Neural signaling regulates various reactions in our body including immune responses. Neuromodulation of this signaling using artificial neural activation and/or suppression is a potential treatment for diseases and disorders. We here review neural signaling regulating the immune system, with a special focus on the gateway reflex. The gateway reflex is a novel neuro-immune crosstalk mechanism that regulates tissue-specific inflammatory diseases. We have discovered six gateway reflexes so far; all are induced by environmental or artificial stimulations including gravity, electrical stimulation, pain sensation, stress, light, and inflammation in joints. In the presence of increased autoreactive T cells in the blood, such stimulation activates specific neural signaling to release noradrenaline (NA) from the nerve endings at specific blood vessels in the central nervous system. NA activates the interleukin-6 (IL-6) amplifier, which leads to the hyper-activation of nuclear factor-kappa B (NF-κB) in non-immune cells, resulting in the formation of a gateway. This gateway allows autoreactive T cells and other immune cells to accumulate in the target tissue to induce inflammatory diseases. In gateway reflexes induced by stress or remote inflammation, adenosine triphosphate (ATP) secreted from inflammation sites activates specific neural pathways, resulting in organ dysfunction and inflammation in other tissues, suggesting that the gateway reflex regulates tissue-specific inflammatory diseases by bidirectional crosstalk between the neural and immune systems. We also discuss other cases of neural signaling including the inflammatory reflex.

Despite advances in approaches to treatment for patients with systemic sclerosis (SSc), the effects have been modest at best. This investigator-initiated study aimed to evaluate the therapeutic benefit, safety and the genetic characteristics related to effect of baricitinib in SSc.

In this 24-week study, eligible SSc patients were randomised to baricitinib 4 mg, 2 mg or control group. The primary outcome was the change in modified Rodnan skin score (mRSS) from baseline to week 12. Secondary outcomes included changes in the American College of Rheumatology Combined Response Index in Systemic Sclerosis (ACR-CRISS) score, forced vital capacity (FVC), Systemic Sclerosis Score, tender and swollen joint counts, digital ulcers, EQ5D (EuroQol five-dimensions) and safety at week 12 and 24. Transcriptome differences in blood samples from patients before and after baricitinib treatment were compared. Gene Ontology enrichment analysis was performed to identify potential biological functions and canonical pathways.

Between April 2021 to January 2022, 48 patients were randomly assigned to three groups. Mean change in mRSS score from baseline to week 12 was - 8.9 in 4 mg group, - 3.8 in 2 mg group, and - 3.6 in control group (P = 0.019). At week 12, the ACR-CRISS scores were 0.5 and 0.3 in baricitinib 4 mg and 2 mg group, as compared with 0.2 among those in control group (P = 0.171). FVC (%), digital ulcers and EQ5D in 4 mg baricitinib group showed favorable responses over 24 weeks. There were no significant differences in adverse events among groups. The differentially expressed genes (DEGs) identified in our analysis were significantly enriched in gene ontology (GO) terms related to the positive regulation of cytokine production, immune response-activating signaling pathway, and activation of immune response pathway. Interleukin- 1 Receptor Like 1 (IL- 1RL1 or ST2) and synaptotagmin- 17 (SYT17) were downregulated and upregulated respectively, after baricitinib treatment.

The therapy with baricitinib 4 mg appeared to improve mRSS of SSc patients, probably by influencing mechanisms of immune inflammation, and had an acceptable safety profile. This study paves the way for further investigations into Janus kinase (JAK) 1/2 inhibition with baricitinib as a prospective treatment for SSc. Key Points • The baricitinib 4 mg seems to improve clinical outcomes of SSc patients with safety profiles. • The mechanism of JAK inhibitors has been confirmed to be related to anti-inflammatory pathways and molecules in clinical samples.

Once regarded as passive bystander cells of the tissue stroma, fibroblasts have emerged as active orchestrators of tissue homeostasis and disease. From regulating immunity and controlling tissue remodelling to governing cell growth and differentiation, fibroblasts assume myriad roles in guiding normal tissue development, maintenance and repair. By comparison, in chronic inflammatory diseases such as rheumatoid arthritis, fibroblasts recruit and sustain inflammatory leukocytes, become dominant producers of pro-inflammatory factors and catalyse tissue destruction. In other disease contexts, fibroblasts promote fibrosis and impair host control of cancer. Single-cell studies have uncovered striking transcriptional and functional heterogeneity exhibited by fibroblasts in both normal tissues and diseased tissues. In particular, advances in the understanding of fibroblast pathology in rheumatoid arthritis have shed light on pathogenic fibroblast states in other chronic diseases. The differentiation and activation of these fibroblast states is driven by diverse physical and chemical cues within the tissue microenvironment and by cell-intrinsic signalling and epigenetic mechanisms. These insights into fibroblast behaviour and regulation have illuminated therapeutic opportunities for the targeted deletion or modulation of pathogenic fibroblasts across many diseases.

Breast cancer (BC) is a health concern worldwide and is often accompanied by depressive symptoms in patients. In BC, elevated interleukin-6 (IL-6) levels contribute to an inflammatory signature linked to cancer stem cell (CSC) stemness and depressive behaviors. Bioactive food components, such as berberine (BBR), have preventative effects against BC by targeting CSCs.

This study aimed to investigate the effects of BBR on breast CSC proliferation, on levels of specific micro (mi)RNAs and IL-6 in vitro and in vivo, and in alleviating depressive-like behaviors in mice with BC.

Mammosphere formation assays were conducted by treating murine 4T1 and human MDA-MB-231 BC cell lines with BBR. qPCR analysis of miRNAs miR-let-7c and miR-34a-5p was performed on 4T1 CSCs exposed to BBR. BBR was administered orally to female BALB/c, followed by injection with mammary carcinoma cells to induce BC. Behavioral tests were conducted to assess depressive-like behaviors. Tumor tissues were collected for ex vivo mammosphere assays, miRNA expression analysis, and IL-6 detection by ELISA. Serum was also collected for IL-6 analysis.

