Veronika Krmeská, Lei Shen, Susanne Nylén, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs
In contrast to delayed-type hypersensitivity (DTH) and other hallmark reactions of cell-mediated immunity that correlate with vaccine-mediated protection against Mycobacterium tuberculosis, the contribution of vaccine dose on responses that emerge early after infection in the skin with Bacille Calmette–Guérin (BCG) is not well understood. We used a mouse model of BCG skin infection to study the effect of BCG dose on the relocation of skin Dendritic cells (DCs) to draining lymph node (DLN). Mycobacterium antigen 85B-specific CD4+ P25 T cell-receptor transgenic (P25 TCRTg) cells were used to probe priming to BCG in DLN. DC migration and T cell priming were studied across BCG inocula that varied up to 100-fold (104 to 106 Colony-forming units—CFUs). In line with earlier results in guinea pigs, DTH reaction in our model correlated with BCG dose. Importantly, priming of P25 TCRTg cells in DLN also escalated in a dose-dependent manner, peaking at day 6 after infection. Similar dose-escalation effects were seen for DC migration from infected skin and the accompanying transport of BCG to the DLN. BCG-triggered upregulation of co-stimulatory molecules on migratory DCs was restricted to the first 24 hour after infection and was independent of BCG dose over a 10-fold range (105 to 106 CFUs). The dose seemed to be a determinant of the number of total skin DCs that move to the DLN. In summary, our results support the use of higher BCG doses to detect robust DC migration and T cell priming.
{"title":"BCG infection dose guides dendritic cell migration and T cell priming in the draining lymph node","authors":"Veronika Krmeská, Lei Shen, Susanne Nylén, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs","doi":"10.1111/sji.13342","DOIUrl":"https://doi.org/10.1111/sji.13342","url":null,"abstract":"In contrast to delayed-type hypersensitivity (DTH) and other hallmark reactions of cell-mediated immunity that correlate with vaccine-mediated protection against <i>Mycobacterium tuberculosis</i>, the contribution of vaccine dose on responses that emerge early after infection in the skin with Bacille Calmette–Guérin (BCG) is not well understood. We used a mouse model of BCG skin infection to study the effect of BCG dose on the relocation of skin Dendritic cells (DCs) to draining lymph node (DLN). <i>Mycobacterium</i> antigen 85B-specific CD4<sup>+</sup> P25 T cell-receptor transgenic (P25 TCRTg) cells were used to probe priming to BCG in DLN. DC migration and T cell priming were studied across BCG inocula that varied up to 100-fold (10<sup>4</sup> to 10<sup>6</sup> Colony-forming units—CFUs). In line with earlier results in guinea pigs, DTH reaction in our model correlated with BCG dose. Importantly, priming of P25 TCRTg cells in DLN also escalated in a dose-dependent manner, peaking at day 6 after infection. Similar dose-escalation effects were seen for DC migration from infected skin and the accompanying transport of BCG to the DLN. BCG-triggered upregulation of co-stimulatory molecules on migratory DCs was restricted to the first 24 hour after infection and was independent of BCG dose over a 10-fold range (10<sup>5</sup> to 10<sup>6</sup> CFUs). The dose seemed to be a determinant of the number of total skin DCs that move to the DLN. In summary, our results support the use of higher BCG doses to detect robust DC migration and T cell priming.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"45 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138509060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dina Leth Møller, Søren Schwartz Sørensen, Michael Perch, Finn Gustafsson, Annemette Hald, Andreas Delhbæk Knudsen, Ranya Abdulovski, Nicoline Stender Arentoft, Jens Lundgren, Allan Rasmussen, Sisse Rye Ostrowski, Susanne Dam Nielsen
Abstract Microglial cells are indispensable for the normal development and functioning of neurons in the central nervous system, where they play a crucial role in maintaining brain homeostasis by surveilling the microenvironment for signs of injury or stress and responding accordingly. However, in neurodegenerative diseases, the density and phenotypes of microglial cells undergo changes, leading to chronic activation and inflammation. Shifting the focus from neurons to microglia in drug discovery for neurodegenerative diseases has become an important therapeutic target. This study was aimed to investigate the potential of Tacrolimus (FK506) an FDA‐approved calcineurin inhibitor, to modulate the pathology of neurodegenerative diseases through anti‐inflammatory and antioxidative effects on microglial activation. The human microglia clone 3 (HMC3) cells were exposed to 1 μg/mL LPS in the presence and absence of doses of FK506. Survival rates of cells were determined using the 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐Diphenyltetrazolium Bromide (MTT) method. Morphological evaluation of cells showed that FK506 restored the normal morphology of activated microglia. Furthermore, FK506 treatment increases the total antioxidant capacity and reduces the total oxidative capacity, indicating its potential antioxidant effects. Data from ELISA and RT‐PCR analyses showed that LPS abolished its promoting effects on the release of proinflammatory IL‐1β and IL‐6 cytokines in HMC3 cells, reflecting the anti‐inflammatory effect of FK506. These findings support the idea that FK506 could be a promising therapeutic agent for neurodegenerative diseases by modulating microglial activation and reducing inflammation and oxidative stress.
