COVID-19-induced immune thrombocytopenia management approach: A case report and literature review.

Key Clinical Message: Vincristine therapy can be effective in refractory Immune thrombocytopenia (ITP) following COVID-19 vaccination. Our case report highlights the need for further research to establish standard management guidelines for COVID-19-vaccine-associated ITP. Abstract: Adult immune thrombocytopenia (ITP) can occur as a rare complication following several viral infections or a rare adverse event or complication of vaccination. In this paper, we report a case of a 39-year-old male patient with severe refractory ITP that began 4-weeks after receiving his third (booster) dose of the COVID-19 vaccine (BNT162b2, Pfizer-BioNTech). He was given oral dexamethasone 40 mg daily for 4 days followed by prednisone at 1 mg/kg (85 mg daily) for 10 days. In the following weeks, we attempted several other lines of therapy to treat his ITP, including anti-RhD immunoglobulin, which, unfortunately, caused moderate hemolysis requiring packed red blood cell transfusion, intravenous immunoglobulin (given at a subtherapeutic dose of 0.4 g/kg for only 1 day since it was not available), rituximab, and eltrombopag. The patient, unfortunately, showed no response to any of these treatments. This was an indicator to initiate salvage therapy with vincristine 2 mg weekly for 3 weeks. The patient's platelet count started to increase remarkably during the third week of vincristine and normalized after 4 weeks. We review the findings, clinical characteristics, and management approaches that were reported in the literature regarding COVID-19-vaccine-induced ITP. More in-depth research is needed to delineate standard guidelines for the management of such cases. This report underscores the importance of resorting to vincristine and eltrombopag as great options for severe and refractory ITP related to the COVID-19 vaccine.

Mortality and Survival Analysis of Burn Patients Admitted in a Critical Care Burn Unit, Saudi Arabia.

Background: Burn injury is associated with a high mortality risk. Recent epidemiological data on burn injury and mortality rate from Saudi Arabia is lacking. Objective: This study aimed to analyze the survival rates and its predictability using the Baux score in patients with burn injury at a tertiary care hospital in Saudi Arabia. Materials and Methods: This retrospective study included all patients admitted to the burn unit at King Fahd Hospital of the University, Al Khobar, between March 2014 and February 2020. Patients' burn characteristics and calculated revised Baux scores were collected. The age, burn wound size, type of burn, burn extension, and Baux score of the survivors and non-survivors were compared. Results: A total number of 102 patients were included, and their mean age was 24.2 years (range: 9 months to 78 years). The mean affected total body surface area was 26.4%. Ninety patients (88%) suffered from flame/scald burn. The mortality rate was 17.6% (18 patients); all these patients had flame burns. No patient with a revised Baux score ≥110 survived (n = 14; 77% of the total deaths), while there was no mortality at score <36. Inhalational injuries were reported in 18 patients, of which 13 (72%) died. Patients with patent airway and no inhalation injury were 19 times more likely to survive than those with a compromised airway (P < 0.001). In terms of the depth of burn, partial thickness increased the likeliness of survival by 10 times compared with full thickness (P < 0.003). Conclusion: Inhalational injury and burn size were the most prognostic factors of burn injury in this study. As all cases of mortality were from flame burns, regulation on flammable materials and safety measures should be promoted to the public.

Intratympanic corticosteroid injection as a first-line treatment of the patients with idiopathic sudden sensorineural hearing loss compared to systemic steroid: A systematic review and meta-analysis.

OBJECTIVES: The current study aimed to investigate if there is a difference in the use of intratympanic steroid therapy (IST), compared to systemic steroid treatment (SST), as an initial treatment for patients with sudden sensorineural hearing loss (SSNHL) by a meta-analysis design performed on the mean pure-tone average (PTA) improvement and the complete recovery rate. METHODS: A systematic literature review was performed on randomized controlled trials published from 1990 to August 2020 in some databases including PubMed/MEDLINE, Scopus, Embase, Web of Science, Cochrane library/CENTRAL, Ovid, ProQuest, Google Scholar, and clinical trials.gov. The primary outcomes of interest were pure-tone average improvement and complete recovery rates. RESULTS: Six eligible studies with 496 patients (250 patients in the IST group and 246 subjects in the SST group) were included in this study. The pooled standardized mean difference of the PTAs was estimated as 0.07 (95% CI = -0.10 to 0.25; I2 = 0.0%, P = 0.668), and the pooled odds ratio of complete recovery rate was obtained as 1.00 (95% CI = 0.66 to 0.151; I2 = 31.6, P = 0.199). Moreover, the pooled standardized mean difference of pure-tone average for the intratympanic steroid treatment group compared to the patients with oral steroid treatment was 0.07 (95% CI = -0.12 to 0.26; I2 = 0.0%, P = 0.526). CONCLUSIONS: The current study demonstrated that the effect of intratympanic injection of corticosteroid, as a first-line treatment, is not statistically different from the systemic route in improving the hearing outcomes among patients with SSNHL.

