Napolitano F, Pietroluongo E, Di Tolla MF
… +9 more, Ottaviano M, D'Esposito V, De Placido P, Servetto A, Portella G, Bianco R, Palmieri G, Formisano P, Malfitano AM
PURPOSE: Thymic epithelial tumors (TETs) are associated with Good Syndrome (GS), a secondary immunodeficiency characterized by hypogammaglobulinemia, B-cell lymphopenia, and recurrent infections. This study investigated...PURPOSE: Thymic epithelial tumors (TETs) are associated with Good Syndrome (GS), a secondary immunodeficiency characterized by hypogammaglobulinemia, B-cell lymphopenia, and recurrent infections. This study investigated the immunological profile of TET patients to identify immune alterations associated with GS, independently of autoimmune diseases (AD) and disease stage. METHODS: Seventy patients with TETs were stratified according to GS status (GS+/GS-), AD status (AD+/AD-), and disease stage (advanced disease, IVA/B, or no evidence of disease, NED). Serum immunoglobulins, peripheral immune cell subsets, and circulating cytokines, chemokines, growth factors, and metabolic markers were evaluated. Results GS+ patients showed reduced IgM and IgG levels compared with GS- patients; however, after stratification, only IgM remained reduced in GS+AD- NED patients. Peripheral B-cell lymphopenia was consistently observed in GS+ patients across both disease stages, independently of AD status. Treg frequencies increased in GS- patients with advanced disease and in GS+AD+ NED patients. Monocytopenia and an inverted CD4+/CD8+ ratio were mainly observed in GS+AD+ patients with advanced disease. Cytokine profiling identified increased levels of IL-1β, IL-10, IL-17, TNFα, IFN-γ, IL-4, IL-5, IL-6, Eotaxin, G-CSF, and IP-10 in GS+ patients. Among these, IP-10 remained consistently elevated regardless of disease stage or AD status. CONCLUSION: Peripheral B-cell lymphopenia and elevated IP-10 levels represent the most consistent immunological features associated with GS, independent of disease stage and AD status, whereas serum immunoglobulin levels appear less reliable in advanced disease. These findings support the diagnostic value of immunophenotyping, particularly B-cell quantification and IP-10 measurement, for identifying GS in patients with TETs.
TRNT1 deficiency (SIFD syndrome) is a rare inborn error of immunity characterized by sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay. We report two Romanian patients with genetically conf...TRNT1 deficiency (SIFD syndrome) is a rare inborn error of immunity characterized by sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay. We report two Romanian patients with genetically confirmed TRNT1 deficiency presenting with characteristic hematologic and immunologic abnormalities and a distinctive facial dysmorphism. One patient additionally developed severe gastrointestinal ischemia and intracranial hemorrhage in the setting of concomitant hereditary antithrombin III deficiency. These observations expand the phenotypic spectrum associated with TRNT1 deficiency and highlight the marked clinical variability of this disorder. The contribution of TRNT1-associated inflammation to the vascular phenotype remains speculative and cannot be distinguished from the effects of the concomitant thrombophilic condition.
