Immunology Letters[JOURNAL]
Sun
200 papers
Rescuing pathogen-specific memory B-cell from PBMC of prior Zika virus-infected individuals.
Silva JM, França RKAO, Barros PH … +4 more , Fontinele HGC, Fonseca SG, Brigido MM, Maranhão AQ
Immunol Lett · 2025 Feb · PMID 39542046 · Publisher ↗
Immunological memory, a fundamental immune system mechanism, is instrumental in long-term protection. Successful vaccines can elicit and sustain immunological memory against pathogens for the long term. Memory B cells (M...
Immunological memory, a fundamental immune system mechanism, is instrumental in long-term protection. Successful vaccines can elicit and sustain immunological memory against pathogens for the long term. Memory B cells (MBC) are key players in secondary responses due to their longevity and rapid differentiation into high-affinity antibody-secreting cells upon second antigen exposure. However, the availability of circulating MBCs is limited. Here we describe a protocol, which presents a straightforward and practical method for activating and expanding Zika virus (ZIKV) specific MBC. PBMCs collected from individuals who had been infected with ZIKV two years prior were cultured by supplementing with IL-2 and R848, a TLR-7/8 agonist, and then pulsed with inactivated virus. After seven days, this stimulation led to a notable rise in virus-specific functional MBC, as evidenced by a significant increase in the production of anti-ZIKV IgG. Importantly, the ZIKV pulse did not induce changes in the PBMC culture of individuals without a history of ZIKV infection. These findings demonstrate that virus-specific MBC can be expanded in vitro, even using PBMC cultures from individuals infected years before. Therefore, our protocol is a practical and effective tool for studies that require a larger number of human MBCs from previously infected individuals that are functional and specific to the pathogen under investigation.
The roles of collectins in renal diseases and transplantation.
Lv F, Zhou W, Li K
Immunol Lett · 2025 Feb · PMID 39542045 · Publisher ↗
The collectins are soluble C-type lectins and a group of proteins characterized with common structural features: a collagen-like domain and a carbohydrate-binding domain. These proteins are essential components of the in...
The collectins are soluble C-type lectins and a group of proteins characterized with common structural features: a collagen-like domain and a carbohydrate-binding domain. These proteins are essential components of the innate immune system, pivotal for recognizing and eliminating pathogens to protect against infections. Over recent decades, research has significantly advanced our understanding of collectins. Beyond their fundamental role in host defense, collectins have been emerged as multifunctional proteins involved in modulating inflammatory and immune responses, facilitating the clearance of cellular debris, and even stimulating cell proliferation. These diverse roles are critical for maintaining physiological balance and hold substantial implications in various disease processes, particularly in renal diseases and transplantation. Here, we review the roles of collectins in renal diseases and transplantation focusing on four prominent members of the collectin family: mannose-binding lectin (MBL), surfactant proteins (SP-A and SP-D), and collectin-11 (CL-11). These proteins have gained considerable attention in current research due to their roles in renal diseases and transplantation, shedding light on their impact beyond traditional immune defense mechanisms. Understanding their involvement in these contexts is crucial for exploring potential therapeutic avenues and interventions aimed at mitigating renal pathology and improving outcomes in transplantation settings.
Human dendritic cell differentiation in hematopoietic stem cell-transplanted NOG hFLT3L Tg/mFlt3 KO humanized mice.
Mu Y, Ohno Y, Mochizuki M … +6 more , Kawai K, Goto M, Ogura T, Takahashi R, Ito M, Ito R
Immunol Lett · 2024 Dec · PMID 39536946 · Publisher ↗
Human immune system-reconstituted humanized mice are useful animal models to study human immunology in vivo. Human hematopoietic stem cell-transferred NOG mice are well recognized as humanized immune system models with r...
