Dissecting Sources of Quantitative Gene Expression Pattern Divergence Between Drosophila Species

The function of a transcriptional circuit is compared in three closely related species of Drosophila. Using quantitative imaging of gene expression, targeted transgenic reporter fly lines, and a computational framework, the sources of their differing expression outputs are identified

Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator

Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity

Differential Inflammatory Vascular Cytokine Profiles Associated with Angiotensin II Type 1 Receptor Antibodies and Human Leukocyte Antibodies in Pediatric Renal Transplantation

Background: Both human leukocyte antigen donor specific antibodies (HLA DSA) and non-HLA autoantibodies have been implicated in antibody-mediated rejection (AMR), allograft dysfunction, and allograft failure in kidney transplantation. Angiotensin II type 1 receptor antibody (AT1R-Ab), is a non-HLA antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different mechanistic pathway than HLA DSA. Objective: Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients. Methods: 65 pediatric kidney transplant patients were monitored for 2 years post-transplant. Blood samples from early post-transplant and at 6, 12, and 24 months post-transplant and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated. Results: AT1R-Ab, but not HLA DSA, was associated with elevations in TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17. This relationship remained significant even when controlling for relevant clinical factors and potential confounders, and was consistent across time points. Conclusion: In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years post-transplant. This profile of vascular cytokines may be informative for designing further studies to understand the distinct pathophysiology of AT1R-Ab mediated allograft injury in kidney transplantation

Differential Inflammatory Vascular Cytokine Profiles Associated with Angiotensin II Type 1 Receptor Antibodies and Human Leukocyte Antibodies in Pediatric Renal Transplantation

Background: Both human leukocyte antigen donor specific antibodies (HLA DSA) and non-HLA autoantibodies have been implicated in antibody-mediated rejection (AMR), allograft dysfunction, and allograft failure in kidney transplantation. Angiotensin II type 1 receptor antibody (AT1R-Ab), is a non-HLA antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different mechanistic pathway than HLA DSA. Objective: Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients. Methods: 65 pediatric kidney transplant patients were monitored for 2 years post-transplant. Blood samples from early post-transplant and at 6, 12, and 24 months post-transplant and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated. Results: AT1R-Ab, but not HLA DSA, was associated with elevations in TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17. This relationship remained significant even when controlling for relevant clinical factors and potential confounders, and was consistent across time points. Conclusion: In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years post-transplant. This profile of vascular cytokines may be informative for designing further studies to understand the distinct pathophysiology of AT1R-Ab mediated allograft injury in kidney transplantation