BBR treatment inhibited mammosphere formation and proliferation of CSCs derived from 4T1 and MDA-MB-231 cell lines. Quantification of mammosphere formation showed a significant decrease in both cell lines at 75 μM BBR (4T1: P < 0.001; MDA-MB-231: P < 0.0001). BBR upregulated the expression of miRNAs miR-let-7c and miR-34a in both cell lines, with miR-34a showing a significant increase (P < 0.001) and let-7c showing a significant increase (P < 0.05) in expression. In vivo, oral administration of BBR reduced mammosphere formation in breast tumor tissues (P < 0.0001) and elevated expression of miR-145 and miR-34a, with both showing significant upregulation (P < 0.0001), indicating its potential tumor-suppressive effects. BBR treatment resulted in a significant decrease in serum IL-6 levels (P < 0.05), suggesting anti-inflammatory properties, while the IL-6 in tumor tissue did not show significant changes (P > 0.05). However, no significant differences were observed in depressive-like behaviors between control and treatment groups.

BBR may have the potential to be used as an "Epi-Natural Compound" to prevent cancer by reducing inflammation and affecting epigenetics.

Ankylosing spondylitis (AS) is an autoimmune rheumatic disease that primarily affects the axial joints, with its etiology complex and still not fully understood. The unknown pathogenesis of AS limits the development of treatment strategies, so keeping up-to-date with the current research on AS can help in searching for potential therapeutic targets. In addition to the classic HLA-B27 genetic susceptibility and Th17-related inflammatory signals, increasing research is focusing on the influence of autoantigen-centered autoimmune responses and bone stromal cells on the onset of AS. Autoantigens derived from gut microbiota and preferential TCR both exacerbate the autoimmune response in patients with AS. Furthermore, dysregulated bone metabolism also promotes pathological new bone formation in AS. Current treatments approved for AS almost focus on the management of inflammation with inconsistent treatment results due to the heterogeneity of patients. In this review, we systematically summarized various pathogenesis and management of AS, meanwhile discussed the underlying risk factors and potential therapeutic targets.

Examining cytokine profile complexities in chronic autoimmune disorders holds significant clinical importance. In order to address the similarities and differences related to SLE and RA, it was necessary to evaluate their cytokine chemokine profiles. Such analyses would give pointers towards differences, leading thereby to explore the potential of cytokines/chemokines as biomarkers. The study was therefore driven by the concept of understanding the major differences at this level with a hope of contribution towards diagnostics/theranostics. A multiplex study was carried out on systemic autoimmune disorders, such as SLE and RA, analysing forty analytes in comparison with healthy controls.

Age and sex matched healthy donors and patients (n=38) were recruited and plasma cytokine profiling was done by Bio-plex multiplex immunoassay system.

A comparison with healthy volunteers revealed differential alteration in various chemokines in SLE and RA, respectively. Protein interaction analysis identified a core complex of chemokines (CXCL10, CCL5, CXCL12, CXCL9, CXCL1, and CXCL27) as central modulators, suggesting their potential as biomarkers. Drug prediction using the DSigDB database identified acetovanillone as a potential drug against this core complex. In comparing lupus patients with or without arthritis comorbidity, elevated levels of cytokines: IL-12, SCF, and TNF-a were prominently associated with arthritis in SLE. TNF-a emerged as a potential indicator specifically for arthritis.

This study enhances our understanding of the complex interplay of cytokine/chemokine in these systemic conditions and suggests their utility as targets and diagnostic paradigms for detection.

In 2020, the coronavirus disease 2019 (COVID-19) pandemic began worldwide. We examined the association between dental visit status and the incidence of COVID-19 and hospitalisation for it among older people based on medical claims data to help reduce COVID-19 severity. The study included 170,232 people who were 75-85 years old in fiscal 2019, with fiscal 2020 and 2021 serving as the follow-up period to ascertain the status of COVID-19. Using medical claims data, we investigated four types of dental visit (no visit, only periodontal treatment, periodontal and other treatment, and only other treatment) during fiscal 2019 and the incidence of COVID-19 and hospitalisation for COVID-19 during the follow-up period. Logistic regression analyses were performed with the incidence of COVID-19 and hospitalisation for COVID-19 as the dependent variables. Of the participants, 3206 (1.9%) developed COVID-19, of whom, 559 (17.4%) were hospitalised. There was not a significant association between the incidence of COVID-19 and type of dental visit. Participants with dental visits for periodontal treatment during the baseline year had a significantly lower odds ratio (OR) for hospitalisation due to COVID-19 compared to those without dental visits (OR: 0.71, 95% confidence interval: 0.58-0.78). The results suggest that dental visits for periodontal treatment including maintenance are important not only for maintaining oral health but also for preventing severe COVID-19.

Biological monoclonal antibody drugs inhibit overactive cytokine signalling that drives chronic inflammatory disease in different organ systems. In the last 10 years, interleukin (IL)-23 inhibitors have attained an important position in the treatment of psoriatic skin and joint disease as well as inflammatory bowel diseases. Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response that extends dosing intervals up to 3 months. Pooled clinical trial data show objective disease improvement for more than 70% of patients with psoriasis and up to 50% of patients with inflammatory bowel disease. The first antibody inhibitor for IL-23A targeted a p40 subunit shared with IL-12. Subsequently, even greater improvement was established for inhibitors of the p19 protein unique to IL-23A. IL-23 p19 inhibitors elicit clinical response in both bio-naive and bio-exposed patients and show superiority to tumour necrosis factor α inhibitors in plaque psoriasis. Reported differences in efficacy between p19 inhibitors suggest that individual drug action might be modulated by antibody affinity. Although long-term safety data are accumulating, rates of serious adverse events and infections for interleukin (IL)-23 inhibitors are similar to the rates for placebo across approved indications.

