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 5

Adult patients with SMA treated with nusinersen exhibit a more pronounced change in PBMC composition compared with those treated with risdiplam.

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Adult patients with SMA treated with nusinersen exhibit a more pronounce...
(A) Distribution of SMN2 gene copy numbers among patients with SMA. Controls (gray, n = 16) and patients with SMA (type II, n = 9; type III, n = 14) are shown. The number of SMN2 copies (copies 2, 3, 4, and 6) is indicated by different shades of blue; n.d., not determined. (B) Age distribution for healthy controls (blue) and patients with SMA (orange). Data indicate the mean ± SD. (C) Sex distribution of study participants. (D) Clinical motor function scores for patients with SMA at initial presentation and at the time of analysis. The HFMSE and RULM scores are shown for ambulatory (black) and nonambulatory (red) individuals. (E) SMN expression levels (gMFI) of CD45+ in controls (blue), nusinersen-treated patients (n = 15, orange, circle), and risdiplam-treated patients (n = 8, orange stripes, triangle). One-way ANOVA followed by Šidák’s multiple-comparison test was performed to analyze differences between groups; P < 0.05 was considered significant (red); exact P values are displayed. (F and G) Correlation of SMN levels (gMFI) to SMN2 gene copy number (F) and age (G) by linear regression with 95% CI; coefficient of determination (r2) and P values are shown. Treatment groups are indicated by data point shape. The legend is shown in H. (H and I) Quantification of immune cell subset frequencies as a percentage of CD45+ cells (H) and gMFI SMN levels (I) in control individuals (blue) and treated patients with SMA (nusinersen – orange + circle, risdiplam – striped orange + triangle). Data represent the mean ± SD. Statistical significance was assessed using 1-way ANOVA followed by Šidák’s multiple-comparison test; P < 0.05 was considered significant (red); exact P values are displayed.