PURPOSE: Systemic autoimmune diseases and primary immunodeficiencies/inborn errors of immunity (PIDs/IEIs) have traditionally been viewed as opposing immunological entities. However, growing genetic, immunological, and c...PURPOSE: Systemic autoimmune diseases and primary immunodeficiencies/inborn errors of immunity (PIDs/IEIs) have traditionally been viewed as opposing immunological entities. However, growing genetic, immunological, and clinical evidence challenges this dichotomy, revealing a shared spectrum of immune dysregulation, genetic vulnerability, and convergent phenotypes. Advances in next-generation sequencing have identified monogenic IEIs presenting with autoimmune manifestations indistinguishable from polygenic systemic autoimmune diseases, blurring diagnostic boundaries and carrying therapeutic implications. This review aims to explore the relationships between autoimmunity, immunodeficiency, and malignancy, emphasizing how immune dysregulation underlies susceptibility to infections, cancer, and treatment-related complications. METHODS: We performed a narrative review of the literature with a focus on underlying mechanisms, clinical manifestations, and implications for diagnosis and management. RESULTS: Immune dysregulation underlies susceptibility to infections, cancer, and treatment-related complications. Immunosuppressive and biologic/targeted therapies remain cornerstone treatments but entail risks, including serious and opportunistic infections, organ toxicity, and malignancy, particularly when underlying PIDs/IEIs remain unrecognized. Failure to recognize underlying PID/IEI in patients with early-onset, refractory, syndromic, or otherwise atypical autoimmune disease leads to misdiagnosis and harmful therapeutic escalation, underscoring the need for prompt immunological screening. Immunological screening, including immunoglobulin profiling, lymphocyte subsets, and genetic testing, may improve diagnostic accuracy and guide treatment strategies. Malignancy represents an intersection point, with disease-specific cancer patterns reflecting distinct pathogenic mechanisms across autoimmune diseases and IEIs, highlighting the clinical relevance of disease-specific cancer risk stratification and surveillance. CONCLUSION: Integrating mechanistic insights and genetic profiling may enable a precision medicine approach that optimizes efficacy while minimizing harm across this expanding immunological continuum.
Arslan S, Sert A, Özçelik M
… +8 more, Barış S, Aydoğmuş Ç, Kaba Ö, Çil Yılmaz B, Erdil S, Yırgın K, Gökmirza P, Çatak MC
J Clin Immunol
· 2026 Jun · PMID 42319627
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BACKGROUND: Gain-of-function (GOF) mutations in the STAT1 gene result in heightened interferon signaling and impaired IL-17 immunity. While chronic mucocutaneous candidiasis (CMC) remains the hallmark feature, affected i...BACKGROUND: Gain-of-function (GOF) mutations in the STAT1 gene result in heightened interferon signaling and impaired IL-17 immunity. While chronic mucocutaneous candidiasis (CMC) remains the hallmark feature, affected individuals often display a broader phenotype including viral infections, mycobacterial susceptibility, and autoimmune diseases. CASE PRESENTATION: We describe a 4-year-old girl who initially presented with abdominal pain and was diagnosed with acute appendicitis. During surgery, marked mesenteric lymphadenopathy was discovered, and histopathology revealed acid-fast bacilli. Mycobacterium tuberculosis was confirmed by gastric fluid PCR, prompting initiation of anti-tuberculosis therapy. Her past medical history included hospitalization for herpes zoster and recurrent episodes of oral candidiasis during febrile illnesses. Immunologic evaluation showed normal immunoglobulin levels, vaccine responses, oxidative burst, and lymphocyte proliferation. However, low NK cells, reduced recent thymic emigrants, and decreased class-switched memory B cells were noted. Genetic testing revealed a previously unreported heterozygous STAT1 variant (p.Thr387Arg), classified as likely pathogenic according to ACMG criteria with a CADD score of 23.4. Parental genetic testing was negative, suggesting a de novo mutation. Although STAT1 phosphorylation could not be assessed, the proportion of IL-17-producing CD4⁺ T cells was markedly reduced, supporting impaired Th17 immunity. Based on clinical, immunologic, and genetic findings, a clinical and immunological phenotype consistent with STAT1 GOF was established. One year later, the patient developed arthritis and was diagnosed with systemic lupus erythematosus (SLE) based on autoantibody positivity and low complement levels. During follow-up, she also developed hemophagocytic lymphohistiocytosis (HLH), further reflecting severe immune dysregulation. Ruxolitinib was initiated as bridging therapy, resulting in partial clinical improvement, and hematopoietic stem cell transplantation (HSCT) was planned as definitive therapy. CONCLUSION: This report describes a novel STAT1 variant consistent with a gain-of-function phenotype associated with disseminated tuberculosis and early-onset SLE, expanding the clinical and molecular spectrum of this disorder. In children presenting with overlapping infectious and autoimmune features, underlying inborn errors of immunity should be considered.
