Progression Of Autoimmune Diseases Research Articles

Sirtuin family in autoimmune diseases.

In recent years, epigenetic modifications have been widely researched. As humans age, environmental and genetic factors may drive inflammation and immune responses by influencing the epigenome, which can lead to abnormal autoimmune responses in the body. Currently, an increasing number of studies have emphasized the important role of epigenetic modification in the progression of autoimmune diseases. Sirtuins (SIRTs) are class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and SIRT-mediated deacetylation is an important epigenetic alteration. The SIRT family comprises seven protein members (namely, SIRT1-7). While the catalytic core domain contains amino acid residues that have remained stable throughout the entire evolutionary process, the N- and C-terminal regions are structurally divergent and contribute to differences in subcellular localization, enzymatic activity and substrate specificity. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are predominantly found in the nucleus. SIRTs are key regulators of various physiological processes such as cellular differentiation, apoptosis, metabolism, ageing, immune response, oxidative stress, and mitochondrial function. We discuss the association between SIRTs and common autoimmune diseases to facilitate the development of more effective therapeutic strategies.

Inflammasomes: Mechanisms of Action and Involvement in Human Diseases.

Inflammasome complexes and their integral receptor proteins have essential roles in regulating the innate immune response and inflammation at the post-translational level. Yet despite their protective role, aberrant activation of inflammasome proteins and gain of function mutations in inflammasome component genes seem to contribute to the development and progression of human autoimmune and autoinflammatory diseases. In the past decade, our understanding of inflammasome biology and activation mechanisms has greatly progressed. We therefore provide an up-to-date overview of the various inflammasomes and their known mechanisms of action. In addition, we highlight the involvement of various inflammasomes and their pathogenic mechanisms in common autoinflammatory, autoimmune and neurodegenerative diseases, including atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We conclude by speculating on the future avenues of research needed to better understand the roles of inflammasomes in health and disease.

Multiple sclerosis and ketogenic diets

George Winter discusses the extent to which an anti-inflammatory ketogenic diet can influence the progress of a chronic autoimmune and/or inflammatory disease, such as multiple sclerosis.

A current and future perspective on T cell receptor repertoire profiling.

T cell receptors (TCR) play a vital role in the immune system's ability to recognize and respond to foreign antigens, relying on the highly polymorphic rearrangement of TCR genes. The recognition of autologous peptides by adaptive immunity may lead to the development and progression of autoimmune diseases. Understanding the specific TCR involved in this process can provide insights into the autoimmune process. RNA-seq (RNA sequencing) is a valuable tool for studying TCR repertoires by providing a comprehensive and quantitative analysis of the RNA transcripts. With the development of RNA technology, transcriptomic data must provide valuable information to model and predict TCR and antigen interaction and, more importantly, identify or predict neoantigens. This review provides an overview of the application and development of bulk RNA-seq and single-cell (SC) RNA-seq to examine the TCR repertoires. Furthermore, discussed here are bioinformatic tools that can be applied to study the structural biology of peptide/TCR/MHC (major histocompatibility complex) and predict antigenic epitopes using advanced artificial intelligence tools.

Ferroptosis: A potential therapeutic target in autoimmune disease (Review).

Ferroptosis is a distinct type of regulated cell death characterized by iron overload and lipid peroxidation. Ferroptosis is regulated by numerous factors and controlled by several mechanisms. This cell death type has a relationship with the immune system, which may be regulated by damage-associated molecular patterns. Ferroptosis participates in the progression of autoimmune diseases, including autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, Parkinson's Disease, psoriasis and insulin-dependent diabetes mellitus. The present review summarizes the role of ferroptosis in autoimmune disorders and discusses ferroptosis as a potential therapeutic target for autoimmune disease.

Extracellular vesicle-encapsulated miR-10a-5p derived from MDSCs restrains germinal center B cells in experimental Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a progressive systemic autoimmune disease characterized by chronic inflammation of the exocrine glands, resulting in damage to the salivary and lacrimal glands. Our group and other researchers have reported that myeloid-derived suppressor cell-derived extracellular vesicles (MDSC-EVs) could attenuate the progression of autoimmune disease by impairing T-cell function. However, the effect of MDSC-EVs on B-cell function and the underlying mechanism remains largely unknown. In this study, we found that MDSC-EVs significantly attenuated the progression of experimental Sjögren's syndrome (ESS). Moreover, treatment with MDSC-EVs via intravenous injection markedly reduced the percentage of germinal center (GC) B cells in ESS mice. In vitro, MDSC-EVs could directly suppress the generation of GC B cells and theexpression of B cell lymphoma 6 (Bcl-6) in B cells under GC B-cell-polarizing conditions. Mechanistically, miR-10a-5p carried by MDSC-EVs regulated the differentiation of GC B cells by targeting Bcl-6, and inhibition of miR-10a-5p in MDSC-EVs significantly reversed the effect of MDSC-EVs involved in alleviating the development of ESS. Taken together, our findings demonstrated that miR-10a-5p carried by MDSC-EVs inhibited the generation of B cells by targeting Bcl-6 and eventually alleviated the progression of ESS, which may provide novel therapeutic targets for the treatment of pSS.