Inflammatory Cytokine Profiles Do Not Differ Between Patients With Idiopathic Cytopenias of Undetermined Significance and Myelodysplastic Syndromes.

Immune dysregulation has been highlighted as a key player in the pathogenesis of myelodysplastic syndromes (MDS), but little is known about cytokine profiles in patients with unexplained cytopenia with or without mutations in MDS-associated genes (clonal cytopenias of undetermined significance [CCUS] and idiopathic cytopenias of undetermined significance [ICUS], respectively), which often precede MDS. Here, we study the cytokine profiles in 111 patients with ICUS (N = 41), CCUS (N = 30), lower-risk MDS (LR-MDS; N = 22) and higher-risk MDS (HR-MDS; N = 18), and in healthy elderly controls (N = 21). Twenty cytokines were examined in blood plasma at time of diagnosis using Luminex assays and enzyme linked immunosorbent assays. The cytokine levels were compared between patient groups, and in patients versus controls. Associations between cytokines and MDS-associated mutations were evaluated. An aberrant cytokine profile was observed in all patient groups relative to healthy elderly controls. Patients had significantly higher levels of IL-6 (P< 0 .001), tumor necrosis factor α (P < 0.001), IL-10 (P < 0.001), and C-X-C motif chemokine 10 (P < 0.001) and lower levels of transforming growth factor beta 1 (P < 0.001), CCL5/regulated on activation normal T-cell expressed and secreted (P < 0.001), and S100A4 (P < 0.001) compared with healthy controls. Survival was significantly shorter in CCUS and MDS patients with a high systemic inflammatory cytokine load (median overall survival [OS] 21 months) compared with those with low-moderate systemic inflammatory cytokine load (median OS 64 months; P < 0.0001). These data suggest that patients with ICUS and CCUS have cytokine levels as abnormal as in LR-MDS. Indeed, high cytokine levels are present before MDS is diagnosed and cytokine levels are elevated irrespective of the presence or size of the myeloid clones. Cytokines may have a prognostic impact at a very early premalignant stage of myeloid disorders.

Evaluation of Nanofiltration Membranes for Pure Lactic Acid Permeability.

Lactic acid (LA) is an organic acid produced by fermentation or chemical synthesis. It plays a crucial role in the pharmaceutical, food and plastic industries. In the fermentation of, for example, grass silage, LA and different compounds are produced. To purify lactic acid, researchers have tried to investigate membrane technology to achieve a high yield of lactic acid permeance. This study tested four commercially available nanofiltration membranes (NF270, MPF-36, Toray NF, and Alfa Laval NF). Nanofiltration experiments were performed to investigate the rejection levels of lactic acid from a binary solution by using distinct molecular weight cut off membranes. All of the experiments were conducted with a lab-scale cross-flow membrane unit. Different operating conditions (pH, temperature) were studied for each membrane; the optimal process condition was found at 25 °C and pH 2.8. With higher temperatures and pH, an increase in LA rejection was observed. The MPF-36 membrane shows the lowest lactic acid rejection yield of 7%, while NF270 has the highest rejection yield of 71% at 25 °C and pH 2.8. These results will be helpful in the future to understand both the interaction of lactic acid permeance through nanofiltration membranes and process scale-up.

Prediction of fracture initiation and propagation in pelvic bones.

The objective is developing an XFEM model that is capable of predicting different types of fracture in the pelvic bone under various loading conditions. Previously published mechanical and failure characteristics of cortical and cancellous tissues were implemented and assigned to an intact pelvic bone with specified cortical and cancellous tissues. Various loading conditions, including combined load directions, were applied to the acetabulum to model different types of fracture (e.g., anterior/posterior wall fracture and transverse fracture) in the pelvic bone. The predicated types of fracture and the maximum force at fracture were compared to those acquired from previously published experimental tests. Anterior/posterior wall fracture and transverse fracture were the most common types of fractures determined in the simulations. The XFEM simulations were able to predict similar fractures to those reported in the experimental tests. The maximum fracture force in the XFEM model was found to be 18.6 kN compared to 8.85 kN reported in the previous experimental tests. The results revealed that different types of fracture in the pelvic bones can be caused by the various loading conditions in unstable high-rate impact loads. Using proper mechanical and failure behaviors of cortical and cancellous tissues, XFEM modeling of pelvic bone is capable of predicting bone fracture. In future work, the XFEM models of cancellous and cortical tissues can be assigned to other bones in human body skeleton so that the failure mechanism in such bones can be investigated.