Human immune system-reconstituted humanized mice are useful animal models to study human immunology in vivo. Human hematopoietic stem cell-transferred NOG mice are well recognized as humanized immune system models with reconstitution of mature lymphoid lineage cells such as T and B cells. However, human myeloid lineage cells including dendritic cells (DCs) do not fully differentiate in conventional NOG mice. DCs play a crucial role in adaptive immunity through antigen presentation to T cells to acquire antigen specificity. In this study, we established a novel humanized mouse with human DC differentiation. To induce DCs, we generated human Fms-like tyrosine kinase 3 ligand (hFLT3L) transgenic NOG (hFLT3L-Tg) mice and transferred human CD34 hematopoietic stem cells (HSC) into them. Unexpectedly, low frequency of human cell engraftment was observed in the hFLT3L-Tg mice after HPC reconstitution. In the Tg mice, mouse CD11bGr1 myeloid cells were markedly expanded in the bone marrow due to the cross-reaction between hFLT3L and mouse Flt3 receptor, and these myeloid leukemia-like cells interfered with the engraftment of human hematopoietic cells in hFLT3L-Tg mice. To avoid this cross-reaction, we further generated NOG FLT3 receptor KO (mFlt3 KO) mice by CRISPR/Cas9 technique, and the KO mice combined with hFLT3L Tg mice to create hFLT3L Tg/mFlt3 KO (FL Tg/KO) mice. Mouse CD11bGr1 leukemia-like cells did not proliferate in FL Tg/KO mice due to blockade of the FLT3 signals in mouse leukocytes. After human HSC transplantation, human CD45 cells were successfully engrafted in FL Tg/KO mice. Furthermore, major subsets of human DC populations, cDC1, cDC2, and pDC, and skin Langerhans cells were significantly differentiated in FL Tg/KO mice. Therefore, these humanized mouse models are potentially valuable in the investigation of DC-mediated human adaptive immune responses in vivo.
Eosinophils are sparse in homeostatic rectal tissue which impedes studying resident eosinophils.
Pelgrim TC, Jukema BN, Vrisekoop N … +1 more , Koenderman L
Immunol Lett · 2024 Dec · PMID 39510392 · Publisher ↗
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The importance of type I interferon in orchestrating the cytotoxic T-cell response to cancer.
Busselaar J, Sijbranda M, Borst J
Immunol Lett · 2024 Dec · PMID 39490629 · Publisher ↗
Both type I interferon (IFN-I) and CD4 T-cell help are required to generate effective CD8 T-cell responses to cancer. We here outline based on existing literature how IFN-I signaling and CD4 T-cell help are connected. Bo...
Both type I interferon (IFN-I) and CD4 T-cell help are required to generate effective CD8 T-cell responses to cancer. We here outline based on existing literature how IFN-I signaling and CD4 T-cell help are connected. Both impact on the functional state of dendritic cells (DCs), particularly conventional (c)DC1. The cDC1s are critical for crosspresentation of cell-associated antigens and for delivery of CD4 T-cell help for cytotoxic T-lymphocyte (CTL) effector and memory differentiation. In infection, production of IFN-I is prompted by pathogen-associated molecular patterns (PAMPs), while in cancer it relies on danger-associated molecular patterns (DAMPs). IFN-I production by tumor cells and pDCs in the tumor micro-environment (TME) is often limited. IFN-I signals increase the ability of migratory cDC1s and cDC2s to transport tumor antigens to tumor-draining lymph nodes (tdLNs). IFN-I also enables cDC1s to form and sustain the platform for help delivery by stimulating the production of chemokines that attract CD4 and CD8 T cells. IFN-I promotes delivery of help in concert with CD40 signals by additive and synergistic impact on cross-presentation and provision of critical costimulatory and cytokine signals for CTL effector and memory differentiation. The scenario of CD4 T-cell help therefore depends on IFN-I signaling. This scenario can play out in tdLNs as well as in the TME, thereby contributing to the cancer immunity cycle. The collective observations may explain why both IFN-I and CD4 T-cell help signatures in the TME correlate with good prognosis and response to PD-1 targeting immunotherapy in human cancer. They also may explain why a variety of tumor types in which IFN-I signaling is attenuated, remain devoid of functional CTLs.
Could tolerance to DNA be broken in the gut in systemic lupus erythematosus?
Spencer J, Jain S
Immunol Lett · 2024 Dec · PMID 39490628 · Publisher ↗
The bacteria in the human colon outnumber the total number of nucleated cells in the human body by approximately 10:1. The DNA that the bacteria contain is enriched around 20-fold in immune stimulatory CpG motifs compare...
