Clinical And Experimental Immunology[JOURNAL]
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200 papers
Distinctive T-cell receptor repertoire in paediatric inflammatory multisystem syndrome temporally associated with coronavirus disease 2019/multisystem inflammatory syndrome in children patients: possible thymus involvement.
Yanez DC, Rowell J, Woodall M … +11 more , Adams S, O'Neill L, Mengrelis K, Lau CI, Ross S, Benkenstein S, Plant K, Smith CM, Chain B, Peters MJ, Crompton T
Clin Exp Immunol · 2025 Jan · PMID 40331338 · Full text
During the coronavirus disease 2019 (COVID-19) pandemic a rare new paediatric inflammatory condition (paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS)/MIS-C) was identified which...
During the coronavirus disease 2019 (COVID-19) pandemic a rare new paediatric inflammatory condition (paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS)/MIS-C) was identified which correlated with previous or recent SARS-CoV-2 infection. PIMS-TS led to severe multiorgan inflammation, suggestive of disruption of central tolerance and thymus function. Here we investigated the possible role of the thymus in paediatric PIMS-TS. We confirmed that human thymus explants can be infected with SARS-CoV-2 in vitro. Comparison of T-cell populations in blood from PIMS-TS patients and age-matched healthy control children showed that although the overall proportions of CD4 and CD8 T-cell populations were decreased in PIMS-TS patients, the proportion of naïve cells in the CD4 population was higher in the PIMS-TS group. In PIMS-TS patients, the number of TREC in Peripheral blood mononuclear cells (PBMC) correlated strongly with the proportion of naïve CD4 and CD8 T cells, whereas this correlation was not present in healthy children. Sequencing rearranged TCRβ and TCRɑ transcripts from FACS-sorted CD4+CD8-CD3+ and CD4-CD8+CD3+ from blood from PIMS-TS, healthy children, and additionally paediatric severe COVID-19 patients showed that while all three groups showed similar diversity and distribution, the repertoire of the PIMS-TS and COVID-19 groups had distinctive patterns of TCR gene segment usage and VJ combinatorial usage compared to healthy controls (TRBV11-2 × TRBJ2-7, TRBV11-2 × TRBJ1-1, TRBV11-2 × TRBJ2-5, TRBV11-2 × TRBJ2-1; TRBV29-1 × TRBJ2-7, TRBV29-1 × TRBJ1-1 enriched in PIMS-TS; TRBV7-9 × TRBJ1-2, TRAV9-2 × TRAJ30, and TRAV26-1 × TRAJ39 enriched in COVID-19). The non-productive TCR rearrangements in the PIMS-TS group were also enriched for TRBV11-2, and showed bias towards distal (5'TRAV to 3'TRAJ) TCRɑ gene segment usage, suggesting involvement of the thymus in PIMS-TS.
Pharmacodynamic effect of mTOR inhibition-based immunosuppressive therapy on dendritic cell and natural killer cell subsets after renal transplantation.
Weber S, Wei X, Chen G … +10 more , Yankouskaya K, Yin D, Allabauer I, Jobst-Schwan T, Wiesener M, Schiffer M, Dudziak D, Lehmann CHK, Woelfle J, Hoerning A
Clin Exp Immunol · 2025 Jan · PMID 40289708 · Full text
BACKGROUND: mTOR inhibitor therapy is solely monitored via pharmacokinetics after kidney transplantation, which may not accurately reflect the effectiveness of PI3K-Akt-mTOR pathway blockade, potentially leading to inade...
