Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.

Substantial evidence highlights divergences in immune responses between men and women. Women are more susceptible to autoimmunity, whereas men suffer from the more severe presentation of autoimmune disorders. The molecular mechanism of this sexual dimorphism remains elusive. Herein, we conducted a comprehensive analysis of sex differences in whole-blood gene expression focusing on alternative splicing (AS) events in systemic lupus erythematosus (SLE), which is a prototype sex-biased disease. This study included 79 SLE patients with active disease and 58 matched healthy controls who underwent whole-blood RNA sequencing. Sex differences in splicing events were widespread, existent in both SLE and a healthy state. However, we observed distinct gene sets and molecular pathways targeted by sex-dependent AS in SLE patients as compared to healthy subjects, as well as a notable sex dissimilarity in intron retention events. Sexually differential spliced genes specific to SLE patients were enriched for dynamic cellular processes including chromatin remodeling, stress and inflammatory responses. Remarkably, the extent of sexual differences in AS in the SLE patients and healthy individuals exceeded those in gene expression. Overall, this study reveals an unprecedent variation in sex-dependent splicing events in SLE and the healthy state, with potential implications for understanding the molecular basis of sexual dimorphism in autoimmunity.

Nuclear architectural proteins are increasingly recognized as multifunctional regulators whose roles extend well beyond static genome organization. Here we report that SMC1A, a core subunit of the cohesin complex, undergoes a striking redistribution upon inflammatory stimulation in human monocytes, dissociating from nuclear speckles and accumulating at genomic regions enriched for stress-response genes with distinct exon-intron architectural properties. Through integrative analysis of RNA-seq, chromatin organization, and nuclear spatial data, we demonstrate that this redistribution has functional consequences at multiple levels of gene expression. SMC1A dissociation from speckles is accompanied by a reduction in intron retention events -consistent with a transition from a poised, pre-loaded transcriptional state toward active, efficient co-transcriptional processing- and by selective engagement with genes whose exon-intron architecture favors exon definition splicing, shorter nuclear mRNA residence times, and peripheral radial positioning. Genes affected by SMC1A silencing, by contrast, occupy more central nuclear positions and display fundamentally different structural properties, demonstrating that the two modes of SMC1A perturbation -stress-induced redistribution and depletion- are functionally and spatially non-equivalent. These findings suggest a genome compartmentalization in which DNA compositional preferences, gene architecture, radial positioning, and splicing mode converge to define gene sets capable of rapid, precise activation. SMC1A navigates this pre-existing landscape upon inflammatory cues, coordinating transcriptional and posttranscriptional responses simultaneously. We propose that stress-induced redistribution of architectural proteins within a largely invariant nuclear compartmental framework represents a general regulatory mechanism, one whose logic is encoded in the structural organization of the genome itself.