Aberrant inflammasome activation as a driving force of human autoimmune skin disease.

Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 years ago, contribute to autoimmune disease progression. The inflammasome and its contribution to the bioactivation of interleukins IL-1β and IL-18 play an essential role in combating foreign pathogens or tissue damage, but may also act as a pathogenic driver of myriad chronic inflammatory diseases when dysfunctionally regulated. Inflammasomes containing the NOD-like receptor family members NLRP1 and NLRP3 as well as the AIM2-like receptor family member AIM2 have been increasingly investigated in inflammatory skin conditions. In addition to autoinflammatory diseases, which are often associated with skin involvement, the aberrant activation of the inflammasome has also been implied in autoimmune diseases that can either affect the skin besides other organs such as systemic lupus erythematosus and systemic sclerosis or are isolated to the skin in humans. The latter include, among others, the T-cell mediated disorders vitiligo, alopecia areata, lichen planus and cutaneous lupus erythematosus as well as the autoantibody-driven blistering skin disease bullous pemphigoid. Some diseases are characterized by both autoinflammatory and autoimmune responses such as the chronic inflammatory skin disease psoriasis. Further insights into inflammasome dysregulation and associated pathways as well as their role in forming adaptive immune responses in human autoimmune skin pathology could potentially offer a new field of therapeutic options in the future.

Mapping current status and emerging trends in NETosis: A bibliometric study.

NETosis is a critical innate immune mechanism of neutrophils that contributes to the accelerated progression of autoimmune diseases, thrombosis, cancer, and coronavirus disease 2019 (COVID-19). This study qualitatively and quantitatively analyzed the relevant literature by bibliometric methods in order to provide a more comprehensive and objective view of the knowledge dynamics in the field. The literature on NETosis was downloaded from the Web of Science Core Collection, analyzed with VOSviewer, CiteSpace, and Microsoft for co-authorship, co-occurrence, and co-citation analysis. In the field of NETosis, the United States was the most influential countries. Harvard University was the most active institutions. Mariana J. Kaplan and Brinkmann V were, respectively, the most prolific and most co-cited authors. Frontiers in Immunology, Journal of Immunology, Plos One, Blood, Science, Journal of Cell Biology, and Nature Medicine were the most influential journals. The top 15 keywords are associated with immunological and NETosis formation mechanisms. The keywords with the strongest burst detection were mainly related to COVID-19 (coronavirus, ACE2, SARS coronavirus, cytokine storm, pneumonia, neutrophil to lymphocyte ratio), and cancer (circulating tumor cell). Research on NETosis is currently booming. The mechanism of NETosis and its role in innate immunity, autoimmune diseases, especially systemic lupus erythematosus and rheumatoid arthritis, and thrombosis are the focus of research in the field of NETosis. A future study will concentrate on the function of NETosis in COVID-19 and recurrent metastasis of cancer.

IMPACTing autoimmunity through dual targeting of antigen presenting cells and T cells via inhibitory receptor agonism

Abstract Autoimmune diseases are triggered by a critical break in peripheral tolerance, thereby allowing the immune system to target and destroy host tissues. Tolerance mechanisms, such as inhibitory receptor (IRs) on T cells, can greatly influence autoimmune disease progression and outcomes, representing an opportunity for therapeutic intervention. Indeed, evidence in both animal models and patients suggests that IRs play a major role in limiting autoimmunity. Immunotherapies targeting IRs have revolutionized the treatment of many cancers and provided evidence that IR modulating therapeutics can significantly impact patient outcomes. However importantly, analogous IR-targeted autoimmune therapeutics have just begun to be tested. Despite interest, IR agonist antibodies have proven difficult to generate. Optimal agonist antibodies require IR superclustering, which is not efficiently induced by Fc-null antibodies. Successful agonists will likely rely on simultaneous Fc (constant region) tethering on antigen presenting cells (APC), thereby allowing efficient IR superclustering and downstream signaling. Current agonistic antibodies targeting IRs contain an IgG1 wild-type Fc, which by binding both activating and inhibitory Fc receptors can trigger unwanted production of inflammatory cytokines by APCs. Here we show that antibodies binding selectively FcγRIIb, support superior agonism compared to IgG1 wild-type antibodies and mitigate potential liability of current IR agonists under clinical investigation. Indeed, dual targeting of the APC and T cells shows promising pre-clinical results and will be used to create novel IR agonists.

