Single-cell mapping of the immune system has uncovered roles of multiple cell types and a checkpoint molecule in myasthenia gravis (MG), according to a recent study in Clinical Immunology. 

Rui Fan and colleagues at the Chongqing Medical University in China wielded mass cytometry/cytometry time-of-flight (CyTOF) to map the multidimensional immune landscape in MG. Comparing CyTOF maps from 12 patients with MG and 10 controls revealed alterations in natural killer (NK) cells as well as cells expressing an immune checkpoint molecule.

The findings complicate the classical theory—established more than 40 years ago—that MG is due to abnormal activity of helper T cells and the B cells that produce autoantibodies. One problem with the classical theory is that autoantibody levels do not relate to MG severity and thus cannot explain disease progression.

Fan and colleagues identified a subset of NK cells that did indeed relate to MG severity scores. “From a clinical perspective,” the authors suggested, “our results show the potential of CD56+ CD16+ and CD56+ CD16+ CD8+ NK cells as diagnostic cellular markers and indicators of disease severity.”

Read more about the etiology of MG

The classical theory for MG pathogenesis also stops short of explaining what causes T and B cell malfunction. Immune checkpoint cascades have been increasingly characterized in other autoantibody-mediated diseases. Fan and colleagues honed in on the V-domain immunoglobulin suppressor of T cell activation (VISTA) immune checkpoint, expressed on subsets of monocytes and T cells in their samples.

“To the best of our knowledge, this study is the first to identify VISTA+ monocytes and reveal their gene signatures,” the authors highlighted. The mechanism by which VISTA+ cells contribute to MG pathogenesis will require further elucidation. Defying expectations that an immune checkpoint system would underperform in autoimmune disease, VISTA+ cells were overrepresented in MG. 

In support of the above findings, Fan and colleagues repeated analyses in a publicly available validation dataset containing 38 patients with MG and 21 controls. Limitations of the study included its small sample sizes and cross-sectional design.

The stakes for future work on VISTA+ cells may prove to be especially high. The authors concluded, “Our results suggest the potential value of cellular therapies related to VISTA, such as downregulating VISTA+ monocytes to reduce their antigen processing/presentation ability in autoimmune diseases.”

References

Fan R, Que W, Liu Z, et al. Single-cell mapping reveals dysregulation of immune cell populations and VISTA+ monocytes in myasthenia gravis. Clin Immunol. Published online November 11, 2022. doi:10.1016/j.clim.2022.109184 

Shinomiya N, Yata J. B and T cell involvement in anti-acetylcholine receptor antibody formation in myasthenia gravis. Clin Exp Immunol. 1981;46(2):277-285.