BACKGROUND: mTOR inhibitor therapy is solely monitored via pharmacokinetics after kidney transplantation, which may not accurately reflect the effectiveness of PI3K-Akt-mTOR pathway blockade, potentially leading to inadequate or excessive immunosuppression. The pharmacodynamic effect of mTOR inhibition on natural killer (NK) cells and dendritic cell (DC) subsets after renal transplantation has not been investigated so far. METHODS: Phosphoflow cytometry was employed in this cross-sectional study to evaluate the extent of mTOR inhibition in peripheral DC and NK cell subsets by assessing p70S6 kinase phosphorylation in kidney transplant recipients treated with mTOR inhibitors either in combination with calcineurin inhibitors (mTORi + CNI, n = 17) or mycophenolate sodium (mTORi + MPA, n = 9). The control group comprised nine end-stage renal disease patients undergoing dialysis therapy and 17 healthy volunteers. RESULTS: mTOR inhibitor-based therapy significantly reduced p70S6K phosphorylation levels in CD3-CD56+ NK cells compared to healthy controls, while p70S6K phosphorylation among HLA-DR+ Lin- total DCs was not different. In comparison to mTORi + MPA therapy, renal transplant patients receiving mTORi + CNI treatment exhibited a stronger inhibition of p70S6K phosphorylation in HLA-DR+ Lin- total DCs, CD123+CD11c- plasmacytoid DCs, CD123-CD11c+ myeloid DCs, and CD16-CD56bright NK cells. However, the serum trough levels of mTORi showed no correlation with p70S6K phosphorylation levels in all investigated cell subsets. CONCLUSION: mTORi selectively suppressed p70S6K phosphorylation in specific DC and NK subtypes. Evaluating p70S6K phosphorylation through phosphoflow cytometry might serve as a clinically applicable method to comprehend immune cell subset-specific effects of mTOR inhibition, providing detailed pharmacodynamic insights for tailoring mTORi therapy on an individual basis.
Prospective analysis of the number and function of two T regulatory cell subsets in healthy individuals.
Colunga-Bolaños E, Doniz-Padilla L, Vitales-Noyola M … +5 more , González-Baranda L, Hernández-Castro B, Niño-Moreno P, Portales-Pérez DP, González-Amaro R
Clin Exp Immunol · 2025 Jan · PMID 40259466 · Full text
INTRODUCTION: T regulatory (Treg) cells play a crucial role in immune system homeostasis and in the pathogenesis of immune-mediated inflammatory diseases. Accordingly, numerous studies have examined the number and functi...
INTRODUCTION: T regulatory (Treg) cells play a crucial role in immune system homeostasis and in the pathogenesis of immune-mediated inflammatory diseases. Accordingly, numerous studies have examined the number and function of these lymphocytes in patients with different conditions as well as in healthy controls. The aim of this study was to analyze potential variations in the number and function of two Treg cell subsets in healthy adults over a 2-month period. METHODS: In a pilot study, blood samples were collected from 20 healthy individuals on Days 0, 30, and 60, and the levels of natural Treg cells (CD4+CD25highFoxp3+) and CD69+ Treg cells (CD4+CD69+CD25-/+LAP+IL-10+Foxp3-) were analyzed by flow cytometry. In addition, the function of these regulatory cells was evaluated using an in vitro assay that measures the inhibition of activation of autologous T lymphocytes. RESULTS: Although no significant differences were observed across the three serial measurements of the number or function of the Treg cells analyzed (P > 0.05 in both cases), a substantial proportion of individuals showed notable changes (either an increase or decrease) in these parameters during the study. These variations were not apparently associated with any factors affecting immune system homeostasis, including infections, medication use, or immunizations. CONCLUSION: Our findings suggest that significant fluctuations of causes to be determined occur in the levels and function of Treg cells in healthy individuals. This phenomenon should be considered in studies investigating immunoregulation in humans.
Clinical and experimental treatment of residual immune activation in people living with HIV.
Nganou-Makamdop K
Clin Exp Immunol · 2025 Jan · PMID 40243265 · Full text
Potent inflammatory responses stemming from innate and T cell activation are initiated during acute human immunodeficiency virus infection. Suppression of the virus replication by antiretroviral therapy reduces but does...
Potent inflammatory responses stemming from innate and T cell activation are initiated during acute human immunodeficiency virus infection. Suppression of the virus replication by antiretroviral therapy reduces but does not normalize immune activation. By now, it is clear that residual immune activation can persist even after years of antiretroviral therapy and associates with increased risks for co-morbidities, thereby raising interest for strategies that can resolve the residual immune activation in people with human immunodeficiency virus on antiretrovirals. This brief review reports the human studies with various drugs with anti-inflammatory properties and their effects on measures of systemic immune activation on people with human immunodeficiency virus. Along with the possible reasons for conflicting outcomes, considerations for ongoing and future approaches are outlined.
Sulforaphane relieved inflammation symptoms in EAP mice by blocking oxidative stress and NLRP3 inflammasome activation through the Nrf2 pathway.
Meng T, Feng R, Zhu Y … +5 more , Luo J, Zhang A, Liu Y, Chen J, Yang C
Clin Exp Immunol · 2025 Jan · PMID 40207573 · Full text
Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) are diagnosed in patients with various pelvic or genitourinary symptoms irrespective of the presence of a tender prostate. The etiology of chronic nonbacteri...
Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) are diagnosed in patients with various pelvic or genitourinary symptoms irrespective of the presence of a tender prostate. The etiology of chronic nonbacterial prostatitis remains unclear. Current treatments such as alpha-blockers, neuroleptics, anti-inflammatory, medications, and physical therapy, are often unsatisfactory. New treatments, as well as an improved knowledge of the underlying CP/CPPS pathogenesis, are thus needed. Sulforaphane (SFN), an isothiocyanate found in large quantities in Brassica species, has shown therapeutic effects on inflammation and cancer, and can protect against DNA damage and modulate the cell cycle to control apoptosis, angiogenesis, and metastasis. At the molecular level, SFN modulates cell homeostasis by activating the transcription factor Nrf2. However, its effect on CP/CPPS is not clear. Here, SFN was found to alleviate inflammation by suppressing NLRP3 inflammasomes via the Nrf2/HO-1 axis, as demonstrated in both animal and cellular analyses.
Comprehensive flow cytometry-based diagnosis of XIAP deficiency.
Tomomasa D, Nishimura M, Ohya A … +26 more , Tanita K, Wakatsuki R, Watanabe R, Miyamoto S, Hoshino A, Kamiya T, Isoda T, Kaneko S, Shimizu M, Hijikata A, Eguchi K, Ishimura M, Maeda Y, Izawa K, Meguro T, Fujimoto K, Ishikita-Murayama E, Suzuki K, Okura E, Uehara T, Takayama T, Okada S, Takagi M, Morio T, Marsh RA, Kanegane H
Clin Exp Immunol · 2025 Jan · PMID 40128104 · Full text
Deficiency of X-linked inhibitor of apoptosis protein (XIAP) is an X-linked recessive inborn error of immunity characterized by abnormal immune responses leading to inflammatory bowel disease and hemophagocytic lymphohis...
Deficiency of X-linked inhibitor of apoptosis protein (XIAP) is an X-linked recessive inborn error of immunity characterized by abnormal immune responses leading to inflammatory bowel disease and hemophagocytic lymphohistiocytosis. Although XIAP protein expression analysis by flow cytometry (XIAP flow) is commonly used to diagnose XIAP deficiency, certain variants may not affect the protein expression, thereby complicating the diagnostic process. XIAP is crucial for the nucleotide-binding and oligomerization domain 2 (NOD2) signaling pathway. 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 (TNFα) production by flow cytometry in patient monocytes (MDP flow). The median mean fluorescence intensity in healthy controls with XIAP flow was 711 (95% confidence interval [CI], 653-815) compared to 195 (95% CI, 161-386) in patients with XIAP deficiency (P < 0.0001). The median percentage of TNFα-producing monocytes in controls with MDP flow was 29.1% (95% CI, 19.6-53.7), while in patients it was 0.34% (95% CI, 0.18-0.82) (P = 0.0008). The receiver operating characteristic curves demonstrated that both XIAP flow and MDP flow exhibited 100% sensitivity and specificity. Taken together, combining XIAP flow and MDP flow analyses allows for a highly accurate diagnosis.
Type I interferon signature: a quantitative standardized method for clinical application.
Tesser A, Bocca P, Ulivi M … +10 more , Pin A, Pastorino C, Cangelosi D, Santori E, Drago E, Caorsi R, Candotti F, Gattorno M, Tommasini A, Volpi S
Clin Exp Immunol · 2025 Jan · PMID 40127048 · Full text
Type I Interferon (IFN) induced gene expression analysis ("IFN signature") is employed to categorize pathological conditions that exhibit Type I IFN dysregulation and to direct customized therapeutic strategies. For inst...
Type I Interferon (IFN) induced gene expression analysis ("IFN signature") is employed to categorize pathological conditions that exhibit Type I IFN dysregulation and to direct customized therapeutic strategies. For instance, it is used to differentiate patients with IFN-related inflammation from those with conditions primarily mediated by other cytokines, such as juvenile idiopathic arthritis and periodic fevers. Nevertheless, there is currently no standardized method available for clinical practice, and comparing values at different time points or between centers poses a challenge. 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, and juvenile idiopathic arthritis). The proposed method proved to be highly reproducible among centers and able to discriminate among IFN-related or non-IFN-related inflammation. The use of a synthetic control minimized the inter-assay and inter-laboratory variability, and thus facilitate data sharing among centers to improve knowledge of IFN-related inflammation and patient's care.