PURPOSE: Transient neutropenia in early childhood is a relatively common condition often associated with neutrophil-specific autoantibodies; however, its connection to broader humoral immune system abnormalities remains...PURPOSE: Transient neutropenia in early childhood is a relatively common condition often associated with neutrophil-specific autoantibodies; however, its connection to broader humoral immune system abnormalities remains poorly understood. METHODS: The current study investigated this relationship through a retrospective cohort analysis at a pediatric tertiary center in Switzerland. RESULTS: In total, 92 children aged 0 to 6 years seen at our hospital between January 2014 and December 2023 were included in the final cohort. Of the 68 children who underwent detailed immunological testing, 52 (77%) exhibited humoral abnormalities, with 24 (35%) classified as moderate and 28 (41%) as mild. Patients with humoral abnormalities exhibited neutrophil-specific autoantibodies less commonly (56% vs. 100%, p = 0.003), had higher minimum absolute neutrophil counts (ANC) (median minimum ANC 0.26 vs. 0.05 × 10/L, p = 0.002), and a shorter duration of neutropenia (median duration 12.1 vs. 28.5 months, p = 0.001) compared to patients without abnormalities. Additionally, 36% of patients with humoral abnormalities had inadequate vaccine antibodies, compared to none in the group without abnormalities. These findings suggest that patients with humoral abnormalities may have a higher risk of infection and could benefit from additional counseling and timely booster vaccinations. CONCLUSION: This study highlights a potential causal relationship between humoral immune system abnormalities and transient neutropenia in early childhood. Routine immunological assessments in children with early-onset (autoimmune) neutropenia are likely to aid in patient management and family counseling.
PURPOSE: To perform a systematic review and meta-analysis of prevalence and function of anti-interferon auto-antibodies in acute infectious diseases. METHODS: We performed a search on the following electronic bibliograph...PURPOSE: To perform a systematic review and meta-analysis of prevalence and function of anti-interferon auto-antibodies in acute infectious diseases. METHODS: We performed a search on the following electronic bibliographic databases: Medline, Embase, Web of Science and Cochrane. Eligible studies generated a systematic review and random effects model meta-analysis of pooled seroprevalence and neutralisation status of anti-interferon auto-antibodies in acute infectious diseases. RESULTS: Thirty-seven studies including 12,629 individuals with SARS-CoV-2 infection were analysed. There are insufficient data for meta-analyses of auto-antibodies in non-SARS-CoV-2 infectious diseases, with crude seroprevalence of auto-antibodies varying widely (0.0-77.0%). The pooled seroprevalence of anti-IFNɑ and/or anti-IFN⍵ auto-antibodies in individuals with SARS-CoV-2 infection was 14% (95%CI 9-18%, I = 92%, [Formula: see text] = 0.0151, p < 0.01). Pooled prevalence of neutralising auto-antibodies were slightly lower (12%; 95%CI 8-17%, I = 77%, [Formula: see text] = 0.0027, p < 0.01). The high heterogeneity may reflect divergent SARS-CoV-2 disease severity across studies, and methodological diversity for measurement and definition of auto-antibody binding and neutralisation. Pooled seroprevalence for anti-IFNɑ auto-antibodies in uninfected healthy controls were < 1% (95%CI 0-1%, I = 90%, [Formula: see text] = 0.0028, p < 0.01). CONCLUSION: Anti-interferon auto-antibodies may impair immune responses to diverse infections leading to life-threatening disease. These auto-antibodies have not been studied at all in most infectious diseases, most notably for bacterial infection. This study illustrates the urgent need to standardise methodology and reporting of auto-antibodies in the setting of infectious diseases so that the immunopathology and translational impact of these novel biomarkers can be realised.