STAT3 gain-of-function syndrome, characterized by early-onset autoimmunity and primary immune regulatory disorder, remains poorly understood in terms of its immunological mechanisms. We employed whole-genome sequencing of familial trios to elucidate the pivotal role of de novo mutations in genetic diseases. We identified 37 high-risk pathogenic loci affecting 23 genes, including a novel STAT3 c.508G>A mutation. We also observed significant down-regulation of pathogenic genes in affected individuals, potentially associated with inflammatory responses regulated by PTPN14 via miR378c. These findings enhance our understanding of the pathogenesis of STAT3 gain-of-function syndrome and suggest potential therapeutic strategies. Notably, combined JAK inhibitors and IL-6R antagonists may offer promising treatment avenues for mitigating the severity of STAT3 gain-of-function syndrome.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflammatory lesions, which affect skin and hair follicles in intertriginous areas. HS has a multifactorial aetiology resulting in barrier dysfunction associated with aberrant immune activation. There is increased evidence for the role of inflammasomes in the pathophysiology of inflammatory skin diseases, including HS. Inflammasomes are multiprotein complexes activated following exposure to danger signals, including microbial ligands and components of damaged host cells. Inflammasome activation induces many signalling cascades and subsequent cleavage of proinflammatory cytokines - most notably interleukin (IL)-1β - which have a role in HS pathogenesis. Limited immunotherapies are approved for treating moderate-to-severe HS, with variable response rates influenced by disease heterogeneity. Inflammasomes represent attractive targets to suppress multiple inflammatory pathways in HS, including IL-1β and IL-17. This review aims to summarize the role of inflammasomes in HS and to evaluate evidence for inflammasomes as therapeutic targets for HS treatment.

Major psychotic disorders (MPD), including schizophrenia (SCZ) and schizoaffective disorder (SAD), are severe neuropsychiatric conditions with unclear causes. Understanding their pathophysiology is essential for better diagnosis, treatment, and prognosis. Recent research highlights the role of inflammation and the immune system, particularly the Interleukin 17 (IL-17) family, in these disorders. Elevated IL-17 levels have been found in MPD, and human IL-17 A antibodies are available. Changes in chemokine levels, such as CCL20, are also noted in SCZ. This study investigates the relationship between serum levels of IL-17 A and CCL20 in MPD patients and their clinical characteristics.

We conducted a case-control study at the Ibn Sina Psychiatric Hospital (Mashhad, Iran) in 2023. The study involved 101 participants, of which 71 were MPD patients and 30 were healthy controls (HC). The Positive and Negative Symptom Scale (PANSS) was utilized to assess the symptoms of MPD patients. Serum levels of CCL20 and IL-17 A were measured using Enzyme-Linked Immunosorbent Assay (ELISA) kits. We also gathered data on lipid profiles and Fasting Blood Glucose (FBS).

The mean age of patients was 41.04 ± 9.93 years. The median serum levels of CCL20 and IL-17 A were significantly elevated in MPD patients compared to HC (5.8 (4.1-15.3) pg/mL and 4.2 (3-5) pg/mL, respectively; p < 0.001). Furthermore, CCL20 and IL-17 A levels showed a positive correlation with the severity of MPD. MPD patients also had significantly higher FBS, cholesterol, and Low-Density Lipoprotein (LDL) levels, and lower High-Density Lipoprotein (HDL) levels compared to HC. No significant relationship was found between PANSS components and blood levels of IL17 and CCL20.

The current study revealed that the serum levels of IL-17 A and CCL20 in schizophrenia patients are higher than those in the control group. Metabolic factors such as FBS, cholesterol, HDL, and LDL also showed significant differences between MPD and HC. In conclusion, the findings suggest that these two inflammatory factors could serve as potential therapeutic targets and prognostic biomarkers for schizophrenia.

Multiple sclerosis (MS) is an autoimmune inflammatory condition affecting the central nervous system, and experimental autoimmune encephalomyelitis (EAE) animal models have been extensively used to study it. T-helper 17 cells, which produce interleukin-17(IL-17), play crucial roles in MS pathogenesis, and the JAK2/STAT3 pathway has an essential function in their differentiation from naive CD4 + T cells. This study investigated the effects of the JAK2/STAT3 pathway inhibitor AG490 on EAE in vivo and in vitro, as well as the underlying mechanisms. AG490 ameliorated EAE severity and attenuated its typical symptoms by downregulating proteins associated with the JAK2/STAT3 pathway. Furthermore, it decreased T-helper 17 cell differentiation from naive CD4 + T cells by inactivating STAT3. In addition, it conferred protective effects against EAE by restoring autophagy. These findings indicate the potential of AG490 as a candidate anti-MS therapeutic.

Preterm birth is a major public health concern, requiring a deeper understanding of its underlying inflammatory mechanisms and to develop effective therapeutic strategies. This review explores the complex interaction between inflammation and preterm labor, highlighting the pivotal role of the dysregulation of inflammation in triggering premature delivery. The immunological environment of pregnancy, characterized by a fragile balance of immune tolerance and resistance, is disrupted in preterm labor, leading to a pathological inflammatory response. Feto-maternal infections, among other pro-inflammatory stimuli, trigger the activation of toll-like receptors and the production of pro-inflammatory mediators, promoting uterine contractility and cervical ripening. Emerging anti-inflammatory therapeutics offer promising approaches for the prevention of preterm birth by targeting key inflammatory pathways. From TLR-4 antagonists to chemokine and interleukin receptor antagonists, these interventions aim to modulate the inflammatory environment and prevent adverse pregnancy outcomes. In conclusion, a comprehensive understanding of the inflammatory mechanisms leading to preterm labor is crucial for the development of targeted interventions in hope of reducing the incidence of preterm birth and improving neonatal health outcomes.

This article aims to investigate the changes of T helper 17 (Th17) cells, regulatory T (Treg) cells and their associated cytokines in patients with systemic lupus erythematosus (SLE).

Multiple databases were investigated to identify articles that explored Th17 cells, Treg cells and relevant cytokines in SLE patients. A random effects model was used for calculating pooled standardized mean differences. Stata version 15.0 was utilized to conduct the meta-analysis.

The levels of Th17 cells, IL-17, IL-6, IL-21 and IL-10 were higher in SLE patients than in healthy controls (HCs), but the TGF-β levels were lower. The percentage of Treg cells was lower than HCs in SLE individuals older than 33. Among studies that had 93% or lower females, the percentage of Th17 cells was greater in patients than in HCs. However, the percentage of Treg cells was lower when the proportion of females was less than 90%. Patients with lupus nephritis or active SLE had an increased proportion of Th17 cells and a decreased proportion of Treg cells.