Successful Elbow Flexion Reconstruction Using Latissimus Dorsi Muscle Transfer Following a Road Traffic Accident and Upper Limb Trauma.

BACKGROUND Several surgical procedures to restore elbow flexion have been reported in the literature. Multiple factors direct the selection of appropriate procedures for each patient, including hand dominance, neurovascular injury, and comorbidities. Traumatic damage to the anterior compartment of the arm is an indication for latissimus dorsi transfer, which can restore elbow flexion. Bipolar pedicled latissimus dorsi (LD) flap is a design used very rarely to simultaneously reconstruct biceps brachii soft-tissue defects and regain complete flexion function. We report the case of a 30-year-old man who underwent successful elbow flexion reconstruction using latissimus dorsi muscle transfer following a road traffic accident and upper limb trauma. CASE REPORT A 30-year-old man presented with acute compartment syndrome caused by a road traffic accident and impact trauma to the left arm. The surgical evaluation revealed proximal biceps tendons rapture; therefore, immediate repair and therapeutic fasciotomy were done. Subsequently, unsuccessful repair resulted in total necrosis of the biceps muscle, which necessitated debridement of the biceps muscle. Delayed reconstruction with an LD flap was successfully done after stabilization of the patient's condition. The flap was harvested as free-pedicled, then modified into a tube-like shape to resemble the biceps muscle. CONCLUSIONS This report has shown that the surgical procedure of latissimus dorsi muscle transfer can successfully restore elbow function following upper limb trauma; however, preoperative planning and postoperative follow-up are crucial for functional reconstruction of the upper extremity. In addition, carefully selecting reconstructive surgery considering patient factors, degree of injury, and the institution's capacity are essential factors in achieving optimal function restoration with minimal complications.

Synthesis and biological evaluation of new coumarin derivatives as cytotoxic agents.

New coumarin derivatives 9a-f, 10a-e, and 11a-f were synthesized and evaluated for their cytotoxic activity against a human breast cancer cell line (MCF-7). All compounds exhibited good activity in the nanomolar range, using doxorubicin and erlotinib as positive controls. The most active compound 9d with IC50 of 21 nM was tested against the HCT-116, HepG-2, A549, and SGC-7901 cell lines, with IC50 values of 0.021, 0.170, 0.028, and 0.11 µM, respectively. Compound 9d was further investigated for its ability to suppress the expression of epidermal growth factor receptor (EGFR). Compound 9d decreased the concentration of EGFR by 87%, using erlotinib as a positive control. A docking study revealed similar or higher scores than for erlotinib and similar binding poses providing interactions with the hinge region of the tyrosine kinase (TK). Besides the effect on expression, this in silico investigation predicts the possibility of direct binding between the new coumarin derivatives and the EGFR TK. Moreover, computational calculation for ADME properties for the most active compounds 9d, 9e, 10c, and 11c revealed the expected high gastrointestinal tract absorption, moderate water solubility with no central nervous system toxicity, and druglikeness.

Metabolomic profiling and biological investigation of Tabebuia Aurea (Silva Manso) leaves, family Bignoniaceae.

Both ethyl acetate and aqueous fractions of Tabebuia aurea leaves exhibited noteworthy antioxidant and nephroprotective activities against carbon tetrachloride (CCl4)-induced nephrotoxicity in rats, as evidenced by the remarkable improvements of renal serum biomarkers and histopathological features. Additionally, the ethyl acetate fraction displayed a prominent in vitro antitrypanosomal activity against Trypanosoma brucei; consequently, the leaves were subjected to LC-HR-ESI-MS metabolomic profiling to discover the constituents that possibly underlie their bioactivities. Therefore, ten metabolites were characterized, mostly dominated by flavonoids. Interestingly, two identified constituents viz., 3,9,12,15-octadecatetraenoic acid (9) and 9,11,13-octadecatrienoic acid (10) are reported firstly herein from the genus Tabebuia. Furthermore, among the dereplicated constituents, rutin (5) and kaempferol 3-O-rutinoside (6) exhibited the highest docking scores as effective antitrypanosomal compounds.

