Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis and neuromyelitis optica spectrum disorder - recommendations from ECTRIMS and the EBMT.

Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for relapsing forms of multiple sclerosis (MS) that are refractory to disease-modifying therapy (DMT). AHSCT after failure of high-efficacy DMT in aggressive forms of relapsing-remitting MS is a generally accepted indication, yet the optimal placement of this approach in the treatment sequence is not universally agreed upon. Uncertainties also remain with respect to other indications, such as in rapidly evolving, severe, treatment-naive MS, progressive MS, and neuromyelitis optica spectrum disorder (NMOSD).

The Toxoplasma rhoptry protein ROP55 is a major virulence factor that prevents lytic host cell death.

Programmed-cell death is an antimicrobial defense mechanism that promotes clearance of intracellular pathogens. Toxoplasma counteracts host immune defenses by secreting effector proteins into host cells; however, how the parasite evades lytic cell death and the effectors involved remain poorly characterized. We identified ROP55, a rhoptry protein that promotes parasite survival by preventing lytic cell death in absence of IFN-γ stimulation.

Pitfalls in gut single-cell eukaryote research.

Gut single-celled eukaryotes (GSCEs) are found in billions of people worldwide, but we still know little about their functions and relationships in human gut ecology. Lately, retrospective analysis of bacterial data obtained by next-generation sequencing (NGS) methods has been used to identify links between GSCEs, gut bacteria, host metabolism, and host phenotypical traits, suggesting possible direct or indirect associations to favorable gut microbiome features and other health parameters. Here, we highlight some of the pitfalls related to the research strategy typically used so far and propose action points that could pave the way for a more accurate understanding of GSCEs in human health and disease.

Pulmonary Arterial Hypertension Incidence in Scleroderma Patients Treated with Bosentan for Digital Ulcers: Evidence from the Italian SPRING Registry.

Objective: Bosentan (BOS) is approved for treating pulmonary arterial hypertension (PAH) and preventing digital ulcers (DU) in systemic sclerosis (SSc). Our study aimed to evaluate whether BOS prescribed for DU could reduce the incidence of PAH in a large SSc cohort from the SPRING registry.

Methods: Patients with SSc from the SPRING registry, meeting ACR/EULAR 2013 classification criteria with data on PAH onset, DU status, BOS exposure, and at least a one-year follow-up between 2015 and 2020, and no known PAH at baseline were included.

IP-to-MS: An Unbiased Workflow for Antigen Profiling.

Immunoprecipitation is among the most widely utilized methods in biomedical research, with applications that include the identification of antibody targets and associated proteins. The path to identifying these targets is not straightforward, however, and often requires the use of chemical cross-linking and/or gel electrophoresis to separate targets from an overabundance of immunoglobulin protein. Such experiments are labor intensive and often yield long lists of candidate antibody targets.

Development of a StIW111C-based bioresponsive pore-forming conjugate for permeabilizing the endosomal membrane.

Gene expression manipulation is pivotal in therapeutic approaches for various diseases. Non-viral delivery systems present a safer alternative to viral vectors, with reduced immunogenicity and toxicity. However, their effectiveness in promoting endosomal escape, a crucial step in gene transfer, remains limited.

The structural organisation of pentraxin-3 and its interactions with heavy chains of inter-α-inhibitor regulate crosslinking of the hyaluronan matrix.

Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) of the inter-α-inhibitor (IαI) family of proteoglycans are covalently attached, playing a key role in the (non-covalent) crosslinking of HC•HA complexes. These interactions stabilise the cumulus matrix, essential for ovulation and fertilisation in mammals, and are also implicated in the formation of pathogenic matrices in the context of viral lung infections.

Antigenic determinants underlying IgE-mediated anaphylaxis to peanut.

Background: Studies of human IgE and its targeted epitopes on allergens have been very limited. We have an established method to immortalize IgE encoding B cells from allergic individuals.

Objective: To develop an unbiased and comprehensive panel of peanut-specific human IgE mAbs to characterize key immunodominant antigenic regions and epitopes on peanut allergens to map the molecular interactions responsible for inducing anaphylaxis.

Multimodal hierarchical classification of CITE-seq data delineates immune cell states across lineages and tissues.

Single-cell RNA sequencing (scRNA-seq) is invaluable for profiling cellular heterogeneity and transcriptional states, but transcriptomic profiles do not always delineate subsets defined by surface proteins. Cellular indexing of transcriptomes and epitopes (CITE-seq) enables simultaneous profiling of single-cell transcriptomes and surface proteomes; however, accurate cell-type annotation requires a classifier that integrates multimodal data. Here, we describe multimodal classifier hierarchy (MMoCHi), a marker-based approach for accurate cell-type classification across multiple single-cell modalities that does not rely on reference atlases.

Restimulation by macrophages exhausts T cells.

Inhibiting T cell exhaustion is an attractive cancer immunotherapy strategy. In this issue of Immunity, Waibl Polania et al. examine the microenvironmental signals regulating terminal T cell exhaustion and find that antigen presentation by tumor-associated macrophages, not tumor cells, drives terminal T cell exhaustion in glioblastoma.

The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease.