The bacteria in the human colon outnumber the total number of nucleated cells in the human body by approximately 10:1. The DNA that the bacteria contain is enriched around 20-fold in immune stimulatory CpG motifs compared to the DNA of host cells. In addition, this DNA can have alternative more immunogeneic DNA structures and it may be presented to the immune system alongside other proinflammatory bacterial innate ligands such as LPS. To ensure that this immunostimulatory combination is not pathogenic, the luminal boundary of host tissues in the human gastrointestinal tract is protected by cells secreting bactericides together with the secreted enzyme DNASE1L3 that can break down bacterial DNA. Cells with RNA encoding DNASE1L3 are particularly abundant in the gut-associated lymphoid tissue where bacteria are specifically sampled into the body, alongside B cells noted for their T independent function. Importantly, individuals with loss of function mutations in DNASE1L3 develop anti-DNA antibodies and lupus symptoms. In this review, we explore the possibility that a perfect storm might break tolerance to DNA: when bacterial DNA from microbiota that is not digested by DNASE1L3 directly encounters B cells that are not necessarily restricted by T cell dependence.
Long-term monocyte activation after coronary artery bypass grafting: An exploratory prospective observational study.
Broeders W, van Tuijl J, Duindam HB … +7 more , Peters van Ton AM, Noz MP, Pickkers P, Abdo WF, Netea MG, Bekkering S, Riksen NP
Immunol Lett · 2024 Dec · PMID 39489184 · Publisher ↗
Major surgery such as coronary artery bypass grafting (CABG) is associated with an increased post-operative risk of atherosclerotic cardiovascular events. Cells of the innate immune system can adopt a long-lasting pro-in...
Major surgery such as coronary artery bypass grafting (CABG) is associated with an increased post-operative risk of atherosclerotic cardiovascular events. Cells of the innate immune system can adopt a long-lasting pro-inflammatory and atherogenic phenotype after brief exposure to exogenous or endogenous inflammatory stimuli, a process called "trained immunity". We hypothesized that the surgery-induced inflammation leads to sustained alterations in monocyte function, which promote the subsequent occurrence of cardiovascular events. Blood from 13 patients undergoing elective CABG was obtained before, 3-7 days (median 4) after, and 6-8 weeks (median 6) weeks after surgery. At 3-7 days postoperatively, circulating C-reactive protein (CRP) concentration, leukocyte counts and ex vivo Peripheral Blood Mononuclear Cell (PBMC) IL-6, TNFα and IL-1Ra production after stimulation (with various inflammatory stimuli) were significantly increased. Simultaneously, there was a reduction in monocyte HLA-DR expression. 6-8 weeks after CABG there was an ongoing systemic pro-inflammatory state with higher CRP concentrations, increased stimulated ex vivo PBMC IL-6 production, changes in monocytes subsets, and a higher expression of CCR2 on monocytes compared to baseline. In conclusion, CABG induces a persistent systemic inflammatory reaction with a sustained activated monocyte phenotype. This might contribute to the increased atherosclerotic cardiovascular event risk observed in cardiac surgery patients.
T cell landscape in the microenvironment of human solid tumors.
Maggi E, Munari E, Landolina N … +3 more , Mariotti FR, Azzarone B, Moretta L
Immunol Lett · 2024 Dec · PMID 39486594 · Publisher ↗
T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differenti...
T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells. In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.
The effect of abnormal lipid metabolism on immunosenescence of the colonic lamina propria in mice of different ages.
Cong F, Zhang Y, Xu J … +5 more , Fang X, Li X, Xue Q, Wang J, Liu Y
Immunol Lett · 2024 Dec · PMID 39477189 · Publisher ↗
Immunosenescence is an age-associated change in immunological function. The intestinal mucosal immune system is considered the largest immune system in the human body, and its immunosenescence is closely related to the o...
