Evaluation of the therapeutic effects of Photodynamic Therapy in vulvar lichen sclerosus and impact on patient quality of life and sexual funtion.

BACKGROUND: Vulvar lichen sclerosus (VLS) is often associated with irritable symptoms of itching, burning pain and can lead to scarring, architectural changes and sexual dysfunction as well as a decline in quality of life.The etiology of the disease is unknown. This study sought to assess the therapeutic effects of Photodynamic Therapy (PDT) in VLS, and improvment of patient quality of life and sexual funtion. METHODS: From January 2022 to April 2023, a total of 65 patients with vulvar sclerosi (VLS) were treated with PDT in our hospital. All 65 patients were divided into two groups: early-stage group and late-stage group. The Cattaneo scoring method, the Dermatology Life Quality Index (DLQI) and the Female Sexual Function Index (FSFI) scores were used to evaluate the clinical effectiveness of the treatment on patients' symptoms and clincal signs, quality of life as well as sexual function before and at 6-month after treatment. RESULTS: The total effective rate of early-stage patients was significantly greater than that of late-stage patients at 6-month after PDT treatment (90.91% [40/44] vs 76.19% [16/21], p <0.05). At 6-month follow-up, the symptoms and clinical signs of patients in early-stage group were significantly improved compared with baseline, the average scores of itching, skin elasticity, whitening and lesion range were significantly lower than the scores before treatment (p <0.05). In late-stage group, The decrease in scores of itching, whitening and lesion range at the 6-months follow-up is significant(p <0.05), but skin elasticity (p=0.0625). On post-treatment follow-up examination, FSFI score was seen to have significantly improved in early-stage patients(from a median score of 17.45 to 21.1, p<0.05); DLQI also significantly improved after treatment (from a median score of 7 to 4, p<0.05). In late stage patients, The DLQI score improved significantly after treatment (from a median score of 18 to 15, p<0.05). However, the improvement in sexual function is not statistically significant (pre-treatment: median=10.55, post-treatment: median=10, p=0.1865). CONCLUSION: Photodynamic therapy can effectively improve most symptoms and clinical signs, as well as quality of life of patients with VLS, especially for earlly stage patients. Moreover, improvement in sexual function is observed in early stage patients after PDT treatment. This study suggests that early and timely PDT treatment are recommended to achieve better results.

A Polymer Nanocomposite with Strong Full-Spectrum Solar Absorption and Infrared Emission for All-Day Thermal Energy Management and Conversion.

Realizing efficient energy utilization from the heat source of the sun and the cold source of outer space is of great significance for addressing the global energy and environmental crisis. Materials with ideal full-spectrum solar absorption and infrared emission are highly desirable for adapting to the continuous weather dynamic throughout the day, nonetheless, their development remains challenging. Here, a polymer nanocomposite with full-spectrum strong solar (280-2500 nm) absorption ranging from 88.8% to 94.8% with an average value of 93.2% and full-spectrum high infrared (8-13 µm) emission ranging from 81.3% to 90.0% with an average value of 84.2%, is reported by melt-processing polypropylene and uniformly dispersed low-loading MXene nanosheets (1.9 vol%). The nanocomposite can achieve daytime photothermal enhancement of ≈50 °C and nighttime radiative cooling of 8 °C. The temperature difference throughout the day ensures all-day uninterrupted thermoelectric generation, yielding a power density output of 1.5 W m-2 (daytime) and 7.9 mW m-2 (nighttime) in real outdoor environment without any additional energy consumption. This work provides an impressive polymer nanocomposite with ideal full-spectrum solar absorption and infrared emission for all-day uninterrupted thermal energy management and conversion.

suPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury.

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

Dual-Mode Porous Polymeric Films with Coral-like Hierarchical Structure for All-Day Radiative Cooling and Heating.

Passive radiative cooling (PRC) and passive radiative heating (PRH) have drawn increasing attention as green and sustainable cooling and heating approaches, respectively. Existing material designs for PRC/PRH are usually static and unsuitable for dynamic seasonal and weather changes. Herein, we demonstrate an all-day dual-mode film fabricated by decorating MXene nanosheets on porous poly(vinylidene fluoride) with abundant coral-like hierarchical structures obtained via phase inversion. The cooling side of the dual-mode film exhibits high solar reflectivity (96.7%) and high infrared emissivity (96.1%). Consequently, daytime subambient radiative cooling of 9.8 °C is achieved with a theoretical cooling power of 107.5 W/m2 and nighttime subambient cooling of 11.7 °C is achieved with a theoretical cooling power of 140.7 W/m2. Meanwhile, the heating side of the dual-mode film exhibits low infrared emissivity (11.6%) and high solar absorptivity (75.7%), contributing to a PRH capability of 8.1 °C, and excellent active solar and Joule heating as effective compensation for PRH. The dual-mode film could be easily switched between cooling and heating modes by flipping it to adapt to dynamic cooling and heating scenarios, which is important for alleviating the energy crisis and reducing greenhouse emissions.

