INTRODUCTION:Thyroid peroxidase (TPO) autoantibodies are defining features of autoimmune thyroid disease (AITD), yet the relationship between epitope specificity and antibody function remains incompletely understood. METHODS:In this study, we generated patient-derived human monoclonal anti-TPO antibodies from a single donor with AITD (T-011) and characterized their competition-defined epitope relationships, reporter-based Fcγ receptor activity, and direct effects on TPO enzymatic function. RESULTS:Although the antibodies exhibited comparable FcγRIIIa reporter activation, FcγRIIa reporter responses varied according to epitope specificity. Notably, TPO036 demonstrated enhanced FcγRIIa reporter signaling and, following conversion to an F(ab')2 format, competitively inhibited Fc-mediated reporter activation. Direct TPO activity assays demonstrated that representative antibodies produced either no or only minimal inhibition of TPO enzymatic activity under the conditions tested. These findings indicate that competition-defined anti-TPO antibody groups within a single-donor repertoire can exhibit distinct functional profiles, particularly with respect to Fc-mediated reporter responses, without evidence of broad inhibition of TPO catalytic activity. CONCLUSION:Overall, our results support the existence of intra-individual, epitope-associated functional heterogeneity among anti-TPO antibodies and provide a proof-of-concept foundation for future studies evaluating epitope-targeted and Fc-modulating strategies in physiologically relevant models.
Autoantibodies to zinc transporter 8 (ZnT8A) are important diagnostic and predictive markers for type 1 diabetes (T1D). Current methods to detect ZnT8A use C-terminal ZnT8 (aa268-369). Previous research identified three major ZnT8A epitopes (R325, W325, and a four-residue conformational epitope [R332/E333/K336/K340]), but the human-specific cysteine region has not been investigated. We sought to examine ZnT8A binding to three C-terminal cysteines and confirm previously known ZnT8A epitopes. Assay buffer constituent (Tween-20) and site-directed mutagenesis of radiolabelled ZnT8 antigen were utilized to compare ZnT8A binding in R325-ZnT8 and W325-ZnT8 monomeric radiobinding assays (RBAs). Truncated ZnT8 (D360X) and cysteine-to-serine mutations (C361S, C364S, and C368S) were compared with wild-type R325-ZnT8/W325-ZnT8 RBAs in 71 newly diagnosed T1D cases. Samples were indexed to controls and the median reduction in binding (MRB, %) was compared using Wilcoxon signed-ranked tests. Unbiased hierarchical clustering analysis was used to review effects of all ZnT8 mutations. A higher Tween-20 concentration reduced ZnT8A binding (P < 0.0001). All cysteine region mutations reduced 325-agnostic ZnT8A binding towards wild-type R325-ZnT8 (MRB range -37.0 to -66.4%, P < 0.0001) and W325-ZnT8 (MRB range -32.1 to -43.8%, P < 0.0001). Mutating the cysteine region nearly abolished binding (>75%) in 7.7-36.8% of R325-ZnT8/W325-ZnT8 positive ZnT8A, and in 10.5-13.2% of subjects studied, reduced binding below that of major ZnT8A epitopes. The cysteine region of C-terminal ZnT8 constitutes an independent epitope for ZnT8A, but mature ZnT8A responses in newly diagnosed T1D are heterogeneous. Epitope spreading of ZnT8A during the natural history of preclinical T1D remains unclear and requires further investigation in larger studies.
