Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus.

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

Review article: Contemporary management of gastrointestinal, pancreatic and hepatic toxicities of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities. AIM: To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities. METHODS: We searched Cochrane and PubMed databases for articles published through August 2023. RESULTS: Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific. CONCLUSIONS: Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.

The Neuropeptides of Ocular Immune Privilege, α-MSH and NPY, Suppress Phagosome Maturation in Macrophages.

The ocular microenvironment has evolutionarily adapted several mechanisms of immunosuppression to minimize the induction of inflammation. Neuropeptides produced by the retinal pigment epithelial cells regulate macrophage activity. Two neuropeptides, α-melanocyte-stimulating hormone (α -MSH) and neuropeptide Y (NPY), are constitutively expressed by the retinal pigment epithelial cells. Together these two neuropeptides induce anti-inflammatory cytokine production in endotoxin-stimulated macrophages and suppress phagocytosis of unopsonized bioparticles. These neuropeptides do not suppress the phagocytosis of opsonized bioparticles; however, they do suppress phagolysosome activation or formation. In this report, we studied the possibility that α-MSH with NPY suppress phagosome maturation within macrophages using opsonized OVA-coated magnetic beads to isolate and analyze the phagosomes. The magnetic bead-containing intercellular vesicles were isolated and assayed for Rab5, Rab7, LAMP1, Iad, and OVA. The macrophages cotreated with α-MSH and NPY were suppressed in Rab7 recruitment to the phagosome with suppression in LAMP1 expression but not in Iad expression. The results demonstrated that the α-MSH/NPY cotreatment suppressed phagosome maturation. In addition, the a-MSH/NPY-cotreated macrophages were suppressed in their ability to Ag stimulate CD4+ T cell proliferation. These results imply a potential mechanism of ocular immune privilege to divert Ag processing to prevent autoreactive effector T cells from binding their target cognate Ag within the ocular microenvironment.