently expressed, small amounts of IL-2 mRNA that was completely suppressed by cyclosporine. Costimulation of T cells with CD3 MoAb and either CD28 MoAb or PMA, but not calcium ionophore, induced a 50-100-fold increased in IL-2 gene expression and secretion. High levels of IL-2 gene expression could also be achieved by stimulation with calcium ionophore and PMA or CD28 MoAb and PMA, but not by CD28 MoAb plus calcium ionophore. IL-2 gene expression and T-cell proliferation induced by CD3 MoAb plus PMA or calcium ionophore plus PMA were completely suppressible by cyclosporine. In contrast, IL-2 gene expression and T-cell proliferation induced by CD28 MoAb plus PMA were unaffected by cyclosporine. The CD28 signal was dependent on new protein synthesis. Nuclear run-on transcription assays showed that anti-CD28 did not affect lymphokine transcription. A major effect of CD28 stimulation on mRNA stability was shown by studies using actinomycin D; CD28 stimulation substantially increased the half-life of IL-2 and TNF-alpha mRNA. The effects of anti-CD28 stimulation were specific for growth factors, and thus differ from previously described effects of cycloheximide on mRNA stability. These studies suggest the existence of two biochemical pathways for the induction of IL-2 production, one that occurs at the transcriptional level and is mediated by intracellular calcium release and protein kinase C and is cyclosporine-sensitive, and one that acts post-transcriptionally, is mediated by CD28 stimulation, and is cyclosporine-resistant.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27894/1/0000314.pd

Views of Diagnostic Radiology Residency Program Directors Regarding Methods to Increase Female and Under-Represented in Medicine Residents: A Cross-sectional Study

RATIONALE AND OBJECTIVES: Diagnostic radiology remains one of the least diverse medical specialties. Recent reports have found that the number of female and under-represented in medicine (URiM) residents have not increased despite efforts to increase representation over the last decade. Given the critical role of residency program directors in selecting diverse applicants, this study was performed to identify which strategies were most preferred to increase the number of female and/or URiM residents by directors of diagnostic radiology residency training programs. MATERIALS AND METHODS: This was an anonymous, cross-sectional study of diagnostic radiology residency program directors that included a survey about program characteristics, demographics, and strategies to increase the number of female and/or URiM residents. RESULTS: The questionnaire was submitted to 181 potential participants with a 19.9% response rate. The most preferred strategies to increase diversity involved directly recruiting medical students, promoting mentorship, increasing the number of diverse teaching faculty, and unconscious bias training. The least supported strategies included deemphasizing exam scores, accepting more international graduates, accepting a minimum number of female and/or URiM applicants, and de-identifying applications. Female and/or URiM program directors indicated a statistically significant preference for medical student recruitment and providing an opportunity to discuss workplace issues for female and/or URiM trainees (p \u3c 0.05). CONCLUSION: Diagnostic radiology residency program directors endorsed a wide variety of strategies to increase diversity. Recruitment of female and/or URiM medical students and promoting the number of diverse faculty members and mentorship of trainees by these faculty appear to be the most preferred strategies to increase female and/or URiM residents. Female and/or URiM program directors placed a greater importance on recruiting diverse applicants and supporting safe discussion of workplace issues faced by female and/or URiM radiology residents