IKAROS, encoded by IKZF1, is a crucial transcription factor regulating hematopoiesis and B cell development. While IKZF1 haploinsufficiency variants are associated with various immunological disorders, inflammatory bowel disease (IBD) has been rarely reported. We report a case of IKZF1 haploinsufficiency presenting with an atypical IBD phenotype and its response to filgotinib. The patient was previously diagnosed with IKZF1 haploinsufficiency and presented with chronic diarrhea, fatigue and anemia. Laboratory findings indicated folate deficiency-induced megaloblastic anemia and malabsorption syndrome. Endoscopic examination showed inflammation with erythema in the colon and extensive villous blunting of the small intestine. Immunohistochemical analysis revealed increased pSTAT3/5 in the colon. Considering the clinical features and increased JAK-STAT cascade, treatment with filgotinib was initiated. At 10 weeks post-treatment, we observed improvement in endoscopic findings and suppression of pSTAT3/5. This case extends the clinical spectrum of IKZF1 haploinsufficiency. A JAK1 inhibitor is considered to be useful for IKZF1 haploinsufficiency-associated IBD.

Currently, IgA nephropathy (IgAN) is the most common cause of chronic renal failure in patients with primary glomerulonephritis. However, IgAN diagnosis is usually performed by collecting a renal biopsy as gold standard to visualize pathological changes in the glomeruli. The randomized nature of this invasive procedure in clinical practice, together with the need to exclude patients with contraindications, often results in a limited number of eligible people. Therefore, over the past two decades, researchers have explored new biomarkers for IgAN to meet the urgent clinical need for rapid diagnosis and prognosis, as well as realistic prediction of IgAN progression. In addition to traditional common markers with low specificity to detect renal diseases, the classical antibody targeting galactose-deficient IgA1 has been progressively discovered. In addition, new types of diagnostic or prognostic biomarkers are emerging, including microRNA, complement factors, proteases, inflammatory molecules and serum or urinary metabolite profiles.

IKAROS, encoded by IKZF1, is a six zinc-finger (ZF) transcription factor integral to lymphocyte development and function. IKZF1 mutations affecting DNA-binding (ZF1-4) and dimerization (ZF5-6) have been extensively reported and result in human disease. Herein, we investigated IKZF1 mutations affecting protein stability. We identified ten individuals in three families carrying IKZF1 mutations mapping either to the pre-ZF1 area (D22N), or the dimerization domain (M494Vfs*86, Y503*) presenting with infections, immune dysregulation and/or lymphoproliferation with incomplete clinical penetrance. IKAROS expression was reduced in all mutation-carrier evaluated. Protein stability was decreased for D22N, V52L (another pre-ZF1 variant reported in COSMIC), Y503* and Del1-116, a laboratory-designed mutant encompassing the pre-ZF1 area. Mutants Y503* and Del1-116 also exhibited other impaired functions. IKAROS N-terminal pre-ZF1 area, encompassing a previously uncharacterized protein stability-associated region (PSAR), is crucial for IKAROS stability. Variants in the IKAROS PSAR leading to decreased protein stability and IKAROS haploinsufficiency seem sufficient to result in immune defects and IKAROS-associated diseases.

In this case study, we used Digital Spatial Profiling to localize transcripts in a series of 4 biopsies from a single patient before, during and after treatment for acute antibody-mediated rejection that was characterized by strong C4d staining of the glomeruli. Spatial resolution demonstrated that molecular signatures of innate immune cells including NK cells and macrophages are located in glomeruli during AMR, and transcripts for HLA class II antigens were upregulated in the glomeruli. In contrast, transcripts of signature genes for podocytes were decreased during rejection. Treatment with IVIg resolved histological evidence of glomerulitis but did not restore expression of podocyte transcripts. These data demonstrate a vulnerability of podocytes in acute AMR with persistent glomerulitis. Additionally, by using a protocol biopsy from the same patient as a baseline, transcript changes for an informative set of genes were uncovered to test for podocyte dysfunction in future patients.