Infection with LCMV delays the progression of demyelinating disease in EAE.

Abstract Multiple sclerosis is a chronic autoimmune demyelinating disease that affects approximately 2.8 million people worldwide. While several preventative treatments for multiple sclerosis, including Natalizumab and Mitoxantrone exist, there currently is no cure. It is also unknown what provides the initial trigger of disease episodes or exacerbation of the ongoing disease although viral infections might play a role. In contrast to their role as a driver of demyelination, here we investigate whether viral infections play a potential protective role. Using a well-established animal model of chronic-progressive autoimmune disease known as Experimental Autoimmune Encephalomyelitis, we found that infection with lymphocytic choriomeningitis virus (LCMV) infection delayed onset of paralysis as compared to uninfected controls. Consistent with the reduction in EAE disease scores, we identified reduced numbers of myelin-specific CD4 T cells in the CNS. The myelin-specific CD4 T cells were found in the periphery suggesting that the virus impeded their trafficking to the CNS. Additionally, we analyzed that virus-specific CD8 T cells were found in the CNS in preference to the myelin-specific CD4 T cells. Thus, in contrast to the prevailing paradigm of infections driving autoimmune disease progression, we find that viral infection can lessen acute demyelinating disease. R01NS071518 R01AI147641

TET2-mediated upregulation of 5-hydroxymethylcytosine in LRRC39 promoter promotes Th1 response in association with downregulated Treg response in Vogt-Koyanagi-Harada disease

DNA 5-Hydroxymethylcytosine (5-hmC), an oxidative reaction mediated by the ten-eleven translocation (TET) family, has been reported to play an essential role in the progression of auto-inflammatory and autoimmune diseases. By far, little is known about the effect of DNA 5-hmC and the TET family on the development of Vogt–Koyanagi–Harada (VKH) disease. In this study, we discovered that the global DNA 5-hmC level and the TET activity were elevated in association with the up-regulated expression of TET2 at both mRNA and protein levels in CD4+T cells from active VKH patients compared to healthy controls. Integrated analysis of DNA 5-hmC pattern and transcription profile of CD4+ T cells revealed that 6 candidate target genes were involved in the development of VKH disease. The promoter 5-hmC and mRNA levels of leucine rich repeat containing 39 (LRRC39) were verified to be elevated in active VKH patients. Functional experiments showed that TET2 could up-regulate LRRC39 mRNA expression by increasing the promoter 5-hmC level of LRRC39 in CD4+ T cells from active VKH patients. Up-regulated LRRC39 expression could increase the frequencies of IFN-γ+ and IL-17+ CD4+ T cells as well as the secretions of IFN-γ and IL-17 in association with the decreased frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and the reduced production of IL-10. Additionally, restoration of LRRC39 rescued TET2-silencing-mediated reduced frequency of IFN-γ+ CD4+ T cells and increased frequency of CD4+CD25+FOXP3+ Treg cells. Collectively, our study reveals a novel axis, the TET2–5-hmC-LRRC39–Th1/Treg responses axis, in the pathogenesis of VKH and provides a potential target for further investigation into the epigenetic therapy of this disease.

Pyroptosis-triggered pathogenesis: New insights on antiphospholipid syndrome.