Pirfenidone alleviates interstitial lung disease in mice by inhibiting neutrophil extracellular trap formation and NLRP3 inflammasome activation.
Su Q, Feng Y, Guo J … +4 more , Cui X, Zhu J, Yang J, Zhang S
Clin Exp Immunol · 2025 Jan · PMID 40117382 · Full text
BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for th...
BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory, and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD. METHODS: A murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). Pirfenidone was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of citrullinated histone H3 and myeloperoxidase in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot were utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NOD-like receptor protein 3 (NLRP3) inflammasome markers. RESULTS: Pirfenidone treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. Pirfenidone intervention reduced NETs formation in vitro. Pirfenidone treatment significantly reduces NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD downregulated EMT and NLRP3-related proteins in vivo. Pirfenidone treatment also notably reduced serum levels of IL-1β, IL-6, and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. Pirfenidone attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome. CONCLUSION: Pirfenidone alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.
Mimics and challenging presentations of DADA2.
Öztürk A, Yagci L, Ugurlu S
Clin Exp Immunol · 2025 Jan · PMID 40117338 · Full text
Deficiency of adenosine deaminase 2 (DADA2) has been a challenging diagnosis to make since it was first described in 2014. The disease represents a wide range of phenotypes. Therefore, it may present with various clinica...
Deficiency of adenosine deaminase 2 (DADA2) has been a challenging diagnosis to make since it was first described in 2014. The disease represents a wide range of phenotypes. Therefore, it may present with various clinical patterns. Throughout the years, several difficult-to-diagnose cases of DADA2 were reported in the literature. Although several studies and reviews were published regarding different phenotypes and manifestations of DADA2, a review of challenging cases with diverse combinations of DADA2 manifestations was needed to integrate the knowledge from the literature into the clinical practice. Immunological, hematologic, autoinflammatory, and adult-onset polyarteritis-nodosa patterns were reported in the literature as cases challenging to diagnose. 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. Thus, early testing for DADA2 in suspected cases is recommended. Family history and genetic testing of the patient and the first-degree relatives are essential for accurate diagnosis. Thorough systemic examination and imaging might help detect clinically silent findings of vasculitis. Enzymatic activity of ADA2, when available, is also a key diagnostic tool that complements genetic testing and clinical evaluation.
In-depth immune profiling of a patient with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 caused by a novel mutation in ZBTB24.
Roark CM, Ramírez-Vásquez D, Giron Martinez JY … +7 more , Zhen X, Del Bene AN, Gibson SE, Dobrose MM, Halasa NB, Blancas-Galicia L, Martinez-Barricarte R
Clin Exp Immunol · 2025 Jan · PMID 40103177 · Full text
Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare genetic disorder characterized by recurrent, severe infections. Mutations in DNA methylation genes such as DNMT3B (ICF1), ZBTB24 (I...
Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare genetic disorder characterized by recurrent, severe infections. Mutations in DNA methylation genes such as DNMT3B (ICF1), ZBTB24 (ICF2), CDCA7 (ICF3), and HELLS (ICF4) cause ICF. ICF2 syndrome has been previously described, yet the extent of its clinical presentation and immunological consequences needs to be further elucidated. We describe a patient with a novel homozygous mutation in ZBTB24 (Q375Hfs*3). While infections with extracellular pathogens are frequent in other reported ICF2 patients, our patient also displays infections by intracellular pathogens. At the molecular level, we showed that the novel mutation results in a truncated ZBTB24 protein that disrupts its function in DNA methylation. 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. Despite observing normal cell frequencies within the T and myeloid compartments, the clinical presentation of this patient suggests a functional defect in immune cells known to be critical to combat intracellular pathogens. Overall, this study expands the clinical and immunological features of ZBTB24 deficiency and highlights the importance of ZBTB24 to the human immune response.
FcγRIIB (CD32B) antibodies enhance immune responses through activating FcγRs.
Simpson AP, Oldham RJ, Cox KL … +8 more , Taylor MC, James S, White AL, Bogdanov Y, Glennie MJ, Frendeus B, Cragg MS, Roghanian A
Clin Exp Immunol · 2025 Jan · PMID 40089806 · Full text
Fc receptors (FcR) play a key role in coordinating responses from both the innate and adaptive immune system. The inhibitory Fc gamma receptor (FcγRIIB/CD32B; referred to as FcγRII/CD32 in mice) restrains the immune resp...