The increased level of Th17 cells and related cytokines could be the main reason for the elevated Th17/Treg ratio in SLE. The percentages of Th17 and Treg cells were associated with gender, age, disease activity and kidney function. Furthermore, the reduced proportions of Treg cells may primarily result in a rise in the Th17/Treg ratio in older or active SLE patients.

https://www.crd.york.ac.uk/prospero, identifier CRD42023454937.

Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.

Ulcerative colitis is a chronic disease with colonic mucosa injury. Nitazoxanide is an antiprotozoal drug in clinic. Nitazoxanide and its metabolite tizoxanide have been demonstrated to activate AMPK and inhibit inflammation, therefore, the aim of the present study is to investigate the effect of nitazoxanide on dextran sulfate sodium (DSS)-induced colitis and the underlying mechanism. Oral administration of nitazoxanide ameliorated the symptoms of mice with DSS-induced colitis, as evidenced by improving the increased disease activity index (DAI), the decreased body weight, and the shortened colon length. Oral administration of nitazoxanide ameliorated DSS-induced intestinal barrier dysfunction and reduced IL-6 and IL-17 expression in colon tissues. Mechanistically, nitazoxanide and its metabolite tizoxanide treatment activated AMPK and inhibited JAK2/STAT3 signals. Nitazoxanide and tizoxanide treatment increased caudal type homeobox 2 (CDX2) expression, increased alkaline phosphatase (ALP) activity and promoted tight junctions in Caco-2 cells. Nitazoxanide and tizoxanide treatment restored the decreased zonula occludens-1(ZO-1) and occludin protein levels induced by LPS or IL-6 in Caco-2 cells. On the other hand, nitazoxanide and tizoxanide regulated macrophage bias toward M2 polarization, as evidenced by the increased arginase-1expression in bone marrow-derived macrophages (BMDM). Nitazoxanide and tizoxanide reduced the increased IL-6, iNOS and CCL2 pro-inflammatory gene expressions and inhibited JAK2/STAT3 activation in BMDM induced by LPS. In conclusion, nitazoxanide protects against DSS-induced ulcerative colitis in mice through improving intestinal barrier and inhibiting inflammation and the underlying mechanism involves AMPK activation and JAK2/STAT3 inhibition.

Acute liver failure (ALF) is a serious inflammatory disorder with high mortality rates, which poses a significant threat to human health. The IL-33/ST2 signal is a crucial regulator in inflammation responses associated with lipopolysaccharide (LPS)-induced macrophages. The IL-17A signaling pathway promotes the release of chemokines and inflammatory cytokines, recruiting neutrophils and T cells under LPS stimulation, thus facilitating inflammatory responses. Here, the potential therapeutic benefits of neutralizing the IL-17A signal and modulating the IL-33/ST2 signal in ALF were investigated. A novel dual-functional fusion protein, anti-IL-17A-sST2, was constructed, which displayed high purity and biological activities. The administration of anti-IL-17A-sST2 resulted in significant anti-inflammatory benefits in ALF mice, amelioration of hepatocyte necrosis and interstitial congestion, and reduction in TNF-α and IL-6. Furthermore, anti-IL-17A-sST2 injection downregulated the expression of TLR4 and NLRP3 as well as important molecules such as MyD88, caspase-1, and IL-1β. The results suggest that anti-IL-17A-sST2 reduced the secretion of inflammatory factors, attenuated the inflammatory response, and protected hepatic function by regulating the TLR4/MyD88 pathway and inhibiting the NLRP3 inflammasome, providing a new therapeutic approach for ALF.

CD4+CD25+Foxp3+ regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune responses. This review explores the signaling pathways of the cytokines that regulate Treg cells, including transforming growth factor beta (TGF-β), interleukin (IL)-2, IL-10, and IL-35, which foster the differentiation and enhance the immunosuppressive capabilities of Tregs. It also examines how, conversely, signals mediated by IL-6 and tumor necrosis factor -alpha (TNF-α) can undermine Treg suppressive functions or even drive their reprogramming into effector T cells. The B7 family comprises indispensable co-stimulators for T cell activation. Among its members, this review focuses on the capacity of CTLA-4 and PD-1 to regulate the differentiation, function, and survival of Tregs. As Tregs play an essential role in maintaining immune homeostasis, their dysfunction contributes to the pathogenesis of autoimmune diseases. This review delves into the potential of employing Treg-based immunotherapy for the treatment of autoimmune diseases, transplant rejection, and cancer. By shedding light on these topics, this article aims to enhance our understanding of the regulation of Tregs by cytokines and their therapeutic potential for various pathological conditions.

Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system (CNS) characterized by the myelin sheath destruction and compromised nerve signal transmission. Understanding molecular mechanisms driving MS development is critical due to its early onset, chronic course, and therapeutic approaches based only on symptomatic treatment. Cytokines are known to play a pivotal role in the MS pathogenesis with interleukin-6 (IL-6) being one of the key mediators. This study investigates contribution of IL-6 produced by microglia and dendritic cells to the development of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS. Mice with conditional inactivation of IL-6 in the CX3CR1+ cells, including microglia, or CD11c+ dendritic cells, displayed less severe symptoms as compared to their wild-type counterparts. Mice with microglial IL-6 deletion exhibited an elevated proportion of regulatory T cells and reduced percentage of pathogenic IFNγ-producing CD4+ T cells, accompanied by the decrease in pro-inflammatory monocytes in the CNS at the peak of EAE. At the same time, deletion of IL-6 from microglia resulted in the increase of CCR6+ T cells and GM-CSF-producing T cells. Conversely, mice with IL-6 deficiency in the dendritic cells showed not only the previously described increase in the proportion of regulatory T cells and decrease in the proportion of TH17 cells, but also reduction in the production of GM-CSF and IFNγ in the secondary lymphoid organs. In summary, IL-6 functions during EAE depend on both the source and localization of immune response: the microglial IL-6 exerts both pathogenic and protective functions specifically in the CNS, whereas the dendritic cell-derived IL-6, in addition to being critically involved in the balance of regulatory T cells and TH17 cells, may stimulate production of cytokines associated with pathogenic functions of T cells.

