Clinical and Experimental Immunology
ISSN / EISSN: 00099104 / 13652249
Published by: Oxford University Press (OUP)
Total articles ≅ 15,165
Latest articles in this journal
Published: 8 December 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac111
Hantaan virus (HTNV) infection causes an epidemic of hemorrhagic fever with renal syndrome (HFRS) mainly in Asia. Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to play an important role in innate host defense during virus infection. However, their roles and phenotypes during HTNV infection have not yet been explored. We characterized CD8 +MAIT cells from HFRS patients based on scRNA-seq data combined with flow cytometry data. We showed that HTNV infection caused the loss and activation of CD8 +MAIT cells in the peripheral blood, which were correlated with disease severity. The production of granzyme B and IFN-γ from CD8 +MAIT cells and the limitation of HTNV replication in endothelia cells indicated the anti-viral property of CD8 +MAIT cells. In addition, in vitro infection of MAIT cells by HTNV or HTNV-exposed monocytes showed that the activation of MAIT cells was IL-18-mediated. In conclusion, this study identified, for the first time, gene expression profiles of MAIT cells, provided underlying molecular mechanisms for activation of MAIT cells during HTNV infection, and suggested a potential anti-viral role of MAIT cells in HFRS.
Published: 8 December 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac112
Intravenous immunoglobulin (IVIG) is a well-established treatment for various autoimmune and inflammatory diseases. However, the standard dose prescribed for autoimmune diseases, including immune thrombocytopenic purpura (ITP), is 2 g/kg, which is markedly high and leads to a high treatment burden. In this study, we generated fragment crystallizable (Fc)-modified anti-haptoglobin (Hp) monoclonal antibodies with non-inferior efficacy compared to IVIG at considerably lower doses than IVIG, as shown by in vitro experiments. We evaluated binding activity of anti-Hp antibodies to Fc gamma receptors (FcγRs) with ELISA and inhibitory activity against the ADCC reaction. Furthermore, we successfully established a novel cynomolgus monkey ITP model and demonstrated that the anti-Hp antibody exerted its effect in this model with only a single dose. This Fc-modified anti-Hp monoclonal antibody could be a valuable therapeutic replacement for IVIG for the treatment of ITP.
Published: 8 December 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac113
Summary: The importance of antibodies, particularly neutralising antibodies, has been known for decades. When examining the immune responses against a pathogen after a vaccination or infection it is easier to measure the levels of antigen specific antibodies than the T-cell response, but it does not give the whole picture. The levels of neutralising antibodies is harder to determine but gives a better indication of the quality of the antibody response. The induction of long-lived antibody secreting plasma cells are crucial for a persistent humoral immune response, which has been shown for example after vaccination with the vaccinia vaccine, where antibody levels have been shown to persist for decades. With the SARS-CoV-2 pandemic ravaging the world for the past years and the monumental effort in designing and releasing novel vaccines against the virus, much effort has been put in analysing the quantity, quality and persistence of antibody responses. The current review will focus on the plasma cells and discuss how long-lasting immune responses are induced, the importance of antigen availability and retention in evoking a long-lasting persisting antibody response. Since SARS-CoV-2 is a novel disease and many different vaccination strategies have been generated, focus will be put on persisting antibody responses against these different types of vaccines, which will give an insight into the generation of immunological memory and the persistence of antibody responses.
Published: 26 November 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac109
IKAROS/IKZF1 plays a pivotal role in lymphocyte differentiation and development. Germline mutations in IKZF1, which have been shown to associated with primary immunodeficiency, can be classified through four different mechanisms of action depending on the protein expression and its functional defects: haploinsufficiency, dimerization defective, dominant negative, and gain-of-function. These different mechanisms are associated with variable degrees of susceptibility to infectious diseases, autoimmune disorders, allergic diseases, and malignancies. To date, more than 30 heterozygous IKZF1 germline variants have been reported in patients with primary immunodeficiency. Here we review recent discoveries and clinical/immunological characterization of IKAROS-associated disorders that are linked to different mechanisms of action in IKAROS function.
Published: 25 November 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac095
Summary: CD5L/AIM(apoptosis inhibitor of macrophage), as an important component in maintaining tissue homeostasis and inflammation, is mainly produced and secreted by macrophages but partially dissociated and released from blood AIM-IgM. AIM plays a regulatory role in intracellular physiological mechanisms, including lipid metabolism and apoptosis. AIM not only increases in autoimmune diseases, directly targets liver cells in liver cancer and promotes cell clearance in acute kidney injury, but also causes arteriosclerosis and cardiovascular events, and aggravates inflammatory reactions in lung diseases and sepsis. Obviously, AIM plays a pleiotropic role in the body. However, to date, studies have failed to decipher the mechanisms behind its different roles (beneficial or harmful) in inflammatory regulation.The inflammatory response is a "double-edged sword," and maintaining balance is critical for effective host defense while minimizing the adverse side effects of acute inflammation. Enhancing the understanding of AIM function could provide the theoretical basis for new therapies in these pathological settings. In this review, we discuss recent studies on the roles of AIM in lipid metabolism, autoimmune diseases and organic tissues, such as liver cancer, myocardial infarction, and kidney disease.
