Segmental Adrenal Venous Sampling in Unilateral Primary Aldosteronism With Apparent Bilateral Aldosterone Suppression.

Apparent bilateral adrenal suppression (ABAS), where aldosterone/cortisol ratios in both adrenal veins are lower than in the inferior vena cava, yields uninterpretable adrenal venous sampling (AVS) results and is poorly understood. A 57-year-old male with hypertension and spontaneous hypokalemia was admitted to our hospital. Confirmatory tests established a diagnosis of primary aldosteronism (PA). Initial AVS indicated ABAS, but unilateral PA remained possible due to elevated aldosterone, low renin, hypokalemia, and a right adrenal nodule (8 × 7 mm) on computed tomography. Subsequently, a second, super-selective AVS identified tributaries from areas of aldosterone hypersecretion, enabling accurate localization of unilateral PA. ABAS may occur due to anatomical factors such as dilution by tributaries from nonaldosterone-producing adenoma (APA) areas with suppressed aldosterone production. Super-selective AVS proves beneficial in diagnosing unilateral PA concealed within ABAS by pinpointing tributaries from APA regions.

Survey of pharyngeal foreign bodies in Japan: An ecological study using the nationwide claims data.

OBJECTIVE: Pharyngeal foreign bodies (PFBs) are a prevalent disease affected by food culture and dietary habits, with fish bones as the leading cause. Most studies were limited to specific regions, and a nationwide survey was not conducted in Japan. In this ecological study, we aimed to conduct a nationwide analysis of outpatient PFB cases in Japan over three years, focusing on seasonal trends, sex- and age-stratified cases, and regional differences. METHODS: We used the National Database of Health Insurance Claims and Specific Health Checkups of Japan open data from April 2019 to March 2022. The case data were analyzed by month, age, sex, and prefecture. Additionally, we calculated the standardized claim ratios (SCRs) for each prefecture and investigated the association between dietary habits, food culture, and SCR of PFBs using a two-level linear regression model. RESULTS: We analyzed a total of 164,337 outpatient PFB cases in Japan, revealing an average incidence rate of 45.6 per 100,000 persons. The seasonal trend revealed a peak in July each year from 2019 to 2021, confirming seasonality in PFB incidents. Children reported a higher incidence rate. Living west of Japan and expenditure on fish and shellfish had a strongly positive association with the SCR of PFBs. CONCLUSION: Our nationwide survey reveals that, even within Japan, there were regional variations influenced by food culture and dietary habits. The data showed that PFB incidence was higher among children, highlighting the need for preventive education. LEVEL OF EVIDENCE: Level 3.

Pneumocephalus with Inverted Papilloma in the Frontoethmoidal Sinus: Case Report and Literature Review.

Here, we describe the unique case of a pneumocephalus originating from an inverted papilloma (IP) in the frontoethmoidal sinus. A 71-year-old man with diabetes presented with headaches and altered consciousness. Imaging revealed the pneumocephalus together with bone destruction in the left frontal sinus. He underwent simultaneous endoscopic endonasal and transcranial surgery using an ORBEYE exoscope. Pathological diagnosis of the tumor confirmed IP. Post-surgery, the pneumocephalus was significantly resolved and the squamous cell carcinoma antigen level, which had been elevated, decreased. This case underscores the importance of a multidisciplinary approach and innovative surgical methods in treating complex sinonasal pathologies.

Susceptibility to recombinant SARS-CoV-2 spike protein entry in the lungs of high-fat diet-induced obese mice.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Obesity is a major risk factor for the development of COVID-19. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2. The receptor-binding domain of the S1 subunit (S1-RBD protein) in the SARS-CoV-2 spike glycoprotein binds to ACE2 on host cells, through which the virus enters several organs, including the lungs. Considering these findings, recombinant ACE2 might be utilized as a decoy protein to attenuate SARS-CoV-2 infection. Here, we examined whether obesity increases ACE2 expression in the lungs and whether recombinant ACE2 administration diminishes the entry of S1-RBD protein into lung cells. We observed that high-fat diet-induced obesity promoted ACE2 expression in the lungs by increasing serum levels of LPS derived from the intestine. S1-RBD protein entered the lungs specifically through ACE2 expressed in host lungs and that the administration of recombinant ACE2 attenuated this entry. We conclude that obesity makes hosts susceptible to recombinant SARS-CoV-2 spike proteins due to elevated ACE2 expression in lungs, and this model of administering S1-RBD protein can be applied to new COVID-19 treatments.

Effects of esaxerenone on blood pressure, urinary albumin excretion, serum levels of NT-proBNP, and quality of life in patients with primary aldosteronism.