{"title":"<scp>Anti‐inflammatory</scp> and <scp>antioxidative</scp> actions of tacrolimus (<scp>FK506</scp>) on human microglial <scp>HMC3</scp> cell line","authors":"Fatma Gonca Kocanci, Azize Yasemin Goksu","doi":"10.1111/sji.13339","DOIUrl":"https://doi.org/10.1111/sji.13339","url":null,"abstract":"Abstract Microglial cells are indispensable for the normal development and functioning of neurons in the central nervous system, where they play a crucial role in maintaining brain homeostasis by surveilling the microenvironment for signs of injury or stress and responding accordingly. However, in neurodegenerative diseases, the density and phenotypes of microglial cells undergo changes, leading to chronic activation and inflammation. Shifting the focus from neurons to microglia in drug discovery for neurodegenerative diseases has become an important therapeutic target. This study was aimed to investigate the potential of Tacrolimus (FK506) an FDA‐approved calcineurin inhibitor, to modulate the pathology of neurodegenerative diseases through anti‐inflammatory and antioxidative effects on microglial activation. The human microglia clone 3 (HMC3) cells were exposed to 1 μg/mL LPS in the presence and absence of doses of FK506. Survival rates of cells were determined using the 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐Diphenyltetrazolium Bromide (MTT) method. Morphological evaluation of cells showed that FK506 restored the normal morphology of activated microglia. Furthermore, FK506 treatment increases the total antioxidant capacity and reduces the total oxidative capacity, indicating its potential antioxidant effects. Data from ELISA and RT‐PCR analyses showed that LPS abolished its promoting effects on the release of proinflammatory IL‐1β and IL‐6 cytokines in HMC3 cells, reflecting the anti‐inflammatory effect of FK506. These findings support the idea that FK506 could be a promising therapeutic agent for neurodegenerative diseases by modulating microglial activation and reducing inflammation and oxidative stress.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"126 49","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136352249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Due to the high rate of post‐operative sepsis and other infectious complications, a routine immunological screening protocol has been initiated since 2015 in our paediatric surgery clinic for all patients admitted with oesophageal atresia (EA) and warrant a delayed definitive treatment. In our study, we aimed to evaluate the immunodeficiencies in EA patients, by comparing them to healthy age‐matched controls. As a prospective cohort study, EA patients admitted between 2015 and 2022, who had their definitive operation after the newborn period (>28 days of age) were included. On admission, serum concentrations of IgG, IgA, IgM, lymphocyte subset levels, C3 and C4 levels, specific IgG antibody responses against hepatitis B, hepatitis A, measles, varicella zoster were evaluated. The patients were age‐matched with healthy controls to compare the results and followed up until three years of age. If a humoral immunodeficiency was detected, intravenous immunoglobulin treatment was administered before major oesophageal surgery and during follow‐up. 31 EA patients (18 M/13F) with a mean age of 13.3 ± 9.0 months were compared with 40 age‐matched healthy controls. Mean serum IgG levels were found to be statistically lower than controls in all age groups ( P < .05). Transient hypogammaglobulinemia of infancy (THI) and unclassified syndromic immunodeficiencies (USI) were found to be strikingly high, accounting for 29.0% and 22.5%, respectively, adding up to 51.5% of EA patients. This is the first study evaluating immunodeficiencies in EA patients found in the reviewed literature. More than half of EA patients that required delayed surgery had humoral immunodeficiency, so preoperative screening and immunology referral may improve patient outcomes.
