Causal links between blood inflammation markers and postherpetic neuralgia risk: insights from a two-sample Mendelian randomization study.

Introduction: Previous studies have suggested an association between blood inflammation-related factors and postherpetic neuralgia. However, the causal relationship between blood inflammation-related factors and postherpetic neuralgia remains unclear. Methods: We employed a bidirectional Two-sample Mendelian randomization (MR) analysis to explore the causal relationship between blood inflammation-related factors and postherpetic neuralgia. The instrumental variables were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. The instrumental variables of the blood inflammation-related factors come from the database numbers GCST004420 to GCST004460 and GCST90029070. Postherpetic neuralgia has 195,191 samples with a total of 16,380,406 single nucleotide polymorphisms (SNPs). MR analyses were performed using inverse-variance weighted, MR-Egger, and weighted median methods. Results: The MR results revealed a significant causal effect of Macrophage Inflammatory Protein 1 Beta (MIP1ß) on reducing the risk of postherpetic neuralgia (95%CI = 0.492-0.991, p = 0.044). Additionally, higher levels of interleukin (IL)-10 (95%CI = 0.973-0.998, p = 0.019) and IL-12p70 (95%CI = 0.973-0.997, p = 0.013) were associated with a lower risk of postherpetic neuralgia. Other inflammatory markers showed no significant causal relationship with this condition. Conclusion: This study identifies MIP1ß, IL-10, and IL-12p70 as potential therapeutic targets for preventing or treating postherpetic neuralgia, underscoring the need for further research in this area.

Induction of immunogenic cell death and enhancement of the radiation-induced immunogenicity by chrysin in melanoma cancer cells.

Chrysin is a natural flavonoid with anti-cancer effects. Despite its beneficial effects, little information is available regarding its immunogenic cell death (ICD) properties. In this work, we hypothesized that chrysin can potentiate radiotherapy(RT)-induced immunogenicity in melanoma cell line (B16-F10). We examined the effects of chrysin alone and in combination with radiation on ICD induction in B16-F10 cells. Cell viability was assessed using an MTT assay. Cell apoptosis and calreticulin (CRT) exposure were determined using flow cytometry. Western blotting and ELISA assay were employed to examine changes in protein expression. Combination therapy exhibited a synergistic effect, with an optimum combination index of 0.66. The synergistic anti-cancer effect correlated with increased cell apoptosis in cancer cells. Compared to the untreated control, chrysin alone and in combination with RT induced higher levels of DAMPs, such as CRT, HSP70, HMGB1, and ATP. The protein expression of p-STAT3/STAT3 and PD-L1 was reduced in B16-F10 cells exposed to chrysin alone and in combination with RT. Conditioned media from B16-F10 cells exposed to mono-and combination treatments elicited IL-12 secretion in dendritic cells (DCs), inducing a Th1 response. Our findings revealed that chrysin could induce ICD and intensify the RT-induced immunogenicity.

First Brazilian Case Report of Unrelated Patients with Identical ISG15 Mutation.

BACKGROUND: ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial infections (MSMD), a rare inherited condition characterized primarily by recurrent infections from low-virulence mycobacteria and monogenic type I interferonopathy. OBJECTIVE: To characterize the laboratory and molecular features of two patients from different families affected by the same ISG15 variant. METHODS: We began with clinical characterization and investigation, assessed IL-12/IFN-γ production, performed genetic characterization through WES and Sanger sequencing, conducted an in silico molecular analysis of the genetic ISG15 variant's protein impact, and utilized RNAseq for transcriptome analysis to understand pathway impacts on ISG15-deficient subjects from unrelated families. RESULTS: A mutation in the ISG15 gene was identified, affecting two patients treated in different hospitals and cities in Brazil (Fortaleza and Sao Paulo), who are also members of unrelated families. Both patients showed low IFN-γ production when stimulated with BCG or BCG + IL-12. ISG15 deficiency presented with two distinct clinical phenotypes: infectious and neurological. It was identified that both patients are homozygous for the variant (c.83 T > A). Furthermore, it was observed that the mutant protein p.L28Q results in an unstable protein with increased flexibility (ΔΔG: -2.400 kcal/mol). Transcriptome analysis revealed 1321 differentially expressed genes, with significant upregulation in interferon pathways, showing higher expression in patients compared to controls. CONCLUSION: This study describes the first reported cases in Brazil of two unrelated patients with the same ISG15 mutation c.83 T > A, exhibiting infectious features such as mycobacterial infections and systemic candidiasis, neurological findings, and skin lesions, without adverse reactions to the BCG vaccine. CLINICAL IMPLICATIONS: Reporting ISG15 gene mutations in Brazilian patients enhances understanding of genetic susceptibilities, guiding effective diagnostics and treatment. Identifying high-risk individuals aids clinical practices, genetic counseling, and influences public health policies. We have identified the first case in Brazil of the same ISG15 variant c.83 T > A that was identified in two unrelated patients with distinct clinical phenotypes, infectious and neurological.