Primary aldosteronism (PA) is typically managed with mineralocorticoid receptor antagonists (MRAs) barring adrenalectomy. The efficacy of esaxerenone, a nonsteroidal MRA, were explored in patients with PA. Various parameters such as the urinary albumin to creatinine ratio (UACR) and serum levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were evaluated in 25 PA patients before and 3 and 6 months after esaxerenone treatment. Systolic and diastolic blood pressure (BP), and the estimated glomerular filtration rate decreased after treatment, while serum levels of potassium and active renin increased. Significant reductions were observed in UACR 3 and 6 months after treatment. A significant decrease in NT-proBNP was evident at 6 months but not 3 months after treatment. Correlation analysis indicated that the reductions in BP and UACR at 3 months were independent of estimated daily salt intake. Furthermore, the effect of esaxerenone treatment on lowering UACR and NT-proBNP levels was independent of BP reduction. Responders whose systolic BP decreased 6 months after esaxerenone treatment by more than 10 mmHg compared to pretreatment had higher pretreatment NT-proBNP and similar UACR before and after treatment when compared with nonresponders. Esaxerenone improved mental, physical, and social quality of life (QOL) 6 months after treatment compared to healthy controls and increased over time. No patients discontinued treatment due to severe hyperkalemia or renal dysfunction. In conclusion, esaxerenone is a safe and effective MRA for PA treatment, offering significant benefits in terms of hypertension, albuminuria, NT-proBNP levels, and QOL improvement. Esaxerenone effectively lowers BP, UACR, and serum levels of NT-proBNP independent of dietary salt intake in mild PA patients. ARC active renin concentration, DBP diastolic blood pressure, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, NT-proBNP N-terminal pro-brain natriuretic peptide, PA primary aldosteronism, QOL quality of life, SBP systolic blood pressure, SF-36 Medical Outcomes Study 36-Item Short-Form Health Survey, UACR urinary albumin to creatinine ratio.

Associations of Diabetic Retinopathy Severity With High Ambulatory Blood Pressure and Suppressed Serum Renin Levels.

CONTEXT: The relationships between serum renin levels, severity of diabetic retinopathy (DR), and 24-hour blood pressure (BP) have not been previously reported. OBJECTIVE: To explore causes for DR and the relationships of 24-hour ambulatory BP, and hormone levels with the severity of DR. METHODS: The diabetic patients were classified as having no DR, simple DR, or severe DR (preproliferative DR plus proliferative DR) based on funduscopic examination, and we measured 24-hour BP, serum active renin (ARC), aldosterone (SAC), adrenocorticotropic hormone, and cortisol levels in each group. RESULTS: Compared to those with no DR or simple DR, patients with severe DR showed significantly higher 24-hour BPs, including daytime and nighttime systolic and diastolic BP levels, independent of diabetic duration and HbA1c levels. The variability of nighttime systolic BP was greater in patients with severe DR than in those with nonsevere DR, although nocturnal BP reduction was similar between the groups. The ambulatory BPs were significantly inversely associated with ARC. The ARC was significantly lower in severe DR patients than in those with no DR or simple DR (3.2 [1.5-13.6] vs 9.8 [4.6-18.0] pg/mL, P < .05), but there were no differences in SAC in patients taking calcium channel blockers and/or α-blockers. No associations were found between DR severity and other hormone levels. CONCLUSION: Severe DR was associated with higher 24-hour BPs and suppressed ARC. These findings suggest that mineralocorticoid receptor overactivation may play a role in higher BP levels and severe DR in diabetic patients.

Pitfalls in the diagnosis and treatment of a hypertensive patient with unilateral primary aldosteronism and contralateral pheochromocytoma: a case report.

