Carroll, KR; Elfers, EE; Stevens, JJ; McNally, JP; Hildeman, DA; Jordan, MB; Katz, JD. Extending Remission and Reversing New-Onset Type 1 Diabetes by Targeted Ablation of Autoreactive T Cells. Diabetes. 2018; 67(11):2319-2328.
Targeting effector T cells with an approach called “p53 potentiation with checkpoint abrogation” (PPCA) appears to preserve islet β-cells in new-onset type 1 diabetes, and, crucially, the approach appears not to affect other types of T cells, meaning that the wider immune system is not affected with the treatment approach. As a result, we suggest there is a basis for a potential immune intervention in type 1 diabetes. The conclusions come from a series of experiments in NOD mice that explored and tried to manipulate a key characteristic of effector T cells, namely that such cells are naturally poised on the edge of apoptosis due to DNA damage that occurs on activation and the subsequent damage that occurs to p53 regulation of the cell cycle. We hypothesized that small molecular inhibitors (currently under clinical trial) might be able to tip such cells into apoptosis through potentiation of p53. We found that the PPCA combination of inhibitors we used (termed WEE1i and MDM2i) resulted in mice with new-onset diabetes capable of maintaining glycemic control for 50% of the days they were involved in the experiment. In comparison, untreated mice could only maintain control for 5%. 
Deason, K; Troutman, TD; Jain, A; Challa, DK; Mandraju, R; Brewer, T; Ward, ES; Pasare, C. BCAP links IL-1R to the PI3K-mTOR pathway and regulates pathogenic Th17 cell differentiation. The Journal of Experimental Medicine. 2018; 215(9):2413-2428.
The Pasare lab uncovered a new role for TLR signaling adapter B cell adapter for phosphoinositide 3-kinase (BCAP) in IL-1R signaling in CD4 T cells. They had previously BCAP as a novel toll-IL-1 receptor homology domain-containing adapter that regulates inflammatory responses downstream of TLR signaling in macrophages. In the current study, they found that BCAP also functions downstream of IL-1 receptor and plays a critical role in inducing pathogenic Th17 cell differentiation by linking IL-1R to PI3K-mTOR activation. Absence of BCAP, however, did not alter development of naturally arising Th17 lineages that participate in gut barrier function. Mice that lacked BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis (MS). These results suggest that BCAP could potentially be targeted to treat MS and other auto-immune diseases that are caused by pathogenic Th17 cells, without affecting the protective function of naturally arising Th17 cells.
Posgai, MT; Tonddast-Navaei, S; Jayasinghe, M; Ibrahim, GM; Stan, G; Herr, AB. Fc alpha RI binding at the IgA1 CH2-CH3 interface induces long-range conformational changes that are transmitted to the hinge region. Proceedings of the National Academy of Sciences of the United States of America. 2018; 115(38):E8882-E8891.
The Herr laboratory published a paper in PNAS demonstrating that the interaction of a cell-surface Fc receptor with an antibody induces long-range structural changes that could impact an important autoimmune disease.  Based on structural and biophysical data, they realized that interdomain motions in the IgA1 antibody isotype might be important for binding by the receptor FcαRI.  They collaborated with George Stan’s lab (UC Chemistry) to do a series of computational simulations to show that FcαRI binding at the side of the Fc region of IgA1 induced long-range conformational changes that can reach all the way to the hinge that connects the Fc region with the Fab ‘arms’ responsible for antigen recognition.  The computational predictions were validated by biophysical binding experiments, showing that FcαRI binding did in fact alter motions of the hinge.  These results help to explain some puzzling results in the field that reported that the presence of soluble FcαRI ectodomain in serum influenced the formation of circulating immune complexes in the kidney disease IgA nephropathy.  
Muench, DE; Ferchen, K; Velu, CS; Pradhan, K; Chetal, K; Chen, X; Weirauch, MT; Colmenares, C; Verma, A; Salomonis, N; Grimes, HL. SKI controls MDS-associated chronic TGF-beta signaling, aberrant splicing, and stem cell fitness. Blood. 2018; 132(21):e24-e34.
Understanding myelodysplastic-syndrome (MDS) pathobiology is critical to derive and evaluate new therapeutic interventions. Transforming growth factor-beta (TGFβ) signaling is abnormally active in early-stage MDS patient hematopoietic stem and progenitors (HSCP), and the level of TGFβ-signal-induced transcriptional changes may have prognostic value. However, the mechanism of TGFβ signaling resulting in ineffective hematopoiesis in MDS is not known.  This past year in Blood, the Grimes lab delineated the selective pressure of TGFb on HSC during early MDS (cover of Blood). Specifically, inflammatory signals induce miR-21 expression which targets the SKI corepressor; an antagonist of TGFβ signaling. People with MDS and mice that lack Ski display abnormal regulation of RNA splicing, leading to hematopietic stem cell dysfunction. Thus, inflammation-miR-21-Ski-splicing circuit is one factor in MDS that interferes with the TGFβ negative feedback loop to generate a chronic TGFβ signal and select mutant MDS clones.
Kelly, D; Kotliar, M; Woo, V; Jagannathan, S; Whitt, J; Moncivaiz, J; Aronow, BJ; Dubinsky, MC; Hyams, JS; Markowitz, JF; Baldassano, RN; Stephens, MC; Walters, TD; Kugathasan, S; Haberman, Y; Sundaram, N; Rosen, MJ; Helmrath, M; Karns, R; Barski, A; Denson, LA; Alenghat, T. Microbiota-sensitive epigenetic signature predicts inflammation in Crohns disease. JCI insight. 2018; 3(18).
Altered responses to intestinal microbes strongly associates with Inflammatory Bowel Diseases (IBD), however how cues from resident microbes are integrated during IBD is not understood. In this study, we found an epigenetic histone methylation profile of ileal epithelium that can effectively distinguish IBD patients from patients that lack intestinal inflammation. By comparing patient and murine samples, we discovered that microbiota regulate a unique subset of targets that are epigenetically altered in IBD patients.  Histone methylation levels at a substantial proportion of microbiota-sensitive epigenetic targets correlated with inflammation, despite lacking significant differences in expression. This discovery uncovered new targets of interest that may be epigenetically primed by resident microbes and highlighted unexplored pathways for how microbiota may initiate and/or exacerbate IBD.