Immunosenescence is an age-associated change in immunological function. The intestinal mucosal immune system is considered the largest immune system in the human body, and its immunosenescence is closely related to the occurrence and development of many diseases. In recent years, studies have identified a crucial correlation between abnormal lipid metabolism induced by high-fat diet (HFD) and immunity, but the effect and mechanism of HFD on colonic mucosal immunosenescence are still unclear. In this study, we established an abnormal lipid metabolism model at different ages by feeding male wild-type mice HFD and compared the immunosenescence of the spleen, which reflects systemic immunity, and the colonic lamina propria (LP), which reflects local immunity. The results showed that HFD could lead to abnormal lipid metabolism at different ages, accelerate systemic and local immunosenescence, and increase the expression of inflammatory factors in colonic tissue. The levels of abnormal biochemical indicators induced by HFD were closely related to the proportions of T cell subsets associated with immunosenescence. Overall, the results showed that HFD had the most significant impact on aged mice. This study provides new ideas for further understanding the relationship between abnormal lipid metabolism and intestinal mucosal immunosenescence.
Study of the mechanism of fibroblast-like synoviocytes-derived exosomes inducing macrophages M1 polarization and CD8T cells immune regulation ferroptosis and autophagy in rheumatoid arthritis.
Fang F, Hua M, Yu G
Immunol Lett · 2024 Dec · PMID 39447763 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints. The pathogenesis of RA is complex, involving membrane lipid antioxidant systems, oxidative stress, and lipid peroxidation. In this study,...
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints. The pathogenesis of RA is complex, involving membrane lipid antioxidant systems, oxidative stress, and lipid peroxidation. In this study, it was found that cysteine dioxygenase 1 (CDO1) is significantly upregulated in RA fibroblast-like synoviocytes (RA-FLS) and that exosomes derived from these RA-FLS deliver CDO1 to promote M1 polarization of macrophages, thus facilitating RA progression. In the immune microenvironment, CD8T cells play a role in immune regulation by producing cytokines such as interferon gamma (IFNγ) in various diseases. The results of this study suggested that in RA-FLS, CD8T cells deliver IFNγ, which not only inhibits the viability of RA-FLS but also affects glutathione (GSH) through CDO1, regulating the GPX4 antioxidant signaling pathway to promote ferroptosis and autophagy in cells. It was also discovered that IFNγ enhances the expression of TRI69, ubiquitinates and degrades FSP1, thereby forming a cooperative regulation process of GPX4 and FSP1 in ferroptosis. These findings provide a new direction for the treatment of RA.
Fingolimod, an antagonist of sphingosine 1-phosphate, ameliorates Sjögren's syndrome by reducing the number of STAT3-induced germinal center B cells and increasing the number of Breg cells.
Lee YS, Jhun J, Choi JW … +6 more , Hwang SH, Woo JS, Lee KH, Yang SC, Lee AR, Cho ML
Immunol Lett · 2024 Dec · PMID 39396770 · Publisher ↗
BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease caused by infiltrating lymphocytes. FTY720 affects the S1P signaling pathway, which plays a role in T and B cell migration from secondary lymphoid tissues to t...
BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease caused by infiltrating lymphocytes. FTY720 affects the S1P signaling pathway, which plays a role in T and B cell migration from secondary lymphoid tissues to target organs. In this study, we investigate the regulatory mechanism of FTY720 in the context of SS. METHOD: FTY720 was given orally every day to NOD mice. The salivary flow rate (SFR) and blood glucose level were assayed every 3 weeks. Histopathological features were investigated at the end of the study. In vitro, FTY720 was added to mouse splenocytes, and changes in the lymphocyte subsets were assessed. RESULTS: In vivo, FTY720 increased the SFR and reduced the blood glucose level. The salivary gland histological score and infiltration of the salivary glands by B and T cells were dramatically decreased. Furthermore, STAT expression in the salivary gland was decreased. In vitro, FTY720 inhibited Th17 cells, while increasing regulatory T (Treg) cells, respectively. Also, FTY720 decreased and increased the numbers of germinal center (GC) B cells and regulatory B cells (Breg cells), respectively. FTY720 decreased the IgG level in culture supernatants. Also, STAT3 activation was decreased by FTY720. CONCLUSION: Our results show the therapeutic potential of FTY720 in the context of SS; FTY720 prevents lymphocyte migration from secondary lymphoid organs to target organs.