{"title":"Transient hypogammaglobulinemia of infancy and unclassified syndromic immunodeficiencies are highly common in oesophageal atresia patients","authors":"Hilmican Ulman, Ayşe Aygün, Deniz Çağlar, Zafer Dökümcü, Ezgi Topyıldız, Ata Erdener, Güzide Aksu, Neslihan Edeer Karaca, Coşkun Özcan, Necil Kütükçüler","doi":"10.1111/sji.13338","DOIUrl":"https://doi.org/10.1111/sji.13338","url":null,"abstract":"Abstract Due to the high rate of post‐operative sepsis and other infectious complications, a routine immunological screening protocol has been initiated since 2015 in our paediatric surgery clinic for all patients admitted with oesophageal atresia (EA) and warrant a delayed definitive treatment. In our study, we aimed to evaluate the immunodeficiencies in EA patients, by comparing them to healthy age‐matched controls. As a prospective cohort study, EA patients admitted between 2015 and 2022, who had their definitive operation after the newborn period (>28 days of age) were included. On admission, serum concentrations of IgG, IgA, IgM, lymphocyte subset levels, C3 and C4 levels, specific IgG antibody responses against hepatitis B, hepatitis A, measles, varicella zoster were evaluated. The patients were age‐matched with healthy controls to compare the results and followed up until three years of age. If a humoral immunodeficiency was detected, intravenous immunoglobulin treatment was administered before major oesophageal surgery and during follow‐up. 31 EA patients (18 M/13F) with a mean age of 13.3 ± 9.0 months were compared with 40 age‐matched healthy controls. Mean serum IgG levels were found to be statistically lower than controls in all age groups ( P < .05). Transient hypogammaglobulinemia of infancy (THI) and unclassified syndromic immunodeficiencies (USI) were found to be strikingly high, accounting for 29.0% and 22.5%, respectively, adding up to 51.5% of EA patients. This is the first study evaluating immunodeficiencies in EA patients found in the reviewed literature. More than half of EA patients that required delayed surgery had humoral immunodeficiency, so preoperative screening and immunology referral may improve patient outcomes.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"9 11","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135038172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ke Chen, Xin Gu, Shufan Yang, Rui Tao, Menglei Fan, Wenyang Bao, Xiaoyun Wang
Abstract Tissue‐resident memory T (T RM ) cells are a recently discovered subpopulation of memory T cells that reside in non‐lymphoid tissues such as the intestine and skin and do not enter the bloodstream. The intestine encounters numerous pathogens daily. Intestinal mucosal immunity requires a balance between immune responses to pathogens and tolerance to food antigens and symbiotic microbiota. Therefore, intestinal T RM cells exhibit unique characteristics. In healthy intestines, T RM cells induce necessary inflammation to strengthen the intestinal barrier and inhibit bacterial translocation. During intestinal infections, T RM cells rapidly eliminate pathogens by proliferating, releasing cytokines, and recruiting other immune cells. Moreover, certain T RM cell subsets may have regulatory functions. The involvement of T RM cells in inflammatory bowel disease (IBD) is increasingly recognized as a critical factor. In IBD, the number of pro‐inflammatory T RM cells increases, whereas the number of regulatory subgroups decreases. Additionally, the classic markers, CD69 and CD103, are not ideal for intestinal T RM cells. Here, we review the phenotype, development, maintenance, and function of intestinal T RM cells, as well as the latest findings in the context of IBD. Further understanding of the function of intestinal T RM cells and distinguishing their subgroups is crucial for developing therapeutic strategies to target these cells.
{"title":"Research progress on intestinal tissue‐resident memory T cells in inflammatory bowel disease","authors":"Ke Chen, Xin Gu, Shufan Yang, Rui Tao, Menglei Fan, Wenyang Bao, Xiaoyun Wang","doi":"10.1111/sji.13332","DOIUrl":"https://doi.org/10.1111/sji.13332","url":null,"abstract":"Abstract Tissue‐resident memory T (T RM ) cells are a recently discovered subpopulation of memory T cells that reside in non‐lymphoid tissues such as the intestine and skin and do not enter the bloodstream. The intestine encounters numerous pathogens daily. Intestinal mucosal immunity requires a balance between immune responses to pathogens and tolerance to food antigens and symbiotic microbiota. Therefore, intestinal T RM cells exhibit unique characteristics. In healthy intestines, T RM cells induce necessary inflammation to strengthen the intestinal barrier and inhibit bacterial translocation. During intestinal infections, T RM cells rapidly eliminate pathogens by proliferating, releasing cytokines, and recruiting other immune cells. Moreover, certain T RM cell subsets may have regulatory functions. The involvement of T RM cells in inflammatory bowel disease (IBD) is increasingly recognized as a critical factor. In IBD, the number of pro‐inflammatory T RM cells increases, whereas the number of regulatory subgroups decreases. Additionally, the classic markers, CD69 and CD103, are not ideal for intestinal T RM cells. Here, we review the phenotype, development, maintenance, and function of intestinal T RM cells, as well as the latest findings in the context of IBD. Further understanding of the function of intestinal T RM cells and distinguishing their subgroups is crucial for developing therapeutic strategies to target these cells.