Characteristics of Endemic Mycoses Talaromyces marneffei Infection Associated with Inborn Errors of Immunity.

BACKGROUND: Talaromyces marneffei (T. marneffei) is an opportunistic pathogen that causes endemic mycoses, which could lead to multiple organ damage. Talaromycosis is frequently disregarded as an early cautionary sign of immune system disorders in non-HIV-infected children. OBJECTIVE: We conduct a comprehensive review of the genotypes and clinical features of talaromycosis in patients with IEI to enhance clinical awareness regarding T. marneffei as a potential opportunistic pathogen in individuals with immune deficiencies. METHODS: A systematic literature review was performed by searching PubMed, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, and Scopus. Data on IEI patients with talaromycosis, including genotypes and their immunological and clinical features, were collected. RESULTS: Fifty patients with talaromycosis and IEI were included: XHIM (30.0%), STAT3-LOF deficiency (20.0%), STAT1-GOF (20.0%), IL2RG (6.00%), IFNGR1 (6.0%), IL12RB1 (4.0%), CARD9 (4.0%), COPA (4.0%), ADA (2.0%), RELB deficiency (2.0%), and NFKB2 (2.0%). Common symptoms of respiratory (43/50, 86.0%), skin (17/50, 34.0%), lymph node (31/50, 62.0%), digestive (34/50, 68.0%), and hematologic (22/50, 44.0%) systems were involved. The CT findings of the lungs may include lymph node calcification (9/30), interstitial lesions (8/30), pulmonary cavities (8/30), or specific pathogens (4/30), which could be easily misdiagnosed as tuberculosis infection. Amphotericin B (26/43), Voriconazole (24/43) and Itraconazole (22/43) were used for induction therapy. Ten patients were treated with Itraconazole sequentially and prophylaxis. 68.0% (34/50) of patients were still alive, and 4.0% (2/50) of were lost to follow-up. The disseminated T. marneffei infection resulted in the deaths of 14 individuals. CONCLUSIONS: The XHIM, STAT1-GOF, and STAT3-LOF demonstrated the highest susceptibility to talaromycosis, indicating the potential involvement of cellular immunity, IL-17 signaling, and the IL-12/IFN-γ axis in T. marneffei defense. T. marneffei infection may serve as an early warning indicator of IEI. For IEI patients suspected of T. marneffei, metagenomic next-generation sequencing (mNGS) could rapidly and effectively identify the causative pathogen. Prompt initiation of antifungal therapy is crucial for optimizing patient outcomes.

Targeted Delivery of Circular Single-Stranded DNA Encoding IL-12 for the Treatment of Triple-Negative Breast Cancer.

Interleukin-12 (IL-12) is a critical cytokine with notable anticancer properties, including enhancing T-cell-mediated cancer cell killing, and curbing tumor angiogenesis. To date, many approaches are evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Here, it is focused on circular single-stranded DNA (Css DNA), a type of DNA characterized by its unique structure, which could be expressed in mammals. It is discovered that Css DNA can induce sustained luciferase expression for half a year by intramuscular injection and showed effective antitumor results by intratumoral injection. Motivated by these findings, a folate-modified LNP system is now developed for the delivery of Css DNA expressing IL-12 for the therapy of 4T1 triple-negative breast cancer (TNBC). This delivery system effectively activates anti-cancer immune responses, slows tumor growth, significantly prolongs survival in animal models, and prevents tumor recurrence. After 6 months of long-term observation, the elevated level of IL-12 is still detectable in the lymph nodes and serum of the cured mice. This study highlights the long-term sustained expression capacity of Css DNA and its ability to inhibit recurrence, and the potential of tumor-targeted LNPs for Css DNA-based cancer therapy, providing a new insight into gene overexpression strategy.