Ursolic acid attenuates pseudo-allergic reactions via reducing MRGPRX2-mediated mast cell degranulation.
Yan PP, Huang TT, Liu SY … +5 more , Attiogbe MKI, Liu YN, Shen FQ, Mi YN, Cao YX
Immunol Lett · 2024 Dec · PMID 39395727 · Publisher ↗
Mas-related G protein-coupled receptor X2 (MRGPRX2) is a newly identified receptor on mast cells that contribute to IgE-independent pseudo-allergy. Ursolic acid (UA), a pentacyclic triterpenoid, has been reported for its...
Mas-related G protein-coupled receptor X2 (MRGPRX2) is a newly identified receptor on mast cells that contribute to IgE-independent pseudo-allergy. Ursolic acid (UA), a pentacyclic triterpenoid, has been reported for its anti-allergy effects. However, the protective mechanism against pseudo-allergic reactions remains unclear. This study aims to investigate the effects of UA on pseudo-allergic reactions both in vivo and in vitro, focusing on the therapeutical mechanism underlying its effect on mast cells. In present study, UA reduced degranulation and chemokines production induced by MRGPRX2 agonists, including compound 48/80 (C48/80) and substance P (SP), in LAD2 cells in vitro. UA also alleviated C48/80 and SP-induced systemic anaphylaxis and passive cutaneous anaphylaxis (PCA) in vivo. Furthermore, UA demonstrated strong binding affinity to the MRGPRX2 protein, leading to a decrease in calcium influx in both LAD2 cells and MRGPRX2-HEK293 cells stimulated with C48/80 and SP. Moreover, UA effectively suppressed phosphorylation levels within phospholipase C-γ (PLCγ) pathway and nuclear factor kappa-B (NF-κB) pathway of MRGPRX2 downstream proteins. Our findings indicated that UA exerts an attenuating effect in pseudo-allergic reactions by suppressing MRGPRX2-mediated mast cell activation, targeting PLCγ pathway and NF-κB pathway. These results suggest that UA may serve as a promising therapeutic agent for MRGPRX2-dependent pseudo-allergic reactions.
The role of neutrophils in ANCA-associated vasculitis.
Prendecki M, Gurung A, Pisacano N … +1 more , Pusey CD
Immunol Lett · 2024 Dec · PMID 39362307 · Publisher ↗
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare systemic autoimmune diseases characterised by necrotising inflammation of small blood vessels and usually associated with circulati...
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare systemic autoimmune diseases characterised by necrotising inflammation of small blood vessels and usually associated with circulating ANCA. The pathophysiology of AAV is complex, involving many aspects of the innate and adaptive immune system. Neutrophils are central to the pathogenesis of AAV as they are both the target of the autoantibody and effector cells mediating vascular injury. We describe mechanisms for ANCA induced activation of neutrophils, the pathogenic mechanisms by which this leads to endothelial cell injury, and how neutrophil crosstalk modulates other aspects of the immune system in AAV.
Fighting the enemy within: Systemic immune defense against mucosal Salmonella infection.
Nguyen AT, McSorley SJ
Immunol Lett · 2024 Dec · PMID 39343314 · Full text
Salmonella infection remains a persistent global health threat, as different serovars induce a range of clinical disease, depending upon bacterial virulence and host susceptibility. While some Salmonella serovars induce...
Salmonella infection remains a persistent global health threat, as different serovars induce a range of clinical disease, depending upon bacterial virulence and host susceptibility. While some Salmonella serovars induce gastroenteritis in healthy individuals, others can cause more serious systemic enteric fever or invasive nontyphoidal Salmonellosis. The rise of antibiotic resistance, coupled with the absence of effective vaccines for most serovars, perpetuates the spread of Salmonella in endemic regions. A detailed mechanistic understanding of immunity to Salmonella infections has been aided by the availability of mouse models that have served as a valuable tool for understanding host-pathogen interactions under controlled laboratory conditions. These mouse studies have delineated the processes by which early inflammation is triggered after infection, how adaptive immunity is initiated in lymphoid tissues, and the contribution of lymphocyte memory responses to resistance. While recent progress has been made in vaccine development for some causes of enteric fever, deeper understanding of Salmonella-specific immune memory might allow the formation of new vaccines for all serovars. This review will provide a summary of our understanding of vaccination and protective immunity to Salmonella with a focus on recent developments in T cell memory formation.
