-
Gut Jul 2023IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less...
OBJECTIVE
IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.
DESIGN
Transcriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn's disease, n=421 UC and 243 controls) in the Mount Sinai Crohn's and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.
RESULTS
bMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.
CONCLUSION
Transcriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.
Topics: Humans; Colitis, Ulcerative; Inflammation; Crohn Disease; Biopsy; Biomarkers; Intestinal Mucosa
PubMed: 36109152
DOI: 10.1136/gutjnl-2021-326451 -
Nephrology, Dialysis, Transplantation :... Feb 2024Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN... (Review)
Review
Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression.
Topics: Humans; Glomerulonephritis, Membranous; Rituximab; Antibodies, Monoclonal; Autoantibodies; Antigen-Antibody Complex; Receptors, Phospholipase A2
PubMed: 37934599
DOI: 10.1093/ndt/gfad225 -
Annual Review of Medicine Jan 2024Membranous nephropathy (MN), an autoimmune kidney disease and leading cause of nephrotic syndrome, leads to kidney failure in up to one-third of affected individuals.... (Review)
Review
Membranous nephropathy (MN), an autoimmune kidney disease and leading cause of nephrotic syndrome, leads to kidney failure in up to one-third of affected individuals. Most MN cases are due to an autoimmune reaction against the phospholipase A2 receptor (PLA2R) located on kidney podocytes. Serum PLA2R antibody quantification is now part of routine clinical practice because antibody titers correlate with disease activity and treatment response. Recent advances in target antigen detection have led to the discovery of more than 20 other podocyte antigens, yet the clinical impact of additional antigen detection remains unknown and is under active investigation. Here we review recent findings and hypothesize how current research will inform future care of patients with MN.
Topics: Humans; Glomerulonephritis, Membranous; Autoantibodies; Kidney; Forecasting
PubMed: 37552894
DOI: 10.1146/annurev-med-050522-034537 -
Nature Apr 2024The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens....
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (T) cell development and function have been identified, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive T cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector T (eT) cell function. eT cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103SIRPα dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206 macrophages and eT cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Topics: Animals; Female; Male; Mice; Antigens, CD; Dendritic Cells; Gene Expression Profiling; Helicobacter hepaticus; Helicobacter Infections; Immune Tolerance; Inflammation; Integrin alpha Chains; Intestinal Mucosa; Macrophages; Mice, Inbred C57BL; Mucous Membrane; Receptors, Immunologic; Single-Cell Gene Expression Analysis; T-Lymphocytes, Regulatory; Transcriptome
PubMed: 38570678
DOI: 10.1038/s41586-024-07251-0