Robotic surgery of head and neck cancers, a narrative review.

Head and neck cancers are the most common cancers in the body. Treatments are determined on the basis of the location and stage of the primary tumor. The goal of treatment is to eliminate the tumor, prevent recurrence or metastasis, and maintain the quality of life. There are several treatments available for the management of head and neck cancers, including surgery, radiation therapy, chemotherapy, new molecular agents, and a combination of them. Transoral robotic technique is a short-time operation using a type of robotic machine in which the patient undergoes anesthesia for a shorter time and the side effects of this operation and the time of hospitalization are less than open surgery. Due to the importance of speed and accuracy in head and neck cancer surgery and the importance of application of robotics in surgery, the present study was designed and implemented to review the application of robotics in the management of head and neck cancers. In this review study, the keywords: application, robotic, surgical, head cancer, transoral robotic surgery (TORS), and neck cancer, were searched in ISI, PubMed, Scopus, Google scholar databases. Related articles written domestically or abroad that have covered areas such as the background of transoral robotic surgery, maintaining organ function and approaches, the advantages and disadvantages of TORS, the affordability of TORS, the combination of TORS with other therapeutic approaches published from 2003 to 2019 were reviewed. The use of robotic surgery for precise operations such as head and neck cancers seems to be essential. More advanced robotic devices are expected to expand the surgery treatment for head and neck cancers as well as the results of using TORS for oncologic optimization and acceptability of results while maintaining organ function and patient's quality of life.

Increment of Lysosomal Biogenesis by Combined Extracts of Gum Arabic, Parsley, and Corn Silk: A Reparative Mechanism in Mice Renal Cells.

Gum Arabic (GA), parsley, and corn silk have been traditionally used for renal failure patients worldwide. This study aimed at probing the mechanism of the combined extracts, namely, GA (3 g/kg/day), parsley (1 g/kg/day), and corn silk (200 mg/kg/day), as nephroprotective agents in mice after amikacin (1.2 g/kg) single dose through exploration of their action on G-protein coupled receptors (GPR) 41 and 43 and the ensuing lysosomal biogenesis. Western blotting was employed for renal levels of bcl-2-associated X protein (BAX) and cytosolic cathepsin D; cell death markers, nuclear transcription factor EB (TFEB), and lysosomal associated membrane protein-1 (LAMP-1); and lysosomal biogenesis indicators. Liquid chromatography-mass spectrometry (LC-MS) and docking were also employed. After amikacin treatment, BAX and cathepsin D levels were upregulated while LAMP-1 and nuclear TFEB levels were inhibited. The combined extracts inhibited BAX and cytosolic cathepsin D but upregulated LAMP-1 and nuclear TFEB levels. Docking confirmed GPR modulatory signaling. The combined extracts showed GPR signal modulatory properties that triggered lysosome synthesis and contributed to reversing the adverse effects of amikacin on renal tissues.

Prediction of failure in cancellous bone using extended finite element method.

The objective of our study is to develop extended finite element method models of cancellous bone specimens that are capable of accurately predicting the onset and propagation of cracks under mechanical loading. In order to do so, previously published three-point bending test results of a single trabecula were replicated using two different extended finite element method approaches, namely, elastic-plastic-fracture and elastic-fracture that considered different configurations of the elasto-plastic properties of bone from which the best approach to fit the experimental data was identified. The behavior of a single trabecula was then used in 2D extended finite element method models to quantify the strength of the trabecular tissue of the forearm along three perpendicular anatomical axes. The results revealed that the elastic-plastic-fracture model better represented the experimental data in the model of a single trabecula. Considering the 2D trabecular specimens, the elastic fracture model predicted higher strength than the elastic-plastic-fracture model and there was no difference in stiffness between the two models. In general, the specimens exhibited higher failure strain and more ductile behavior in compression than in tension. In addition, strength and stiffness were found to be higher in tension than compression on average. It can be concluded that with proper parameters, extended finite element method is capable of simulating the ductile behavior of cancellous bone. The models are able to quantify the tensile strength of trabecular tissue in the various anatomical directions reporting an increased strength in the longitudinal direction of forearm cancellous bone tissue. Extended finite element method of cancellous bone proves to be a valuable tool to predict the mechanical characteristics of cancellous bones as a function of the microstructure.

Impact of Acamprosate on Chronic Tinnitus: A Randomized-Controlled Trial.