Fc receptors (FcR) play a key role in coordinating responses from both the innate and adaptive immune system. The inhibitory Fc gamma receptor (FcγRIIB/CD32B; referred to as FcγRII/CD32 in mice) restrains the immune response, specifically through regulating immunoglobulin G (IgG) effector functions. FcγRII-deficient mice demonstrate elevated incidence and severity of autoimmunity and increased responses to immunization and infections. To explore the potential of FcγRIIB as a target for augmenting vaccines, we tested the ability of monoclonal antibodies (mAb) against mouse FcγRII and human FcγRIIB to enhance humoral responses in preclinical models. We used wild-type (WT), FcγR-deficient, and human FcγRIIB transgenic (Tg) mice with either a functional intracellular domain (hFcγRIIB Tg) or lacking immunoreceptor tyrosine-based inhibitory motif (ITIM) signalling capacity (NoTIM). Targeting mouse FcγRII and human FcγRIIB with antibodies significantly augmented humoral immune responses against experimental antigens and enhanced tumour clearance in vivo. Surprisingly, mAbs without a functional Fc (N297Q; referred to as Fc-null) lacked efficacy. Similarly, blocking FcγRII in mice lacking activating FcγRs failed to enhance immune responses. Conversely, blocking both signalling-competent and signalling-defective (NoTIM) FcγRIIB in Tg mice with a WT, but not Fc-null, FcγRIIB mAb equally enhanced immunity. These data indicate the redundancy of inhibitory signalling in potentiating immune responses in vivo. Collectively, our data suggest that mAb-targeting of FcγRIIB stabilizes mAb Fc and enhances immune responses via Fc-mediated crosslinking of activating FcγRs, irrespective of the inhibitory function of FcγRIIB. These findings support a strategy to boost immune responses in immunization protocols.
Intratumoral injection of R848 and poly(I:C) synergistically promoted antitumor immune responses by reprogramming macrophage polarization and activating DCs in lung cancer.
Chen S, Li L, Yuan H … +8 more , Gui H, Wan Q, Wang M, Lv H, Wang C, Zhu L, Nie Y, Zhang X
Clin Exp Immunol · 2025 Jan · PMID 40079116 · Full text
INTRODUCTION: Immunotherapy has rapidly become a primary treatment option for many lung cancer patients because of its success in treating this prevalent and deadly disease. However, the success of immunotherapy relies o...
INTRODUCTION: Immunotherapy has rapidly become a primary treatment option for many lung cancer patients because of its success in treating this prevalent and deadly disease. However, the success of immunotherapy relies on overcoming the immunosuppressive tumor microenvironment, making remodeling this environment a potential strategy for lung cancer therapy. Research suggests that Toll-like receptor (TLR) agonists can impede tumor growth by promoting the conversion of tumor-associated macrophages into an M1-like state or enhancing dendritic cell development. However, there is insufficient research on the combined use of TLR agonists for treating lung cancer. METHODS: In this study, we examined how TLR agonists such as resiquimod (R848) and poly(I:C) impact lung cancer treatment when used alone or in combination. In vitro, the regulatory functions and mechanisms of R848 and poly(I:C) were analyzed in primary macrophages, RAW264.7 cells, and primary dendritic cells (DCs). Tumor treatment efficacy was assessed in vivo with a Lewis lung carcinoma (LLC) mouse model. RESULTS: The combination of R848 + poly(I:C) enhances the transformation of macrophages from the M2 phenotype to the M1 phenotype by increasing inflammatory cytokine levels. The percentage of mature DCs expressing MHC-II+CD11c+ and CD86+ cells was significantly higher in the R848 + poly(I:C) group compared with the other groups. Intratumoral injection of the synergistic combination of R848 + poly(I:C) suppressed tumor growth by increasing the M1:M2 ratio in TAMs, activating DCs, and attracting CD4+ and CD8+ T cells. CONCLUSION: R848 + poly(I:C) synergistically induces M1-like polarization of macrophages, activates DCs, and promotes effective antitumor immunity in mice with subcutaneous LLC tumors.
Unveiling WHIM syndrome: Mavorixafor's emerging role in immune restoration and therapy.
