Neuropsychiatric manifestations in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) represent complex clinical challenges due to their diverse presentations and multifactorial pathogenesis. Neuropsychiatric SLE (NPSLE) affects approximately 30–40% of SLE patients, with symptoms ranging from cognitive dysfunction to severe conditions such as stroke, seizures, and psychosis. In APS, cerebrovascular events, including ischemic stroke and transient ischemic attacks, occur in ∼20% of patients, alongside non-thrombotic manifestations like migraine and chorea. The underlying mechanisms involve immune-mediated neuronal injury, vascular thrombosis, and neuroinflammation. In NPSLE, autoantibodies, inflammatory cytokines, and complement activation drive neuronal damage, while APS is primarily characterized by antiphospholipid antibody-mediated thrombosis, with additional direct neuronal effects. Advanced neuroimaging, including diffusion tensor imaging, functional MRI, and positron emission tomography, reveals subtle structural and functional brain alterations. Emerging biomarkers, such as neurofilament light chain and glial fibrillary acidic protein, show promise for detecting neural and glial injury. This review synthesizes current insights into the pathophysiology, diagnostic approaches to neuropsychiatric manifestations in SLE and APS, emphasizing the need for integrated clinical, imaging, and laboratory evaluations to improve diagnostic precision and patient outcomes.
Stefan P. H. van den Berg, Philine E. A. Adolfsen, Thomas P.C. Dorlo
et al.
Antibodies are extensively used in treating various diseases, with over 100 canonical monoclonal antibodies (mAbs) approved. Population pharmacokinetic (PK) models are typically developed for each individual mAb, despite their similarities in size, shape, and susceptibility to lysosomal degradation. However, sparse datasets with limited PK information pose challenges in deriving accurate parameter estimates. Here, we provide a comprehensive overview of 160 published models of 69 mAbs, administered either intravenously or subcutaneously, examining their structural, statistical, and covariate components. Median estimates for the base parameters are linear clearance (0.22 L/d), central volume (3.42 L), peripheral volume (2.68 L), intercompartmental clearance (0.54 L/d), absorption rate (0.25 L/d), and bioavailability (69%). Using these to simulate a ‘generic’ mAb results in plausible kinetics with a terminal half-life of 21 ds. We demonstrated that the median linear clearance was 26% lower in models that included nonlinear target-mediated kinetics, when compared to linear models (0.18 vs. 0.25 L/d). For chimeric mAbs median linear clearance was 50% higher compared to fully human and humanized mAbs. Variability in PK parameter estimates across models was comparable to the inter-individual variability, which have consistently shown to be large for mAbs PK (e.g. 55% vs. 43% for clearance and 25% vs. 30% for central volume, respectively). Our meta-analysis suggests that a priori parameter estimates derived from the large body of existing pharmacokinetic models for mAbs are representative for many mAbs and can facilitate the design of new and/or more complex pharmacokinetic models or assist in dose optimization models.
Amanda Brady, Taylor M. Garrison, Robert K. Ernst
et al.
ABSTRACT Yersinia pestis is the etiological agent of human plague. However, certain evolutionarily divergent subspecies have different host specificities and virulence capacity compared to the more commonly studied strains with pandemic potential. This resource examines 10 diverse isolates representing some of the most understudied subspecies commonly referred to as Yersinia pestis Pestoides.
Amie J. Eisfeld, Lindsey N. Anderson, Shufang Fan
et al.
AbstractHuman infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology.
V. Schichter-Konfino, R. Mubariki, E. Toubi
et al.
BackgroundOmalizumab (OMA) was the first FDA-approved biological drug for severe chronic spontaneous urticaria (CSU), and until today is the only beneficial and truly safe one. The objectives were: To assess the prevalence of CSU patients in whom OMA cannot be stopped over time. We also asked if biomarkers (e.g., anti-TPO antibodies and total IgE) could assist in anticipating this issue.MethodsWe used our prospective registry of 93 patients, which included CSU disease duration, the onset of OMA treatment, Urticaria Activity Score (UAS7) during follow-up, co-morbidities, serum IgE levels and the presence of anti-TPO antibodies. Finally, we assessed the response to OMA during a period of six years.ResultsOut of the 93 treated CSU patients, OMA was stopped in ten patients after six months being defined as failures. In another ten patients, OMA was discontinued after 2–4 years of therapy, achieving a remission. Seventy-three patients are still treated between 2 and 6 years, having different degrees of response. Of these, in thirty-eight (52%) patients, we could not stop OMA even after six years due to CSU relapses. The prevalence of lower serum IgE levels and anti-TPO antibody positivity was significantly higher in CSU patients in whom OMA could not be stopped.ConclusionThis is the first study where OMA-treated CSU patients were followed up to six years. In half of them, long-term therapy of six years is still required.
