New Study from the Grassi’s lab on the discovery of a checkpoint regulator of pathogenic T lymphocytes in systemic lupus erythematosus
on Wednesday, January 23, 2019
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect different organs, including kidney, skin, heart, lung and nervous system. The mechanisms triggering the pathology are unknown, but the progression of the disease depends on the loss of immune system tolerance and generation of antibodies against self-antigens (autoantibodies). The emergence of dysfunctional T and B lymphocytes results in the production of pathogenic high affinity IgG autoantibodies from germinal centers (GCs), microanatomical structures comprised within follicles of secondary lymphoid organs (e.g. lymph nodes and spleen). Herein, T follicular helper (Tfh) cells promote B lymphocytes differentiation to high-affinity antibody secreting cells, which in physiological conditions protect the organism from infections, but in SLE generate pathogenic autoantibodies.
Extracellular adenosine-triphosphate (ATP) is a danger-associated molecular pattern (DAMP) released by damaged tissues to alert the immune system of an inflammatory condition, such as in case of SLE. The group of Fabio Grassi at the IRB-USI of Bellinzona, Switzerland has shown that a receptor activated by extracellular ATP, named P2X7, is important in limiting the generation of pathogenic Tfh cells by inducing a form of cell death defined pyroptosis. Lack of P2X7 amplified pathogenic Tfh cells and dramatically worsened the lupus pathology. The study also shows that P2X7 function is defective in circulating Tfh cells from SLE patients.
|Confocal microscopy of kidneys from lupus of wild-type and P2X7 deficient subjects, stained for nuclei (DAPI, blue), IgG (green) and C3 complement component (red) to detect glomerular immune pathogenic deposits (bars, 20 μm).|
In autoimmune conditions, the identification of molecules to selectively define and eventually target pathogenic cells while sparing the physiological components of the immune system constitutes a major achievement. Such knowledge allows designing therapeutic approaches devoid of dangerous systemic immunosuppressive effects. Drugs used to cure SLE are essentially directed toward effector mechanisms responsible of tissue damage. The IRB researchers defined the function of P2X7 receptor in selectively inhibiting the generation of immunopathogenic Tfh cells. In particular, this regulatory circuit is defective in SLE, but not other systemic autoantibody-mediated diseases.
|Representative time monitoring of YO-PRO permeability upon P2X7 stimulation (arrow) of circulating Tfh cells from healthy donors (HD), patients with SLE and primary anti-phospholipids syndrome (PAPS), a non-lupus systemic autoimmune disease. Note the reduced percentage of responding cells in SLE.|
The study, published in The Journal of Experimental Medicine and performed in collaboration with the University of Milan, University of Modena and Reggio Emilia, Italy, University of Zurich, Novartis Institute for Biomedical Research, Switzerland, and Medical University of Wien, Austria, defines P2X7 as a selective checkpoint for dysfunctional Tfh cells that is deregulated in SLE. In fact, P2X7 does not influence the generation of antigen-specific Tfh cells during vaccination. Therefore, restoring P2X7 activity in SLE patients could selectively limit the progressive amplification of pathogenic autoantibodies, which deteriorate patients’ conditions, without affecting Tfh cells response necessary to protect the organism from pathogens.
Faliti, C. E., R. Gualtierotti, E. Rottoli, M. Gerosa, L. Perruzza, A. Romagnani, G. Pellegrini, B. De Ponte Conti, R. L. Rossi, M. Idzko, E. M. C. Mazza, S. Bicciato, E. Traggiai, P. L. Meroni and F. Grassi
J Exp Med. 2019;