Reassuring humoral and cellular immune responses to SARS-CoV-2 vaccination in participants with systemic sclerosis.
Benoit JM, Breznik JA, Huynh A … +11 more , Cowbrough B, Baker B, Heessels L, Lodhi S, Yan E, Bhakta H, Clare R, Nazy I, Bramson JL, Larché MJ, Bowdish DM
Immunol Lett · 2024 Dec · PMID 39305938 · Publisher ↗
Individuals with systemic sclerosis (SSc) are particularly susceptible to SARS-CoV-2 infections, yet it remains to be determined if they generate humoral and cellular responses comparable to controls following SARS-CoV-2...
Individuals with systemic sclerosis (SSc) are particularly susceptible to SARS-CoV-2 infections, yet it remains to be determined if they generate humoral and cellular responses comparable to controls following SARS-CoV-2 vaccinations. Herein, we collected blood and serum after second, third, and fourth SARS-CoV-2 vaccinations in patients with SSc and controls. Following each dose, participants with SSc mounted comparable serum anti-RBD IgG, anti-RBD IgA, and spike-specific CD4 and CD8T cell responses to those found in controls. At 3 months post dose 2, the frequencies of Th1, Th2, Th17, and Treg spike-specific CD4T cells in participants with SSc did not differ from controls. At 2-6 weeks post dose 3, participants with SSc displayed reduced frequencies, but not numbers, of Th17-polarized spike-specific CD4T cells. Thus, participants with SSc did not display significantly weaker humoral or cellular responses to SARS-CoV-2 vaccination than controls, enabling reassurance of vaccine immunogenicity in participants with SSc.
Gene therapy strategies for RAG1 deficiency: Challenges and breakthroughs.
Gilioli G, Lankester AC, de Kivit S … +2 more , Staal FJT, Ott de Bruin LM
Immunol Lett · 2024 Dec · PMID 39303994 · Publisher ↗
Mutations in the recombination activating genes (RAG) cause various forms of immune deficiency. Hematopoietic stem cell transplantation (HSCT) is the only cure for patients with severe manifestations of RAG deficiency; h...
Mutations in the recombination activating genes (RAG) cause various forms of immune deficiency. Hematopoietic stem cell transplantation (HSCT) is the only cure for patients with severe manifestations of RAG deficiency; however, outcomes are suboptimal with mismatched donors. Gene therapy aims to correct autologous hematopoietic stem and progenitor cells (HSPC) and is emerging as an alternative to allogeneic HSCT. Gene therapy based on viral gene addition exploits viral vectors to add a correct copy of a mutated gene into the genome of HSPCs. Only recently, after a prolonged phase of development, viral gene addition has been approved for clinical testing in RAG1-SCID patients. In the meantime, a new technology, CRISPR/Cas9, has made its debut to compete with viral gene addition. Gene editing based on CRISPR/Cas9 allows to perform targeted genomic integrations of a correct copy of a mutated gene, circumventing the risk of virus-mediated insertional mutagenesis. In this review, we present the biology of the RAG genes, the challenges faced during the development of viral gene addition for RAG1-SCID, and the current status of gene therapy for RAG1 deficiency. In particular, we highlight the latest advances and challenges in CRISPR/Cas9 gene editing and their potential for the future of gene therapy.
NK cell receptors in anti-tumor and healthy tissue protection: Mechanisms and therapeutic advances.
Greppi M, De Franco F, Obino V … +12 more , Rebaudi F, Goda R, Frumento D, Vita G, Baronti C, Melaiu O, Bozzo M, Candiani S, Vellone VG, Papaccio F, Pesce S, Marcenaro E
Immunol Lett · 2024 Dec · PMID 39303993 · Publisher ↗
Natural Killer (NK) cells are integral to the innate immune system, renowned for their ability to target and eliminate cancer cells without the need for antigen presentation, sparing normal tissues. These cells are cruci...