Published: 25 November 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac108
Myasthenia gravis (MG) is a rare but life-threatening adverse event with pembrolizumab. What is known about pembrolizumab-induced MG is largely based on case reports. This analysis collected pembrolizumab-induced MG cases from Chinese and English databases published from September 1, 2014, to June 30, 2022. Demographic and clinical information of the patients, management, and outcome data were collected and analyzed. Sixty-five patients with a median age of 73 years (range 30- 86), including 43 male patients (66.2%), were included. Eight patients (12.3%) with prior MG experienced worsening symptoms after receiving pembrolizumab. The median time to the onset of MG was four weeks (range 0.7-27). The most common symptoms were ptosis (81.5%, 53 patients), diplopia (50.8%, 33 patients), dyspnea (44.6%, 29 patients), trunk or peripheral weakness (43.1%, 28 patients), and dysphagia (30.8%, 20 patients). Concurrent myositis and myocarditis occurred in 13 (20.0%) and 17 patients (26.2%). Pembrolizumab was discontinued in 63 patients (96.9%). Forty-four patients (67.7%) received combination therapies based on steroids (intravenous immune globulin, plasmapheresis, or immunosuppressants). Twenty-seven patients (41.5%) had symptoms completely recovered. Fourteen patients (21.5%) died from immunotoxicity or primary cancers. Clinicians should consider the possibility of pembrolizumab-induced MG, especially during the first eight weeks of therapy. Patients should be treated as early as possible, regardless of the severity of the initial symptoms.
Published: 24 November 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac106
Signal transducer and activator of transcription 1 (STAT1) is a well-known and pivotal molecule in the regulation of the Janus activating kinases (JAK)-STAT pathway, an extensive signalling pathway downstream of several cytokine receptors that plays an indispensable role in immune defence in humans. In the JAK-STAT pathway, STAT1 homodimer-dependent IFN-γ immunity is crucial for defence against intra-macrophagic bacteria, and STAT1/STAT2/IRF9 complex-dependent IFN-α/β immunity is essential for protection against viruses. STAT1 dysfunction causes a wide range of immune dysregulation phenotypes, which have been classified into four disease types, namely, (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD STAT1 gain-of-function (GOF), based on their mode of inheritance and function. Disease types (i, ii, and iii) are caused by STAT1 loss-of-function (LOF) mutations, whereas disease type (iv) is caused by STAT1 GOF mutations. Notably, rapid and accurate diagnosis of these four diseases can be difficult. In particular, the differential diagnosis of AD STAT1 deficiency and AD STAT1 GOF, which are caused by LOF- and GOF-STAT1 mutations, respectively, can be complicated due to their overlapping clinical symptoms. In addition, more than 150 pathological mutations have been identified in STAT1 across all domains, making functional prediction of novel mutations difficult. Thus, the functional analysis of mutations is necessary for diagnosis. The recently proposed reference database of mutant STAT1 functions based on comprehensive alanine scanning is a useful tool for evaluating unknown STAT1 mutations with high accuracy.
Published: 24 November 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac107
Summary: Mitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system towards immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference.
Published: 18 November 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac105
Summary: Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signalling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients.
Published: 16 November 2022
Clinical and Experimental Immunology; https://doi.org/10.1093/cei/uxac103
Memory B cells (MBCs) are an essential part of our immunological memory. They respond fast upon re-encountering pathogens and can differentiate into plasma cells that secrete protective antibodies. The focus of this review is on MBCs that lack, or express low levels of, CD21, hereafter referred to as CD21-/low. These cells are expanded in peripheral blood with age and during chronic inflammatory conditions such as viral infections, malaria, common variable immunodeficiency, and autoimmune diseases. CD21-/low MBCs have gained significant attention; they produce disease-specific antibodies/autoantibodies, and associate with key disease manifestations in some conditions. However, these cells can be divided into subsets based on classical B-cell and other markers, e.g., CD11c, FcRL4 and Tbet that, over the years, have become hallmarks to identify these cells. This has resulted in different names including age-associated, autoimmune-associated, atypical, tissue-like, tissue-resident, tissue-restricted, exhausted or simply CD21-/low B cells. It is however unclear whether the expanded ‘CD21-/low’ cells in one condition are equivalent to those in another, whether they express an identical gene signature and whether they have a similar function. Here, we will discuss these issues with the goal to understand whether the CD21-/low B cells are comparable in the different conditions.