The study examines efgartigimod and intravenous immunoglobulin (IVIg) in elderly patients with generalized myasthenia gravis (GMG), focusing on changes in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, pyridostigmine dosage, and minimal symptom expression (MSE) over an 8-week period. Among 74 enrolled patients, efgartigimod showed greater reduction in MG-ADL scores compared to IVIg at weeks 4 and 8, with no serious adverse events, suggesting its superior efficacy and safety in elderly Chinese patients with acetylcholine receptor antibody-positive (AChR-Ab(+)) GMG.

Viral infections, including respiratory diseases such as Coronavirus disease 2019 (COVID-19), are hypothesized to contribute to the onset of autoimmune disorders. Although elevated levels of autoantibodies have been observed following COVID-19, the role of specific autoantibodies linked to autoimmune diseases and their correlation with disease severity remains poorly defined. In this study, we used a comprehensive autoantibody panel to assess the autoantibody production across different cohorts of COVID-19 patients, categorized by disease severity. We also compared patients with severe COVID-19 to a control group with other severe, non-COVID-related diseases. Our findings indicate that the severity of COVID-19 corresponds to the overall production of specific autoantibodies, which are particularly associated with COVID-19. This association might predispose to an increased risk for the development of autoimmune conditions after a severe course of COVID-19.

Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. Ex vivo T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients. We investigated 20 T-lymphocytopenic patients, including 13 patients awaiting first-line treatment and 7 patients with failed immune reconstitution after previous HCT or thymus transplantation. Whilst developmental blocks in ex vivo T-lymphopoiesis indicated hematopoietic cell-intrinsic defects, successful T-lymphocyte differentiation required careful interpretation, in conjunction with clinical status, immunophenotyping, and genetic investigations. Of the 20 patients, 13 proceeded to treatment, with successful immune reconstitution observed in 4 of the 6 patients post-HCT and 4 of the 7 patients after thymus transplantation, the latter including two patients who had previously undergone HCT. Whilst further validation and standardization are required, we conclude that assessing ex vivo T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.

Mucosal inflammation is associated with increased nasal pneumococcal colonisation, but the specific mechanisms are not fully understood. We aimed to find innate immune factors associated with pneumococcal carriage using a controlled human infection model.

Neutralizing autoantibodies against type I interferons were strongly linked to severe COVID-19 in unvaccinated patients; however, this has yet to be evaluated in vaccinated individuals.

Clinical data and animal models have provided compelling evidence supporting the pathogenic role of complement activation in the progression of focal segmental glomerulosclerosis (FSGS). However, the mechanisms underlying complement-induced podocyte injury and parietal epithelial cell (PEC) activation are not well understood.

Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disease characterized by exocrine gland dysfunction, with hallmarks of B cell and T cell overactivation, whose underlying mechanism remains largely unknown. Herein, we show that pSS plasma contained more extracellular vesicles (EVs) than HC plasma, which promoted CD4 T cell activation, Th1, and follicular T helper cell (Tfh) differentiation, aggravating pSS immunopathology. Notably, pSS plasma EVs were enriched with miR-501-3p, mediating CD4 T cell activation and Tfh cell differentiation. Furthermore, miR-501-3p downregulated special AT-rich sequence-binding protein-1 (SATB1) to promote Tfh differentiation. These findings suggested pSS plasma EVs as an important contributor to pSS pathogenesis, which was of potential clinical interest in managing pSS.