Intratumoral injection and retention hold promise to improve cytokine therapies for cancer.

As powerful activators of the immune system, cytokines have been extensively explored for treating various cancers. But despite encouraging advances and some drug approvals, the broad adoption of cytokine therapies in the clinic has been limited by low response rates and sometimes severe toxicities. This in part reflects an inefficient biodistribution to tumors or a pleiotropic action on bystander cells and tissues. Here, we first review these issues and then argue for the intratumoral delivery of engineered cytokine fusion proteins that have been optimized for tumor retention as a potential solution to overcome these limitations and realize the potential of cytokines as highly effective therapeutics for cancer.

Antitumor properties of traditional lactic acid bacteria: Short-chain fatty acid production and interleukin 12 induction.

This paper presents an in vitro evaluation of antitumor properties through producing short-chain fatty acids and inducing interleukin 12. In addition, it offers the most important and functional probiotic properties of 24 Lactobacillus gasseri, Lactiplantibacillus plantarum, Lactobacillus acidophilus, and Limosilactobacillus fermentum strains isolated from humans, foods, and fermented foods. To this end, survival in an acidic environment (pH = 2.5), tolerance in bile salt, viability in the presence of pepsin-pancreatin, adhesion percentage, antibiotic resistance, auto-aggregation, and potential percentage of co-aggregation are studied in contact with three human intestinal pathogens. These pathogens are Escherichia coli O157: H7 NCTC 12900, Salmonella enterica subsp. enterica ATCC 13076, and Listeria monocytogenes ATTC 7644. Also, in vitro induction amount of IL-12 in mouse splenocytes is investigated to evaluate antitumor properties by 19 strains of L. gasseri and L. plantarum along with the development of short-chain fatty acids (SCFA) by 5 strains of L. fermentum and L. acidophilus. Gas Chromatography Flame Ionization Detector (GC-FID) and enzyme-linked immunosorbent assay (ELISA) were used to measure short-chain fatty acids and IL-12, respectively. All strains had high viability under acidic conditions. The highest levels of pancreatin and pepsin resistance were found in strains LF56, LF57, LF55, OF, and F and strains LF56, LF57, and A7, respectively. All strains except LF56 had high resistance to bile salts. L. gasseri 54C had the highest average adhesion score (hydrophobicity) of 62.9 % among 19 strains. Despite the susceptibility of different strains of L. plantarum to the tested antibiotics, M8 and M11, S2G, A7, LF55, LF57, and 5G were resistant to kanamycin and chloramphenicol, respectively. Also, 21G was resistant to ampicillin, LF56 to tetracycline and M8, and M11, LF56, and 21G to Erythromycin. In addition, L. gasseri showed moderate resistance to ampicillin, erythromycin, and tetracycline, while L. fermentum ATCC 9338 showed good resistance to ampicillin, erythromycin, and chloramphenicol. In this respect, L. plantarum LF56 and gasseri 54C had the highest average auto-aggregation and co-aggregation against three pathogenic bacteria, respectively. The highest and lowest levels of acetic acid as short-chain fatty acids were produced by L. fermentum 19SH isolated from Horre 41.62 and L. fermentum 21SH from fermented seeds 27.047, respectively. Moreover, L. fermentum, with the OF code of traditional-fermented food origin, produced the most isobutyric acid, butyric acid, and valeric acid, with values of 0.6828, 0.74165, and 0.49915 mmol, respectively. L. fermentum isolated from the human origin with code F produced the most isovaleric acid of 1.1874 mmol. All the tested strains produced good propionic acid except L. fermentum 21SH from fermented seeds. Among strains, L. plantarum M11 isolated from milk and L. gasseri 52B from humans had the highest in vitro induction of IL-12, which is probably related to their cell wall compositions and structure.