BACKGROUND: Primary aldosteronism (PA) is a common cause of secondary hypertension, whereas pheochromocytoma is a rare cause of it. Thus, concomitant PA and pheochromocytoma is a very rare condition. CASE PRESENTATION: A 52-year-old woman was admitted to our hospital with suspected PA based on the presence of hypertension, spontaneous hypokalemia, and a high aldosterone-to-renin ratio. She had no catecholamine excess symptoms other than hypertension. Abdominal computed tomography (CT) showed a right lipid-rich adrenal mass and a left lipid-poor adrenal mass. PA was diagnosed by the captopril challenge test. The 24-h urinary fractionated metanephrines were slightly elevated. Adrenal vein sampling (AVS) confirmed that the right adrenal gland was responsible for aldosterone hypersecretion. Medical therapy with eplerenone was started because the patient refused surgery. Five years later, she requested surgery for PA. The second AVS confirmed right unilateral hyperaldosteronism, as expected. Repeated abdominal CT showed the enlargement of the left adrenal mass. The 24-h urinary fractionated metanephrines had risen to the diagnostic level. 123I- metaiodobenzylguanidine (MIBG) scintigraphy showed a marked tracer uptake in the left adrenal mass with no metastatic lesion. After preoperative management with α-blockade, laparoscopic left partial adrenalectomy was performed. Immunohistochemical examination of the tumor showed chromogranin A positivity leading to the diagnosis of left pheochromocytoma. CONCLUSIONS: We report an extremely rare case of concomitant unilateral PA and contralateral pheochromocytoma. When diagnosing unilateral PA by AVS, especially in cases with a lipid-poor adrenal mass, clinicians should rule out the possibility of the presence of pheochromocytoma before proceeding to undergo unilateral adrenalectomy. Although there is no standard treatment for this rare condition, it is essential to select personalized treatment from the perspective of conserving the adrenal gland.

LILRB4/gp49B Co-Localizes with Integrin via Fibronectin at Focal Adhesion Sites on Mast Cells.

Mast cells protect a host from invasion by infectious agents and environmental allergens through activation of innate and adaptive immune receptors, their excessive activation being tightly regulated by inhibitory receptors, such as leukocyte immunoglobulin-like receptor (LILR)B4 (gp49B in mice). However, the regulatory mechanism of LILRB4/gp49B expressed on mast cells remains to be clarified in relation to their recently identified ligand, fibronectin (FN), a direct activator of integrins and an indirect stimulator of high-affinity Fc receptor for IgE (FcεRI). Confocal microscopic analysis suggested that gp49B is spatially close to integrin ß1 on non-adhered bone marrow-derived mast cells (BMMCs). Their spatial relatedness increases further at robust focal adhesion sites on cells adhering to immobilized FN. However, the confocal fluorescence signal of the α subunit of FcεRI was found to be correlated to neither gp49B nor integrin ß1 on non-adherent and adherent BMMCs. Stimulation of FcεRI with an immobilized antigen caused FcεRIα signals to accumulate in an inside area surrounded by robust focal adhesion with a concomitant slight increase in the signal correlation of FcεRIα and integrin ß1, accompanied by a less significant increase of the FcεRIα and gp49 correlation. Thus, activating and inhibitory FN receptors integrin and gp49B, respectively, were co-localized via FN at robust focal adhesion sites on BMMCs, while FcεRI was not close to gp49B spatially.

Fibronectin-LILRB4/gp49B interaction negatively regulates osteoclastogenesis through inhibition of RANKL-induced TRAF6/TAK1/NF-kB/MAPK signaling.

Dysregulation of osteoclasts, the multinucleated cells responsible for bone resorption, contributes to several degenerative bone disorders. Previously, we showed that blocking the leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4), a kind of inhibitory receptor that plays an important role in immune regulation, promotes osteoclast differentiation in vitro. Here, we explored whether gp49B, the murine ortholog of LILRB4, regulates osteoclastogenesis in vivo, and whether fibronectin (FN), a ligand of LILRB4/gp49B, certainly contributes to LILRB4/gp49B-mediated osteoclastogenesis. In comparison with wild-type mice, gp49B deficiency mice exhibited a loss of trabecular bone number and an increase in osteoclast formation. Gp49B knockout improved the bone resorptive capacity of osteoclasts derived from murine Raw264.7 cells by increasing osteoclast formation. We further revealed that gp49B deficiency increased the receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced signaling transduction by increasing the phosphorylation of transforming growth factor (TGF)-activated kinase 1 (TAK1), NF-κB and mitogen-activated protein kinases (MAPKs). Furthermore, the N-terminal 30 kDa proteolytic fragments of FN promoted gp49B-mediated inhibition of osteoclastogenesis by increasing Src homology-2-containing tyrosine phosphatase 1 (SHP-1) phosphorylation and tumor necrosis factor receptor-associated factor 6 (TRAF6)-SHP-1 association. In summary, the FN-LILRB4/gp49B interaction negatively regulates RANKL-induced TRAF6/TAK1/NF-κB/MAPK signaling in osteoclastogenesis.

Importance of dietary salt restriction for patients with primary aldosteronism during treatment with mineralocorticoid receptor antagonists: The potential importance of post-treatment plasma renin levels.