A novel heterozygous missense variant in STAT3 (NM_139276.3: c.1250G > C, NP_644805.1: p.(Arg417Thr) was identified in a Danish family spanning five generations with diverse phenotypes consistent with autosomal dominant...A novel heterozygous missense variant in STAT3 (NM_139276.3: c.1250G > C, NP_644805.1: p.(Arg417Thr) was identified in a Danish family spanning five generations with diverse phenotypes consistent with autosomal dominant STAT3-Hyper-IgE-Syndrome (STAT3-HIES). Genetic analysis confirmed the absence of the variant in population databases, and computational predictions of pathogenicity were conflicting. Functional assessment revealed that the variant STAT3 Arg417Thr maintained normal DNA binding but exhibited reduced IL-6-induced transcriptional activity and no negative-dominance. Further, significantly impaired STAT3-dependent, IL-10-mediated suppression of TNF-α production were found in patient-derived monocytes, consistent with a partial loss-of-function effect. Clinically, affected individuals presented with recurrent staphylococcal skin abscesses, eczema, atopic or infectious complications, and characteristic facial features. There was a marked variability in extra-hematopoietic manifestations such as retained primary teeth, vascular anomalies, and psychiatric disorders. Laboratory findings included elevated serum IgE levels, but only slightly reduced or normal Th17 cell counts. NIH-HIES scores varied within the family (range: 12-34), highlighting the variability of clinical expression. Based on ACMG guidelines, the variant was classified as likely pathogenic due to absence from controls, co-segregation with disease, and supportive functional evidence. This report highlights the challenges in interpreting novel STAT3 variants and the critical need for functional validation in uncertain cases. The findings emphasize the importance of molecular diagnosis irrespective of clinical scoring and address the ethical complexities of genetic testing in familial disease.
Early diagnosis of inborn errors of immunity (IEIs) can make a difference in patient outcomes and even cut healthcare costs. However, there are some challenges to overcome, such as clinical complexity, low awareness, and...Early diagnosis of inborn errors of immunity (IEIs) can make a difference in patient outcomes and even cut healthcare costs. However, there are some challenges to overcome, such as clinical complexity, low awareness, and limited resources. Generative artificial intelligence has attracted considerable global attention in medical domains, particularly when integrated into clinical decision support systems (CDSS), as it has the potential to facilitate data interpretation, clinical reasoning, and the optimal use of knowledge resources. Preliminary studies have explored the potential of large language models (LLMs) in various information retrieval tasks, but a systematic evaluation of LLMs with and without retrieval mechanisms for IEI classification is still unexplored. We evaluated and compared the validity and reliability of the responses generated by four open-source and closed-source LLMs, in their baseline form and with augmented data, across 169 IEI patient records, using two input scenarios and four prompt templates. Our primary finding was that the models varied in terms of reliability and performance. The most reliable models were Gemini-1.5-Pro and Llama-3.1-8B-Instruct ([Formula: see text]) and the best-performing model without data augmentation was Gemini with an F1 score of [Formula: see text]. The results also showed that retrieval strategies improved the average classification performance, increasing the F1 score from [Formula: see text] to [Formula: see text] across all models. DeepSeek-R1, which reasoned over retrieved information through the integration of quality refinement and structured retrieval, achieved the best weighted F1 score of [Formula: see text]. The study highlights the effective use of generative AI and retrieval-augmented models as a decision support tool for IEI classification. However, incorporating retrieval systems into clinical decision-making processes requires adequate input, effective prompt engineering, and the adoption of retrieval strategies.
Liang S, Huang X, Liang X
… +28 more, Wu S, Ning Y, Chen N, Hong L, Luo Z, Wei X, Chen Q, Deng J, Li M, Yang M, Zeng W, Yan P, Wei H, Zhang J, Cao F, Zhong X, Wei Z, Wei Q, Jiang M, Xu C, Chen T, Liang S, Meng X, Qin C, Qu D, Zou L, Li Y, He Z
Adult-onset immunodeficiency syndrome mediated by anti-interferon-gamma autoantibody (AIGA) is a rare disorder that has garnered increasing recognition in recent years. The condition is most prevalent among adults in Sou...Adult-onset immunodeficiency syndrome mediated by anti-interferon-gamma autoantibody (AIGA) is a rare disorder that has garnered increasing recognition in recent years. The condition is most prevalent among adults in Southeast Asia. It is characterized by recurrent disseminated opportunistic infections, frequently involving multiple organ systems such as the lungs, lymph nodes, bones, and skin. The pathogenesis is primarily attributed to the presence of neutralizing AIGAs, which impair the IFN-γ-mediated JAK-STAT1 signaling pathway, leading to compromised host defense against intracellular pathogens. Laboratory diagnosis requires both quantification of AIGA titers and assessment of their neutralizing activity. Clinical diagnosis relies on a combination of characteristic manifestations, demonstrated immunologic dysfunction, and seropositivity for AIGAs. During the acute stage, management focuses on antimicrobial therapy, while during the stable stage, it can be categorized into three clinical subtypes: high AIGA titers with immune damage, high AIGA titers without immune damage, and low AIGA titers without immune damage. Among these, patients with high AIGA titers and immune damage require immunomodulatory strategies-such as glucocorticoids and rituximab-tailored to individual AIGA levels and immune status. Due to the current absence of unified clinical guidelines, this review synthesizes available evidence and clinical expertise to provide a comprehensive overview of the epidemiology, pathogenesis, clinical presentation, diagnostic criteria, and treatment approaches related to AIGA-mediated immunodeficiency. Our aim is to assist clinicians in the recognition and management of this syndrome and to facilitate further clinical research and guideline development.