Daniel F. Q. Smith, Quigly Dragotakes, Madhura Kulkarni
et al.
AbstractA key component of the insect immune response is melanin production, including within nodules, or aggregations of immune cells surrounding microbes. Melanization produces oxidative and toxic intermediates that limit microbial infections. However, a direct fungicidal role of melanin during infection has not been demonstrated. We previously reported that the fungusCryptococcus neoformansis encapsulated with melanin within nodules ofGalleria mellonellahosts. Here we developed techniques to study melanin’s role duringC. neoformansinfection inG. mellonella. We provided evidence that in vivo melanin-encapsulation was fungicidal. To further study immune melanization, we applied tissue-clearing techniques to visualize melanized nodules in situ throughout the larvae. Further, we developed a time-lapse microscopy protocol to visualize the melanization kinetics in extracted hemolymph following fungal exposure. Using this technique, we found that cryptococcal melanin and laccase enhance immune melanization. We extended this approach to study the fungal pathogensCandida albicansandCandida auris. We find that the yeast morphologies of these fungi elicited robust melanization responses, while hyphal and pseudohyphal morphologies were melanin-evasive. Approximately 23% of melanin-encapsulatedC. albicansyeast can survive and breakthrough the encapsulation. Overall, our results provide direct evidence that immune melanization functions as a direct antifungal mechanism inG. mellonella.
Scrub typhus is a poorly studied but life-threatening disease caused by the intracellular bacteriumOrientia tsutsugamushi(Ot). Cellular and humoral immunity inOt-infected patients is not long-lasting, waning as early as one-year post-infection; however, its underlying mechanisms remain unclear. To date, no studies have examined germinal center (GC) or B cell responses inOt-infected humans or experimental animals. This study was aimed at evaluating humoral immune responses at acute stages of severeOtinfection and possible mechanisms underlying B cell dysfunction. Following inoculation withOtKarp, a clinically dominant strain known to cause lethal infection in C57BL/6 mice, we measured antigen-specific antibody titers, revealing IgG2c as the dominant isotype induced by infection. Splenic GC responses were evaluated by immunohistology, co-staining for B cells (B220), T cells (CD3), and GCs (GL-7). Organized GCs were evident at day 4 post-infection (D4), but they were nearly absent at D8, accompanied by scattered T cells throughout splenic tissues. Flow cytometry revealed comparable numbers of GC B cells and T follicular helper (Tfh) cells at D4 and D8, indicating that GC collapse was not due to excessive death of these cell subtypes at D8. B cell RNAseq analysis revealed significant differences in expression of genes associated with B cell adhesion and co-stimulation at D8 versus D4. The significant downregulation ofS1PR2(a GC-specific adhesion gene) was most evident at D8, correlating with disrupted GC formation. Signaling pathway analysis uncovered downregulation of 71% of B cell activation genes at D8, suggesting attenuation of B cell activation during severe infection. This is the first study showing the disruption of B/T cell microenvironment and dysregulation of B cell responses duringOtinfection, which may help understand the transient immunity associated with scrub typhus.
N. N. Kataeva, N. G. Sarkisyan, N. S. Chumakov
et al.
Since the jawbone tissue is injured at the stage of metal dental implant introduction, the problem of inflammatory complication development leading to a breakdown in osseointegration remains relevant. Of interest are the immunological mechanisms of inflammatory process development during the emission of metal nanoparticles, as well as the mechanisms of its subsidence after the removal of a metal object. Microscopic and elemental analysis of the bone tissue of the Wistar rat lower jaw after artificial traumatization was carried out. During the experiment, the situation of presence of a metal foreign body in the bone bed was simulated. An insulin needle was injected into the connective tissue of the lower jaw, followed by its removal after seven days. Microscopic analysis of bone tissue was performed using a Tesscan Vega 4 scanning electron microscope. The teeth alveoli cortical layer surface, connection of the jaws with a gap, stratification of the cartilaginous layer were determined at low magnification in direct projection. Using higher magnification in the direct projection there are visible dense-structural crystalline inclusions, foci of necrosis in the area of junctions of the jaws alveolar processes. The elemental composition of bone tissue was obtained by atomic emission spectroscopy by iCAP 6300 Duo. In the test sample, the quantitative ratio of calcium and phosphorus was 1.68, which slightly exceeds the optimal value of 1.67. An upward change in this ratio indicates a decrease in phosphorus level, which can be interpreted as local osteoporosis. In addition, the following elements were found: Bi, Ga, Pb, Ti, Zn in the amount of 0.03-0.06 mass percent. The list of these elements corresponds to the chemical composition of an insulin needle, indicating the penetration of metal particles into bone bed tissues. The emission of nanoparticles and their subsequent association to micro- and submicron sizes, their persistence, as well as biocorrosion in areas of active bone formation can be a trigger for the development of an aseptic inflammatory process. This effect is due to both a direct damaging factor and an indirect effect through specific signal molecules produced in response to tissue damage.