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory condition characterized by eosinophilic infiltration of the esophagus and dysregulated T-cell responses. Proton pump inhibitors (PPIs) are a treatment option for patients with EoE; however, biomarkers for noninvasive monitoring of treatment response are lacking. In this study, we prospectively enrolled 20 patients with EoE who were treated with PPIs, of whom 19 completed their treatment, and analyzed peripheral blood immune profiles using mass cytometry (CyTOF), comparing them with age- and sex-matched healthy controls. Histologically, 14 of 19 patients achieved histologic remission, whereas immunophenotyping was performed in 17 patients (12 responders and 5 nonresponders) because 2 samples contained insufficient cell numbers. The patients were also evaluated using the EoE Histology Scoring System (EoE-HSS; stage and grade), endoscopic findings, and validated questionnaires. Unsupervised clustering identified key T-cell populations altered by treatment, including Th2 central memory CD4+ T cells and CD8+ terminal effector and naïve subsets. Successful PPI therapy was associated with expansion of FOXP3+ T cells and reduction in cytotoxic CD56+ CD8+ T cells, modulations not detected in nonresponders. Notably, peripheral CD4+ T-cell counts correlated with histologic disease severity (EoE-HSS), whereas eosinophil counts did not. These findings highlight dynamic shifts in circulating T-cell phenotypes following PPI therapy and suggest that expansion of FOXP3+ T-cells and reduction of CD56+ CD8+ T-cell populations may represent candidate treatment-associated immune signatures in EoE. However, given the exploratory nature of this high-dimensional immunophenotyping study and the limited sample size, these findings should be considered hypothesis-generating and require validation in larger independent cohorts.
BACKGROUND:Currently the role of dengue virus (DENV) specific T cell responses in disease pathogenesis and protection are not well understood, including potential differences in those who have obesity. We sought to investigate the functionality and phenotype of T cells in patients with acute dengue fever (DF) or dengue haemorrhagic fever (DHF). METHODS:T cell function was assessed in paired samples (first sample on ≤4 days and second 5-6 since onset of illness) in patients with DF (n=50) and DHF (n=12), using 109 peptides representing CD8+ epitopes and 90 peptides targeting CD4+ T cell epitopes. Phenotypic analysis was in DF (n=21) and DHF patients (n=21), recruited between days 6-8 since onset of illness, by multicolor flow cytometry. RESULTS:The frequency of ex vivo IFNγ ELISpot responses to both the CD4+ and CD8+ peptides pools significantly increased from the first (F) to second time (S) point in patients with DF (p<0.0001) but not with DHF. The frequency of ex vivo IFNγ ELISpot responses to CD4+ (p=0.001) and CD8+ peptides pools (p=0.0002) also significantly increased from the F to S in lean patients but not in obese patients. Cutaneous lymphocyte associated antigen (CLA) expression was significantly higher in the CD8+ T cell subset in patients with DF and DHF compared to HC and these differences were most significant in CD8+CD45RA- T cells. CD8+CD45RA-CLA+ T cells consisted of >50% of the T cells in 9/21 patients with DHF, with 92.7% expressing CD38. CLA expression was highest in the CD8+CD45RA- of obese individuals, which was significantly higher compared to lean individuals (p=0.01). CD27 and CD127 were both significantly downregulated in patients with DHF compared to DF, with ICOS expression being significantly higher in CD8+ T cells in DHF. DISCUSSION:Patients with DHF and obese individuals had impaired T cell functionality compared to patients with DF and lean individuals, with an expansion of activated, skin-homing CD8+ T cells exhibiting downregulation of CD27 and CD127. Our data suggest a contributory role of dysfunctional skin-homing T cells in disease pathogenesis, meriting further investigation.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune dysregulation. Tim-3 is an immune checkpoint receptor implicated in various autoimmune conditions. This study aimed to evaluate Tim-3 expression across monocyte subsets in newly diagnosed, treatment-naive SLE patients and assess its clinical relevance and diagnostic potential. Peripheral blood samples were analyzed using flow cytometry. Tim-3 expression and its co-expression with HLA-DR, DP, DQ, CD226, CD39, VNN2, and CD62L were assessed. Tim-3+ monocytes from healthy individuals displayed higher expression of HLA class II, VNN2, CD226, and CD39, but lower CD62L expression. In SLE patients, Tim-3 expression was significantly increased across all monocyte subsets compared with healthy controls, while VNN2 expression was reduced in Tim-3+ monocytes. Upon LPS stimulation, Tim-3+ monocyte subsets produced more TNF-α. The frequency of Tim-3+ monocytes positively correlated with anti-Ro52 and anti-SSA antibodies. ROC curve analysis demonstrated moderate diagnostic performance of Tim-3+ monocytes for SLE, with an area under the curve of 0.7901. Tim-3+ monocytes exhibit aberrant phenotypic and functional activation in SLE and are associated with disease-related autoantibodies. These findings highlight Tim-3+ monocytes as potential contributors to SLE pathogenesis and candidate biomarkers for early disease identification.