APS (antiphospholipid syndrome) is a systematic autoimmune disease presenting with the high levels of aPLs (antiphospholipid antibodies). These autoantibodies are involved in various clinical manifestations, mainly including arterial or venous thrombosis formation, proinflammatory response, and recurrent pregnant loss. Pyroptosis is a form of lytic programmed cell death, and it aggravates autoimmune diseases progression via activating NOD-like receptors, especially the NLRP3 inflammasome and its downstream inflammatory factors IL (interleukin)-1β and IL-18. However, the underlying mechanisms of pyroptosis-induced APS progression remain to be elucidated. ECs (endothelial cells), monocytes, platelets, trophoblasts, and neutrophils are prominent participants in APS development. Of significance, pyroptosis of APS-related cells leads to the excessive release of proinflammatory and prothrombotic factors, which are the primary contributors to APOs (adverse pregnancy outcomes), thrombosis formation, and autoimmune dysfunction in APS. Furthermore, pyroptosis-associated medicines have made encouraging advancements in attenuating inflammation and thrombosis. Given the potential of pyroptosis in regulating APS development, this review would systematically expound the molecular mechanisms of pyroptosis, and elaborate the role of pyroptosis-mediated cellular effects in APS progression. Lastly, the prospective therapeutic approaches for APS would be proposed based on the regulation of pyroptosis.

Circ_0000479 promotes proliferation, invasion, migration and inflammation and inhibits apoptosis of rheumatoid arthritis fibroblast-like synoviocytes via miR-766/FKBP5 axis

Circular RNAs have been demonstrated to play a critical role in the progression of autoimmune diseases. This study aimed to investigate the function of circ_0000479 in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs). Circ_0000479 was found to be upregulated in RA-FLSs. Flow cytometry analysis, cell counting Kit-8, transwell, wound-healing and enzyme-linked immunosorbent assays were conducted to evaluate RA-FLS apoptosis, proliferation, invasion, migration and inflammation. The results confirmed that circ_0000479 knockdown suppressed pathogenic properties of RA-FLSs. Through bioinformatics analysis and screening, we obtained 18 miRNAs that can bind to circ_0000479, of which miR-766 was most significantly up-regulated after circ_0000479 knockdown. MiR-766 was confirmed to be down-regulated in RA-FLSs and the combination between circ_0000479 and miR-766 was verified by dual-luciferase reporter assays. Moreover, the inhibitory effect of circ_0000479 knockdown in RA-FLS progression was attenuated by miR-766 inhibitor. By intersecting the target genes of miR-766 with the up-regulated genes in RA, we obtained 8 genes, of which FKBP5 was most significantly down-regulated after miR-766 overexpression. The results of dual-luciferase reporter assays also verified that FKBP5 was the target gene of miR-766. In addition, FKBP5 overexpression abated the inhibition of RA-FLS progression caused by circ_0000479 silencing. In summary, circ_0000479 binds to miR-766 to promote RA progression via FKBP5.

Advances in the potential roles of Cullin-RING ligases in regulating autoimmune diseases.

Cullin-RING ligases (CRLs) are the largest class of E3 ubiquitin ligases regulating the stability and subsequent activity of a large number of important proteins responsible for the development and progression of various diseases, including autoimmune diseases (AIDs). However, the detailed mechanisms of the pathogenesis of AIDs are complicated and involve multiple signaling pathways. An in-depth understanding of the underlying regulatory mechanisms of the initiation and progression of AIDs will aid in the development of effective therapeutic strategies. CRLs play critical roles in regulating AIDs, partially by affecting the key inflammation-associated pathways such as NF-κB, JAK/STAT, and TGF-β. In this review, we summarize and discuss the potential roles of CRLs in the inflammatory signaling pathways and pathogenesis of AIDs. Furthermore, advances in the development of novel therapeutic strategies for AIDs through targeting CRLs are also highlighted.

Sinomenine hydrochloride bidirectionally inhibits progression of tumor and autoimmune diseases by regulating AMPK pathway

BackgroundChronic diseases such as tumors and autoimmune disorders are closely linked to metabolism and immunity and require conflicting treatment methods. AMPK can regulate cell growth and inflammation through energy metabolism. Sinomenine is a compound extracted from the traditional Chinese herb sinomenium acutum (Thunb.) Rehd. et Wils. It has been used to treat NSCLC (non-small-cell lung cancer) and RA (rheumatoid arthritis) in some studies, but with limited understanding of its mechanisms. ObjectiveThis study aims to examine the inhibitory effect of sinomenine hydrochloride (SH) on NSCLC and RA and to understand the underlying joint mechanisms. ResultsThe results indicate that SH has a cytotoxic effect specifically on tumor cells, but not on normal cells. SH was found to induce cell apoptosis by activating the AMPK-mTOR pathway. Additionally, in autoimmune disease cell models, SH was shown to reduce the growth of RA-FLS cells by inhibiting the phosphorylation of AMPK, while having no effect on normal macrophages. Moreover, in vivo studies also showed that SH could reduce the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and slow the development of adjuvant arthritis in rats. Furthermore, SH was found to significantly suppress tumor growth in a tumor xenograft experiment in mice. ConclusionsThis study provides new insights into the treatment of tumors and autoimmune diseases by demonstrating that SH can selectively inhibit the growth of NSCLC cells and the progression of RA through activation of the AMPK pathway.