The emergence of SARS-CoV-2 variants has reduced antibody effectiveness, affecting vaccine protection. This study evaluated neutralizing antibodies against Wuhan strain and several variants, including Alpha, Beta, Gamma, Delta, and Omicron, in Brazilians vaccinated twice with CoronaVac, ChAdOx1-S, or BNT162b2 before Delta and Omicron emerged. After the booster, strong antibody responses to the Wuhan strain were seen in all groups, but BNT162b2 resulted in higher anti-Spike and anti-RBD IgG levels. While all vaccines showed some cross-neutralization against Alpha, Beta, Gamma, and Delta, only BNT162b2 was effective against Omicron BA.2 and BA.4/5 subvariants. Furthermore, BNT162b2 vaccination showed a positive correlation between Wuhan RBD-specific IgG and Omicron neutralizing antibodies. This group demonstrated distinct clustering patterns of neutralizing antibodies against all variants, unlike those from CoronaVac and ChAdOx1-S. The findings suggest BNT162b2 offers broader neutralization capability, highlighting the benefit of booster shots with bivalent mRNA vaccines to enhance immune responses against emerging variants.

This study aimed to explore the molecular characteristics of neutrophil extracellular traps (NETs) in chronic rhinosinusitis with nasal polyps (CRSwNP). Differentially expressed gene analysis, weighted gene co-expression network analysis, and machine learning algorithms identified three core NETs-associated genes: CXCR4, CYBB, and PTAFR, which were significantly upregulated in CRSwNP patients. The diagnostic performance of these genes was evaluated using receiver operating characteristic (ROC) curves, and their clinical relevance was validated using multicenter data. Immune infiltration analysis showed strong correlations between these genes and neutrophil and immune cell infiltration. Single-cell RNA sequencing demonstrated that these genes were predominantly expressed in myeloid and immune cells and exhibited dynamic changes during disease progression. These genes may contribute to CRSwNP pathogenesis through IL-17 signaling and metabolism-related pathways. This study identifies novel biomarkers and therapeutic targets for precise diagnosis and personalized treatment of CRSwNP.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that causes immune system overactivity and organ damage. Among T-cell subsets involved in SLE, CD4 and CD8 double-negative αβT (DNT) cells have attracted attention in recent years, although their role in SLE remains poorly understood. Examining the minute intricacies, particularly signaling pathway modifications is crucial, as it may unveil potential therapeutic targets and lead to the development of more effective treatments. Our study found increased DNT cells in pediatric SLE patients, with elevated IL-10 signaling. These IL-10-producing DNT cells were positively related to disease activity defined by SLE Disease Activity Index (SLEDAI), and were further elevated in patients with lupus nephritis. Additionally, our results indicated that IL-10-producing DNT cells correlated positively with anti-Sm autoantibodies. Collectively, our study revealed that modulation of IL-10 production within DNT-cell subset could affect both immune regulation and autoantibody production, contributing to the immunological dysregulation in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the presence of circulating autoantibodies. Autoantibodies targeting C1 complex proteins, particularly C1q, have already been described in lupus nephritis (LN). However, autoantibodies targeting the C1s protease remain poorly studied. We determined the prevalence of anti-C1s autoantibodies in serum of SLE patients, and evaluated their presence in relation to clinical conditions. For this purpose, sera from 187 SLE patients with different disease activity were selected and anti-C1s autoantibodies were measured by ELISA. We observed that patients with LN had significantly higher levels of anti-C1s autoantibodies than SLE patients with other flare types. Anti-C1s autoantibodies recognised mainly the C1s N-terminal part. Interestingly, the combination of anti-C1s, anti-DNA and anti-C1q autoantibodies showed high specificity (94.6 %) and a significant positive predictive value of 80 %. These results suggest the potential interest of anti-C1s autoantibodies as a complementary serological biomarker in the early screening for LN.