Natural Killer (NK) cells are integral to the innate immune system, renowned for their ability to target and eliminate cancer cells without the need for antigen presentation, sparing normal tissues. These cells are crucial in cancer immunosurveillance due to their diverse array of activating and inhibitory receptors that modulate their cytotoxic activity. However, the tumor microenvironment can suppress NK cell function through various mechanisms. Over recent decades, research has focused on overcoming these tumor escape mechanisms. Initially, efforts concentrated on enhancing T cell activity, leading to impressive results with immunotherapeutic approaches aimed at boosting T cell responses. Nevertheless, a substantial number of patients do not benefit from these treatments and continue to seek effective alternatives. In this context, NK cells present a promising avenue for developing new treatments, given their potent cytotoxic capabilities, safety profile, and activity against T cell-resistant tumors, such as those lacking HLA-I expression. Recent advancements in immunotherapy include strategies to restore and amplify NK cell activity through immune checkpoint inhibitors, cytokines, adoptive NK cell therapy, and CAR-NK cell technology. This review provides a comprehensive overview of NK cell receptors, the tumor escape mechanisms that hinder NK cell function, and the evolving field of NK cell-based cancer immunotherapy, highlighting ongoing efforts to develop more effective and targeted cancer treatment strategies.
The alpha2-adrenoceptor agonist clonidine protects against hypoxic-ischemic brain damage in neonatal mice through the Nrf2/NF-κB signaling pathway.
Su D, Gao H, He M … +3 more , Hao H, Liao H, Zheng S
Immunol Lett · 2024 Dec · PMID 39299652 · Publisher ↗
Neonatal hypoxic-ischemic brain damage (HIBD) is a severe condition closely associated with neuroinflammation and oxidative stress. Clonidine, a selective α2-adrenergic receptor agonist, is known for its anti-inflammator...
Neonatal hypoxic-ischemic brain damage (HIBD) is a severe condition closely associated with neuroinflammation and oxidative stress. Clonidine, a selective α2-adrenergic receptor agonist, is known for its anti-inflammatory and antioxidant properties. Despite these recognized therapeutic benefits, the exact mechanisms by which clonidine exerts its effects in the context of HIBD are not fully understood. This study was designed to thoroughly investigate the impact of clonidine on HIBD-induced neuronal injury and to clarify its underlying mechanism of action. We employed a neonatal mouse model of HIBD to meticulously assess the effects of clonidine on neuronal injury, apoptosis, inflammation, and oxidative stress markers. In addition, we conducted extensive in vitro studies to evaluate the neuroprotective effects of clonidine on primary hippocampal neuronal cells, utilizing advanced techniques such as the Cell Counting Kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay, and western blotting. Furthermore, we explored the regulatory effects of clonidine on the nuclear factor erythroid 2-related factor (Nrf2)/nuclear factor-κB (NF-κB) signaling pathway through a combination of in vivo and in vitro experiments. The results showed that clonidine significantly reduced cerebral infarction, neuronal damage, and apoptosis in HIBD mice. It also alleviated neuroinflammation and oxidative stress, improved cell viability, and reduced neuronal injury following oxygen-glucose deprivation/reoxygenation (OGD/R). The neuroprotective effects of clonidine were linked to the activation of the Nrf2/heme oxygenase-1 (HO-1) pathway and the inhibition of the NF-κB pathway. Overall, clonidine exhibited neuroprotective properties in HIBD by reducing neuroinflammation and oxidative stress, likely through the modulation of the Nrf2/NF-κB signaling pathway.
Autoantibody mediated deficiency of IL-36-receptor antagonist in a subset of patients with psoriasis and psoriatic arthritis.
Hoffmann MC, Fadle N, Regitz E … +17 more , Kos IA, Cetin O, Lesan V, Preuss KD, Zaks M, Stöger E, Zimmer V, Klemm P, Assmann G, Pfeifer J, Bittenbring JT, Bewarder M, Vogt T, Pföhler C, Thurner B, Kessel C, Thurner L
Immunol Lett · 2024 Dec · PMID 39265919 · Publisher ↗
OBJECTIVE: Psoriatic arthritis (PsA) is known as a seronegative form of spondylarthropathy. The interleukin-36 cytokine family may have a major role in disease pathogenesis and particularly the related cutaneous manifest...