Heterogeneity of circulating CXCR5-PD-1hiTph cells in patients of type 2 and type 1 diabetes in Chinese population.

Circulating peripheral helper T (Tph) cells are shown to promote the progression of autoimmune diseases. However, the role of Tph cells in inflammatory diseases such as type 2 diabetes mellitus (T2DM) and the differences between T2DM and autoimmune diabetes remain unclear. We recruited 92 T2DM patients, 106 type 1 diabetes mellitus (T1DM) patients and 84 healthy control individuals. Peripheral blood mononucleated cells were isolated and examined by multicolor flow cytometry. We further evaluated the correlations between circulating Tph cells and clinical biochemical parameters, islet function, disease progression and islet autoantibodies. Circulating Tph cells were significantly higher in both T2DM and T1DM patients than in healthy control individuals. A significant positive correlation was observed between Tph cells and B cells in T1DM patients and overweight T2DM patients. Furthermore, Tph cells were negatively correlated with the area under the C-peptide curve (C-PAUC), and Tph cells were significantly positively correlated with fasting glucose and glycated hemoglobin levels in T2DM patients. However, no correlation was found between Tph cells and the above clinical indicators in T1DM patients. The frequency of Tph cells positively correlated with the titer of GAD autoantibodies and duration of disease in T1DM patients. In addition, we demonstrated that the frequency of Tph cells was decreased after rituximab therapy in T1DM patients. Circulating Tph cells are associated with blood glucose levels and islet function in T2DM patients. In T1DM patients, circulating Tph cells are associated with B cells and islet autoantibodies. This may suggest that Tph cells have different pathogenic mechanisms in the two types of diabetes. http://ClinicalTrials.gov NCT01280682 (registered July, 2010).

Role of vitamin D in autoimmune rheumatological diseases

Introduction: Vitamin D is a hormone synthesized in the skin, by the presence of the "precursor molecule 7-dehicrocholesterol" whose action depends directly on the stimulus of ultraviolet rays for the production of cholecalciferol. It has several functions including a fundamental role in mediating the response of the immune system, plays modulatory actions, counteracts inflammatory, oxidative and fibrotic activity, and consequently regulates autoimmune tissue lesions. As it possesses an immunomodulatory property, is related to the appearance and progression of autoimmune disorders. Objective: To describe the role of vitamin D in autoimmune rheumatologic diseases. Methods: A narrative review was performed, collecting information from January 2019 to January 2023 in scientific databases such as: Pubmed, Scopus, Web of Science, and Google Scholar, using keywords. Results: Vitamin D in autoimmune rheumatic diseases influences the control and decrease of inflammatory activity, slows its speed of progression and improves clinical manifestations, although there is no total consensus on the mode of use, however, its supplementation has a great benefit. Conclusions: The role of Vitamin D in autoimmune rheumatic diseases varies according to the underlying pathology, in combination with bisphosphonates it can improve bone mineral density in spondyloarthropathies, prevent osteoporosis, improve the clinical picture of SLE and Systemic Sclerosis, but it can increase antibody levels in Connective Tissue Diseases.

Effect of Umbilical Cord Mesenchymal Stem Cell Transplantation Under LIFPUS Pretreatment on Thyroid Function in EAT Rats.