Implication of IL-12A, IL-12B, IL-6, and TNF single-nucleotide polymorphisms in severity and susceptibility to COVID-19.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has led to significant global morbidity and mortality. Understanding the genetic factors that influence disease outcomes can provide critical insights into pathogenesis and potential therapeutic targets. OBJECTIVE: This study aimed to investigate the potential correlation between single nucleotide polymorphisms (SNPs) in Interleukin 12 Subunit Alpha (IL-12A), Interleukin 12 Subunit Beta (IL-12B), Interleukin 6 (IL-6), and Tumor Necrosis Factor (TNF) genes and the severity as well as susceptibility to COVID-19 among Moroccan patients. PATIENTS AND METHODS: Next-Generation sequencing (NGS) was conducted on 325 Moroccan participants, 207 patients with PCR-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and 118 controls. Among these patients, 51% presented moderate to severe symptoms requiring hospitalization, while 49% were asymptomatic or experienced mild symptoms and did not require hospitalization. Statistical analysis was performed using codominant, dominant, and recessive logistic regression models to assess correlations with the severity and susceptibility to COVID-19 infection. RESULTS: No association was found between SNPs of IL-12A, IL-12B, IL-6 or TNF and COVID-19 severity and susceptibility. However, our results unveiled a noteworthy association with IL-6 rs2069840, which exhibited a negative correlation (OR = 0.21, 95% CI = 0.07-0.69, p = .006), suggesting a protective effect against SARS-CoV-2 infection. CONCLUSION: Polymorphisms in IL-12A, IL-12B, IL-6, and TNF genes are not correlated to the severity and susceptibility of COVID-19.

Structure and assembly of the human IL-12 signaling complex.

Interleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rß1 and IL-12Rß2 at a resolution of 3.75 Å reveals that IL-12Rß2 primarily interacts with the IL-12p35 subunit via its N-terminal Ig-like domain, while IL-12Rß1 binds to the p40 subunit with its N-terminal fibronectin III domain. This binding mode of IL-12 with its receptors is similar to that of IL-23 but shows notable differences with other cytokines. Through structural information and biochemical assays, we identified Y62, Y189, and K192 as key residues in IL-12p35, which bind to IL-12Rß2 with high affinity and mediate IL-12 signal transduction. Furthermore, structural comparisons reveal two distinctive conformational states and structural plasticity of the heterodimeric interface in IL-12. As a result, our study advances our understanding of IL-12 signal initiation and opens up new opportunities for the engineering and therapeutic targeting of IL-12.

Long-term successfull management of recurrent episodes of nontuberculous mycobacterial infection in an apparently healthy Chinese woman.

BACKGROUND: Disseminated non-tuberculous mycobacteria (dNTM) infections are mostly reported among individuals with an underlying congenital or acquired immunodeficiency or receiving immunosuppressive treatment, but are rarely documented in otherwise healthy subjects. CASE PRESENTATION: We describe a case of recurrent disseminated mycobacterial infection in an apparently immunocompetent Chinese woman. Mycobacterium szulgai and Mycobacterium avium-complex were identified in distinct episodes. Long-term antimycobacterial therapy was administered given the occurrence of recurrent events when off-treatment. Successful management over more than 10 years and immunologic data are reported. CONCLUSIONS: This case-report highlights that dNTM should be suspected also among apparently immunocompetent hosts and that thorough assessment of underling immune-impairments is helpful to define patients' management. Long-term antimycobacterial therapy and close monitoring is required to grant successful outcomes in case of recurrent dNTM infections.

Comparative Effectiveness of Bimekizumab and Ustekinumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.