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135992739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tine Simensen Oldereid, Xiaojun Jiang, Kathrine Sivertsen Nordhus, Andrea Ponzetta, Jørgen Vildershøj Bjørnholt, Niklas K. Björkström, Espen Melum, Henrik Rasmussen
Abstract Host–microbiome interplay from birth is essential for immune imprinting and tuning. Live gut microbes and microbial‐derived metabolites regulate the development and modulation of the immune system, but whether microbial metabolites solely are sufficient to induce immune maturation remains unclear. Sterile faecal filtrates (FFT) were generated from murine gut contents. Newborn germ‐free (GF) mice were treated twice daily with FFT (GF‐FFT) or saline (GF‐NaCl) from post‐natal day 5 until 4 weeks of age. A third group of GF neonates were conventionalized by the transfer of caecal microbiota with live gut microbes. Host immune compartments were comprehensively immunophenotyped and systemically analysed in all available immune‐related organs using flow cytometry. Oral FFT was associated with reduced survival among neonates (n = 7/19; 36.8% mortality), while saline treatment was well tolerated (n = 1/17, 5.9% mortality). Four‐week‐old FFT‐treated pups were comparable in body weight to GF‐NaCl, and the major B‐cell, conventional T‐cell and unconventional T‐cell subsets were unchanged from saline‐treated mice. Live bacteria administered during early life induced clear changes in proportions of B cells, T cells and T‐cell subsets in all mucosal tissues and secondary lymphoid organs compared to GF‐FFT, including restoration of intestinal natural killer T (NKT) cells with characteristics similar to conventional pups. Our findings show that oral administration of a FFT made of microbial metabolites, antigens and bacteriophages alone is insufficient to induce normal immune development elicited by the presence of live bacteria. Reduced survival during neonatal FFT treatment suggests a potential bioactive attribute of sterile faecal filtrates.
{"title":"Role of bacteria and microbial metabolites in immune modulation during early life","authors":"Tine Simensen Oldereid, Xiaojun Jiang, Kathrine Sivertsen Nordhus, Andrea Ponzetta, Jørgen Vildershøj Bjørnholt, Niklas K. Björkström, Espen Melum, Henrik Rasmussen","doi":"10.1111/sji.13336","DOIUrl":"https://doi.org/10.1111/sji.13336","url":null,"abstract":"Abstract Host–microbiome interplay from birth is essential for immune imprinting and tuning. Live gut microbes and microbial‐derived metabolites regulate the development and modulation of the immune system, but whether microbial metabolites solely are sufficient to induce immune maturation remains unclear. Sterile faecal filtrates (FFT) were generated from murine gut contents. Newborn germ‐free (GF) mice were treated twice daily with FFT (GF‐FFT) or saline (GF‐NaCl) from post‐natal day 5 until 4 weeks of age. A third group of GF neonates were conventionalized by the transfer of caecal microbiota with live gut microbes. Host immune compartments were comprehensively immunophenotyped and systemically analysed in all available immune‐related organs using flow cytometry. Oral FFT was associated with reduced survival among neonates (n = 7/19; 36.8% mortality), while saline treatment was well tolerated (n = 1/17, 5.9% mortality). Four‐week‐old FFT‐treated pups were comparable in body weight to GF‐NaCl, and the major B‐cell, conventional T‐cell and unconventional T‐cell subsets were unchanged from saline‐treated mice. Live bacteria administered during early life induced clear changes in proportions of B cells, T cells and T‐cell subsets in all mucosal tissues and secondary lymphoid organs compared to GF‐FFT, including restoration of intestinal natural killer T (NKT) cells with characteristics similar to conventional pups. Our findings show that oral administration of a FFT made of microbial metabolites, antigens and bacteriophages alone is insufficient to induce normal immune development elicited by the presence of live bacteria. Reduced survival during neonatal FFT treatment suggests a potential bioactive attribute of sterile faecal filtrates.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"217 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136033522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hilal Ünsal, Canan Caka, Hacer Neslihan Bildik, Saliha Esenboğa, Alphan Kupesiz, Barış Kuşkonmaz, Duygu Uçkan Cetinkaya, Mirjam van der Burg, İlhan Tezcan, Deniz Çağdaş