T cell senescence and exhaustion represent critical aspects of adaptive immune system dysfunction, with profound implications for health and the development of disease prevention and therapeutic strategies. These processes, though distinct, are interconnected at the molecular level, leading to impaired effector functions and reduced proliferative capacity of T cells. Such impairments increase susceptibility to diseases and diminish the efficacy of vaccines and treatments. Importantly, T cell senescence and exhaustion can dynamically influence each other, particularly in the context of chronic diseases. A deeper understanding of the molecular mechanisms underlying T cell senescence and exhaustion, as well as their interplay, is essential for elucidating the pathogenesis of related diseases and restoring dysfunctional immune responses. This knowledge will pave the way for the development of targeted therapeutic interventions and strategies to enhance immune competence. This review aims to summarize the characteristics, mechanisms, and disease associations of T cell senescence and exhaustion, while also delineating the distinctions and intersections between these two states to enhance our comprehension.

Patients with rheumatoid arthritis (RA) are at increased risk of diffuse large B cell lymphoma (DLBCL) compared to the general population. Here, we explored the inflammatory profiles in the blood of RA patients who had developed DLBCL. RA-DLBCL patients had significantly higher levels of the pro-inflammatory markers TNF, IL-8, CXCL9, APRIL, and particularly CXCL13 (median 796 vs. 206 pg/mL, p = 0.001), compared to RA controls. By including an extensive autoantibody panel of rheumatoid factor, IgG anti-CCP2, anti-citrullinated protein antibodies (ACPA) fine-specificities, and other anti-modified protein antibodies, all RA-DLBCL patients were autoantibody seropositive. Yet, RA-DLBCL patients did not display significantly different autoantibody signatures compared to RA controls. The levels of immunoglobulin free light chains and C-reactive protein were similar in RA-DLBCL patients and RA controls. In conclusion, RA-DLBCL patients exhibit pro-inflammatory signatures with elevated markers that are important for B cells and may contribute to enhanced B-cell activation and promote lymphoma development.

The aim of this study was to systematically assess the relationship between Chitinase 3-like protein-1 (CHI3L1) protein and disease progression in multiple myeloma (MM) and to explore its potential clinical value as a biomarker to provide a basis for optimizing treatment strategies.

TLR7 stimulation of T-betCD11cIgDCD27 double-negative 2 (DN2) B cells is crucial for autoantibody formation in systemic lupus erythematosus (SLE). Here, we show that administration of IL-4 for five weeks significantly reduced autoantibodies and T-betCD11c IgD B cells in autoimmune BXD2 mice treated with R848, a TLR7 agonist. Single-cell transcriptomics analysis indicates that following two doses of in vivo administration, IL-4 redirected development toward follicular, CD23 germinal center (GC), and DN4-like memory B cells compared to treatment with R848 alone. While IL-4 enhanced genes related to antigen processing and presentation, it also suppressed R848-induced Ki67 GC B cells in vivo. In vitro stimulation of SLE patient B cells with a DN2 polarizing cocktail revealed that IL-4 reduced the expression of interferon response and DN2 signature genes, promoting a population of CD23T-bet DN4 B population. These findings suggest that developmental reprogramming by IL-4 counteracts TLR7-promoted DN2 and GC B cells in SLE.

Cell-free DNA (cfDNA) is a marker of organ injury and immune response. DNA methylation is an epigenetic regulator of gene expression. Here, we elucidate total plasma cfDNA methylation from kidney transplant recipients in presence versus absence of rejection. In doing so, we exploit cfDNA as a real-time biomarker to define molecular pathways of rejection. Twenty plasma cfDNA samples from pediatric kidney transplant recipients were collected at allograft biopsy. Differentially methylated cytosine residues (>20 % methylation difference, q-value <0.05) were identified in presence (N = 7) versus absence (N = 9) of acute rejection. Separate analyses were performed comparing borderline rejection (N = 4) to rejection and non-rejection. In rejection versus non-rejection, there were 1269 differentially methylated genes corresponding to 533 pathways. These numbers were 4-13× greater than comparisons against borderline samples. Enriched pathways between rejection and non-rejection samples were related to immune cell/inflammatory response, lipid metabolism, and tryptophan-kynurenine metabolism, suggesting differential methylation of these pathways contributes to rejection.