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
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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

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Figure 6

Adult patients with SMA treated with nusinersen or risdiplam show comparable reduction of SMN expression and alterations in PBMC composition relative to untreated patients with SMA.

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Adult patients with SMA treated with nusinersen or risdiplam show compar...
(A) Exploratory cohort scheme: analysis of PBMCs from healthy controls (n = 6), nusinersen-treated patients with SMA, or risdiplam-treated patients with SMA (a subset of the study cohort above and 1 SMA type I patient, n = 5) and untreated patients with SMA (n = 6). Clinical data are listed in Supplemental Table 2. (B and C) SMN expression levels (gMFI) of CD45+ cells (B) and immune cell subsets (C) in controls (blue circles), treated patients (orange circles, type I with red asterisk), and untreated patients (purple diamonds). Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA followed by Šidák’s multiple-comparison test. (D) Histogram overlays showing total SMN protein expression levels across immune cell subsets in 1 representative individual per analysis group, colored according to cluster identity. Histograms were normalized independently for each subpanel, with the y axis representing the percentage of the maximum bin count within that subpanel. The x axis shows SMN expression on a common scale across all panels. Vertical reference lines indicate identical x values for better comparison between control, SMA treated, and SMA untreated samples. (E) Quantification of immune cell subset frequencies as a percentage of CD45+ cells in controls, treated patients with SMA, and untreated patients with SMA. *P < 0.05, by 1-way ANOVA followed by Šidák’s multiple-comparison test.