Abstract Major histocompatibility complex class II (MHC‐II) deficiency or bare lymphocyte syndrome (BLS) is a rare, early‐onset, autosomal recessive, and life‐threatening inborn error of immunity. We aimed to assess the demographic, clinical, laboratory, follow‐up, and treatment characteristics of patients with MHC‐II deficiency, together with their survival. We retrospectively investigated 21 patients with MHC‐II deficiency. Female/male ratio was 1.63. The median age at diagnosis was 16.3 months (5 months–9.7 years). Nineteen patients (90.5%) had parental consanguinity. Pulmonary diseases (pneumonia, chronic lung disease) (81%), diarrhoea (47.6%), and candidiasis (28.6%) were common. Four (19%) had autoimmunity, two developed septic arthritis, and three (14%) developed bronchiectasis in the follow‐up. Three patients (14%) had CMV viraemia, one with bilateral CMV retinitis. Eight (38.1%) had lymphocytopenia, and four (19%) had neutropenia. Serum IgM, IgA, and IgG levels were low in 18 (85.7%), 15 (71.4%), and 11 (52.4%) patients, respectively. CD4+ lymphocytopenia, a reversed CD4+/CD8+ ratio, and absent/low HLA‐DR expressions were detected in 93.3%, 86.7%, and 100% of the patients, respectively. Haematopoietic stem cell transplantation (HSCT) was performed on nine patients, and four died of septicaemia and ARDS after HSCT. The present median age of patients survived is 14 years (1–31 years). Genetic analysis was performed in 10 patients. RFX5 homozygous gene defect was found in three patients (P1, P4 and P8), and RFXANK (P2 and P14) and RFXAP (P18 and P19) heterozygous gene defects were found in each two patients, respectively. This large cohort showed that BLS patients have severe combined immunodeficiency (SCID)‐like clinical findings. Flow cytometric MHC‐II expression study is crucial for the diagnosis, differential diagnosis with SCID, early haematopoietic stem cell transplantation (HSCT), and post‐HSCT follow‐up. Genetic studies are required first for matched family donor evaluation before HSCT and then for genetic counselling.
{"title":"A large single‐center cohort of bare lymphocyte syndrome: Immunological and genetic features in Turkey","authors":"Hilal Ünsal, Canan Caka, Hacer Neslihan Bildik, Saliha Esenboğa, Alphan Kupesiz, Barış Kuşkonmaz, Duygu Uçkan Cetinkaya, Mirjam van der Burg, İlhan Tezcan, Deniz Çağdaş","doi":"10.1111/sji.13335","DOIUrl":"https://doi.org/10.1111/sji.13335","url":null,"abstract":"Abstract Major histocompatibility complex class II (MHC‐II) deficiency or bare lymphocyte syndrome (BLS) is a rare, early‐onset, autosomal recessive, and life‐threatening inborn error of immunity. We aimed to assess the demographic, clinical, laboratory, follow‐up, and treatment characteristics of patients with MHC‐II deficiency, together with their survival. We retrospectively investigated 21 patients with MHC‐II deficiency. Female/male ratio was 1.63. The median age at diagnosis was 16.3 months (5 months–9.7 years). Nineteen patients (90.5%) had parental consanguinity. Pulmonary diseases (pneumonia, chronic lung disease) (81%), diarrhoea (47.6%), and candidiasis (28.6%) were common. Four (19%) had autoimmunity, two developed septic arthritis, and three (14%) developed bronchiectasis in the follow‐up. Three patients (14%) had CMV viraemia, one with bilateral CMV retinitis. Eight (38.1%) had lymphocytopenia, and four (19%) had neutropenia. Serum IgM, IgA, and IgG levels were low in 18 (85.7%), 15 (71.4%), and 11 (52.4%) patients, respectively. CD4+ lymphocytopenia, a reversed CD4+/CD8+ ratio, and absent/low HLA‐DR expressions were detected in 93.3%, 86.7%, and 100% of the patients, respectively. Haematopoietic stem cell transplantation (HSCT) was performed on nine patients, and four died of septicaemia and ARDS after HSCT. The present median age of patients survived is 14 years (1–31 years). Genetic analysis was performed in 10 patients. RFX5 homozygous gene defect was found in three patients (P1, P4 and P8), and RFXANK (P2 and P14) and RFXAP (P18 and P19) heterozygous gene defects were found in each two patients, respectively. This large cohort showed that BLS patients have severe combined immunodeficiency (SCID)‐like clinical findings. Flow cytometric MHC‐II expression study is crucial for the diagnosis, differential diagnosis with SCID, early haematopoietic stem cell transplantation (HSCT), and post‐HSCT follow‐up. Genetic studies are required first for matched family donor evaluation before HSCT and then for genetic counselling.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"143 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135759488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charles W. Armitage, Connor P. O'Meara, Emily R. Bryan, Avinash Kollipara, Logan K. Trim, Danica Hickey, Alison J. Carey, Wilhelmina M. Huston, Gavin Donnelly, Anusch Yazdani, Richard S. Blumberg, Kenneth W. Beagley