Although the relationship between macroautophagy/autophagy and Alzheimer disease (AD) is widely studied, the underlying mechanisms are poorly understood, especially the regulatory role of the initiation signaling of autophagy on AD. Here, we find that the ER transmembrane protein CANX (calnexin) is a novel interaction partner of the autophagy-inducing kinase ULK1 and is required for ULK1 recruitment to the ER under basal or starved conditions. Loss of CANX results in the inactivity of ULK1 kinase and inhibits autophagy flux.

Engineered extracellular vesicles with DR5 agonistic scFvs simultaneously target tumor and immunosuppressive stromal cells.

Small extracellular vesicles (sEVs) are nanosized vesicles. Death receptor 5 (DR5) mediates extrinsic apoptosis. We engineer DR5 agonistic single-chain variable fragment (scFv) expression on the surface of sEVs derived from natural killer cells.

3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity.

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts.

CFTR dictates monocyte adhesion by facilitating integrin clustering but not activation.

Monocytes are critical in controlling tissue infections and inflammation. Monocyte dysfunction contributes to the inflammatory pathogenesis of cystic fibrosis (CF) caused by CF transmembrane conductance regulator (CFTR) mutations, making CF a clinically relevant disease model for studying the contribution of monocytes to inflammation. Although CF monocytes exhibited adhesion defects, the precise mechanism is unclear.

Evolutionary lineage-specific genomic imprinting at the ZNF791 locus.

Genomic imprinting is an epigenetic process that results in parent-of-origin effects on mammalian development and growth. Research on genomic imprinting in domesticated animals has lagged due to a primary focus on orthologs of mouse and human imprinted genes. This emphasis has limited the discovery of imprinted genes specific to livestock.

The Golgi complex governs natural killer cell lytic granule positioning to promote directionality in cytotoxicity.

Cytotoxic immune cells mediate precise attacks against diseased cells to maintain organismal health. Their operational unit of killing and host defense is lytic granules (LGs), which are specialized lysosomal-related organelles. Precision in cytotoxicity is achieved by converging the many LGs to the microtubule-organizing center (MTOC) and polarizing these to the diseased cell for secretion.

Patterns of Tau pathology in patients with anti-IgLON5 disease visualized by Florzolotau (18F) PET.

Background: Anti-IgLON5 disease is a rare autoimmune neurological disorder with prominent Tau protein deposits in the brainstem and hypothalamus. The aim of this study was to visualize the in vivo distribution patterns of Tau protein in patients with anti-IgLON5 disease using the second-generation Tau PET tracer, Florzolotau (18F) PET imaging.

Methods: Patients diagnosed with anti-IgLON5 disease were enrolled consecutively.

Sodium-Directed Crosstalk Between Immune Cells and Lymphatic Vessels.

Purpose Of Review: The role of the lymphatic system in clearing extravasated fluids, lipid transport, and immune surveillance is well established, and lymphatic vasculature can provide a vital role in facilitating crosstalk among various organ systems. Lymphatic vessels rely on intrinsic and local factors to absorb and propel lymph from the interstitium back to the systemic circulation. The biological implications of local influences on lymphatic vessels are underscored by the exquisite sensitivity of these vessels to environmental stimuli.

Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans.

IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features.

Bacterial components-driven intrahepatic CXCR5 B cells are important population for MASH progression through inducing inflammation.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe liver inflammation and fibrosis due to an imbalanced immune response caused by enhanced bacterial components. The progression of MASH is closely linked to increased permeability of intestinal mucosal barrier facilitating enter of bacterial components into hepatic portal venous system. B cells are important immune cells for adaptive responses and enhance hepatic inflammation through cytokine production and T cell activation.

RECQL4 affects MHC class II-mediated signalling and favours an immune-evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma.

Background: Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ-like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear.

Lack of intracranial atherosclerosis in various atherosclerotic mouse models.

Background: Although mice are used extensively to study atherosclerosis of different vascular beds, limited data is published on the occurrence of intracranial atherosclerosis. Since intracranial atherosclerosis is a common cause of stroke and is associated with dementia, a relevant animal model is needed to study these diseases.

Methods And Results: We examined the presence of intracranial atherosclerosis in different atherogenic mouse strains and studied differences in vessel wall characteristics in mouse and human tissue in search for possible explanations for the different atherosclerotic susceptibility between extracranial and intracranial vessels.

Understanding the neurobiological mechanisms of LPS‑induced memory impairment.

In recent years, growing evidence suggests that lipopolysaccharide (LPS), a bacterial endotoxin found in the outer membrane of gram‑negative bacteria, can influence cognitive functions, particularly memory formation and retrieval. However, the underlying mechanisms through which LPS exerts its effects on memory remain incompletely understood. This review used various electronic databases, including PubMed, Scopus, and Web of Science, to identify relevant studies published between 2000 and 2024.

Induction of Antigen-Specific Tolerance in a Multiple Sclerosis Model without Broad Immunosuppression.

Multiple sclerosis (MS) is a severe autoimmune disorder that wreaks havoc on the central nervous system, leading to a spectrum of motor and cognitive impairments. There is no cure, and current treatment strategies rely on broad immunosuppression, leaving patients vulnerable to infections. To address this problem, our approach aims to induce antigen-specific tolerance, a much-needed shift in MS therapy.