PURPOSE: To report a patient with a novel MSN mutation causing X-linked moesin-associated immunodeficiency (X-MAID) and investigate its pathogenic mechanisms. METHODS: Clinical and immunological data of the patient were...PURPOSE: To report a patient with a novel MSN mutation causing X-linked moesin-associated immunodeficiency (X-MAID) and investigate its pathogenic mechanisms. METHODS: Clinical and immunological data of the patient were collected. Autoantibody levels were measured using antigen microarrays. Whole-exome sequencing was performed to identify gene mutations. The stability of the mutant MSN protein was analyzed via transient transfection and cycloheximide chase assay in HEK293T cells. MSN protein expression, immunophenotyping, and T cell activation and apoptosis were assessed by flow cytometry. RESULTS: The patient was a 2-year-old boy, presented with recurrent infections, Kawasaki disease, and early-onset broad-spectrum autoantibody production. A novel hemizygous MSN mutation (c.344T > C, p.I115T) was identified in the patient. The MSN p.I115T mutant showed reduced protein stability and decreased expression in multiple immune cell types. Immunophenotyping revealed follicular regulatory T (Tfr) cell reduction, Th1/Th17 imbalance, enhanced CD4 T cell activation and proliferation, and impaired B cell maturation. CONCLUSION: We report a novel MSN mutation associated with recurrent infections, early-onset broad-spectrum autoantibody production, and Kawasaki disease. MSN deficiency may contribute to autoimmunity through Tfr cell reduction and Th1/Th17 imbalance.
Gain-of-function variants in the TLR7 gene have been associated with a spectrum of clinical manifestations, including systemic lupus erythematosus (SLE)-like disease, neuromyelitis optica, and progressive leukoencephalop...Gain-of-function variants in the TLR7 gene have been associated with a spectrum of clinical manifestations, including systemic lupus erythematosus (SLE)-like disease, neuromyelitis optica, and progressive leukoencephalopathy. The p.(Leu528Ile) variant has previously been shown to underlie this constellation of findings. Here, we report the extended follow-up of a previously described young female patient with TLR7-related interferonopathy, who developed non-paraneoplastic autoimmune retinopathy following a failed attempt to taper her systemic immunomodulatory therapy. This case expands the phenotypic spectrum of TLR7-related disease and highlights a potential link between interferon-driven immune dysregulation and autoimmune retinal pathology.
OBJECTIVE: To perform genetic diagnosis and pedigree analysis in a case of autosomal dominant Familial Behçet-like Autoinflammatory Syndrome type 3 (AIFBL3) caused by a novel RELA variant. METHODS: Peripheral blood sampl...OBJECTIVE: To perform genetic diagnosis and pedigree analysis in a case of autosomal dominant Familial Behçet-like Autoinflammatory Syndrome type 3 (AIFBL3) caused by a novel RELA variant. METHODS: Peripheral blood samples collected from the proband and parents underwent conventional genetic screening, next-generation sequencing (NGS), and Sanger sequencing for familial validation. RESULTS: A de novo heterozygous RELA variant (NM_021975.4:c.539 C > T, p.Ser180Phe) was identified in the proband. Parental testing confirmed its de novo origin. CONCLUSION: The RELA c.539 C > T variant was classified as likely pathogenic for AIFBL3, providing a basis for genetic counseling. In future pregnancies, prenatal diagnosis through targeted familial mutation analysis could be offered to this family to inform reproductive decision-making.