Abstract Chlamydia trachomatis infections are an important sexually transmitted infection that can lead to inflammation, scarring and hydrosalpinx/infertility. However, infections are commonly clinically asymptomatic and do not receive treatment. The underlying cause of asymptomatic immunopathology remains unknown. Here, we demonstrate that IgG produced during male infection enhanced the incidence of immunopathology and infertility in females. Human endocervical cells expressing the neonatal Fc Receptor (FcRn) increased translocation of human IgG‐opsonized C. trachomatis . Using total IgG purified from infected male mice, we opsonized C. muridarum and then infected female mice, mimicking sexual transmission. Following infection, IgG‐opsonized Chlamydia was found to transcytose the epithelial barrier in the uterus, where it was phagocytosed by antigen‐presenting cells (APCs) and trafficked to the draining lymph nodes. APCs then expanded both CD4 + and CD8 + T cell populations and caused significantly more infertility in female mice infected with non‐opsonized Chlamydia . Enhanced phagocytosis of IgG‐opsonized Chlamydia significantly increased pro‐inflammatory signalling and T cell proliferation. As IgG is transcytosed by FcRn, we utilized FcRn −/− mice and observed that shedding kinetics of Chlamydia were only affected in FcRn −/− mice infected with IgG‐opsonized Chlamydia . Depletion of CD8 + T cells in FcRn −/− mice lead to a significant reduction in the incidence of infertility. Taken together, these data demonstrate that IgG seroconversion during male infection can amplify female immunopathology, dependent on FcRn transcytosis, APC differentiation and enhanced CD8 T cell responses.
{"title":"<scp>IgG</scp> exacerbates genital chlamydial pathology in females by enhancing pathogenic <scp>CD8</scp><sup>+</sup> T cell responses","authors":"Charles W. Armitage, Connor P. O'Meara, Emily R. Bryan, Avinash Kollipara, Logan K. Trim, Danica Hickey, Alison J. Carey, Wilhelmina M. Huston, Gavin Donnelly, Anusch Yazdani, Richard S. Blumberg, Kenneth W. Beagley","doi":"10.1111/sji.13331","DOIUrl":"https://doi.org/10.1111/sji.13331","url":null,"abstract":"Abstract Chlamydia trachomatis infections are an important sexually transmitted infection that can lead to inflammation, scarring and hydrosalpinx/infertility. However, infections are commonly clinically asymptomatic and do not receive treatment. The underlying cause of asymptomatic immunopathology remains unknown. Here, we demonstrate that IgG produced during male infection enhanced the incidence of immunopathology and infertility in females. Human endocervical cells expressing the neonatal Fc Receptor (FcRn) increased translocation of human IgG‐opsonized C. trachomatis . Using total IgG purified from infected male mice, we opsonized C. muridarum and then infected female mice, mimicking sexual transmission. Following infection, IgG‐opsonized Chlamydia was found to transcytose the epithelial barrier in the uterus, where it was phagocytosed by antigen‐presenting cells (APCs) and trafficked to the draining lymph nodes. APCs then expanded both CD4 + and CD8 + T cell populations and caused significantly more infertility in female mice infected with non‐opsonized Chlamydia . Enhanced phagocytosis of IgG‐opsonized Chlamydia significantly increased pro‐inflammatory signalling and T cell proliferation. As IgG is transcytosed by FcRn, we utilized FcRn −/− mice and observed that shedding kinetics of Chlamydia were only affected in FcRn −/− mice infected with IgG‐opsonized Chlamydia . Depletion of CD8 + T cells in FcRn −/− mice lead to a significant reduction in the incidence of infertility. Taken together, these data demonstrate that IgG seroconversion during male infection can amplify female immunopathology, dependent on FcRn transcytosis, APC differentiation and enhanced CD8 T cell responses.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"77 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135917847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In a letter dated December 2022, Polykretis and McCullough reported that there had been an increase in sudden cardiac death (SCD) and survived sudden cardiac arrest (SCA) among athletes from 2021 until the date the letter was submitted.1 In the letter, they cited a database purportedly containing 1598 instances of athletes having experienced SCA or SCA during the mentioned timeframe.2 When I examined the database, however, I did not find support for the claim. A number of the cases in the database were unrelated to elite sports as well as SCD or SCA. For example, in some cases, the stated cause of death was suicide. In a different instance, a 70-year-old man reportedly experienced SCD while cycling. The referenced