INTRODUCTION: A matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy at 52 weeks (Wk52) of bimekizumab 160 mg every 4 weeks (Q4W) and ustekinumab 45 or 90 mg every 12 weeks (Q12W) in patients with psoriatic arthritis (PsA) who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or who had a previous inadequate response or an intolerance to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Relevant trials were systematically identified. Individual patient data from the bimekizumab trials BE OPTIMAL (NCT03895203; N = 431) and BE COMPLETE (NCT03896581; N = 267) were matched with summary data on patients receiving ustekinumab in the PSUMMIT 1 trial (NCT01009086; 45 mg, N = 205; 90 mg; N = 204) and a subgroup of TNFi-IR patients receiving ustekinumab in the PSUMMIT 2 trial (NCT01077362; 45 mg, N = 60; 90 mg, N = 58), respectively. Patients from the bimekizumab trials were re-weighted using propensity scores to match the baseline characteristics of the ustekinumab trial patients. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Non-placebo-adjusted comparisons of recalculated bimekizumab and ustekinumab outcomes for the American College of Rheumatology (ACR) 20/50/70 response criteria (non-responder imputation) were analyzed. RESULTS: In patients who were bDMARD naïve, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (odds ratio [95% confidence interval] 45 mg: 2.14 [1.35, 3.40]; 90 mg: 1.98 [1.24, 3.16]), ACR50 (45 mg: 2.74 [1.75, 4.29]; 90 mg: 2.29 [1.48, 3.55]), and ACR70 (45 mg: 3.33 [2.04, 5.46]; 90 mg: 3.05 [1.89, 4.91]). In patients who were TNFi-IR, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (45 mg: 4.17 [2.13, 8.16]; 90 mg: 4.19 [2.07, 8.49]), ACR50 (45 mg: 5.00 [2.26, 11.05]; 90 mg: 3.86 [1.70, 8.79]), and ACR70 (45 mg: 9.85 [2.79, 34.79]; 90 mg: 6.29 [1.98, 20.04]). CONCLUSIONS: Using MAIC, bimekizumab showed greater efficacy than ustekinumab in achieving all ACR responses in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. TRIAL REGISTRATION: NCT03895203, NCT03896581, NCT01009086, NCT01077362.

The IL-12 family of cytokines: pathogenetic role in diabetic retinopathy and therapeutic approaches to correction.

One vision-threatening side effect of systematic diabetes mellitus is diabetic retinopathy (DR). Recent studies have revealed that the development and progression of DR depend critically on inflammation resulting from diabetes. By attracting leukocytes to endothelium, the higher production of the inflammatory mediators induces degeneration of retinal capillaries, hence increasing vascular permeability and thrombosis probability. The leukocytes that are recruited eventually generate additional proinflammatory and proangiogenic substances, resulting in the increased infiltration of leukocytes in the retina. This process also leads to changes in the blood retinal barrier and the formation of new blood vessels, which helps to counteract the damage caused by the blockage of blood flow. IL-12 family members, IL-12, IL-23, IL-27, and IL-35, play a crucial role in regulating the responses of T helper (Th)1 and Th17 cell populations. The collected data from studies investigating the levels of IL-12 family members in the blood and eye tissues suggest that IL-12 is linked to DR, indicating that it may have a role in the development of DR as a sequential component of the immune response. This review specifically examines the possibility of using IL-12 family cytokines as a therapeutic approach for diabetes, taking into consideration their involvement in the development of DR.

The active form of vitamin D (calcitriol) promotes CXCR5 expression during follicular helper T cell differentiation.

Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator, programmed cell death-1 (PD-1), and the chemokine receptor CXCR5. Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naïve CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis towards CXCL13, expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B-cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation.

Anti-IL12p40 autoantibodies in a teenage girl with multiple recurrent abscesses.

More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of anti-IL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective.

HLA-C*06:02 in Danish patients with psoriasis and response to biological treatment.

Whether clinical and genetic markers can be used to differentiate patients with varying responses to different psoriasis therapies needs to be elucidated. Here, we assess whether human leukocyte antigen C (HLA-C)*06:02 is associated with response to biologics. Response to treatment was defined as a Psoriasis Area and Severity Index score of ≤2 (PASI≤ 2) after 3 months. In total, 648 patients with psoriasis initiating treatment with biologics were included; 289 were HLA-C*06:02 positive and 359 were HLA-C*06:02 negative. Patients were treated with tumor necrosis factor (TNF) inhibitors (n = 469), interleukin (IL)-12/23 inhibitors (n = 92), IL-17 inhibitors (n = 78), and IL-23 inhibitors (n = 9). Significantly more patients positive for HLA-C*06:02 achieved PASI≤ 2 compared with patients negative for HLA-C*06:02 when treated with IL-12/23 inhibitors. There was no significant difference between response in HLA-C*06:02 positive and negative patients for TNF inhibitors or IL-17 inhibitors. No analyses were conducted for IL-23 inhibitors because of the limited number of patients. The data confirm that HLA-C*06:02 may be used as a biomarker for response to anti-IL12/23 treatment.

Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease.