Chronic antibody mediated rejection (AMR) is the major cause of solid organ graft rejection. Th17 contributes to AMR through the secretion of IL17A, IL21 and IL22. These cytokines promote neutrophilic infiltration, B cell proliferation and donor specific antibodies (DSAs) production. In the current study we investigated the role of Th17 in transplant sensitization. Additionally, we investigated the therapeutic potential of novel inverse agonists of the retinoic acid receptor-related orphan receptor gamma t (RORγt) in the treatment of skin allograft rejection in sensitized mice. Our results show that RORγt inverse agonists reduce cytokine production in human Th17 cells in vitro. In mice, we demonstrate that the RORγt inverse agonist TF-S14 reduces Th17 signature cytokines in vitro and in vivo and leads to blocking neutrophilic infiltration to skin allografts, inhibition of the B-cell differentiation, and the reduction of de novo IgG3 DSAs production. Finally, we show that TF-S14 prolongs the survival of a total mismatch grafts in sensitized mice. In conclusion, RORγt inverse agonists offer a therapeutic intervention through a novel mechanism to treat rejection in highly sensitized patients.

Psoriasis is one of the most common inflammatory skin diseases with a chronic, relapsing-remitting course. The last decades of intense research uncovered a pathological network of interactions between immune cells and other types of cells in the pathogenesis of psoriasis. Emerging evidence indicates that dendritic cells, TH17 cells, and keratinocytes constitute a pathogenic triad in psoriasis. Dendritic cells produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells that produce key psoriatic cytokines IL-17, IFN-γ, and IL-22. Their activity results in skin inflammation and activation and hyperproliferation of keratinocytes. In addition, other cells and signaling pathways are implicated in the pathogenesis of psoriasis, including TH9 cells, TH22 cells, CD8+ cytotoxic cells, neutrophils, γδ T cells, and cytokines and chemokines secreted by them. New insights from high-throughput analysis of lesional skin identified novel signaling pathways and cell populations involved in the pathogenesis. These studies not only expanded our knowledge about the mechanisms of immune response and the pathogenesis of psoriasis but also resulted in a revolution in the clinical management of patients with psoriasis. Thus, understanding the mechanisms of immune response in psoriatic inflammation is crucial for further studies, the development of novel therapeutic strategies, and the clinical management of psoriasis patients. The aim of the review was to comprehensively present the dysregulation of immune response in psoriasis with an emphasis on recent findings. Here, we described the role of immune cells, including T cells, B cells, dendritic cells, neutrophils, monocytes, mast cells, and innate lymphoid cells (ILCs), as well as non-immune cells, including keratinocytes, fibroblasts, endothelial cells, and platelets in the initiation, development, and progression of psoriasis.

Anti-IL-17A antibodies, such as secukinumab and ixekizumab, are effective proinflammatory cytokine inhibitors for autoimmune disorders, including psoriasis. However, anti-IL-17A small molecule treatments are yet to be commercialized. Celastrol, a natural compound extracted from the roots of traditional Chinese medicinal plants, has anti-inflammatory and antioxidant properties. However, the binding of celastrol to IL-17A and the associated anti-inflammatory mechanisms remain unclear. This study investigated whether celastrol could directly bind to IL-17A and regulate inflammation in psoriatic in vitro and in vivo models. The results showed that celastrol directly binds to IL-17A and inhibits its downstream signaling, including the NF-kB and MAPK pathways. Interestingly, celastrol restored autophagy dysfunction and reduced proinflammatory cytokine secretion in keratinocytes. In addition, celastrol increased autophagy in the epidermis of a mouse model of psoriasis. Celastrol decreased Th17 cell populations and proinflammatory cytokine levels in mice. Thus, IL-17A-targeting celastrol reduced inflammation by rescuing impaired autophagy in in vitro and in vivo models of psoriasis, demonstrating its potential as a substitute for anti-IL-17A antibodies for treating psoriasis.

Ge Gen Decoction (GGD) is a classic traditional Chinese medicine (TCM) prescription that originated in the ancient Chinese medical book "Treatise on Febrile Diseases". The prescription consists of 7 herbs: Pueraria lobata (Willd.) Ohwi, Ephedra sinica Stapf, Cinnamomum cassia (L.) J.Presl, Paeonia lactiflora Pall., Glycyrrhiza uralensis Fisch., Zingiber officinale Rosc., and Ziziphus jujuba Mill. It can alleviate high fever and soreness in the neck and shoulders caused by exogenous wind chill and is widely used in both China and Japan. Currently, GGD is primarily utilized for treating flu and the common cold. GGD has been reported to show significant anti-influenza A virus (IAV) activity both in vitro and in vivo. However, the active ingredients responsible for its anti-influenza properties have not been elucidated, and the mechanisms underlying its anti-influenza effects require further research.

This study aims to investigate the active ingredients and molecular mechanisms of GGD in treating influenza.

HPLC chromatograms were established for GGD water and different polar extracts. The effect of different GGD extracts on pulmonary virus titers and TNFα expression was assessed through RT-PCR analysis. Spectrum-effect relationships between chromatographic peaks of GGD and its virus inhibition rate and TNFα inhibition rate were investigated using partial least squares regression (PLSR) analysis. HPLC-Q-TOF-MS was utilized to identify the constituents absorbed into the blood after oral administration of GGD. Network analysis of the absorbed forms of active ingredients was conducted to predict the potential mechanisms of GGD. Subsequently, total SOD activity, CAT and HO-1 expression and Nrf2 nuclear translocation were then analyzed. Finally, the impact of interfering with HO-1 expression on the anti-IAV activity of GGD was examined.

The study identified 11 anti-influenza active ingredients in GGD, which are daidzein, ononin, genistin, daidzin, 3'-methoxypuerarin, puerarin, pseudoephedrine, paeoniflorin, pormononetin-7-xylosyl-glucoside, penistein-7-O-apiosyl-glucoside, and ephedrine. Network analysis revealed various biological activities of GGD, including responses to ROS and oxidative stress. GGD also involves multiple antiviral pathways, such as hepatitis B, IAV, and Toll-like receptor pathways. Experimental assays demonstrated that GGD possesses independent antioxidant activity both in vitro and in vivo. In vitro, GGD inhibits the increase in intracellular ROS induced by IAV. In vivo, it reduces MDA levels and increases total pulmonary SOD activity. Applying siRNA and flow cytometry analysis revealed that GGD alleviates IAV-induced oxidative burst by promoting the expression of HO-1 and CAT. Western blot analysis revealed that GGD effectively promotes Nrf2 nuclear translocation and enhances Nrf2 expression. Furthermore, this study found that the enhancement of HO-1 expression by GGD contributed to its anti-IAV activity.

