Volume 219, Issue 1, 2025

Systemic sclerosis is a rare autoimmune disease characterized by immune system abnormalities that affect blood vessels. Specific autoantibodies are linked to clinical manifestations and prognosis, though their exact role in the disease remains unclear. This review focuses on B-cell dysfunction in systemic sclerosis and explores current and potential B-cell-targeted therapies.

This paper provides an overview of the evolution of Phase 3 vaccine trial design and statistical analysis methods from traditional to more innovative contemporary methods.

Genetic anomalies in key components of the type I interferon pathway, encompassing TLR3, TLR7, STAT2, IRF3, IFNAR1/2, TBK1, IRF7, TICAM1, TYK2, MYD88, IRAK4, and UNC93B1, contributing to 3–5% of patients developing critical COVID-19 pneumonia. Additionally, autoantibodies, which neutralize the antiviral activity of type I interferons against SARS-CoV-2, are observed in 10–20% of cases.

This article discusses the essential function of neutrophils in preserving periodontal health and how the deficiency in these immune cells can lead to severe periodontal inflammation, highlighting the necessity for customized therapeutic strategies that target both the underlying immunodeficiency and the inflammatory mechanisms associated with periodontitis.

Oral vaccines have been developed and used with much success globally. However, despite their undeniable impact, oral vaccines against rotavirus, polio, and cholera do not always perform equally across different populations. In this article, we summarize the state of oral vaccines for these diseases and discuss potential hypotheses for performance disparities, including maternal and infant factors, environmental factors, and vaccine characteristics.

Longer-term data comparing the efficacy of leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, versus standard of care in individuals with activated PI3Kδ syndrome (APDS), are lacking. This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin M (IgM) levels versus current standard of care, using data from the leniolisib single-arm open-label extension study 2201E1 and the European Society for Immunodeficiencies (ESID) registry. Significant reductions in the annual rate of respiratory tract infections and serum IgM levels were observed in leniolisib-treated individuals versus standard of care, consistent across all sensitivity analyses, highlighting the potential for leniolisib to deliver long-term benefits.

In this study, we evaluated neuropsychiatric manifestations in mice with pristane-induced lupus and the effects of vitamin D supplementation on the brain of these animals.

This study aims to characterize the abilities of mouse colonic intraepithelial (IE) and lamina propria (LP) CD8+ T cell subsets to differentiate into Tc17 cells. Using flow cytometry, we found that normal TCRβ+CD4-CD8αα+ cells (CD8αα T cells) and TCRβ+CD4-CD8αβ T cells, (CD8αβ T cells), either IE or LP, expressed abundant granzymes and IFN-γ but minute IL-17A. Collectively, LP CD8αβ T cells have the strongest Tc17 differentiation ability and might play a more significant role than the other subsets in Tc17-mediated immunity or inflammation in the colon.

This study aimed to establish a novel mouse model of myositis-associated interstitial lung disease (MAILD) by using a TLR9 agonist (ODN2395). ODN2395 and muscle homogenate were used to induce MAILD in BALB/c mice. MAILD was evaluated using histopathology, immunohistochemistry, serum NETs determination, and myositis-specific antibody profile. Furthermore, TLR9 and IRF3 were examined in a lung biopsy tissue from a dermatomyositis patient with ILD. MAILD mice developed inflammatory myopathy with positive expression of myositis specific antibodies.

Comparing single and multiple intracranial aneurysms (SIA and MIAs) using mass cytometry, patients with MIAs showed T-cell dysfunction, reduced CD8 + T cells and CD27 − CD4 + Tem cells, and enhanced T-cell immune activation compared to SIA, indicating a potential role of immune dysfunction in MIAs development.

Severe trauma profoundly affects polymorphonuclear neutrophils (PMNs), crucial for trauma response. CCAAT/enhancer-binding protein ε (C/EBPε) deficiency impairs PMN function, while its overexpression enhances antimicrobial protein expression, aiding trauma recovery. Reduced C/EBPε in trauma patients correlates with severity scores, suggesting its prognostic value, and targeting C/EBPε acetylation through SIRT1 and P300 modulation emerges as a potential therapeutic approach, improving survival in traumatic mice.