A growing number of studies have demonstrated that mesenchymal stem cells (MSCs) can effectively regulate the progression of multiple autoimmune diseases and can respond positively to mechanical stimulation by ultrasound in an in vitro setting to improve transplantation efficacy. The aim of this study was to activate hUC-MSCs by pretreatment with low-intensity focused pulsed ultrasound (LIFPUS) in an in vitro environment and transplant them into a rat model of EAT via tail vein. To investigate the efficacy and potential mechanism of action of hUC-MSCs in the treatment of EAT. In this study, 40 female lewis rats were divided into control, EAT, hUC-MSCs treatment and LIFPUS pretreatment transplantation group. EAT models were established by subcutaneous multi-point injection of PTG+Freund's adjuvant, and the primary hUC-MSCs were treated with different gradients of LIFPUS irradiation or sham irradiation in an in vitro environment and screened by Western Blot (WB), flow cytology cycle analysis, and cellular immunofluorescence to find the optimal treatment parameters for LIFPUS to promote cell proliferation. After tail vein injection of different pretreatment groups of hUC-MSCs, Homing sites of hUC-MSCs in vivo, circulating autoantibody expression levels and local thyroid histopathological changes were assessed by enzyme-linked immunosorbent assay (ELISA), spleen index, tissue hematoxylin-eosin (HE) staining and immunohistochemistry. The expression levels of apoptotic proteins Bcl-2, Bax and endoplasmic reticulum stress-related proteins Chop and EIF2α in thyroid tissue were also examined by WB. LIFPUS can effectively stimulate hUC-MSCs in vitro to achieve the most optimal proliferative and secretory activity. In the EAT model, hUC-MSCs can effectively reduce thyroid cell apoptosis, improve thyroid function and reduce excessive accumulation of autoimmune antibodies in the body. in comparison, the LIFPUS pretreatment group showed a more favorable treatment outcome. Further experiments demonstrated that hUC-MSCs transplantation may effectively inhibit the apoptotic state of thyroid follicles and follicular epithelial cells by down-regulating the unfolded protein reaction (UPR) of the PERK pathway, thus providing a therapeutic effect for AIT. hUC-MSCs can effectively reverse the physiological function of EAT thyroid tissue and reduce the accumulation of circulating antibodies in the body. in comparison, hUC-MSCs under LIFPUS pretreatment showed more desirable therapeutic potential. hUC-MSCs transplanted under LIFPUS pretreatment may be a new class of safe therapeutic modality for the treatment of AIT.

Progress and unmet needs in understanding fundamental mechanisms of autoimmunity

The rising incidence of autoimmune diseases is straining the healthcare system's capacity to care for patients with autoimmunity. To further compound this growing crisis, this rise occurs at a time when virulent infectious diseases exacerbate pre-existing conditions. Despite some novel targeted therapies introduced over the preceding decades, current treatment strategies must often fall back on non-specific immunosuppression, inflicting its own toll on patient morbidity. To improve patient care, we must re-double our efforts to understand and target the fundamental mechanisms of autoimmune disease initiation and progression. Technologic innovations have recently accelerated our ability to discover key components of the processes leading to loss of tolerance and propagation of self-tissue damage in autoimmune conditions. The special issue "Cellular and Molecular Mechanisms of Autoimmunity" highlights many of these findings through primary research and review articles which detail advances in genetics, molecular processes, cellular functions, and host-pathogen interactions. Discussion of topics ranging from non-coding RNA and the complement cascade to T-cell aging and the microbiome uncovers exciting avenues for basic and clinical investigation. Importantly, the issue seeks to focus attention on both established and emerging mechanisms of autoimmunity to ultimately help improve the specificity, safety, and efficacy of treatments for this group of challenging immune disorders.

Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus.

Neutrophil extracellular traps (NETs) serve to immobilize and kill pathogens, but also can contribute to the progression of several inflammatory and auto-immune diseases, as well as cancer. Whence the importance of elucidating the mechanisms underlying NET formation. In this regard, the PI3K signaling pathway has been shown to be crucial; yet little is known about which of its components are involved. Here, we identified the PI3K isoforms and associated signaling partners that are mobilized in response to different classes of physiological NET inducers (inflammatory cytokines, growth factors, chemoattractants). NET generation was assessed by microscopy and signalling molecule activation by immunoblot using phospho-antibodies. Across the various stimuli, PI3Kα and PI3Kγ isoforms clearly contributed to NET induction, while the participation of other isoforms was stimulus-dependent. Some PI3K isoforms were also found to signal through Akt, the canonical downstream effector of PI3K, while others did not. Downstream of PI3K, mTOR and PLCγ2 were used by all stimuli to control NET generation. Conversely, the involvement of other kinases depended on the stimulus - both TNFα and GM-CSF relied on PDK1 and Akt; and both TNFα and fMLP additionally used S6K. We further established that all PI3K isoforms and downstream effectors act belatedly in NET generation, as reported previously for PI3K. Finally, we revisited the PI3K-PDK1-Akt signaling hierarchy in human neutrophils and again found stimulus-dependent differences. Our data uncover unsuspected complexity and redundancy in the signaling machinery controlling NET formation through the all-important PI3K pathway. Conserved signaling molecules represent therapeutic targets for pathologies involving NETs and in this regard, the existence of drugs currently used in the clinic or undergoing clinical trials (which target PI3K isoforms, mTOR or Akt), underscores the translational potential of our findings.