Khan MS, Azeem B, Kanwal A … +11 more , Ahmed IE, Zehra A, Kabir A, Ahmed W, Nasir H, Khan M, Manzoor A, Hasanain M, Moeen W, Khan M, Ahmed G
Clin Exp Immunol · 2025 Jan · PMID 40065526 · Full text
WHIM syndrome is a rare autosomal dominant immunodeficiency disorder and is an abbreviation formed from the initial letters of its main clinical presentations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis....
WHIM syndrome is a rare autosomal dominant immunodeficiency disorder and is an abbreviation formed from the initial letters of its main clinical presentations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It stems mainly from mutations where there is a gain of function in the chemokine receptor CXCR4, which is extensively located on leukocytes and significantly affects the balance of the immune system. Many therapeutic strategies have been widely explored for several years for this immunodeficiency disorder. Mavorixafor, a CXCR4 antagonist, is a recently approved drug by the Food and Drug Administration (FDA) that is being studied for its longer half-life and oral drug route against WHIM syndrome. This review aims to investigate briefly the underlying mechanisms and pathogenesis of WHIM syndrome, and the current effective treatment approaches, for example CXCR4 antagonists or Hematopoietic Stem Cell Transplantation (HSCT), against it. The review also aims to thoroughly assess the efficacy and safety of Mavorixafor in managing WHIM syndrome, exploring its pharmacokinetics, pharmacodynamics, dosing regimens, and safety. Finally, we also investigate important additional therapeutic uses of Mavorixafor.
Dynamic changes of host immune response during Helicobacter pylori-induced gastric cancer development.
Fu W, Han X, Hao X … +6 more , Zhang J, Zhang H, Ma C, Xu M, Zhang J, Ding S
Clin Exp Immunol · 2025 Jan · PMID 40057755 · Full text
INTRODUCTION: Helicobacter pylori infection is the main risk factor for gastric cancer (GC). Chronic inflammation is usually induced by H. pylori infection and is accompanied by inherent immune disorders. However, the dy...
INTRODUCTION: Helicobacter pylori infection is the main risk factor for gastric cancer (GC). Chronic inflammation is usually induced by H. pylori infection and is accompanied by inherent immune disorders. However, the dynamic changes in the host immune response associated with the transition from normal to metaplasia, dysplasia, and GC are largely undefined. METHOD: We established the H. pylori-induced GC mice model. The gastric mucosa of H. pylori-infected mice was subjected to RNA-sequencing analysis at different stages. We analyzed systemic immune disturbances in the spleen and changes in serum inflammatory cytokines during GC development, including gastritis, premalignant lesions (pre-GC), and GC stages. RESULTS: RNA-sequencing analysis of the gastric mucosa of H. pylori-infected mice highlighted the important role of immune-associated pathways (especially inflammatory pathways) during GC development. Immune cell proportion analysis revealed the stage-dependent involvement of key immune cell types, including increased Th17 cells in early gastritis and pre-GC stages and decreased central memory CD4+ and CD8+ T cells during GC transition. Serum inflammatory cytokine analysis showed that IL-6 and IL-10 levels significantly increased, whereas IL-23 levels decreased during the GC stage. CONCLUSION: In summary, we illustrated systemic immune disturbances in the spleen and changes in serum inflammatory cytokines during GC development. Th17 cells were involved in early gastritis and premalignant processes, while central memory T cells participated in GC transition. Our findings provide valuable insights into identifying key inflection points and associated biomarkers for the early detection, diagnosis, and treatment of GC.
Understanding immunological insights of liver transplantation: a practice for attaining operational tolerance.
Dhayanithy G, Radhakrishnan S, Ann Martin C … +5 more , Caroline Martin J, Hakeem AR, Jothimani D, Kalkura SN, Rela M
Clin Exp Immunol · 2025 Jan · PMID 39973343 · Full text
Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronic...
Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.
The small molecule inhibitor 3PO is a modulator of neutrophil metabolism, ROS production, and NET release.
Fresneda Alarcon M, Abdullah GA, Nolan A … +6 more , Linford C, Meschis MM, Cross AL, Sellin A, Phelan MM, Wright HL
Clin Exp Immunol · 2025 Jan · PMID 39969221 · Full text
Neutrophils are key effector leukocytes of the innate immune system and play a pivotal role in defending the host against microbial infections. Recent studies have identified a crucial link between glycolysis and neutrop...