The study identified the active ingredients of GGD against influenza and demonstrated the beneficial role of GGD's antioxidant activity in treating flu. The antioxidant activity of GGD is associated with the promotion of Nrf2 nuclear translocation and the upregulation of antioxidant enzymes such as SOD, HO-1, and CAT. Overall, this study provides evidence supporting the use of GGD as an adjunctive or complementary therapy for influenza.

Olacein (OLA), one of the main secoiridoids derived from extra virgin olive oil (EVOO), has been shown to modulate oxidative and inflammatory responses in various pathological conditions; however, its potential benefit in joint disorders such as rheumatoid arthritis (RA) is unknown. Therefore, this study was designed to evaluate the preventive role of the effects of an OLA-supplemented diet in the murine model of collagen-induced arthritis (CIA), delving into the possible mechanisms and signaling pathways involved. Animals were fed an OLA-enriched preventive diet for 6 weeks prior to CIA induction and until the end of the experimental time course. On day 43 after the first immunization, mice were sacrificed: blood was collected, and paws were histologically and biochemically processed. Dietary OLA prevented collagen-induced rheumatic bone, joint and cartilage conditions. Circulating matrix metalloproteinase (MMP)-3 and proinflammatory cytokine (IL-6, IL-1β, TNF-α, IL-17) levels were significantly decreased in the joint, as well as MMP-9 and cathepsin-K (CatK) expression in secoiridoid-fed animals. In addition, dietary OLA was able to decrease COX-2, mPGES-1 and iNOS protein expressions and, also, PGE2 levels. The mechanisms possibly involved in these protective effects could be related to the activation of the Nrf-2/HO-1 axis and the inhibition of proinflammatory signaling pathways, including JAK-STAT, MAPKs and NF-κB, involved in the production of inflammatory and oxidative mediators. These results support the interest of OLA, as a nutraceutical intervention, in the management of RA.

Among the proposed mechanisms for autism spectrum disorders (ASD) is immune dysregulation. The proinflammatory cytokine Interleukine-17A (IL-17A) was shown to play a key role in mediating immune-related neurodevelopmental impairment of social behavior. Nevertheless, post-developmental administration of IL-17A was found to increase social behavior. In the present study, we explored the effect of post-developmental administration of IL-17A on ASD-like behaviors induced by developmental exposure to valproic acid (VPA) at postnatal day 4. At the age of seven weeks, VPA-exposed mice were intravenously injected twice with recombinant murine IL-17A (8 μg), and a week later, they were assessed for ASD-like behavior. IL-17A administration increased social behavior and alleviated the ASD-like phenotype. Behavioral changes were associated with increased serum levels of IL-17 and Th17-related cytokines. Exogenous IL-17A also increased neuritogenesis in the dendritic tree of doublecortin-expressing newly formed neurons in the dentate gyrus. Interestingly, the effect of IL-17A on neuritogenesis was more noticeable in females than in males, suggesting a sex-dependent effect of IL-17A. In conclusion, our study suggests a complex role for IL-17A in ASD. While contributing to its pathology at the developmental stage, IL-17 may also promote the alleviation of behavioral deficits post-developmentally by promoting neuritogenesis and synaptogenesis in the dentate gyrus.

The aim is to explore the roles of phosphorylated signal transduction and activator of transcription 3 (p-STAT3) and interleukin (IL)-17 in patients with dermatomyositis (DM).

A total of 20 DM patients and 12 healthy controls were enrolled. Flow cytometry combined with counting was used to detect the number of Th17 cells. Western blotting and immunohistochemistry were used to examine the muscle levels of p-STAT3 and IL-17, and serum levels of IL-17 were measured by enzyme-linked immunosorbent assays.

Muscle p-STAT3 and IL-17 levels, the number of Th17 cells, and serum IL-17 levels were markedly increased in DM. p-STAT3 and IL-17 were co-expressed in the muscle of DM patients. The p-STAT3 levels were correlated with the number of Th17 cells as well as muscle and serum IL-17 levels. The correlations of the p-STAT3 level with elevated levels of transaminases, myocardial enzymes, and the health assessment questionnaire score were significantly positive, while the correlation with manual muscle testing-8 was significantly negative. A receiver operating characteristic curve indicated the good predictive value of p-STAT3 for the occurrence of DM.

The increased p-STAT3/IL-17 signaling pathway activation in DM patients may induce muscle inflammation and necrosis, and it may be a potential target for DM.

Hydroxysafflor yellow A (HSYA) is derived from Carthamus tinctorius L. (Honghua in Chinese) and is used to treat cardiovascular and cerebrovascular disease. However, the mechanism by which HSYA treats ischemic stroke following atherosclerosis (ISFA) remains unclear. The targets and pathways of HSYA against ISFA were obtained using network analysis. A total of 3335 potential IFSA-related targets were predicted using the GenCards and Drugbank databases, and a total of 88 potential HSYA-related targets were predicted using the Swiss Target Prediction database. A total of 62 HSYA-related targets against IFSA were obtained. The network was composed of HSYA, 62 targets, and 20 pathways. The top 20 targets were constructed via the protein-protein interaction (PPI) network. Gene Ontology analysis revealed that the targets were involved in signal transduction, protein phosphorylation, the cytoplasm, the plasma membrane, the cytosol, zinc ion binding, ATP binding, protein kinase binding/activity, and enzyme binding. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the pathways were associated with cancer, inflammatory mediator regulation of the transient receptor potential channels, and microRNA in cancer. Additionally, molecular docking indicated that HSYA mainly interacts with five targets, namely interleukin 1 beta (IL-1β), signal transducer and activator of transcription 3 (STAT3), E1A-binding protein p300 (EP300), protein kinase C alpha (PRKCA), and inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB). In animal experiments, HSYA administration ameliorated the infarct size, neurological deficit score, histopathological changes, carotid intima-media thickness (IMT), and blood lipid level (total cholesterol and triglycerides). Immunochemistry and quantitative PCR showed that HSYA intervention downregulated the expression of STAT3, EP300, PRKCA, and IKBKB, and the enzyme-linked immunoassay showed reduced IL-1β levels. The findings of this study provide a reference for the development of anti-ISFA drugs.