Pei Y, Jin B, Abasi R
… +6 more, Cheng C, Zhuang H, Zeng S, Jiang M, Pei H, Jiang X
J Clin Immunol
· 2026 May · PMID 42105147
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The Janus Kinase 3 (JAK3) germline gain-of-function (GOF) mutation is a rare inborn error of immunity, first reported in 2020, characterized by lymphopenia and chronic NK-cell proliferation. However, its role in autoimmu...The Janus Kinase 3 (JAK3) germline gain-of-function (GOF) mutation is a rare inborn error of immunity, first reported in 2020, characterized by lymphopenia and chronic NK-cell proliferation. However, its role in autoimmunity remains unclear, and no direct association with hyper-IgE syndrome (HIES) has been established. In this study, we describe a patient presenting with HIES, myositis, lymphopenia, and autoimmune hypothyroidism. Whole-exome sequencing identified a novel compound heterozygous JAK3 mutation (c.2524_2525delinsTT and c.2805G > C), predicted to be deleterious. Flow cytometry and RNA sequencing of peripheral blood mononuclear cells revealed a significant reduction in T cells and NK cells, particularly naïve CD4 T cells, accompanied by a marked imbalance in T cell subsets. This led to constitutive activation of JAK1 and JAK3, along with increased STAT3 and STAT5 phosphorylation. Tofacitinib treatment significantly improved the patient's symptoms. Our findings expand the clinical spectrum of JAK3-associated immune dysregulation, linking it for the first time to HIES and multiple autoimmune manifestations. Furthermore, this study suggests that tofacitinib may be a potential therapeutic option for JAK3 signaling-associated immune dysregulation.
Beit-Halevi T, Broides A, Lev A
… +4 more, Simon AJ, Nahum A, Somech R, Lee YN
J Clin Immunol
· 2026 May · PMID 42090074
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Dedicator of cytokinesis protein 8 (DOCK8) is a crucial regulator for the formation of immune synapses, allowing for a proper function of innate and adaptive immune systems. DOCK8 deficiency is a primary immunodeficiency...Dedicator of cytokinesis protein 8 (DOCK8) is a crucial regulator for the formation of immune synapses, allowing for a proper function of innate and adaptive immune systems. DOCK8 deficiency is a primary immunodeficiency, currently known as Inborn Errors of Immunity (IEI) affecting both cellular and humoral immunity, thus leading to various clinical presentations ranging from infections, autoimmunity, inflammations and malignancies. We aimed to identify unique molecular signatures in the adaptive immune repertoire of DOCK8-deficient patients through comprehensive sequencing and analysis of the T-cell receptor (TCR) and B-cell receptor (BCR) repertoires, correlating these signatures with clinical features of the patients, ultimately providing a "fingerprint" of both individual's immunological status and disease conditions. We characterized the TCR repertoires of αβ T- and γδ T-cells, together with BCR repertoires of B-cells, in peripheral blood of 13 patients and age matched healthy donor controls using next generation sequencing. TCR repertoire in patients with DOCK8 deficiency demonstrated restricted diversity and clonal expansions, favorable use of specific gene in the V-D-J recombination process, and a unique finding of longer complementarity-determining-region-3 (CDR3) length, revealing an impaired T-cell development and activation. Furthermore, BCR repertoire demonstrated high diversity without clonal expansions, portraying an abnormal B-cell development leading to a possible mechanism for atopy and autoimmunity, alongside inadequate activation in DOCK8 deficiency. Lastly, various DOCK8 mutations demonstrated a more profound defects in immune repertoire. These findings expand our knowledge on the role DOCK8 plays in shaping the TCR and BCR repertoires in DOCK8 deficiency.