A Facile yet Versatile Strategy to Construct Liquid Hybrid Energy-Saving Windows for Strong Solar Modulation.

Smart windows with light management and indoor solar heating modulation capacities are of paramount importance for building energy conservation. Thermochromic poly(N-isopropylacrylamide) (PNIPAm) hydrogel smart windows exhibit advantages of the relatively suitable transition temperature of 32 °C, high cost-effective and automatic passive sunlight regulation, but sustain slow response rate and unsatisfactory solar modulation efficiency. Herein, a strategy of one-step copolymerization of NIPAm and different olefine acids (OA) using reverse atom transfer radical polymerization method is developed to fabricate various chain/microparticle hybrids (CMH) for liquid energy-saving windows. Synergetic mechanisms of thermal-induced dissolution and aggregation of linear polymer chains integrated with water capture and release of microgel particles contribute to tunable light-scattering behaviors and adaptive solar modulation. Without any post-treatment, the as-prepared poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAm-co-AA))-based CMH suspension is injected into sandwich glass to construct energy-saving windows, which exhibits appreciated near-room-temperature transition (26.7 °C), rapid response (5 s), extraordinary luminous transmittance (91.5%), and solar modulation efficiency (85.8%), resulting in a substantial decline of indoor temperature of 24.5 °C in simulation experiment. Combining the versatile strategy with flexible adjustment on transition temperature, multifarious P(NIPAm-co-OA)-based CMH windows with eminent light management capacity are obtained. This work will powerfully promote the development and renovation of energy-efficient windows.

High-strength, low infrared-emission nonmetallic films for highly efficient Joule/solar heating, electromagnetic interference shielding and thermal camouflage.

High-strength nonmetallic materials with low infrared (IR) emission are rare in nature, yet highly anticipated especially in military and aerospace fields for thermal camouflage, IR stealth, energy-saving heating. Here, we reported a high-strength (422 MPa) nonmetallic film with very low IR emissivity (12%), realized by constructing alternating multilayered structures consisting of successive MXene functionalized outer layers and continuous GO reinforced inner layers. This nonmetallic film is capable of competing with typical stainless steel (415 MPa, 15.5%), and exhibits remarkable thermal camouflage performance (ΔT = 335 °C), ultrahigh Joule heating capability (350 °C at 2 V), excellent solar-to-thermal conversion efficiency (70.2%), and ultrahigh specific electromagnetic interference shielding effectiveness (83 429 dB cm-1). Impressively, these functionalities can be maintained well after prolonged outdoor aging, and even after undergoing harsh application conditions including strong acid/alkali and boiling water immersion, and cryogenic (-196 °C) temperature.

Impact of homodyne receiver bandwidth and signal modulation patterns on the continuous-variable quantum key distribution.

In continuous-variable quantum key distribution (CV-QKD), the key information are encoded on quadratures of the optical field, which are measured via balanced homodyne detector (BHD). The bandwidth of the BHD is one of key parameters for precise characterization of quantum states. We establish a theoretical model to analyze the impact of the BHD bandwidth and signal modulation patterns on the channel parameters estimation of CV-QKD systems. Based on the proposed model, the secure key rate of a practical CV-QKD system under different BHD bandwidths and signal modulation patterns are investigated. Our results show that insufficient BHD bandwidth will result in wrong estimate of the transmission loss and excess noise, which significantly affects the performance of CV-QKD systems. Given the BHD bandwidth, there exists an optimal signal repetition rate that maximizes the secure key rate. The BHD bandwidth requirement of the QKD system increases with the transmission distance for large duty cycle pulse. Furthermore, the root raised-cosine pulse signal modulation performs better than the square pulse signal modulation in general.

Ti3C2Tx MXene-Decorated Nanoporous Polyethylene Textile for Passive and Active Personal Precision Heating.