database was clearly disorganized and did not provide evidence of the stated claim. Whether or not there was an increase in SCD and SCA has been the subject of considerable debate, but as far as I am aware no scientific investigation has been conducted.3 This prompted me to look further. In the letter, Polykretis and McCullough compared the data with a systematic review by Bille, Figueiras, Schamasch, et al, who reported that from 1966 to 2004, a total of 1101 athletes under the age of 35 had died as a result of various heart-related conditions. However, such a broad comparison may not be the best approach for assessing whether athletes were at an increased risk of SCA and SCD in 2021 in comparison with pre-COVID data. I would argue that a more appropriate comparison can be drawn if we exclusively focus on cases of SCA and SCD among elite footballers, as this subject has been extensively studied. As elite footballers are in the media spotlight, cases of SCA and SCD are unlikely to be overlooked. Cases occurring at recreational and competitive levels are less likely to receive significant media coverage or be recorded by surveillance systems. The pre-COVID rate of SCA and SCD among footballers was assessed in a prospective, observational study by Egger et al4 known as the FIFA study. Globally, the study found a total of 617 cases of SCD and SCA from 2014 to 2018. A total of 475 died. The study also included a few cases from related sports, including beach soccer, walking football, and futsal. Out of the 617 cases, a total of 95% occurred at the amateur level, which encompassed both recreational and competitive players. It only found 33 cases classified as elite level, amounting to 6.6 cases per year on average. The study was confined to cases during football-specific exercise, such as during training or a match, or within 1 h after cessation of such activity. In the context of this letter, let x denote the number of cases of SCD and SCA in 2021, that is, 10 cases, and let x! = 1 × 2 × 3 × 4 × … × x. Further, let λ be the average rate, namely 6.6 cases. Euler's constant, e ≈ $$ approx $$ 2.71828. It can easily be shown that the 10 cases are not statistically significant, that is, P X ≥ 10 = 0.131 > 0.05 = α $$ Pleft[Xge 10right]=0.131>0.0
在一封日期为2022年12月的信中，Polykretis和McCullough报告说，从2021年到这封信提交之日，运动员中心脏性猝死(SCD)和心脏骤停(SCA)存活的人数有所增加在信中，他们引用了一个据称包含1598名运动员在上述时间段内经历过SCA或SCA的数据库然而，当我检查数据库时，我没有找到支持这种说法的证据。数据库中的许多病例与精英运动以及SCD或SCA无关。例如，在某些案件中，所陈述的死亡原因是自杀。在另一个案例中，据报道，一名70岁的男子在骑车时出现了SCD。所引用的数据库显然杂乱无章，没有提供所述索赔的证据。是否有SCD和SCA的增加一直是一个相当有争议的话题，但据我所知，没有进行过科学调查这促使我进一步研究。在信中，Polykretis和McCullough将这些数据与Bille, Figueiras, Schamasch等人的系统回顾进行了比较，他们报告说，从1966年到2004年，共有1101名35岁以下的运动员死于各种心脏相关疾病。然而，与covid前的数据相比，如此广泛的比较可能不是评估2021年运动员患SCA和SCD风险是否增加的最佳方法。我认为，如果我们只关注精英足球运动员的SCA和SCD病例，可以得出更合适的比较，因为这个主题已经得到了广泛的研究。由于精英足球运动员是媒体关注的焦点，SCA和SCD的案例不太可能被忽视。在娱乐和竞技级别发生的病例不太可能得到媒体的大量报道或被监测系统记录。埃格等人在一项被称为国际足联研究的前瞻性观察研究中评估了足球运动员中SCA和SCD的前冠状病毒感染率。在全球范围内，该研究发现，从2014年到2018年，共有617例SCD和SCA病例。共有475人死亡。这项研究还包括了一些相关运动的案例，包括沙滩足球、步行足球和五人制足球。在617起案件中，共有95起% occurred at the amateur level, which encompassed both recreational and competitive players. It only found 33 cases classified as elite level, amounting to 6.6 cases per year on average. The study was confined to cases during football-specific exercise, such as during training or a match, or within 1 h after cessation of such activity. In the context of this letter, let x denote the number of cases of SCD and SCA in 2021, that is, 10 cases, and let x! = 1 × 2 × 3 × 4 × … × x. Further, let λ be the average rate, namely 6.6 cases. Euler's constant, e ≈ $$ approx $$ 2.71828. It can easily be shown that the 10 cases are not statistically significant, that is, P X ≥ 10 = 0.131 > 0.05 = α $$ Pleft[Xge 10right]=0.131>0.05=alpha $$ , where α is the significance level. It should be pointed out that the data are preliminary and surveillance systems might have picked up additional cases. Furthermore, two potentially relevant cases were excluded due to insufficient corroborating information. If there had been 12 cases or more, then P < 0.05. If evidence eventually emerges that a non-coincidental surge in SCD and SCA took place in 2021, a number of potential causes should be considered. First, as entire football leagues were put to a standstill for long periods in 2020 as a result of lockdowns and restrictions, it is likely that there were significantly fewer cases than the average. If this happened, the cases that under normal circumstances would have taken place in 2020 could have been postponed to 2021, resulting in an increase. Alternatively, myocarditis, which is a major cause of sudden, unexpected death in young adults, may have been induced via a SARS-CoV-2 infection or via mRNA SARS-CoV-2 vaccination. It is well documented that post-viral myocarditis can result in SCD in athletes. However, to my knowledge, there have been no reported cases associated with SARS-CoV-2.5 With respect to vaccination, it should be mentioned that an autopsy-based histopathological characterization of myocarditis found that “myocarditis can be a potentially lethal complication following mRNA-based anti-SARS-CoV-2 vaccination”.6 Moreover, an endomyocardial biopsy-proven case series found that 9 out of 15 pat