T cells of pediatric inflammatory bowel disease (IBD) patients display an activated and Th1/Th17-shifted phenotype. The increased expression of the checkpoint molecule Lag-3 on T cells of IBD patients may represent a more exhausted phenotype and appears a relevant predictive marker for therapy failure.

Serum TBK1 levels correlate with the severity of colitis in mice with DSS-induced acute colitis. By targeting TBK1 with Amlexanox, we found that it exacerbates DSS-induced colitis in mice and participates in the negative regulation of IBD by affecting the function of various immune cells.

This review will investigate recent discoveries concerning the impact of EVs derived from macrophages/microglia under various states on the progression of ischemic stroke and acute lung injury. The focus will be on the involvement of miRNAs within these vesicles. The concluding remarks of this review will underscore the clinical possibilities linked to EV-miRNAs, accentuating their potential as both biomarkers and therapeutic targets.

Migraine, chronic migraine, and episodic migraine exhibit abnormalities in monocyte counts and PIMs, which possess diagnostic predictive value for differentiating migraine and its subtypes. This suggests that systemic inflammation may play a role in the pathogenesis of migraine.

In our cohort of patients treated with infliximab (IFX), over 10% of patients developed anti-drug antibodies (ADA). ADA levels were influenced by sex and concomitant prescription of immunosuppressant drugs but not by the number of injections or brand of IFX administered.

Neuro-Behçet’s disease (NBD) is a more severe but rare symptom of Behçet’s disease (BD), which is mainly divided into parenchymal NBD (p-NBD) involving brain stem, spinal cord, and cerebral cortex. Non-p-NBD manifests as intracranial aneurysm, cerebral venous thrombosis, peripheral nervous system injuries, and mixed parenchymal and non-parenchymal disease. We summarized opinions on the clinical diagnosis, biomarkers, and pathological findings of NBD.

B cells can be recruited to the wound site and facilitate the polarization of M2-like-macrophages, thereby accelerating the wound healing process.

In this work we described a standardized method based on the development and validation of a synthetic control to solve the problem of test comparison. Inter-assay and inter-laboratory variability were assessed by multiple repeated analyses within the same laboratory, and between two different laboratories involved in the study. The method has been validated by evaluating the IFN signature of 39 patients with inflammatory disorders known to be related or not to Type I IFN (i.e. monogenic interferonopathies, systemic lupus erythematosus, juvenile dermatomyositis, periodic fevers, juvenile idiopathic arthritis).

This study aims to clarify its efficacy and mechanism in treating IIM-ILD. A murine myositis-associated interstitial lung disease model was used to assess the therapeutic effect of PFD. The serum levels of IL-1ß, IL-6, and TNF-a were detected by ELISA. Pirfenidone was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro , and its inhibitory effect on NETs was assessed through immunohistochemistry of CitH3 and MPO in the lung tissue and the serum cfDNA level in mice.

The small molecule inhibitor 3PO blocks pathogenic reactive oxygen species (ROS) and neutrophil extracellular trap (NET) production by neutrophils. Using human neutrophils, we have investigated the intricate relationship between glycolysis, extracellular glucose availability, and the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, in the regulation of ROS and NET production.

During chronic and acute allograft rejection, as well as during ischemic reperfusion injury, a complex immunological event is orchestrated in the liver. Early on during post liver transplantation, a repertoire of signatures are transcribed depending on the donor category (dead/live). Identifying molecular parameters to be considered prior to transplantation, understanding the inherent immune landscapes of liver, and improving the post-transplantation strategies to attain operational tolerance is essential for a succesful transplantation procedure.

Immunotherapy is highly effective in melanoma, but intrinsic resistance is present and biomarkers to predict treatment response are essential. Despite the pathophysiological rationale, TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with melanoma. Based on this finding, we expect limited efficacy of agents blocking TGF-β signaling in melanoma. In contrast, the Hedgehog pathway activity was identified as a possible predictive biomarker associated with both treatment response and survival.

This study aims to identify the concentration of soluble B7-H4(sB7-H4) in the plasma of patients with ovarian cancer and to evaluate its clinical significance. Through a comprehensive analysis involving enzyme-linked immunosorbent assay, immunohistochemistry, and multicolor immunofluorescence, we quantified sB7-H4 levels in patient plasma and ascites, correlating these findings with tissue expression and clinical outcomes.