Heating the human body to maintain a relatively constant temperature is pivotal for various human functions. However, most of the current heating strategies are energy-consuming and energy-wasting and cannot cope with the complex and changing environment. Developing materials and systems that can heat the human body precisely via an efficient energy-saving approach no matter indoors/outdoors, day/night, and sunny/cloudy is highly anticipated for mitigating the growing energy crisis and global warming but is still a great challenge. Here, we demonstrate the low mid-infrared radiative (mid-IR) emissivity characteristic of Ti3C2Tx MXene and then apply it for energy-free passive radiative heating (PRH) on the human body. Our strategy is realized by simply decorating the cheap nanoporous polyethylene (nanoPE) textile with MXene. Impressively, the as-obtained 12 µm thick MXene/nanoPE textile shows a low mid-IR emissivity of 0.176 at 7-14 µm and outstanding indoor PRH performance on the human body, which enhances by 4.9 °C compared with that of traditional 576 µm thick cotton textile. Meanwhile, the MXene/nanoPE textile exhibits excellent active outdoor solar heating and indoor/outdoor Joule heating capability. The three heating modes integrated in this wearable MXene/nanoPE heating system can be switched easily or combined arbitrarily, making this thin heating system able to heat the human body precisely in various scenarios like indoors/outdoors, day/night, and sunny/cloudy, providing multiple promising and energy-saving solutions for future all-day personal precision thermal management.

A multi-model, large range and anti-freezing sensor based on a multi-crosslinked poly(vinyl alcohol) hydrogel for human-motion monitoring.

Conductive hydrogels are capturing intensive attention for versatile applications in flexible wearable devices on account of their unique combination of softness, stretchability, conductivity and biocompatibility. However, most of the hydrogel sensors can only serve as single-type sensors to detect strain or pressure, accompanied by a limited detection range. Moreover, the poor anti-freezing performance is also a serious problem to be addressed for their practical applications. Herein, a multi-model, large range and anti-freezing hydrogel sensor was constructed from a high-mechanical and ionic conductive multi-crosslinked poly(vinyl alcohol) (M-PVA) hydrogel, which was prepared via incorporating chain entanglement interaction and complexation between Fe3+ ions and hydroxyl groups into the microcrystalline network through immersion treatment in Fe2(SO4)3 solution. The three reversible and reconstructable crosslinks within the M-PVA hydrogel worked in tandem to achieve ultra-stretchability (1120%), supercompressibility (98%), high toughness, fast self-recoverability and excellent fatigue resistance. Meanwhile, the introduction of Fe3+ and SO42- ions endowed the M-PVA hydrogel with good ionic conductivity and remarkable anti-freezing properties (-50 °C), which benefited the M-PVA hydrogel to act as a freezing-tolerant dressing. The assembled multi-model hydrogel sensor can sensitively and stably detect large range elongation (∼900%), compression (∼70%), bend and pressure (up to 4.60 MPa) concurrently, as well as various human activities including speaking, finger bending and treading behavior. Notably, the hydrogel sensor was capable of maintaining excellent mechanical flexibility and sensitive sensing capacity at low temperature. The M-PVA hydrogel is a promising flexible sensing material for versatile applications in ionic skin, motion recognition and intelligent wearable devices.

Multifunctional MXene-Based Fireproof Electromagnetic Shielding Films with Exceptional Anisotropic Heat Dissipation Capability and Joule Heating Performance.

The burgeoning development of wearable electronic devices has resulted in urgent demands for electromagnetic interference (EMI) shielding films that feature excellent fireproof and heat dissipation capability. Herein, multifunctional fireproof EMI shielding films with excellent anisotropic thermal conductivity are constructed based on MXene and montmorillonite (MMT) via a simple vacuum-assisted filtration technique. The presence of MMT can protect the MXene from oxidation and endow the composite films with exceptional fire-resistant ability. The impressive thermal conductivity performance, high in-plane thermal conductivity (28.8 W m-1 K-1) and low cross-plane thermal conductivity (0.27 W m-1 K-1), ingeniously enables highly efficient in-plane heat dissipation and cross-plane heat insulation in the MXene-based films simultaneously. The high electrical conductivity (4420 S m-1) of the composite film enables an excellent EMI shielding effectiveness of over 65 dB in the entire X-band and a high specific shielding effectiveness of over 10 000 dB cm2 g-1 at a thickness of only 25 µm. Importantly, the EMI shielding effectiveness is maintained at above 60 dB even after burning for 30 s. Besides, the composite films show outstanding Joule heating performance with a fast thermal response (<10 s) and a low driving voltage (<5 V). These multifunctional films are highly promising for applications concerning fire protection, de-icing, heat dissipation/insulation, and EMI shielding devices.