{"title":"Were athletes at increased risk of sudden cardiac death and survived sudden cardiac arrest in 2021?","authors":"Søren Roest Korsgaard","doi":"10.1111/sji.13334","DOIUrl":"https://doi.org/10.1111/sji.13334","url":null,"abstract":"In a letter dated December 2022, Polykretis and McCullough reported that there had been an increase in sudden cardiac death (SCD) and survived sudden cardiac arrest (SCA) among athletes from 2021 until the date the letter was submitted.1 In the letter, they cited a database purportedly containing 1598 instances of athletes having experienced SCA or SCA during the mentioned timeframe.2 When I examined the database, however, I did not find support for the claim. A number of the cases in the database were unrelated to elite sports as well as SCD or SCA. For example, in some cases, the stated cause of death was suicide. In a different instance, a 70-year-old man reportedly experienced SCD while cycling. The referenced database was clearly disorganized and did not provide evidence of the stated claim. Whether or not there was an increase in SCD and SCA has been the subject of considerable debate, but as far as I am aware no scientific investigation has been conducted.3 This prompted me to look further. In the letter, Polykretis and McCullough compared the data with a systematic review by Bille, Figueiras, Schamasch, et al, who reported that from 1966 to 2004, a total of 1101 athletes under the age of 35 had died as a result of various heart-related conditions. However, such a broad comparison may not be the best approach for assessing whether athletes were at an increased risk of SCA and SCD in 2021 in comparison with pre-COVID data. I would argue that a more appropriate comparison can be drawn if we exclusively focus on cases of SCA and SCD among elite footballers, as this subject has been extensively studied. As elite footballers are in the media spotlight, cases of SCA and SCD are unlikely to be overlooked. Cases occurring at recreational and competitive levels are less likely to receive significant media coverage or be recorded by surveillance systems. The pre-COVID rate of SCA and SCD among footballers was assessed in a prospective, observational study by Egger et al4 known as the FIFA study. Globally, the study found a total of 617 cases of SCD and SCA from 2014 to 2018. A total of 475 died. The study also included a few cases from related sports, including beach soccer, walking football, and futsal. Out of the 617 cases, a total of 95% occurred at the amateur level, which encompassed both recreational and competitive players. It only found 33 cases classified as elite level, amounting to 6.6 cases per year on average. The study was confined to cases during football-specific exercise, such as during training or a match, or within 1 h after cessation of such activity. In the context of this letter, let x denote the number of cases of SCD and SCA in 2021, that is, 10 cases, and let x! = 1 × 2 × 3 × 4 × … × x. Further, let λ be the average rate, namely 6.6 cases. Euler's constant, e ≈ $$ approx $$ 2.71828. It can easily be shown that the 10 cases are not statistically significant, that is, P X ≥ 10 = 0.131 > 0.05 = α $$ Pleft[Xge 10right]=0.131>0.0","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Axel Rosell, Cecilia Karlström, Joakim S. Dahlin, Daryl Boey, Monika Klimkowska, Kajsa Ax, Charlotte Thålin, Johanna Ungerstedt
Abstract In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit‐DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit‐DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit‐DNA levels in SM patients compared with healthy controls. H3Cit‐DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit‐DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.
{"title":"No indication of aberrant neutrophil extracellular trap release in indolent or advanced systemic mastocytosis","authors":"Axel Rosell, Cecilia Karlström, Joakim S. Dahlin, Daryl Boey, Monika Klimkowska, Kajsa Ax, Charlotte Thålin, Johanna Ungerstedt","doi":"10.1111/sji.13333","DOIUrl":"https://doi.org/10.1111/sji.13333","url":null,"abstract":"Abstract In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit‐DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit‐DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit‐DNA levels in SM patients compared with healthy controls. H3Cit‐DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit‐DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"46 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135250744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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