María Eugenia Cortina, R. Clayton Bishop, Brittany A. DeVasure
et al.
All Chlamydia species are obligate intracellular bacteria that undergo a unique biphasic developmental cycle strictly in the lumen of a membrane bound compartment, the inclusion. Chlamydia specific Type III secreted effectors, known as inclusion membrane proteins (Inc), are embedded into the inclusion membrane. Progression through the developmental cycle, in particular early events of conversion from infectious (EB) to replicative (RB) bacteria, is important for intracellular replication, but poorly understood. Here, we identified the inclusion membrane protein IncS as a critical factor for Chlamydia development. We show that a C . trachomatis conditional mutant is impaired in transition from EB to RB in human cells, and C . muridarum mutant bacteria fail to develop in a mouse model of Chlamydia infection. Thus, IncS represents a promising target for therapeutic intervention of the leading cause of sexually transmitted infections of bacterial origin.
Dendritic cell (DC) vaccines are a safe and effective means of inducing tumor immune responses, however, a better understanding of DC biology is required in order to realize their full potential. Recent advances in DC biology have identified a crucial role for cDC1 in tumor immune responses, making this DC subset an attractive vaccine target. Human cDC1 exclusively express the C-type-lectin-like receptor, CLEC9A (DNGR-1) that plays an important role in cross-presentation, the process by which effective CD8+ T cell responses are generated. CLEC9A antibodies deliver antigen specifically to cDC1 for the induction of humoral, CD4+ and CD8+ T cell responses and are therefore promising candidates to develop as vaccines for infectious diseases and cancer. The development of human CLEC9A antibodies now facilitates their application as vaccines for cancer immunotherapy. Here we discuss the recent advances in CLEC9A targeting antibodies as vaccines for cancer and their translation to the clinic.
Sven Mostböck, Helen Haixia Wu, Timothy Fenn
et al.
VISTA (PD-1H) is an immune regulatory molecule considered part of the next wave of immuno-oncology targets. VISTA is an immunoglobulin (Ig) superfamily cell surface molecule mainly expressed on myeloid cells, and to some extent on NK cells and T cells. In previous preclinical studies, some VISTA-targeting antibodies provided immune inhibitory signals, while other antibodies triggered immune stimulatory signals. Importantly, for therapeutic antibodies, the isotype backbone can have a strong impact on antibody function. To elucidate the mode of action of immune stimulatory anti-VISTA antibodies, we studied three different anti-human VISTA antibody clones, each on three different IgG isotypes currently used for therapeutic antibodies: unaltered IgG1 (IgG1-WT), IgG1-KO (IgG1-LL234,235AA-variant with reduced Fc-effector function), and IgG4-Pro (IgG4- S228P-variant with stabilized hinge region). Antibody functionality was analysed in mixed leukocyte reaction (MLR) of human peripheral blood mononuclear cells (PBMCs), as a model system for ongoing immune reactions, on unstimulated human PBMCs, as a model system for a resting immune system, and also on acute myeloid leukemia (AML) patient samples to evaluate anti-VISTA antibody effects on primary tumor material. The functions of three anti-human VISTA antibodies were determined by their IgG isotype backbones. An MLR of healthy donor PBMCs was effectively augmented by anti-VISTA-IgG4-Pro and anti-VISTA-IgG1-WT antibodies, as indicated by increased levels of cytokines, T cell activation markers and T cell proliferation. However, in a culture of unstimulated PBMCs of single healthy donors, only anti-VISTA-IgG1-WT antibodies increased the activation marker HLA-DR on resting myeloid cells, and chemokine levels. Interestingly, interactions with different Fc-receptors were required for these effects, namely CD64 for augmentation of MLR, and CD16 for activation of resting myeloid cells. Furthermore, anti-VISTA-IgG1-KO antibodies had nearly no impact in any model system. Similarly, in AML patient samples, anti-VISTA-antibody on IgG4-Pro backbone, but not on IgG1-KO backbone, increased interactions, as a novel readout of activity, between immune cells and CD34+ AML cancer cells. In conclusion, the immune stimulatory effects of antagonistic anti-VISTA antibodies are defined by the antibody isotype and interaction with different Fc-gamma-receptors, highlighting the importance of understanding these interactions when designing immune stimulatory antibody therapeutics for immuno-oncology applications.
Marcel Wüthrich, Hannah E. Dobson, Cleison Ledesma Taira
et al.
Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immunocompetent and -deficient hosts, with worldwide mortality rates ranking 7th, even ahead of tuberculosis.