Freezing-Tolerant, Highly Sensitive Strain and Pressure Sensors Assembled from Ionic Conductive Hydrogels with Dynamic Cross-Links.

Conductive hydrogels have attracted intensive attention for versatile functions in flexible electronics because of their unique combination of mechanical flexibility and conductivity. However, hydrogels containing plenty of water inevitably freeze at subzero temperature, leading to invalid electronics with failed mechanical advantages and negligible conductivity. Moreover, the inferior elasticity and fatigue resistance of hydrogels result in unstable sensing performance and poor reusability of hydrogel-based electronics. Herein, a freezing-tolerant, high-sensitive, durable strain and pressure sensor was constructed from an ionic conductive chitosan-poly(acrylamide-co-acrylic acid) double-network [CS-P(AM-co-AA) DN] hydrogel with dual-dynamic cross-links (chitosan physical network and ionic coordination [CO2LFeIII]), which was feasibly fabricated by soaking the CS-P(AM-co-AA) composite hydrogel in FeCl3 solution. The ions immobilized in dynamic cross-links exerted crucial effects on improving mechanics [prominent tensile performance, supercompressibility, extraordinary elasticity, fast self-recovery capacity, and remarkable fatigue resistance (1000 cycles)]; meanwhile, the free ions in the hydrogel rendered the hydrogel excellent conductivity and strong freezing tolerance concurrently. The sensor assembled from the DN hydrogel exhibited cycling stability and good durability in detecting pressure, various deformations (elongation, compression, and bend), and human motions even at a low temperature (-20 °C). Notably, the sensitivity on detecting strain and pressure at both room and subzero temperature was superior than most of the reported organohydrogel and hydrogel sensors. Thus, we believe that this work will provide a platform for construction and application of high-sensitive strain and pressure hydrogel sensors with cycling stability and good durability in a wide temperature range.

Nonimmune cell-derived ICOS ligand functions as a renoprotective αvß3 integrin-selective antagonist.

Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvß3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven't been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvß3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of αvß3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to αvß3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvß3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli, glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL, which serves as an endogenous αvß3-selective antagonist to maintain glomerular filtration.

FPR1 gene silencing suppresses cardiomyocyte apoptosis and ventricular remodeling in rats with ischemia/reperfusion injury through the inhibition of MAPK signaling pathway.

Ischemia/reperfusion (I/R) injury, one of the leading health problems in the world, is defined as a cause of cardiomyocytes death. In the present study, we investigate the role of formyl peptide receptor 1 (FPR1) in cardiomyocyte apoptosis and ventricular remodeling of I/R injury rats and the underlying mechanism involving mitogen-activated protein kinase (MAPK) signaling pathway. The important differentially expressed genes (DEGs) in I/R injury were screened out and downstream pathways affected by DEGs were predicted. We grouped 90 rats into sham, I/R, NC siRNA, FRP1 siRNA, empty vector, and FRP1 vector groups and established a model of I/R injury in rats. CVF value, myocardial infarct areas and positive expression rate of FPR1 and MAPK were detected. Levels of FPR1 and MAPK pathway-related genes were determined by RT-qPCR and western blot analysis. MTT assay was performed to evaluate cell proliferation and flow cytometry to evaluate cell cycle progression and apoptosis. GSE19804 and GSE27262 were screened from Gene Expression Omnibus database. FPR1 was higher in patients with I/R injury and activate the MAPK signaling pathway. FRP1 gene silencing decreased CVF value, infarct area, apoptotic index, positive expression rates of FPR1 and MAPK, decreased FPR1, p38, ERK, JNK, MMP-2, TIMP-2, NF-kB, Bax, p-p38, p-ERK, and p-JNK levels, increased Bcl-2 level, promoted cell proliferation and cell cycle progression, and inhibited cell apoptosis rate. Overall, our study demonstrates that the silencing of FPR1 gene depresses inflammation, cardiomyocyte apoptosis and ventricular remodeling in rats with I/R injury through the suppressing the activation of the MAPK signaling pathway.

IL-15 Complexes Induce Migration of Resting Memory CD8 T Cells into Mucosal Tissues.