Tumor-associated macrophages (TAMs) are the dominant component of the tumor microenvironment and exhibit remarkable phenotypic plasticity and heterogeneity that extends beyond the classical M1/M2 polarization, as revealed by single-cell transcriptomics across multiple cancer types. Downregulation of major histocompatibility complex class I (MHC-I) on tumor cells is a common immune evasion strategy that profoundly shapes TAM composition and function. Conversely, TAMs reciprocally modulate tumor MHC-I expression. This review provides an overview of the verified and hypothetical mechanisms of bidirectional regulatory interactions between MHC-I on tumor cells and TAMs. Since these interactions likely differ between tumors with reversible and irreversible MHC-I downregulation, their potential significance in tumor immunotherapy should be assessed separately for each MHC-I reduction mechanism.
Visceral leishmaniasis (VL), caused by Leishmania donovani, is characterized by progressive immune dysregulation that supports parasite persistence. The CD40-CD40L axis is essential for antigen-presenting cell (APC) licensing and Th1-mediated nitric oxide-dependent parasite control; however, how its function evolves during infection remains incompletely understood. Here, we define the temporal regulation and functional polarity of CD40 signalling during experimental VL. Using BALB/c mice and primary macrophage assays, we investigated the temporal regulation of CD40 signalling during experimental VL. CD40 expression, cytokine production, nitric oxide levels, antibody responses, T-cell phenotypes, immune checkpoint expression, and macrophage activation were evaluated during progressive infection. Functional studies included CD40 agonism, CD40 knockdown, and TRAF-selective CD40 reconstitution to assess stage-specific effects on parasite control and immune regulation. Increasing parasite burden drove a gradual shift in CD40 signalling from protective to suppressive outcomes. In vitro infection reduced CD40 expression and IL-12 production while increasing IL-10, indicating early impairment of APC licensing. In vivo, progressive splenic infection was associated with diminished nitric oxide production, a declining IgG2a/IgG1 ratio, expansion of GATA3+ Th2 and FOXP3+ regulatory T-cell populations, and increased PD-L1 and TIM-3 expression, consistent with a regulatory and exhausted immune environment. Despite partial recovery of CD40 expression on myeloid APCs at later stages, declining CD40L+ T-cell availability and sustained IL-10/Arg1 signalling limited functional responsiveness. Early CD40 agonism failed to restore parasite control, whereas late activation exacerbated disease. CD40 knockdown increased parasite burden and reduced iNOS+ macrophages, confirming the requirement for CD40-dependent licensing. Finally, TRAF2-biased CD40 signalling promoted macrophage activation and parasite restriction, whereas TRAF6-biased signalling reinforced immunosuppression. These findings identify a stage-dependent functional threshold beyond which CD40 signalling no longer sustains protective immunity during VL, highlighting the importance of restoring APC competence and selectively directing CD40 signalling through TRAF2-linked pathways.