The COVID-19 pandemic has uncovered many mysteries about SARS-CoV-2, including its potential to trigger abnormal autoimmune responses. Emerging evidence suggests women may face higher risks from COVID-induced autoimmunity manifesting as persistent neurological symptoms. Elucidating the mechanisms underlying this female susceptibility is now imperative. We synthesize key insights from existing studies on how COVID-19 infection can lead to immune tolerance loss, enabling autoreactive antibodies and lymphocyte production. These antibodies and lymphocytes infiltrate the central nervous system. Female sex hormones like estrogen and X-chromosome mediated effects likely contribute to dysregulated humoral immunity and cytokine profiles among women, increasing their predisposition. COVID-19 may also disrupt the delicate immunological balance of the female microbiome. These perturbations precipitate damage to neural damage through mechanisms like demyelination, neuroinflammation, and neurodegeneration - consistent with the observed neurological sequelae in women. An intentional focus on elucidating sex differences in COVID-19 pathogenesis is now needed to inform prognosis assessments and tailored interventions for female patients. From clinical monitoring to evaluating emerging immunomodulatory therapies, a nuanced women-centered approach considering the hormonal status and immunobiology will be vital to ensure equitable outcomes. Overall, deeper insights into the apparent female specificity of COVID-induced autoimmunity will accelerate the development of solutions mitigating associated neurological harm.

Neuroinflammation is an important biological process induced by complex interactions between immune cells and neuronal cells in the central nervous system (CNS). Recent research on the bidirectional communication between neuronal and immunological systems has provided evidence for how immune and inflammatory processes are regulated by nerve activation. One example is the gateway reflex, in which immune cells bypass the blood brain barrier and infiltrate the CNS to cause neuroinflammation. We have found several modes of the gateway reflex in mouse models, in which gateways for immune cells are established at specific blood vessels in the spinal cords and brain in experimental autoimmune encephalomyelitis and systemic lupus erythematosus models, at retinal blood vessels in an experimental autoimmune uveitis model, and the ankle joints in an inflammatory arthritis model. Several environmental stimulations, including physical and psychological stresses, activate neurological pathways that alter immunological responses via the gateway reflex, thus contributing to the development/suppression of autoimmune diseases. In the manuscript, we describe the discovery of the gateway reflex and recent insights on how they regulate disease development. We hypothesize that artificial manipulation of specific neural pathways can establish and/or close the gateways to control the development of autoimmune diseases.

Alzheimer's disease (AD) is the most common form of dementia. Unfortunately, despite numerous studies, an effective treatment for AD has not yet been established. There is remarkable evidence indicating that the innate immune mechanism and adaptive immune response play significant roles in the pathogenesis of AD. Several studies have reported changes in CD8+ and CD4+ T cells in AD patients. This mini-review article discusses the potential contribution of CD4+ and CD8+ T cells reactivity to amyloid β (Aβ) protein in individuals with AD. Moreover, this mini-review examines the potential associations between T cells, heme oxygenase (HO), and impaired mitochondria in the context of AD. While current mathematical models of AD have not extensively addressed the inclusion of CD4+ and CD8+ T cells, there exist models that can be extended to consider AD as an autoimmune disease involving these T cell types. Additionally, the mini-review covers recent research that has investigated the utilization of machine learning models, considering the impact of CD4+ and CD8+ T cells.

Oral lichen planus (OLP) is a chronic inflammatory disease associated with T cell infiltration. The crosstalk between oral epithelium and mucosal T cells was considered to be crucial in the pathogenesis of OLP. Here, we selectively extracted the normal epithelium (NE) and lesional epithelium (LE) of buccal mucosa specimens from three patients with OLP by laser capture microdissection due to identify the pathogenic factors. Cathepsin K (CTSK) was identified as one of common upregulated genes in the LE by DNA microarray. Immunohistochemically, CTSK was distinctly detected in and around the LE, while it was rarely seen in the NE. Recent studies showed that CTSK enhanced Toll-like receptor 9 (TLR9) signaling in antigen-presenting cells, leading to Th17 cell differentiation. TLR9 expression mainly co-localized with CD123+ plasmacytoid dendritic cells (pDCs). The number of RORγt-positive cells correlated with that of CTSK-positive cells in OLP tissues. CD123+ pDCs induced the production of Th17-related cytokines (IL-6, IL-23, and TGF-β) upon stimulation with TLR9 agonist CpG DNA. Moreover, single cell RNA-sequencing analysis revealed that TLR9-positive pDCs enhanced in genes associated with Th17 cell differentiation in comparison with TLR9-negative pDCs. CTSK could induce Th17-related production of CD123+ pDCs via TLR9 signaling to promote the pathogenesis of OLP.

Fibrosis is associated with dramatic changes in extracellular matrix (ECM) architecture of unknown etiology. Here we exploit keloid scars as a paradigm to understand fibrotic ECM organization. We reveal that keloid patient fibroblasts uniquely produce a globally aligned ECM network in 2-D culture as observed in scar tissue. ECM anisotropy develops after rapid initiation of a fibroblast supracellular actin network, suggesting that cell alignment initiates ECM patterning. Keloid fibroblasts produce elevated levels of IL-6, and autocrine IL-6 production is both necessary and sufficient to induce cell and ECM alignment, as evidenced by ligand stimulation of normal dermal fibroblasts and treatment of keloid fibroblasts with the function blocking IL-6 receptor monoclonal antibody, tocilizumab. Downstream of IL-6, supracellular organization of keloid fibroblasts is controlled by activation of cell-cell adhesion. Adhesion formation inhibits contact-induced cellular overlap leading to nematic organization of cells and an alignment of focal adhesions. Keloid fibroblasts placed on isotropic ECM align the pre-existing matrix, suggesting that focal adhesion alignment leads to active anisotropic remodeling. These results show that IL-6-induced fibroblast cooperativity can control the development of a nematic ECM, highlighting both IL-6 signaling and cell-cell adhesions as potential therapeutic targets to inhibit this common feature of fibrosis.