R848 and poly(I:C) promote effective anti-tumor immunity in mice with subcutaneous LLC tumors by inducing M1-like polarization of macrophages and activating DCs.

HYCO-3 activates Nrf2/HO-1 and counteracts inflammatory properties of T cells, macrophages/dendritic cells (Mf/DC), and microglial cells (Mg) relevant for the CNS autoimmunity pathogenesis.

DRB1*04:04 presents citrullinated peptide aggrecan, CILP, α-enolase, vimentin, and fibrinogen peptides to T cells antigen-specific T cells include Th1-like and Th2-like subsets antigen-specific T cells expand to higher numbers and are more strongly polarized in RA subjects with high disease activity.

In this study, we found an upregulation of CXCL10 and CCL3 in Primary Sjögren’s syndrome (pSS) patients compared with non-SS sicca controls. Additionally, our results implicate that there is a correspondence between the expression of CXCL10 and the size of the inflammatory infiltrate in the pSS cohort. CXCL10 expression also correlates with more severe clinical manifestations and might be a predictor of glandular destruction in pSS and a potential disease biomarker.

Spectral flow cytometry uncovers a distinct B-cell composition profile in granulomatosis with polyangiitis (GPA). GPA patients have altered expression of FcγRIIB, CD21, CD22, and CD86 on B cells. FcγRIIB, BTLA, and CD21 expression on B cells are strongly associated with disease activity in GPA.

In the present study, we show a significant increase in the concentration of sPD-L1 following ischemia-reperfusion injury in a hepatic ex vivo model. Additionally, we were able to demonstrate that sPD-L1 concentration correlates with established perfusate parameters during NMP as well as with donor laboratory values.

IRF4 is induced by the intensity of TCR stimulation and leads to the activation of antigen-specific CD4+ T cells depending on glycolytic metabolism, which results in the proliferation and differentiation of T cells toward the progression of diabetes. In innate immunity, IRF4 may affect an antigen presentation system on DCs, which plays an adjunctive role in promoting the development of diabetes.

This study investigates the role of GzmB⁺ cell subsets in Takayasu arteritis (TAK). The study included 105 TAK patients and 58 healthy controls. We found that age, age at onset, body mass index, disease duration month, hypertension, and hyperlipidemia were significantly different between TAK patients with and without coronary artery involvement (CAI; P  = 0.000, P  = 0.038, P  = 0.003, P  = 0.031, P  = 0.039, P  = 0.000). Our results indicate that CD8 cell-derived Gzm B may be a predictor for CAI and major adverse cardiovascular events in TAK patients. Targeting CD3⁺ CD8⁺ GzmB⁺ lymphocytes or using GzmB inhibitors could be a potential therapeutic approach for the treatment of CAI in TAK.

Our current investigation shows the potential of autologous extracellular vesicles, derived from the blood of rheumatoid arthritis patients, to serve in the future, as therapeutic vectors to improve drug delivery.

We hypothesized that rabbits/mice immunized with 4-hydroxy-2-nonenal (HNE)-modified/unmodified Ro60 will develop an autoimmunity, specifically a SjD phenotype, thus expressing increased levels of anti-M3R antibodies. Our data shows induction of increasing anti-M3R antibodies in rabbits immunized with Ro60/HNE-Ro60 or Ro60 peptides and differential induction of these antibodies in mice immunized with Ro60 modified with increasing HNE. These findings suggest that M3R ECL2/ECL3 are involved in SjD autoimmunity progression.

The clinical biology of cladribine is explained by selective deoxycytidine kinase expression and loss during B cell to plasma cell differentiation. This allows the targeting of circulating B cells, notably memory B cells, to inhibit disease and sparing of long-lived plasma cells to maintain infection control and vaccine responses. Central nervous system oligoclonal immunoglobulin production may however be targeted by direct central and/or peripheral activity on precursor populations and slower indirect influence on the long-lived plasma cells survival niche. Created with BioRender.com

This study aimed to develop a method to detect ASC aggregates originating from NLRP3 inflammasomes. We validated FACS as a reliable method for detecting ASC/NLRP3 specks in human sera, with potential diagnostic and monitoring applications in certain systemic autoinflammatory diseases.