Neutrophils are key effector leukocytes of the innate immune system and play a pivotal role in defending the host against microbial infections. Recent studies have identified a crucial link between glycolysis and neutrophil cellular functions. 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 (PFKFB3), in the regulation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) production. We have identified that PFKFB3 is elevated in rheumatoid arthritis (RA) neutrophils and that the small molecule PFKFB3 inhibitor 3PO is a key regulator of neutrophil ROS and NET production. 3PO blocked the production of ROS and NETs in a dose-dependent manner in both RA and healthy neutrophils (P < 0.01), and RA neutrophils were more sensitive to lower concentrations of 3PO. Bacterial killing was only partially inhibited by 3PO, and the proportion of live neutrophils after 24 h incubation was unchanged. Using NMR metabolomics, we identified that 3PO increases the concentration of lactate, phenylalanine, and L-glutamine in neutrophils, as well as significantly decreasing intracellular glutathione (adj. P-value < 0.05). We also demonstrated that RA neutrophils produce ROS and NETs in culture conditions which mimic the low glucose environments encountered in RA synovial joints. Our results also suggest that 3PO may have molecular targets beyond PFKFB3. By dissecting the intricate interplay between metabolism and neutrophil effector functions, this study advances the understanding of the molecular mechanisms governing pro-inflammatory neutrophil responses and identifies 3PO as a potential therapeutic for conditions characterized by dysregulated neutrophil activation.
Peripheral immune biomarkers associated with response to adoptive cell therapy with tumor infiltrating lymphocytes.
Madsen CO, Velasco Santiago M, Martinenaite E … +4 more , Holz Borch T, Donia M, Svane IM, Hansen M
Clin Exp Immunol · 2025 Jan · PMID 39965099 · Full text
Adoptive cell therapy (ACT) with ex-vivo expanded tumor-infiltrating lymphocytes (TILs, TIL-ACT) has shown clinical efficacy in a significant proportion of patients with metastatic melanoma. To further target TIL-ACT tow...
Adoptive cell therapy (ACT) with ex-vivo expanded tumor-infiltrating lymphocytes (TILs, TIL-ACT) has shown clinical efficacy in a significant proportion of patients with metastatic melanoma. To further target TIL-ACT toward responsive patients, identifying predictive biomarkers and understanding broader immune dynamics remain critical. This study investigated the peripheral blood immune landscape in 47 patients with metastatic melanoma undergoing TIL-ACT, assessing antitumor reactivity and peripheral immune cell profiles before and after treatment. Responders displayed increased frequency of circulating tumor-reactive cells post-treatment, and higher baseline levels of activated CD57-expressing T cells, serving as potential biomarkers of response. In contrast, persistent high serum levels of interleukin (IL)-6 and IL-8, higher frequencies of CD38-expressing T cells, and regulatory T cells (Tregs) post-treatment, correlated with unfavorable outcomes. These findings contribute to understanding the peripheral immune landscape associated with response to TIL-ACT, offering valuable insights into predictive biomarkers and mechanisms to improve patient selection.
Discovery and Phase 1 study of a novel monoclonal antibody against human IL-1β for the treatment of IL-1β-mediated diseases.
Cho M, Tam SH, Shi L … +7 more , Fung I, Tornetta M, Canziani GA, Fung MC, Chiu ML, Han C, Zhang D
Clin Exp Immunol · 2025 Jan · PMID 39964852 · Full text
Interleukin-1β (IL-1β) is a key mediator of innate immunity against pathogen infections. However, dysregulated IL-1β activity is associated with various autoinflammatory, autoimmune, degenerative, atherosclerotic disease...
Interleukin-1β (IL-1β) is a key mediator of innate immunity against pathogen infections. However, dysregulated IL-1β activity is associated with various autoinflammatory, autoimmune, degenerative, atherosclerotic diseases, and cancers. Biologic drugs that neutralize excess IL-1β activity, such as canakinumab, have been effective in treating IL-1β-mediated diseases. This article reports the discovery and development of a novel humanized anti-IL-1β antibody, designated as TAVO103A, which exhibited potent binding affinities to human and monkey IL-1β. TAVO103A demonstrated more potent neutralization of IL-1β activities compared to canakinumab in multiple assays, including tests on the IL-1β-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. Ex vivo studies showed that TAVO103A effectively neutralized IL-1β-mediated release of pro-inflammatory cytokines from peripheral blood mononuclear cells. In addition, TAVO103A exhibited dose-dependent efficacy in a knee joint inflammation mouse model. TAVO103A underwent Fc engineering to reduce binding to Fcγ receptors, increase affinity to FcRn receptors, and enhance its resistance to proteolytic degradation. In a Phase 1 study, TAVO103A was found to be safe, well tolerated, and demonstrated a median half-life of 63 days in healthy subjects. By recognizing a different epitope, TAVO103A provided more potent neutralization of IL-1β activities, a longer circulating half-life, and improved safety profiles compared to canakinumab, positioning it to be a potential best-in-class therapeutic option for various IL-1β-mediated diseases.