Traumatic brain injury (TBI) is a common and often devastating illness, with wide-ranging public health implications. In addition to the primary injury, victims of TBI are at risk for secondary neurological injury by numerous mechanisms. Current treatments are limited and do not target the profound immune response associated with injury. This immune response reflects a convergence of peripheral and central nervous system-resident immune cells whose interaction is mediated in part by a disruption in the blood-brain barrier (BBB). The diverse family of cytokines helps to govern this communication and among these, Interleukin (IL)-6 is a notable player in the immune response to acute neurological injury. It is also a well-established pharmacological target in a variety of other disease contexts. In TBI, elevated IL-6 levels are associated with worse outcomes, but the role of IL-6 in response to injury is double-edged. IL-6 promotes neurogenesis and wound healing in animal models of TBI, but it may also contribute to disruptions in the BBB and the progression of cerebral edema. Here, we review IL-6 biology in the context of TBI, with an eye to clarifying its controversial role and understanding its potential as a target for modulating the immune response in this disease.

Several rheumatologic diseases are primarily distinguished by their involvement of bone tissue, which not only serves as a mere target of the condition but often plays a pivotal role in its pathogenesis. This scenario is particularly prominent in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Given the immunological and systemic nature of these diseases, in this review, we report an overview of the pathogenic mechanisms underlying specific bone involvement, focusing on the complex interactions that occur between bone tissue's own cells and the molecular and cellular actors of the immune system, a recent and fascinating field of interest defined as osteoimmunology. Specifically, we comprehensively elaborate on the distinct pathogenic mechanisms of bone erosion seen in both rheumatoid arthritis and spondyloarthritis, as well as the characteristic process of aberrant bone formation observed in spondyloarthritis. Lastly, chronic inflammatory arthritis leads to systemic bone involvement, resulting in systemic bone loss and consequent osteoporosis, along with increased skeletal fragility.

The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the infiltration of immune cells into the joints of F759 mice. The result is a disease that resembles human rheumatoid arthritis. However, the kinetics and regulatory mechanisms of how augmented transcriptional activation by STAT3 and NF-κB leads to F759 arthritis is unknown. We here show that the STAT3-NF-κB complex is present in the cytoplasm and nucleus and accumulates around NF-κB binding sites of the IL-6 promoter region and established a computer model that shows IL-6 and IL-17 (interleukin 17) signaling promotes the formation of the STAT3-NF-κB complex followed by its binding on promoter regions of NF-κB target genes to accelerate inflammatory responses, including the production of IL-6, epiregulin, and C-C motif chemokine ligand 2 (CCL2), phenotypes consistent with in vitro experiments. The binding also promoted cell growth in the synovium and the recruitment of T helper 17 (Th17) cells and macrophages in the joints. Anti-IL-6 blocking antibody treatment inhibited inflammatory responses even at the late phase, but anti-IL-17 and anti-TNFα antibodies did not. However, anti-IL-17 antibody at the early phase showed inhibitory effects, suggesting that the IL-6 amplifier is dependent on IL-6 and IL-17 stimulation at the early phase, but only on IL-6 at the late phase. These findings demonstrate the molecular mechanism of F759 arthritis can be recapitulated in silico and identify a possible therapeutic strategy for IL-6 amplifier-dependent chronic inflammatory diseases.

Inflammation, characterized by the overexpression of IL-6 in various tissues, has been reported as a symptom of coronavirus disease 2019. In this study, we established an experimental system for overexpression of IL-6 in HeLa cells stimulated by TNF-α and IL-17, along with identification of anti-inflammatory materials and components from local agricultural, forestry, and fishery resources. We constructed a library of extracts from natural sources, of which 111 samples were evaluated for their anti-inflammatory activities. The MeOH extract of Golden Berry (Physalis peruviana L) leaf was found to exhibit strong anti-inflammatory properties (IC50 = 4.97 µg/mL). Preparative chromatography identified two active constituents, 4β-hydroxywithanolide E (4β-HWE) (IC50 = 183 nM) and withanolide E (WE) (IC50 = 65.1 nM). Withanolides are known anti-inflammatory ingredients of Withania somnifera, an Ayurvedic herbal medicine. P. peruviana leaves containing 4β-HWE and WE should be considered as useful natural resources for anti-inflammatory products.

In this review, we discuss a variety of immune modulating approaches that could be used to counteract tissue-damaging viral immunoinflammatory lesions which typify many chronic viral infections. We make the point that in several viral infections the lesions can be largely the result of one or more aspects of the host response mediating the cell and tissue damage rather than the virus itself being directly responsible. However, within the reactive inflammatory lesions along with the pro-inflammatory participants there are also other aspects of the host response that may be acting to constrain the activity of the damaging components and are contributing to resolution. This scenario should provide the prospect of rebalancing the contributions of different host responses and hence diminish or even fully control the virus-induced lesions. We identify several aspects of the host reactions that influence the pattern of immune responsiveness and describe approaches that have been used successfully, mainly in model systems, to modulate the activity of damaging participants and which has led to lesion control. We emphasize examples where such therapies are, or could be, translated for practical use in the clinic to control inflammatory lesions caused by viral infections.

The biological role of interleukin 17 (IL-17) has been explored during recent decades and identified as a pivotal player in coordinating innate and adaptive immune responses. Notably, IL-17 functions as a double-edged sword with both destructive and protective immunological roles. While substantial progress has implicated unrestrained IL-17 in a variety of infectious diseases or autoimmune conditions, IL-17 plays an important role in protecting the host against pathogens and maintaining physiological homeostasis. In this review, we describe canonical IL-17 signaling mechanisms promoting neutrophils recruitment, antimicrobial peptide production, and maintaining the epithelium barrier integrity, as well as some noncanonical mechanisms involving IL-17 that elicit protective immunity.

Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with post-transplant cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflammatory biomarkers, and reconstitution of various T cell populations. Of 35 patients, 4 developed LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.