Autoantibodies targeting post-translational modified proteins represent key immunological hallmarks of Rheumatoid Arthritis (RA). In a previous study we demonstrated the presence of citrullinated and carbamylated proteins in extracellular microvesicles (EMVs) from plasma of RA patients. Since the pivotal role of TNFα in sustaining inflammatory and oxidative processes that promote protein modification, in this study we investigated the patterns of these post-translational modifications in EMVs isolated from RA patients before and after anti-TNFα treatment. Twelve consecutive RA patients, naïve to biological therapy, were enrolled and subjected to anti-TNFα therapy, which remained stable throughout the 8-month follow-up. EMVs, isolated from baseline (T0) and 8 months of follow-up (T8) plasma of RA patients, were measured by Nanoparticle Tracking Analysis or lysed and subjected to western blot analysis, using anti-citrulline or anti-carbamyl lysine antibodies. Anti-citrullinated and anti-carbamylated protein antibodies were also detected. Anti-TNFα treatment induced a significant reduction in the concentration of EMVs isolated from plasma of RA patients after 8 months of anti-TNFα treatment (P < 0.01). Moreover, in EMVs extracts citrullinated and carbamylated protein levels were significantly lower at T8, as compared to T0 (P < 0.01). Anti-TNFα treatment also induced a significant decrease of both anti-citrullinated and anti-carbamylated protein antibody levels, as well as of activity scores (SDAI and DAS28). These findings suggest the role of EMVs, as well as of citrullinated and carbamylated protein levels, as potential indicators of RA activity.
Hereditary Angioedema (HAE) is a rare disorder of recurrent swellings of the subcutaneous and/or mucosal tissues due to defects in the contact system regulation of bradykinin production. The swellings can be disfiguring, cause debilitating abdominal pain, or be fatal with laryngeal obstruction. Over the last decade there has been immense successes in management of HAE owing to development of drugs targeting the contact system. This review focuses on management of HAE due to C1-INH deficiency/dysfunction including a global perspective which is under-represented in the literature. HAE with normal C1-INH is outside the scope of this article. The review provides summaries of clinical trials that has led to licensing of new HAE medications and discusses access to these modern drugs from a global perspective.
Immune dysregulation (ID), defined as aberrant immune activation or suppression, may result in autoimmune or inflammatory disorders, lymphoproliferative malignancies, and allergic diseases. Apoptosis, nuclear factor-κB, and phosphoinositide 3-kinase pathways are major pathways involved in ID. This study aimed to assess ID using targeted inflammatory gene-expression profiles in comparison with controls. We grouped patients according to presenting features: autoimmune lymphoproliferative syndrome (Group 1), immune cytopenia (Group 2), and EBV-associated lymphoproliferation (Group 3). We established real-time quantitative polymerase chain reaction analysis for selected genes (CASP8, CASP10, FAS, FASL, AKT, MAP3K7, MAP3K14, mTOR, NFKB1, NFKB2, NFKBIA, and TRAF3) involved in inflammatory pathways, and calculated gene expression fold changes using the logarithmic Delta-Delta Ct (2^(-delta delta CT)) method. The median age of symptom onset in Group 1 (n = 10), Group 2 (n = 12), and Group 3 (n = 10) was 9.3 (0.5-38.7), 5.7 (0.7-19), and 22.5 (0.7-45) years, respectively (P = 0.181). The median age at hospital admission was 12 (1.9-38.7), 9.4 (2.3-35), and 34.8 (0.9-54.7) years in Groups 1, 2, and 3, respectively (P = 0.152). There was a significant difference between patient and control groups (P < 0.05), but none among patient groups regarding targeted gene expression (relative quantification values). According to ROC curve analysis, the most discriminative target genes are NFKB2, MAP3K7, AKT, mTOR, NFKB1, and FAS. We propose an ID signature that includes targeted gene expression profiles (NFKB1, NFKB2, MAP3K7, AKT, mTOR, and FAS) and suggest using these specific gene expressions as a biomarker for diagnosis and therapy response in ID.
