Biology subjects

Raska, M.

Publications and source records attributed to Raska, M..

4 recordsLinked to original sources

bioRxiv2026

Mucosal Inflammation as a Driver of Gd-IgA1 Production in IgA Nephropathy: Mechanistic Support for Targeted Therapies

Rationale & Objective: Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1), predominantly with {lambda} light chains and Gd-IgA1 glycans-recognizing antibodies. Disease exacerbations are frequently linked to mucosal infections, underscoring the role of dysregulated mucosal immunity. Whereas current therapeutic strategies targeting Gd-IgA1-producing cells are largely evaluated based on clinical endpoints, a critical gap remains in understanding how these therapies influence Gd-IgA production and whether targeting mucosal immunity represents an effective therapeutic strategy. Here, we provide a mechanistic insight into Gd-IgA1+ B cell behavior within inflammatory mucosal-like microenvironment. Study Design: Case-control study with ex vivo functional analysis. Setting & Participants: Peripheral blood mononuclear cells from patients with biopsy-proven IgAN and healthy controls. Exposure(s): Stimulation with a cytokine combination mimicking mucosal immune activation (IL-6, IL-21, BAFF, APRIL). Outcome(s): Differentiation of B cell subsets involved in IgAN and production of IgA, Gd-IgA1, and IgG. Analytical Approach: Flow cytometry, ELISA, cytometric bead array, and Western blotting. Results: Mucosal cytokine stimulation induced robust differentiation of B cells into CD38high plasmablasts and CD138high plasma cells, with a disproportionate expansion of Gd-IgA1 populations in IgAN. Compared with controls, PBMCs from IgAN patients demonstrated markedly increased production of Gd-IgA1, predominantly in polymeric form and strongly enriched for {lambda} light chains (~90% vs ~51%). This response was accompanied by selective expansion of Gd-IgA1{lambda} plasma cells, identifying a disease-specific, highly responsive B cell compartment. Limitations: The cytokine combination was selected to reflect key signals present in mucosal immune environments, although in vivo conditions are more complex. Conclusions: Mucosal cytokine signals directly amplify pathogenic B cell responses in IgAN, driving production of polymeric, {lambda}-enriched Gd-IgA1. These findings provide mechanistic validation for therapies targeting the mucosal-systemic axis and offer a biologic explanation for the clinical efficacy of gut-directed corticosteroids and BAFF/APRIL inhibition.

immunology↗

bioRxiv2026

Biochemical and Immunological Properties of Engineered Low-Immunogenic Staphylokinases for Next-Generation Thrombolytic Therapy

Staphylokinase (SAK) is a highly fibrin-specific plasminogen activator with significant potential as a safe and affordable thrombolytic. Yet, its clinical translation can be limited by potential immunogenicity. To accelerate the development of improved thrombolytics, a critical step is identifying the most suitable molecular template. Therefore, we performed a comparative analysis of biochemical and immunological properties of three engineered low-immunogenic variants (SAK SY155, SAK THR174, and SAK STAR FRIDA) and two wild-types (SAK STAR and SAK 42D), using a newly established panel of assays. All variants retained potent thrombolytic activity, with SAK SY155 displaying the highest catalytic efficiency and fibrin-clot permeability. However, this advantage did not fully translate into improved clot reduction under flow conditions. Comprehensive immunological profiling, including T lymphocyte proliferation, dendritic cell maturation, mouse immunization models, and human serum reactivity tests, confirmed decreased immunogenicity for two low-immunogenic variants. Overall, low-immunogenic SAK SY155 emerged as the most promising template for rational engineering of next-generation thrombolytics.

biochemistry↗

bioRxiv2023

Concurrent infection of human brain with multiple species of Lyme disease spirochetes

Lyme disease (LD) spirochetes are well known to be able to disseminate into the tissues of infected hosts, including humans. The diverse strategies used by spirochetes to avoid the host immune system and persist in the host include active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, and, importantly, incursion into immune privileged sites such as the brain. Invasion of immune privileged sites, like the brain allows the spirochetes not only escape from the host immune system but also can reduce the efficacy of antibiotic therapy. Here we present a case of the detection of DNA of spirochetes from Borrelia burgdorferi sensu lato complex from multiple loci of LD patients post-mortem brain. The presence of co-infection with Borrelia burgdorferi sensu stricto and Borrelia garinii in LD patients brain was confirmed by PCR. The presence of atypical spirochete morphology was confirmed by immunohistochemistry of the brain samples and also in tissues of experimental mice, infected with Borrelia by simultaneous injection of spirochetes subcutaneously and intraperitoneally. Even though both spirochete species were simultaneously present in brain, the brain regions where the two species were detected were different and non-overlapping.

microbiology↗

bioRxiv2020

Impact of glycan positioning on HIV-1 Env glycan shield density, function, and antibody recognition

N-glycans, which represent >50% mass of the HIV-1 envelope (Env) trimer, play important roles for virus-cell entry and immune evasion. How each glycan unit interacts to shape the Env protein-sugar complex and affects Env function is not well understood. Here, high-resolution glycomics analysis of two Env variants from the same donor, with differing functional characteristics and N-glycosylation-site composition, revealed that changes to key N-glycosylation-site not only affected the Env structure at distant locations, but also had a ripple effect on Env-wide glycan processing, virus infectivity, and antibody recognition and virus neutralization. Specifically, the N262 glycan, although not located in the CD4-binding site, controlled Env binding to the CD4 receptor, affected the recognition of Env by several glycan-dependent broadly neutralizing antibodies, and altered heterogeneity of glycosylation at several sites, with N156, N160, and N448 displaying limited glycan processing. Molecular dynamic simulations visualized how specific oligosaccharide positions can move to compensate for loss of a glycan. This study demonstrates how changes in individual glycan units can alter molecular dynamics and processing of the Env-glycan shield and, consequently, Env function.

microbiology↗