OBJECTIVE: Psoriatic arthritis (PsA) is known as a seronegative form of spondylarthropathy. The interleukin-36 cytokine family may have a major role in disease pathogenesis and particularly the related cutaneous manifestations. In light of our recent observations on (transient) autoantibody phenotypes neutralizing endogenous anti-inflammatory receptor antagonists (progranulin, IL-1Ra) in different inflammatory conditions, we set out to investigate the potential role of such antibodies targeting IL-36 cytokine family members in PsA and psoriasis without arthritic manifestations (Pso). METHODS: In the present study we screened for hypothetic autoantibodies against the anti-inflammatory mediators IL-36 receptor antagonist (IL-36Ra) and anti-inflammatory IL-38 in PsA, Pso and inflammatory and healthy controls. Serum samples of patients with PsA (n = 254), Pso (n = 100), systemic lupus erythematosus (SLE, n = 50), rheumatoid arthritis (RA, n = 100), ulcerative colitis (UC, n = 50), Crohn´s disease (CD, n = 50), and healthy controls (n = 237) were screened for autoantibodies against IL-36Ra and IL-38 as well as IL-36Ra levels by ELISA. Biochemical analysis for immune complexes and atypic protein isoforms as well as IL-36 signaling reporter assays were performed. RESULTS: Anti-IL-36Ra antibodies were detected in five out of 100 (5.0 %) patients with Pso, in 12 of 254 (4.72 %) patients with PsA and in one of 50 (2 %) patients with CD, but in none of the other investigated inflammatory or healthy controls. The IL-36Ra autoantibodies belonged to the IgG1 subclass and their titers ranged between 1:200 to 1:1600. They resulted in immune-complex formation, depletion of serum IL-36Ra levels and were functional in terms of facilitating unrestricted IL-36 signaling. CONCLUSION: IL-36Ra autoantibodies were found in subgroups of patients with Pso and PsA and may drive respective pathology.
Acute effects of TLR3 agonist Poly(I:C) on bone marrow hematopoietic progenitor cells in mice.
Shu X, Xie Y, Shu M … +7 more , Ou X, Yang J, Wu Z, Zhang X, Zhang J, Zeng H, Shao L
Immunol Lett · 2024 Dec · PMID 39265918 · Publisher ↗
Hematopoietic progenitor cells (HPCs) in bone marrow with limited abilities for self-renewal and differentiation continuously supply hematopoietic cells through life. When suffering infection or inflammation, HPCs will a...
Hematopoietic progenitor cells (HPCs) in bone marrow with limited abilities for self-renewal and differentiation continuously supply hematopoietic cells through life. When suffering infection or inflammation, HPCs will actively proliferate to provide differentiated hematopoietic cells to maintain hematopoietic homeostasis. Poly(I:C), an agonist of TLR3, can specifically activate Type I interferon (IFN-I) signaling which exerts anti-inflammatory effects and influence hematopoiesis after infection. However, the effects of Poly(I:C)-induced IFN-I on the bone marrow hematopoietic system still deserve attention. In this study, our results revealed the efficacy of the IFN-I model, with a remarkably decrease in HPCs and a sharp elevation in LSKs numbers after single dose of Poly(I:C) injection. Apoptotic ratios of HPCs and LSKs significantly increased 48 h after Poly(I:C) treatment. Application of Poly(I:C) prompted the transition of HPCs and LSKs from G0 to G1 phases, potentially leading to the accelerated exhaustion of HPCs. From the cobblestone area-forming cell (CAFC) assay, we speculate that Poly(I:C) impairs the differentiation capacity of HPCs as well as their colony-forming ability. RT-qPCR and immunohistochemistry revealed significant upregulation of IFN-I associated genes and proteins following Poly(I:C) treatment. In conclusion, a single dose of Poly(I:C) induced an acute detrimental effect on HPCs within 48 h potentially due to TLR3 engagement. This activation cascaded into a robust IFN-I response emanating from the bone marrow, underscoring the intricate immunological dynamics at play following Poly(I:C) intervention.
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