IL-15 is an essential cytokine known to promote T cell survival and activate the effector function of memory phenotype CD8 T cells. Blocking IL-15 signals also significantly impacts tissue-specific effector and memory CD8 T cell formation. In this study, we demonstrate that IL-15 influences the generation of memory CD8 T cells by first promoting their accumulation into mucosal tissues and second by sustaining expression of Bcl-6 and T-bet. We show that the mechanism for this recruitment is largely dependent on mammalian target of rapamycin and its subsequent inactivation of FoxO1. Last, we show that IL-15 complexes delivered locally to mucosal tissues without reinfection is an effective strategy to enhance establishment of tissue resident memory CD8 T cells within mucosal tissues. This study provides mechanistic insight into how IL-15 controls the generation of memory CD8 T cells and influences their trafficking and ability to take up residence within peripheral tissues.

Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease.

Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic). Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD), such as focal segmental glomerulosclerosis (FSGS). The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the pathological uPAR is circulating and FSGS can recur even after a damaged kidney is replaced with a healthy donor organ. Here we report that bone marrow (BM) Gr-1lo immature myeloid cells are responsible for the elevated, pathological levels of suPAR, as evidenced by BM chimera and BM ablation and cell transfer studies. A marked increase of Gr-1lo myeloid cells was commonly found in the BM of proteinuric animals having high suPAR, and these cells efficiently transmit proteinuria when transferred to healthy mice. In accordance with the results seen in suPAR-associated proteinuric animal models, in which kidney damage is caused not by local podocyte-selective injury but more likely by systemic insults, a humanized xenograft model of FSGS resulted in an expansion of Gr-1lo cells in the BM, leading to high plasma suPAR and proteinuric kidney disease. Together, these results identify suPAR as a functional connection between the BM and the kidney, and they implicate BM immature myeloid cells as a key contributor to glomerular dysfunction.

Noninvasive Swansea criteria are valuable alternatives for diagnosing acute fatty liver of pregnancy in a Chinese population.

BACKGROUND: This study aims to assess the diagnostic and prognostic value of Swansea criteria in diagnosing acute fatty liver of pregnancy (AFLP) in a Chinese population. METHODS: A retrospective study was conducted on 52 Chinese women diagnosed with AFLP. All selected cases were reassessed using the Swansea criteria with special focus on the noninvasive criteria, since performing a liver biopsy for this indication is rare in a Chinese population. RESULTS: Ninety point four percent of patients fulfilled five or more of the Swansea criteria. Thirty-one cases were positive for six or more Swansea criteria, but there were no significance differences between patients when using a cutoff criteria <6 or >6. When patients were positive for less than seven criteria, frequency of stillbirth, continuous blood purification (CBP) treatment, hysterectomy, and postpartum hemorrhage were not increased. However, patients who were positive for seven or more criteria had a significantly higher risk of stillbirth and a higher rate of CBP treatment (p < 0.05). Areas under the receiver operating characteristic (ROC) curve of postpartum hemorrhage was 0.670, which reached a statistical significance (p = 0.040). We observed a significantly elevated postpartum hemorrhage along with positivity of the Swansea criteria (p = 0.040). CONCLUSIONS: Swansea criteria without liver biopsy are good screening tools for AFLP diagnosis, and may be useful for assessing disease severity.

B cells expressing IFN-γ suppress Treg-cell differentiation and promote autoimmune experimental arthritis.

Clinical efficacy in the treatment of rheumatoid arthritis with anti-CD20 (Rituximab)-mediated B-cell depletion has garnered interest in the mechanisms by which B cells contribute to autoimmunity. We have reported that B-cell depletion in a murine model of proteoglycan-induced arthritis (PGIA) leads to an increase in Treg cells that correlate with decreased autoreactivity. Here, we demonstrate that the increase in Treg cells after B-cell depletion is due to an increase in the differentiation of naïve CD4(+) T cells into Treg cells. Since the development of PGIA is dependent on IFN-γ and B cells are reported to produce IFN-γ, we hypothesized that B-cell-specific IFN-γ plays a role in the development of PGIA. Accordingly, mice with B-cell-specific IFN-γ deficiency were as resistant to the induction of PGIA as mice that were completely IFN-γ deficient. Importantly, despite a normal frequency of IFN-γ-producing CD4(+) T cells, B-cell-specific IFN-γ-deficient mice exhibited a higher percentage of Treg cells compared with that in WT mice. These data indicate that B-cell IFN-γ production inhibits Treg-cell differentiation and exacerbates arthritis. Thus, we have established that IFN-γ, specifically derived from B cells, uniquely contributes to the pathogenesis of autoimmunity through prevention of immunoregulatory mechanisms.

