Systemic lupus erythematosus (SLE) is the prototypical autoimmune disease driven by pathological interactions between T cells and B cells. The expansion of T follicular helper cells (TFH) and peripheral T helper cells (TPH), two populations of T cells that provide help to B cells, is an important feature of SLE. Human TFH and TPH cells typically produce high levels of the B cell chemoattractant CXCL13, yet the regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remain unclear. Lupus can cause life-threatening damage to multiple organs including the kidneys, brain and heart. Existing treatments often fail to control the disease and have unwanted side effects that reduce the immune system’s ability to fight infections.
Scientists at Northwestern Medicine and Brigham and Women’s Hospital have discovered a molecular defect that promotes the pathological immune response in SLE and demonstrate that reversing this defect has the potential to reverse the disease. In a study to be published in Nature this month, scientists report a new disease-driving pathway in lupus. There are disease-associated changes in multiple molecules in the blood of lupus patients. Ultimately, these changes lead to insufficient activation of a pathway controlled by the aryl hydrocarbon receptor (AhR), which regulates the response of cells to environmental pollutants, bacteria, or metabolites. Insufficient AhR activation results in too many disease-promoting immune cells, called peripheral helper T cells, which promote the production of pathogenic autoantibodies.
Using CRISPR screens, scientists identify the aryl hydrocarbon receptor (AhR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomics studies then demonstrated that AhR coordinates with the proto-oncogene c-Jun, to prevent the differentiation of CXCL13+ TPH/TFH cells and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE, antagonizes the AhR and c-Jun to promote the production of CXCL13 by T cells. To demonstrate that this discovery can be exploited for treatments, the researchers returned the molecules that activate the AhR in blood samples from lupus patients. This appeared to reprogram these lupus-causing cells into a lymphocyte subtype called a Th22 cell that can promote wound healing from the damage caused by this autoimmune disease.
This menas that AhR ligands (activators) can be suitable committed as potential and powerful dedicated immune suppressants for specific autoimmune conditions. Apart synthetic medicinal drugs opportunities, the deeper comprehension of immune cell metabolism and signaling could open more specific and even natural options. Natural AhR activators are several flavonoids present in many plants and vegetal foods, like luteolin, apigenin and kaempferol; or aromatics present in Crucifereae like indol-3-carbinol (I3C), di-indolyl-methane (DIM) and indoleacetic acid (IAA), whiche have the additional advantage of chemopreventive properties. These aromatic substances have also additional targets like protein kinases and transcription factors involved in immune responses like the JAK/STAT axis. But it looks like there are also other natural modulating substances previously ignored to affect immune resposes.
Through metabolomics analyses of IFN-β-activated macrophages and an IFN-stimulated-response-element reporter screening, scientists from the Chinese Academy of Medical Sciences, Beijing, identified spermine as an endogenous brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral white blood cells from individuals with SLE exhibited enhanced IFN-I and lupus gene signatures and showed decreased intracellular spermine concentrations. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from patients with SLE.
Indeed, scientists synthesized a spermine derivative (labeled SD1) and showed that it had a potent immunosuppressive function. Therefore, a regular metabolite involved in cellular proliferation may have opposite activities related to the biological context where it is working.
Pubblicazioni scientifiche
Law C, Vacleche VS et al. Nature Jul 10; in press.
Zhang Y et al. Mol Immunol 2024 Jul; 171:22-35.
Xu H, Zhang X et al. Immunity 2024 Jun; in press.
Pålsson-McDermott EM et al. Cell Res. 2020; 30:300.