OBJECTIVES: Tinnitus is a common and distressing otologic symptom, with various probable pathophysiologic mechanisms, such as an imbalance between excitatory and inhibitory mechanisms. Acamprosate, generally used to treat alcoholism, is a glutaminergic antagonist and GABA agonist suggested for treating tinnitus. Thus, we aimed to evaluate the efficacy and safety of acamprosate in the treatment of tinnitus. METHODS: The current randomized-controlled trial study included 20 subjects with chronic tinnitus. After performing psycho-acoustic, psychometric and electrophysiological evaluations, all studied tinnitus subjects were randomly divided into two groups of acamprosate and placebo. The first group received oral acamprosate (two tablets of 333 mg/d, three times a day), whereas the second group was given placebo treatment (two tablets, three times a day). After the first 30 days, all evaluations were repeated for the studied groups just in the same manner before the study. Subsequently, the final results of each evaluation were compared together with the baseline values. RESULTS: Nine studied subjects randomly received acamprosate, whereas eleven others received a placebo. There was no significant improvement in the psycho-acoustic tests, except a decrease was observed in the pitch match of tinnitus (P = .039). For those subjects who were receiving acamprosate, a significant reduction was observed in tinnitus handicap inventory (P = .006), tinnitus questionnaire scores (P = .007), and the visual analog scores (P = .007) compared to the placebo group. There was a significant reduction in Action Potential latency (P = .048) as well as an increase in the amplitude of distortion product otoacoustic emissions at 4 kHz (P = .048). CONCLUSIONS: The study results indicated a subjective relief of tinnitus as well as some degree of the electrophysiological improvement at the level of the cochlear and the distal portion of the auditory nerve among the subjects who received the acamprosate. CLINICAL TRIAL REGISTRATION CODE: IRCT2013121115751N1.

An Equivalent Constitutive Model of Cancellous Bone With Fracture Prediction.

To simulate the mechanical and fracture behaviors of cancellous bone in three anatomical directions and to develop an equivalent constitutive model. Microscale extended finite element method (XFEM) models of a cancellous specimen were developed with mechanical behaviors in three anatomical directions. An appropriate abaqus macroscale model replicated the behavior observed in the microscale models. The parameters were defined based on the intermediate bone material properties in the anatomical directions and assigned to an equivalent nonporous specimen of the same size. The equivalent model capability was analyzed by comparing the micro- and macromodels. The hysteresis graphs of the microscale model show that the modulus is the same in loading and unloading; similar to the metal plasticity models. The strength and failure strains in each anatomical direction are higher in compression than in tension. The microscale models exhibited an orthotropic behavior. Appropriate parameters of the cast iron plasticity model were chosen to generate macroscale models that are capable of replicating the observed microscale behavior of cancellous bone. Cancellous bone is an orthotropic material that can be simulated using a cast iron plasticity model. This model is capable of replicating the microscale behavior in finite element (FE) analysis simulations without the need for individual trabecula, leading to a reduction in computational resources without sacrificing model accuracy. Also, XFEM of cancellous bone compared to traditional finite element method proves to be a valuable tool to predict and model the fractures in the bone specimen.

Tecoma stans: Alkaloid Profile and Antimicrobial Activity.

AIM: Tecoma stans (L.) Kunth is a promising species in the trumpet creeper family Bignoniaceae. This study aimed at showing the antibacterial and antifungal potentials of T. stans methanolic leaf extract (TSME) correlated to its phytoconstituents. MATERIALS AND METHODS: The antimicrobial potential of TSME was evaluated using agar diffusion method. The main alkaloids were separated on silica gel column and identified using nuclear magnetic resonance spectral analysis. Molecular docking was performed for the isolated compounds against MurD ligase, penicillin-binding protein, and dihydropteroate synthase enzyme to rationalize the observed antibacterial effect. RESULTS AND DISCUSSION: TSME showed significant antibacterial effect against all tested microorganisms with comparable minimum inhibitory concentration (MIC) to the ampicillin and gentamicin with MIC values ranging between 0.98 and 1.95 µg/mL, in addition to a promising antifungal effect when compared to amphotericin with MIC values 3.9 and 15.63 µg/mL for Aspergillus flavus and Candida albicans, respectively. Several alkaloids were separated, purified, and identified as tecostanine, 4-OH tecomanine, 5-hydroxyskytanthine, and tecomanine, which were previously isolated from T. stans. The docking study showed that the alkaloids bind in a similar fashion to the co-crystallized ligands of the crystal structures of MurD ligase. The binding poses and scores in the case of penicillin-binding protein and dihydropteroate synthase did not match the co-crystallized ligands in their crystal structures. The in silico results suggest an antibacterial mechanism that involves the inhibition of MurD ligase. CONCLUSION: T. stans alkaloids could represent the basic skeleton for a powerful antimicrobial agent.