J Clin Immunol
· 2026 Apr · PMID 42053701
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Blocking CD154 (CD40L) has the potential to prolong transplanted solid organ graft survival and treat autoimmune diseases. However, first-generation anti-CD154 IgG1 monoclonal antibodies (mAbs) were associated with an in...Blocking CD154 (CD40L) has the potential to prolong transplanted solid organ graft survival and treat autoimmune diseases. However, first-generation anti-CD154 IgG1 monoclonal antibodies (mAbs) were associated with an increased risk of thrombosis linked to Fc binding to FcγRIIa (CD32A). Here, we describe a first-in-human, phase 1 clinical trial of TNX-1500, a novel Fc-modified IgG4 anti-CD154 mAb designed to decrease binding to FcγRIIa. Healthy volunteers (N = 26) were enrolled into single-ascending dose (3, 10, and 30 mg/kg) cohorts and received TNX-1500 intravenously. TNX-1500 was generally well tolerated. Among participants receiving TNX-1500 3, 10, and 30 mg/kg, 1 (25%), 3 (38%), and 3 (38%) participants, respectively, reported ≥ 1 treatment-emergent adverse event; all were mild or moderate in severity, and none resulted in study discontinuation. There were no thromboembolic events. Pharmacokinetic analyses of TNX-1500 demonstrated a mean half-life of 37.8 and 33.8 days for 10 and 30 mg/kg, respectively, supportive of monthly dosing; dose-proportional exposure was suggested over the 3 to 30 mg/kg range. TNX-1500 blocked the primary T cell-dependent antibody response to keyhole limpet hemocyanin (KLH) at all doses and blocked the secondary response at the 10 and 30 mg/kg doses. At 3 mg/kg, TNX-1500 reduced peak secondary response to KLH by ~ 70% relative to placebo. TNX-1500 administration was associated with immediate and sustained reduction in soluble CD154. Overall, TNX-1500 demonstrated a safety profile and pharmacologic properties that support further development as an agent with potential for prevention of organ transplant rejection and treatment for autoimmune conditions.
Ringleb M, Bizjak DA, Nieß AM
… +8 more, Notbohm H, Predel HG, Puta C, Steinacker JM, Widmann M, Zacher J, Bloch W, Javelle F
J Clin Immunol
· 2026 Apr · PMID 42043637
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BACKGROUND: Over 10% of all SARS-CoV-2 infections lead to persistent symptoms, a condition called post-COVID condition (PCC). For elite athletes, whose performance is central, PCC poses significant challenges. It is sugg...BACKGROUND: Over 10% of all SARS-CoV-2 infections lead to persistent symptoms, a condition called post-COVID condition (PCC). For elite athletes, whose performance is central, PCC poses significant challenges. It is suggested that immune cells, particularly regulatory and effector T cells, play a key role in symptom persistence nonetheless it has not yet been investigated. OBJECTIVE: This study investigates immune dynamics after SARS-CoV-2 infection and assesses whether symptom persistence is accompanied by T cell dysregulation in highly trained athletes. METHODS: Thirty-six highly trained athletes were included in this study after experiencing SARS-CoV-2 infection. Athletes’ data were analyzed 2–4 weeks after infection (T0) and 3–4 months later (T1). They were categorized into two groups: those with persistent symptoms (PS) and those without (SF). Their immune cell distribution was assessed via flow cytometry. RESULTS: In the PS group, there was an increase in T helper (Th) cell 17 and Th2 cells from T0 to T1, whereas in the SF group, these cell types either decreased or remained unchanged, respectively. Furthermore, Th1 cells decreased and natural (NK) cells increased from T0 to T1 in the PS group, while no changes were observed in the SF group. No changes were observed in Tregs nor in other cell types. CONCLUSION: This dysregulation of the immune system toward humoral immunity indexed by a rise in Th2 and Th17 cells and a decrease in Th1 cells over time could be indicative of a possible virus persistence contributing to persistent symptoms. CLINICAL TRIAL REGISTRATION: The study has been registered in the German Clinical Trials Register (DRKS00023717).