RESUMO
While autoreactive T cells are known to induce ß-cell death in type 1 diabetes (T1D), self-reactive B cells also play an important role in the pathogenesis of T1D. Studies have shown that individuals living with T1D have an increased frequency of self-reactive B cells that escape from the bone marrow and populate peripheral organs, become activated, and participate in disease. These failed tolerance mechanisms may be attributed to genetic risk alleles that are associated with the development of T1D. Once in the periphery, these self-reactive B cells act as important antigen-presenting cells to autoreactive T cells and produce autoantibodies that are used to predict individuals at risk for or diagnosed with T1D. Here, we discuss the evidence that B cells are important in the pathogenesis of T1D, how these cells escape normal tolerance mechanisms, their role in disease progression, and how targeting these cells and/or monitoring them as biomarkers for response to therapy will be of clinical benefit.
RESUMO
Autoreactive B cells play an important but ill-defined role in autoimmune type 1 diabetes (T1D). To better understand their contribution, we performed single cell gene and BCR-seq analysis on pancreatic islet antigen-reactive (IAR) B cells from the peripheral blood of nondiabetic (ND), autoantibody positive prediabetic (AAB), and recent-onset T1D individuals. We found that the frequency of IAR B cells was increased in AAB and T1D. IAR B cells from these donors had altered expression of B cell signaling, pro-inflammatory, infection, and antigen processing and presentation genes. Both AAB and T1D donors demonstrated a significant increase in certain heavy and light chain V genes, and these V genes were enriched in islet-reactivity. Public clones of IAR B cells were restricted almost entirely to AAB and T1D donors. IAR B cells were clonally expanded in the autoimmune donors, particularly the AAB group. Notably, a substantial fraction of IAR B cells in AAB and T1D donors appeared to be polyreactive, which was corroborated by analysis of recombinant monoclonal antibodies. These results expand our understanding of autoreactive B cell activation during T1D and identify unique BCR repertoire changes that may serve as biomarkers for increased disease risk.
RESUMO
CONTEXT: Poor knee biomechanics contribute to knee joint injuries. Neuromuscular control over knee position is partially derived from the hip. It is unknown whether isolated activation training of the gluteal muscles improves lower-extremity frontal plane mechanics. This study examined if a home-based hip muscle activation program improves performance on the Forward Step-Down Test as well as increases surface electromyography (sEMG) activation of the gluteal muscles. DESIGN: The study utilized a single-group repeated-measures design. METHODS: Thirty-five participants (24 females, mean age = 23.17 [SD 1.36] years) completed an 8-week hip muscle activation program. The Forward Step-Down Test score and sEMG of gluteus maximus and medius were assessed preintervention and postintervention. RESULTS: Forward Step-Down Test scores improved significantly from preintervention (Mdn = 3.5) to postintervention (Mdn = 3.0, T = 109, P = .010, r = .31.), but this result did not meet clinical significance. sEMG analysis revealed a significant increase in mean gluteus maximus activation (P = .028, d = 1.19). No significant dose-response relationship existed between compliance and the Forward Step-Down Test scores or sEMG results. CONCLUSIONS: A home-based hip activation program increases gluteus maximus activation without clinically significant changes in frontal plane movement quality. Future studies may find clinical relevance by adding motor learning to the activation training program to improve functional muscle use.