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 1

SMA mice show a significant loss of B cells in the spleen at P3.

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SMA mice show a significant loss of B cells in the spleen at P3. (A) Sch...
(A) Schematic representation of the experimental workflow. Transgenic (mSmn–/– hSMN2tg/tg) and heterozygous (mSmn+/–) mice were bred to obtain control (mSmn+/– hSMN2tg/0) and SMA (mSmn-/-; hSMN2tg/0) offspring. Spleens were extracted at P3 from littermates (SMA n = 5, control n = 5), followed by tissue dissociation, RBC lysis, and spectral flow cytometric analysis of single-cell suspensions. FSC, forward scatter; SSC, side scatter. (B) UMAP representation of splenic immune cells calculated from all samples and phenotypic markers; colored according to cell type. Clustering is based on gating shown in Supplemental Figure 1A. Mφ, macrophages. (C) Heatmap-coded UMAPs showing expression intensity of individual surface markers across the identified clusters. (D) Contour UMAPs showing immune cell abundance and clustering patterns of splenocytes from SMA and control animals (E) Density UMAPs comparing the local distribution and abundance of immune cell populations between control and SMA animal data. (F and G) Quantification of flow cytometric data for relative abundances (F) and total cell counts (G) of immune cell subsets in control (blue, filled) and SMA mouse spleens (orange, circle). Data represent the mean ± SD. Each data point is an individual biological replicate. An unpaired, 2-tailed Student’s t test without multiple comparisons for each cell type data set was used separately. *P < 0.05.