Immune cell–specific SMN expression and sustained immune alterations in treated spinal muscular atrophy
Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus
Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus
View: Text | PDF
Research Article Immunology Muscle biology Neuroscience

Immune cell–specific SMN expression and sustained immune alterations in treated spinal muscular atrophy

Abstract

Mutations in the survival of motor neuron 1 (SMN1) can reduce functional SMN protein levels, which causes spinal muscular atrophy (SMA), a disease affecting the nervous system and peripheral tissues, including the immune system. Yet, SMN expression across immune cell subsets and the effect of SMN-modulating therapies on the immune system remain underexplored. We found that in neonatal mouse spleens, SMN expression was highest in B cells, and was massively reduced in SMA mice. In human PBMCs from adults, DCs and monocytes expressed the highest SMN levels, whereas patients with SMA showed reduced DC frequencies and increased B cell frequencies. Patients receiving systemic versus CNS-restricted therapy showed similar differences in immune cell composition and SMN expression levels. Similarly, an exploratory cohort including untreated patients did not show a substantial treatment-specific effect relative to controls. To assess the effect of differentiation on SMN, we analyzed PMA-treated THP-1 cells and found enhanced aberrant SMN splicing and increased SMN+ Cajal bodies. SMN levels varied across immune cell types, and reduced SMN levels were associated with altered immune cell composition. Immune alterations and decreased SMN levels were observed in both treated and untreated patients with SMA and may have contributed to dysfunctions of the immune system.

Authors

Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus

×

Figure 2

B cells and macrophages express particularly high SMN levels in the spleens of neonatal mice.

Options: View larger image (or click on image) Download as PowerPoint
B cells and macrophages express particularly high SMN levels in the sple...
(A) UMAP with heatmap visualization of SMN expression in immune cells from control mice. (B) Histogram overlays displayed on a subpanel-specific relative half-offset scale (y axis) showing total SMN protein expression (x axis) across all immune cells in control mice (n = 5, left) and in individual immune cell clusters of 1 representative animal (right), colored according to cluster identity. 2nd AB only, secondary antibody only. (C) UMAP visualization of SMN expression in immune cells from SMA mice, using the same heatmap scale as in A. (D) Histogram overlays displayed as in B for SMA mice (n = 5, left) and the corresponding immune cell clusters of 1 representative animal (right), matching the cluster identities shown in B. Histograms were independently normalized within each subpanel, with the y axis representing the percentage of the maximum bin count in that subpanel. Therefore, the histogram heights do not reflect the absolute immune cell subset frequencies and should only be compared within a given subpanel. For comparisons of immune cell frequencies between subpanels, refer to Figure 1. The x axis uses a common scale for SMN expression (x axis) across all panels. Vertical reference lines indicate identical x values for better comparison between control and SMA samples. (E) Quantification of gMFI SMN protein expression levels across immune cell clusters in control (blue) and SMA (orange) littermates at P3. Each data point represents an individual biological replicate. Data indicate the mean ± SD. An unpaired, 2-tailed Student’s t test without multiple comparisons was used for each cell-type data set. *P < 0.05.