Nck1 regulates the in vitro development of human regulatory T cells through AKT pathway.
Nuiyen A, Sanguansermsri D, Sayasathid J … +4 more , Thatsakorn K, Thapmongkol S, Ngoenkam J, Pongcharoen S
Clin Exp Immunol · 2025 Jan · PMID 39963999 · Full text
T cell receptor (TCR) signalling is crucial in determining the fate of thymocyte differentiation in the thymus. The high-avidity interaction between TCR and self-peptide-MHC complexes induces development of regulatory T...
T cell receptor (TCR) signalling is crucial in determining the fate of thymocyte differentiation in the thymus. The high-avidity interaction between TCR and self-peptide-MHC complexes induces development of regulatory T cells (Tregs), lineage commitment for which is controlled by expression of transcription factor Forkhead box P3 (FoxP3). The non-catalytic region of the tyrosine kinase (Nck) comprises two members, Nck1 and Nck2, with Nck1 playing a dominant role in TCR-mediated T cell activation and function. Nck's role, while established in thymocyte development, remains unelucidated in development of Tregs. 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. The number of FoxP3+ Tregs decreased noticeably in Nck1 knockdown thymocytes after co-cultivation with myeloid dendritic cells (mDCs) and thymic epithelial cells for 14 days. Furthermore, decreased phosphorylation of AKT and FoxO1 was observed in Nck1-silenced thymocytes, in association with reduced FoxO1 nuclear localization. Taken together, these findings identify the pivotal role of Nck1 in Treg development.
The role of IgA and IgG in Mycobacterium tuberculosis infection: a cross-sectional study in Ethiopia.
Islam RE, Zewdie M, Mussa D … +5 more , Abebe Y, Ottenhoff THM, Franken KLMC, Wassie L, Abebe F
Clin Exp Immunol · 2026 Jan · PMID 39946288 · Full text
INTRODUCTION: Despite the high global prevalence of Mycobacterium tuberculosis (Mtb) infection in humans, most infected individuals achieve a stable immunological equilibrium, without showing clinical signs and symptoms...
INTRODUCTION: Despite the high global prevalence of Mycobacterium tuberculosis (Mtb) infection in humans, most infected individuals achieve a stable immunological equilibrium, without showing clinical signs and symptoms of tuberculosis (TB). Although the role of antibodies in TB is assumed to be relatively small compared with cell-mediated immunity, their role in TB has been documented in a few recent studies. METHODS: In this cross-sectional study, we quantitated antibody responses to Mtb antigens, lipoarabinomannan (LAM), and heparin-binding hemagglutinin adhesin (HBHA) by determining antigen-specific immunoglobulin A(IgA) and G(IgG) secretion levels using enzyme-linked immunosorbent assay in serum and saliva of pulmonary TB patients (PTB), their household contacts, and community controls (determined by QuantiFERON TB Gold assay QFT-test result). RESULTS: The HBHA-specific IgA levels were significantly higher in both saliva and serum in household contacts groups compared with PTB patients (P = 0.013, P = 0.023). Exposed contacts, who were QFT-negative, had higher serum HBHA-specific IgA responses compared with PTB patients (P = 0.04). QFT-negative household contacts and QFT-positive community controls showed higher HBHA and lipoarabinomannan-specific IgG responses (P = 0.006, P = 0.002, P = 0.0009, P = 0.006, respectively) than PTB patients. Generally, lipoarabinomannan and HBHA-specific IgA levels were significantly higher in saliva compared with serum (P < 0.0001) in all study groups. CONCLUSION: Overall, the observed higher levels of IgA and IgG in controls, and exposed but QFT-negative contacts suggest a correlation with, and perhaps a role for these antibodies in preventing the development of active TB. The findings highlighted the potential involvement of saliva IgA in the immune response to Mtb, underscoring the relevance of mucosal immunity in TB infection.
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