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

Effects of Mucuna pruriens (L.) DC. and Levodopa in Improving Parkinson's Disease in Rotenone Intoxicated Mice.

Parkinson's disease (PD) is the second leading neurodegenerative disease after Alzheimer's disease. Mucuna pruriens (L.) DC. (MP) is a plant that contains Levodopa (L-DOPA) and has been known to improve the symptoms of PD. In this preliminary study, we investigated the anti-parkinsonian potential of MP to compare the effects of L-DOPA. We first developed an in vivo model of the PD in C57BL/6 male mice using rotenone. A total of twelve mice were used for this experiment. Nine mice were injected with rotenone (28 mg/kg) daily for 28 days. The mice experiments were performed to validate the effectiveness of MP to treat PD. Synthetic L-DOPA in a ratio of 1:20 with MP was used as MP contains 5% L-DOPA by weight in it. MP and L-DOPA were injected for 19 days on a daily basis. Cognitive function was evaluated using beam balance and olfactory tests. Serum analysis was performed using serum enzyme-linked immunosorbent assay (ELISA) analysis test. IL-12, IL-6, and TGF-ß 1 were evaluated to validate the PD inducement and treatment. The levels of IL-12, IL-6, and TGF-ß1 (p < 0.0001) in the PD mice group were significantly higher than those in the control group. The PD mice also showed higher latencies in beam balance and olfactory tests (p < 0.0001) compared to the control group. Both MP and L-DOPA-treated groups showed alleviation in latencies in beam balance and olfactory tests and decreased neuroinflammation in ELISA analysis (p < 0.001). The results treated by MP and L-DOPA showed insignificant differences in their values (p > 0.05). This proved that the MP and L-DOPA had similar effects in improving the symptoms of PD when used in the ratio of 1:20. Furthermore, both MP and L-DOPA reduced the level of IL-6 and TGF-ß1 in this study. It may be inferred that a reduction in the level of IL-6 and TGF-ß1 eventually leads to a reduction in the Th17 cells. The pathogenic Th17 is thought to be present in virtually all chronic inflammatory disorders. This can be an interesting area of research in further understanding the immunological effect of MP in ameliorating PD symptoms.

Intestinal epithelial damage-derived mtDNA activates STING-IL12 axis in dendritic cells to promote colitis.

Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 fl/fl Lyz2-Cre ert2 mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-κB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC.

Hepatitis B reactivation in PsA patients: an SLR and meta-analysis for IL-17, IL-23 and JAK inhibitors.

OBJECTIVES: Hepatitis B reactivation (HBVr) constitutes a side effect of the treatment of autoimmune rheumatic diseases. Even though HBVr risk of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) and anti-tumor necrosis factor (anti-TNF) agents has long been established, the risk of targeted synthetic (ts)DMARDs and anti-interleukin (anti-IL) agents remains largely unknown. METHODS: We conducted a SLR (PubMed, Scopus and EMBASE) and metanalysis to examine the HBVr risk for the following: anti-IL17, anti-IL12/23, anti-IL23 and JAK-inhibitors in patients with chronic HBV infection (HBsAg presence or detectable HBV-DNA) and in patients with prior HBV infection (HBcAb-positive and HBsAg-negative). Meta-analysis was performed using both the fixed and random effects method and was conducted using the R computing language. RESULTS: Overall, our study revealed a low HBVr risk of < 6% in all agents; the risk was significantly higher for people having chronic compared with those with resolved HBV (14,4% vs 5.1%, respectively p< 0.01). There was no difference among different drugs in the HBVr rates [anti-IL-17: 4% (95% CI: 1-9%), anti-IL-12/IL-23: 2% (95% CI: 0-5%), JAK-inhibitors: 4% (95% CI: 1-8%), anti-IL23: 0%]. Of note, HBVr rate reached 28% in patients with chronic HBV who did not receive anti-viral treatment. For patients with resolved hepatitis the respective percentage was 4.7%. CONCLUSION: Overall, our meta-analysis shows that patients with chronic HBV receiving anti-IL-17, anti-IL-12/23, anti-IL-23 and JAK-inhibitors have significant risk for HBVr, especially if they are not under anti-viral treatment. In contrast, resolved HBV seems to offer minor risk for HBVr even without anti-viral treatment.