SLE patients exhibit a lower antibody response to SARS-CoV-2 vaccination compared to healthy controls. SLE patients show reduced antibody class-switch recombination after SARS-CoV-2 vaccination compared to healthy controls. High concentrations of IFN-alpha impair class-switch recombination to IgG.

Juvenile systemic lupus erythematosus (JSLE) is a severe autoimmune disease affecting children and young people. Here we report that frequencies of perforin, IFN-γ and TNF-α-expressing CD8+ T cells are reduced in JSLE compared with healthy controls. The reduction in CD8+ T cell cytotoxic potential in JSLE is accompanied by enlargement of CD8+ T cell mitochondria and increased susceptibility to apoptosis, which leads to a deficiency in effector memory (EM) CD8+ T cells, all of which are associated with increased type I interferon.

Extracellular vesicles (EVs) are small vesicles that are secreted from cells under both physiological and pathological conditions. In multiple sclerosis (MS), individuals experiencing a longitudinal increase in clinical disability, MRI disease activity, and axonal injury had significantly elevated plasma levels of specific T-cell-derived EVs, thereby suggesting the utility of circulating EVs as novel biomarkers in MS.

This article reports the discovery and development of a novel humanized anti-IL-1ß antibody, designated as TAVO103A, which exhibited potent binding affinities to human and monkey IL-1ß. TAVO103A demonstrated more potent neutralization of IL-1ß activities compared to canakinumab in multiple assays, including tests on the IL-1ß-driven signal transduction cascade, inflammatory cytokine release from MRC-5 cells, chemokine release from A549 cells, and the proliferation of D10.G4.1 helper T cells.

This paper investigates whether T-bet+ B cells, as well as age-associated B cells/ABCs (CD19+CD21-CD11c+T-bet+) and double-negative B cells/DN (CD19+IgD-CD27-CXCR5-T-bet+), serve as prognostic and/or therapeutic tools for systemic lupus erythematosus (SLE) in humans. Flow cytometry was used for enumerating T-bet+ B cells and ABCs/DN subsets, found in the peripheral blood of 10 healthy donors and 22 active SLE patients.

In this study, we assessed the utility of saliva as a non-invasive medium for measuring Vibrio cholerae -specific serum antibodies in naturally infected individuals. We tested paired serum and saliva samples obtained from a total of 63 patients with cholera enrolled in a cohort study.

Our findings demonstrate a robust presence of a CD8 T cell signature associated with both localized cutaneous leishmaniasis (LCL) and mucosal leishmaniasis (MLP) lesions. Moreover, both inflammatory and cytotoxic signatures were significantly upregulated, showing a strong increase in MLP and LCL groups, but not diffuse cutaneous leishmaniasis (DCL). Collectively, our findings contribute to a comprehensive understanding of immunosenescence in ATL and suggest that senescence may represent the latest and most important signature of the immunopathogenisis. This highlights its potential value in predicting disease severity.

Public health agencies, like the UK Health Security Agency (UKHSA), play a key role in evaluating immunization programmes through their routine surveillance and evaluation activities, as well as by undertaking large-scale research studies. An individual-level national vaccine register with an accurate population denominator is essential for evaluating immunization programmes. During the COVID-19 pandemic, England developed its first vaccine register, which provided valuable insights into vaccine effectiveness and rare risks. This review article highlights the importance of surveillance, data linkage, and research studies in evaluating vaccination programs in England, focusing on vaccine coverage, real-world effectiveness, and post-licensure safety.

In this study, we aimed to characterize how B-cell populations are impacted by continuous and substantial pathogen exposition using a 36-marker mass cytometry panel. By applying an unbiased multidimensional approach, we studied B-cell subset differences between regions with higher and lower microbial exposure, i.e. by comparing peripheral blood B-cells from people living in Indonesia and Ghana to those from healthy Dutch residents. We observed differences in the balance between the naïve and memory compartments, with more atypical and DN MB-cells and less naïve B-cells in individuals from higher pathogen exposure areas compared to residents from an area with less pathogen exposure.