Tissue specific CD4+ T cell priming determines the requirement for interleukin-23 in experimental arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease with striking heterogeneity in (i) clinical presentation, (ii) autoantibody profiles and (iii) responses to treatment suggesting that distinct molecular mechanisms may underlie the disease process. Proteoglycan-induced arthritis (PGIA) is induced by two pathways either by intraperitoneal (i.p.) or subcutaneous (s.c.) exposure to PG. CD4+ T cells primed by the i.p. route are T helper (Th)1 cells expressing interferon gamma (IFN-γ) whereas CD4+ T cells primed by the s.c. route are Th17 cells expressing interleukin (IL)-17. IL-23 is necessary for maintaining the phenotype of Th17 cells; however, IL-23 is inflammatory independent of IL-17. The aim of this study was to determine if PGIA induced by different routes of immunization is dependent on IL-23. METHODS: BALB/c wild type (WT), IL-12p40-/- and IL-23p19-/- littermate mice were immunized with recombinant G1 (rG1) domain of human PG in adjuvant either i.p. or s.c. and development of arthritis monitored. Joint histology was assessed. CD4+ T cell cytokines in spleen, lymph node (LN), and joint were assessed by intracellular staining and cytokine enzyme-linked immunosorbent assay. RNA transcripts for cytokines and transcription factors were examined. RESULTS: PGIA was suppressed in the p40-/- and p19-/- mice immunized by the s.c. route but only inhibited in p40-/- mice by the i.p. route. The joints of s.c. but not i.p. sensitized mice contained a population of CD4+ T cells expressing single positive IFN-γ and IL-17 and double positive IFN-γ/IL-17 which were dependent on IL-23 expression. The IFN-γ and IL-17 response in spleen and inguinal LN was inhibited in p19-/- mice and p40-/- mice after s.c. immunization, whereas in i.p. immunized p19-/- mice, IL-17 but not IFN-γ was reduced. Inguinal LN CD11c+ dendritic cells (DC) from s.c. immunized, but not spleen DC from i.p. immunized mice, produced IL-23, IL-1ß, and IL-6 and activated T cells to produce IL-17. CONCLUSION: IL-23 is necessary for the activity of Th17 after s.c. immunization and does not play a role independent of IL-17 after i.p. immunization. These data demonstrate that the molecular pathways IL-23/17 and IL-12/IFN-γ may represent subtypes of arthritis determined by the mode of induction.

B cell-specific expression of inducible costimulator ligand is necessary for the induction of arthritis in mice.

OBJECTIVE: Inducible costimulator (ICOS)-ICOSL interactions are necessary for activation of Teff cells and follicular helper T (Tfh) cells. ICOSL is expressed on B cells, macrophages, and dendritic cells and can be induced on nonhematopoietic cells. The aim of this study was to determine whether expression of ICOSL on B cells is necessary for the development of proteoglycan (PG)-induced arthritis (PGIA). METHODS: PGIA was initiated by immunizing wild-type and ICOSL-deficient (ICOSL(-/-) ) or B cell-specific ICOSL(-/-) chimeric BALB/c mice with human PG in adjuvant. The onset and severity of arthritis were monitored over time. CD4+ T cell proliferation and CD4+ T cell cytokine production were measured in vitro after the cells were restimulated with PG. Germinal center (GC) B cells, plasma cells, Tfh cells, and Treg cells were identified by staining with specific antibodies. RESULTS: Arthritis progression was completely inhibited in both ICOSL(-/-) mice and B cell-specific ICOSL(-/-) chimeric mice. Production of the Teff cell-produced cytokines interferon-γ and interleukin-17 (IL-17) and the antiinflammatory cytokine IL-4 was suppressed. The reduced percentages of GCs and Tfh cells and the decreased production of IL-21 correlated with a decrease in the anti-mouse PG antibody response. However, the percentage of plasma cells was not reduced despite a reduction in IgG responses. CONCLUSION: These data indicate that the signals provided by ICOSL-expressing B cells to Teff cells and Tfh cells are necessary for the development of arthritis. Thus, therapeutic blockade of ICOSL-ICOS interactions may be an effective strategy for the treatment of rheumatoid arthritis.