Cytokine storm syndrome is a life-threatening hyperinflammatory condition characterized by excessive and dysregulated immune activation, leading to multiorgan dysfunction and poor clinical outcomes if not promptly recognized and adequately treated. Rather than representing a single disease entity, cytokine storm syndrome is increasingly understood as a final common pathogenic pathway shared by a broad spectrum of clinical conditions converging on overlapping immunopathological mechanisms driven by sustained cytokine production, immune-cell hyperactivation, and failure of immune-regulatory pathways. The clinical presentation of cytokine storm syndrome is characterized by a rapidly progressive nature, multisystem involvement, and the diagnostic challenges arising from nonspecific symptoms and overlapping laboratory features. Hyperferritinaemia emerges as a central laboratory hallmark with both diagnostic and potential pathogenic relevance. Therapeutic management of cytokine storm syndrome requires early recognition and is guided by three core principles: supportive care for organ dysfunction, control of underlying triggers, and timely immunomodulatory or immunosuppressive interventions. Overall, cytokine storm syndrome represents a complex and heterogeneous clinical syndrome in which improved mechanistic understanding, biomarker development, and tailored therapeutic strategies are essential to optimize patient outcomes.
Plaque psoriasis (PP) is a chronic immune-mediated inflammatory disease driven by dysregulation of the IL-23/Th17/IL-17 axis. Although IL-17A-targeted biologics achieve robust clinical efficacy, the systemic immune remodeling accompanying successful treatment remains incompletely understood. We performed longitudinal immune profiling in seven patients with PP before treatment and after achieving a 90% reduction in the Psoriasis Area and Severity Index (PASI 90) following secukinumab therapy. Circulating T-cell subsets, programmed cell death protein 1 (PD-1)-expressing populations, cutaneous lymphocyte antigen-positive (CLA+) T cells, and plasma cytokines were analyzed by flow cytometry and multiplex assays. Ex vivo responses to the PD-1 agonist peresolimab were further evaluated in an independent cohort. At baseline, patients exhibited reduced frequencies of regulatory T cells compared with healthy controls. Following PASI 90, circulating Th17 and Th2 cell frequencies increased despite minimal sustained changes in plasma cytokine levels, suggesting dissociation between effector T-cell expansion and soluble inflammatory mediators during IL-17A blockade. Circulating CD4+CLA+ T cells were partially restored, and treatment was accompanied by increased frequencies of PD-1-expressing CD4+ T-cell subsets, which were inversely associated with disease activity over time. Ex vivo PD-1 engagement selectively suppressed IL-17A-producing CD4+ T cells while largely preserving IFN-γ production. These findings suggest that clinical improvement during IL-17A blockade is accompanied by coordinated immune remodeling rather than generalized systemic immunosuppression and that PD-1 signaling may contribute to restraining Th17 effector function during therapeutic response.
Mendelian susceptibility to mycobacterial disease (MSMD), caused by IL12RB1 or IL12B mutations, typically presents with intra-cellular infections such as BCG-adenitis or Salmonella. Rarely, patients with IL12RB1/IL12B defects can exhibit cutaneous manifestations such as Henoch-Schonlein purpura (HSP). This study aimed to evaluate such vasculitic manifestations in genetically confirmed cases with MSMD in India and review the literature for similar associations. We included nine patients with genetically proven MSMD presenting with features of HSP-like small vessel vasculitis from pediatric immunology clinics across three tertiary care centers in India. Clinical, laboratory, histopathological, and genetic data were recorded using a structured proforma. Skin biopsy findings, IgA levels, renal involvement, and infection history were analyzed. Additionally, a literature review was performed using PubMed, Scopus, and Google Scholar databases to identify similar reported cases. In our cohort, eight patients had IL12RB1 defect, and one had IL12B defect. All had maculopapular purpuric rash in lower limbs, predominantly in the anterior aspect of legs and posterior thighs resembling the rash of HSP. Leukocytoclastic vasculitis was observed in 77.7% patients (n = 7), with two out of five had IgA deposits in dermo-epidermal junction. Concurrent infections due to Salmonella sp. and Pandorea apista were documented in 44.4% (n = 4) and 22.2% (n = 2), respectively. Treatment focused on antimicrobial therapy led to clinical improvement. The HSP-like vasculitic rash usually occurred in setting of underlying bacterial infections in patients with particularly IL12RB1/IL12B defects. These skin lesions can also be considered as one of the potential clinical clues for underlying IL12RB/IL12B defects.