This study aimed to investigate the effects of CpG oligodeoxynucleotide (CpG-ODNs)-coated chitosan nanoparticles (CNP) on the phenotype of murine macrophages and their proinflammatory cytokine profile in vitro .

In this study, we aimed to determine the function of Nck1 in the in vitro development and differentiation of human thymocytes. Human thymocytes were transfected with shRNA plasmid to silence Nck1 expression.

WT anti-mouse FcγRII and -human FcγRIIB mAbs augment humoral immune responses via interaction of their Fc with activating FcγRs. This study reveals that the enhancement of immune responses is not as a direct consequence of blocking FcγRIIB and its downstream ITIM-mediated signalling. Rather, their binding to FcγRIIB acts as an anchor to promote the engagement of adjacent (cis or trans) activating FcγRs via the mAb Fc domain, thereby inducing a more potent immune response upon immunization.

This retrospective review identified 182 patients with recurrent oto-sinopulmonary infections (131 required an immune workup and 99 had low pneumococcal titers leading to a PCV13 vaccine booster). In pediatric patients with recurrent oto-sinopulmonary infections, an additional pneumococcal booster proved to be effective in the protection of these children against further infections, across all age groups.

B cells with NFKB2 mutations exhibit impaired activation (①) and differentiation into plasma cells (②) in response to T-I stimuli, such as CpG. Although they retain the ability to undergo Ig gene CSR (③), these mutant B cells show impaired activation and differentiation into plasma cells (④) and memory B-like cells (⑤) in response to both T-I and T-D stimuli, such as CMIL2 and CD40L + IL-4. T-I: T-independent; T-D: T-dependent; CSR: class-switch recombination; GC B: germinal center B cell; PC: plasma cell. Red arrows indicate an increase or decrease in a B-cell subset.

Two different variants in the patients were reported, one previously defined and one novel homozygous mutation [c.306C>A (p.Tyr102Ter)]. In total, 19 patients with FCHO1 deficiency, recurrent sinopulmonary infections, low IgM, and CD4+T cell lymphopenia are frequent. Since all transplanted patients were alive, allogeneic hematopoietic stem cell transplantation emerged as a potential curative therapy.

The genetic testing identified 33 potentially causal variants, 16 (48%) new and 17 (52%) previously reported. Of 45 patients with sepsis, 8 (18%) had genetic variants. Similarly, 25/149 (17%) patients with severe infection presented genetic variants.

Mavorixafor blocks the overactive SDF-1/CXCR4 signaling pathway, which normally regulates neutrophil and lymphocyte release from the bone marrow. In WHIM syndrome, defective CXCR4 internalization blocks their mobilization, causing immunodeficiency. Mavorixafor restores normal immune cell release by disrupting the SDF-1/CXCR4 interaction, improving immune function.

In this study, we aimed to perform a comprehensive analysis of nine patients diagnosed with XIAP deficiency through genetic testing. In addition to XIAP flow, we employed a previously reported method utilizing muramyl dipeptide (MDP) stimulation, a specific agonist of NOD2, to quantitatively evaluate the downstream tumor necrosis factor-alpha (TNFa) production by flow cytometry in patient monocytes (MDP flow)

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare genetic disorder characterized by recurrent, severe infections. We describe a patient with a novel homozygous mutation in ZBTB24 (Q375Hfs*3). We thoroughly characterized the immunological consequences of ZBTB24 deficiency using mass cytometry coupled with state-of-the-art computational methods. Our analysis revealed reduced frequencies of natural killer cells and class-switched memory B cell populations in our patient, along with low levels of the immunoglobulin isotypes IgG4 and IgM.

In this review, we aim to summarize the challenging case reports from the literature, provide an algorithmic approach for these kinds of presentations, and share our perspective and recommendations on the topic. Diagnosing DADA2 on time is a vital issue for preventing fatal and debilitating vascular events with anti-TNF-alpha therapy.

Neutrophils play a potential amplifying role in food and drug allergy. Neutrophilic inflammation drives a discrete phenotype of treatment-resistant and often severe asthma. Neutrophil dysfunction is a feature of atopic dermatitis contributing to skin flora dysbiosis.