Patient-reported outcomes after breast reconstructive surgery: A prospective cross-sectional study.

BACKGROUND: With advancements in and the evolution of the medical field, several methods and surgical techniques have been developed for breast reconstruction after mastectomy. Generally, we can categorize these strategies into two broad groups: autologous reconstruction and implant-based reconstruction. This study aimed to analyze the satisfaction rate between these groups, considering age, timing of breast reconstruction, body mass index (BMI), major complications, and the need for radiotherapy or chemotherapy. MATERIALS AND METHODS: All the patients who underwent a mastectomy and subsequent breast reconstruction surgery at our institution between August 1, 2013, and August 31, 2017, were invited to complete a BREAST-Q questionnaire. To compare the quality of life and complication rate between the autologous and implant-based reconstruction groups, data were collected from specific patients. All participants completed the Arabic version of the postoperative reconstruction module. RESULTS: Among 61 patients, 43 (70.5%) completed the two domains of the BREAST-Q questionnaire, about the satisfaction with the implanted breast and satisfaction with the surgical outcome. These patients were divided into two groups: autologous (n = 21) and implant-based (n = 22) groups. The mean score of satisfaction with the implanted breast was 43.5 for the autologous group and 39.6 for the implant-based group. For the surgical outcome, the scores for the autologous and implant-based groups were 45.4 and 56.0, respectively. However, there was neither a statistical significance in the satisfaction with the implanted breast nor the surgical outcome between the two groups. CONCLUSION: Although there are many different surgical techniques to reconstruct a breast after mastectomy, there is still no specific surgical method that is perfect or well-suited for all patients undergoing breast reconstruction surgery. In our study, we found that there was no significant difference in satisfaction between the ABR and IBR group.

GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon.

Activated regulatory T (Treg) cells express the surface receptor glycoprotein-A repetitions predominant (GARP), which binds and activates latent TGFß. How GARP modulates Treg function in inflammation and cancer remains unclear. Here we demonstrate that loss of GARP in Treg cells leads to spontaneous inflammation with highly activated CD4+ and CD8+ T cells and development of enteritis. Treg cells lacking GARP were unable to suppress pathogenic T-cell responses in multiple models of inflammation, including T-cell transfer colitis. GARP-/- Treg cells were significantly reduced in the gut and exhibited a reduction in CD103 expression, a colon-specific migratory marker. In the colitis-associated colon cancer model, GARP on Treg cells dampened immune surveillance, and mice with GARP-/- Treg cells exhibited improved antitumor immunity. Thus, GARP empowers the functionality of Treg cells and their tissue-specific accumulation, highlighting the importance of cell surface TGFß in Treg function and GARP as a potential therapeutic target for colorectal cancer therapy.Significance: These findings uncover functions of membrane-bound TGFß and GARP that tune the activity of Treg cells, highlighting a potential treatment strategy in autoimmune diseases and cancer.

B lymphocytes confer immune tolerance via cell surface GARP-TGF-ß complex.

GARP, a cell surface docking receptor for binding and activating latent TGF-ß, is highly expressed by platelets and activated Tregs. While GARP is implicated in immune invasion in cancer, the roles of the GARP-TGF-ß axis in systemic autoimmune diseases are unknown. Although B cells do not express GARP at baseline, we found that the GARP-TGF-ß complex is induced on activated human and mouse B cells by ligands for multiple TLRs, including TLR4, TLR7, and TLR9. GARP overexpression on B cells inhibited their proliferation, induced IgA class-switching, and dampened T cell-independent antibody production. In contrast, B cell-specific deletion of GARP-encoding gene Lrrc32 in mice led to development of systemic autoimmune diseases spontaneously as well as worsening of pristane-induced lupus-like disease. Canonical TGF-ß signaling more readily upregulates GARP in Peyer patch B cells than in splenic B cells. Furthermore, we demonstrated that B cells are required for the induction of oral tolerance of T cell-dependent antigens via GARP. Our studies reveal for the first time to our knowledge that cell surface GARP-TGF-ß is an important checkpoint for regulating B cell peripheral tolerance, highlighting a mechanism of autoimmune disease pathogenesis.