CARD11 is a scaffold protein expressed primarily in hematopoietic tissues, shaping key processes in B and T cells via regulation of Ag-linked signaling pathways, including NF-κB, mTOR, JNK, and AKT. Heterozygous, gain-of-function (GOF) variants in its encoding gene, CARD11, are implicated in a human disorder characterized by frequent upper respiratory infections, poor responses to polysaccharide vaccines, vulnerability to certain opportunistic viruses, and polyclonal B-cell expansion, likely predisposing these patients to lymphoma. Over the past decade, several studies have elucidated some of the B-cell functional defects that likely underlie the patients' infectious phenotype. However, the potential contributions of CARD11 GOF variants to subpopulations of T cells have not been explored in detail. Therefore, our study sought to investigate the effect of increased CARD11 activity on the development, maturation, activation, differentiation, and effector function of adaptive lymphocytes from a cohort of five individuals harboring monoallelic CARD11 GOF variants through detailed ex vivo immunophenotyping and in vitro analyses. Our findings revealed intrinsic requirements for CARD11 in activation, differentiation, and effector function of human naïve B cells. Contrary to previous reports, intact CARD11 activity is also required for multiple aspects of CD4+ T-cell homeostasis alongside its notable role in the humoral immune response. Overall, these results shed light on mechanisms underlying disease pathogenesis due to not only CARD11 GOF variants but also LOF variants and reveal opportunities to consider targeted therapies in CARD11 GOF patients.
The nuclear factor κB (NF-κB)-related disorders encompassed not only common variable immunodeficiency but also manifestations of autoinflammation, autoimmunity, and malignancies. While most cases have been reported in European populations, reports in the Chinese population are sparse. Clinical data and genetic variants from four Chinese patients with NFKB1 variants, alongside four previously reported cases, were analyzed and compared with an international cohort. Additionally, comprehensive in vitro functional assays-including immunoblotting, transcript analyses, dual-luciferase reporter, and co-immunoprecipitation assays-were conducted to explore the molecular defects of the novel variants. Our cohort included three men and one woman, all presenting with recurrent fever and hypogammaglobulinemia. Three patients experienced recurrent sinopulmonary infections, accompanied by decreased B cells and NK cells, while two patients developed pneumonia, bronchiectasis, and hepatitis. Three novel NFKB1 (NM_003998) variants were identified: c.559C > T (p. Arg187Trp), c.1509del (p. Glu504Argfs*19), and c.1753-11_1760del (p. Thr585Alafs*9). Functional analyses revealed distinct pathomechanisms: the frameshift/splicing variants drive classical haploinsufficiency via nonsense-mediated mRNA decay (NMD), triggering compensatory inflammatory hyperactivation; conversely, the p.Arg187Trp missense variant maintains protein stability and heterodimerization but strictly abolishes DNA-binding capacity. Compared to a previously reported cohort, Chinese patients were predominantly male, had a later median age of onset and diagnosis. Notably, Chinese patients exhibited a higher prevalence of hepatitis (25%) and cirrhosis (12.5%), potentially reflecting the high endemicity of hepatitis B virus in China. They also showed increased rates of viral infections, sepsis, and bronchiectasis, with more pronounced reductions in NK and B cells. In contrast, autoimmune diseases and bronchitis were less frequent than in the foreign cohort. This study represents the first and largest case series of Chinese patients with NF-κB1-related diseases, providing molecular characterization for three novel variants. In this limited case series, the observed delayed onset and frequent hepatic complications in our cohort may reflect regional factors, such as HBV endemicity, or ascertainment bias. Our findings underscore that suspected AOSD accompanied by hypogammaglobulinemia warrants immediate genetic investigation. Early diagnosis is essential to prioritize immunoglobulin replacement and prevent fatal complications from immunosuppressive therapy.
Lupus nephritis (LN) is a major cause of organ damage in systemic lupus erythematosus and is driven in part by overactivation of the lectin pathway (LP) and alternative pathway (AP) of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2) initiates LP through C4/C2 cleavage, whereas MASP-3 enables AP amplification by activating pro-factor D. We hypothesized that concurrent inhibition of both proteases would provide superior renoprotection compared with single-pathway blockade in established disease. Female BALB/c mice with pristane-induced LN received anti-MASP-2, anti-MASP-3, bispecific antibodies, or vehicle for 4 weeks. Bispecific MASP-2/3 inhibition produced greater improvements in albuminuria, renal activity index, and glomerular C3d and C5b-9 deposition than either monotherapy. Functional assays confirmed selective LP suppression with MASP-2 blockade and AP suppression with MASP-3 blockade, whereas dual inhibition maximally reduced both pathways and their downstream complement effectors. Kidney transcriptomics demonstrated broad down-regulation of complement, coagulation, and inflammatory gene networks. Together, these findings indicate that bispecific MASP-2/3 blockade provides robust complement-directed protection in established LN and may represent an effective therapeutic strategy for complement-mediated kidney disease.
Second-generation CAR T-cells have transformed the management of B-cell malignancy. However, in vivo functional persistence is often limited, highlighting a key mechanism of treatment failure. We have engineered a parallel (p)CAR platform that delivers dual CD28 and 4-1BB co-stimulation via a co-expressed CAR and chimeric co-stimulatory receptor (CCR). To target CD19, we employed an avidity-optimized FMC63 scFv to direct CAR specificity while utilizing an unmodified FMC63 scFv to target the CCR. Here, we describe the late-stage optimization of this system for Phase 1 clinical evaluation. First, we confirmed that the avidity-optimized scFv lacked off-target specificity. To minimize risk of insertional mutagenesis and immunogenicity, respectively, we transitioned from a gammaretrovirus to a third-generation lentiviral expression vector and removed epitope tags used to discriminate between CAR and CCR expression. Most strikingly, we found that inactivation of immune tyrosine activation motif 2 and 3 within our pCAR prototype markedly potentiated efficacy in xenograft-bearing NSG mice. Mechanistically, this resulted from increased pCAR T-cell functional persistence and organ infiltration, with enhanced local clearance of malignant B-cells. These data set the scene for evaluation of this iteratively honed pCAR candidate in a clinical trial in relapsed/refractory B-cell non-Hodgkin's lymphoma.
Cholesteatoma is abnormal epithelial tissue in the middle ear cleft and an important cause of chronically discharging ears and hearing loss. Its proximity to important middle ear structures and the brain can lead to significant complications. Cholesteatoma presents both as congenital and acquired types and can occur both in children and adults. The mainstay of treating cholesteatoma is a destructive surgery with attendant morbidity. Despite radical surgery cholesteatomas can recur, sometimes repeatedly, causing a significant impact on quality of life. The role of inflammation in cholesteatoma is an area of keen interest. However, immune processes are highly complex, and while various individual components of the process have been studied in cholesteatoma, we are far from a cohesive understanding of the role of immune cells and inflammation pathways in the pathogenesis of cholesteatoma. Better understanding of its immune-pathogenesis would enable identification of disease-modifying therapies and novel pharmacological targets. In this review, we provide a detailed overview of the existent knowledge and recent developments on immune cells and inflammatory pathways implicated in cholesteatoma pathogenesis, progression, and damaging bone eroding properties. As cholesteatoma surgery is inherently destructive with poor hearing results, there is a definite necessity for new treatments to reduce the surgical burden and enable functional preservation in the management of this condition. We focus on the current and future areas of research that could lead to new therapies targeting inflammation and bring about a step change in the management of this aggressive ear condition.