We measured dietary salt intake in 26 patients with primary aldosteronism treated with mineralocorticoid receptor antagonists and evaluated whether plasma renin levels were affected by dietary salt intake pre-treatment and post 6 months of mineralocorticoid receptor antagonist treatment. The dietary salt intake level was calculated using spot urine sodium and creatinine concentrations, body weight, height, and age. The clinical parameters pre- and post- treatment were compared. The systolic and diastolic blood pressure levels decreased, and the serum potassium and active renin concentration increased significantly. Although the dietary salt intake did not change after treatment, the differences in dietary salt intake and active renin concentration pre- and post- treatment were inversely correlated (r = -0.418, p = 0.03). The 26 patients were divided into two groups with active renin concentration levels ≥5 pg/mL (Group 1) and <5 pg/mL (Group 2) after treatment. The Group parameters did not differ pre- and post- treatment. Group 1 evidenced improvements in systolic and diastolic blood pressures, and the potassium level and active renin concentration over time; Group 2 did not. Group 1 evidenced no significant correlation between the differences in dietary salt intake and active renin concentration levels (r = -0.481, p = 0.11) but Group 2 showed a strong inverse correlation (r = -0.7599, p = 0.01). In conclusion, we found that an active renin concentration level <5 pg/mL post-mineralocorticoid receptor antagonist treatment may indicate that salt sensitivity has not adequately improved, emphasizing the importance of measuring plasma renin levels after such treatment.

The Effectiveness of GLP-1 Receptor Agonist Semaglutide on Body Composition in Elderly Obese Diabetic Patients: A Pilot Study.

BACKGROUND AND OBJECTIVES: This study aimed to investigate the changes in obesity severity, glucose metabolism, and body composition in patients with obesity and type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP1-RA) semaglutide. MATERIALS AND METHODS: Body weight (BW), metabolic parameters, and body composition were examined before and 3 months after semaglutide administration. The mass of body fat (FM), fat weight percentage (%FM), mass of skeletal muscle (MM), skeletal MM percentage (%MM), and limb muscles were measured using the bioelectrical impedance method. RESULTS: Semaglutide dramatically reduced the weight, the body mass index (BMI), and the levels of the glucose metabolic markers, including fasting blood glucose and hemoglobin A1c, and accelerated the loss of excess BW. FM, MM, and %FM after semaglutide treatment also decreased. Conversely, semaglutide had no effect on the %MM after 3 months. In limb muscle analyses, right upper and lower leg muscle percentages, left upper and lower leg muscles, and the ratios of the lower/upper muscles were maintained by semaglutide treatment. CONCLUSIONS: These results suggest that the GLP1-RA semaglutide effectively reduces body adiposity while maintaining the MM in obese type 2 diabetic patients.

Re-Assessment of the Oral Salt Loading Test Using a New Chemiluminescent Enzyme Immunoassay Based on a Two-Step Sandwich Method to Measure 24-Hour Urine Aldosterone Excretion.

Since April 2021, the plasma aldosterone concentration has been measured by chemiluminescent enzyme immunoassay (CLEIA) in Japan. In the present study, we developed a new CLEIA using a two-step sandwich method to measure the 24-hour urine aldosterone level. We collected 115 urine samples and measured 24-hour urine aldosterone levels employing radioimmunoassay (RIA), CLEIA, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that the 24-hour urine aldosterone levels measured using CLEIA and LC-MS/MS were significantly correlated (ρ = 0.992, P < 0.0001). Based on the results of Passing-Bablok regression analysis, the slope was 0.992 and the intercept -19.3. The 24-hour urine aldosterone levels measured using CLEIA and RIA were also significantly correlated (ρ = 0.905, P < 0.0001). However, the aldosterone level measured by CLEIA was lower than that measured by RIA (slope, 0.729; intercept, 120.9). In Japan, a new guideline for primary aldosteronism has been announced, with changes in the aldosterone measurement method. The cutoff values for oral sodium loading test (OSLT) were changed, but clinical verification using real-world urine samples has not been performed. Therefore, we examined the cut-off value of the 24-hour urine aldosterone level after the OSLT. Receiver operating characteristic analysis revealed a cut-off value for primary aldosteronism of 3 µg/day.

Clinicopathologic Analysis of Sinonasal Inverted Papilloma, with Focus on Human Papillomavirus Infection Status.

Sinonasal inverted papilloma (SNIP) can recur; however, the factors related to tumor recurrence remain unclear. This study aimed to analyze risk factors, including human papillomavirus (HPV) infection, as well as other factors associated with SNIP recurrence. Thirty-two patients who were diagnosed with SNIP and underwent surgery between 2010 and 2019 were enrolled: 24 men and 8 women, with a mean age of 59.2 years. The mean follow-up was 57.3 months. Demographics and information about history of smoking, diabetes mellitus (DM), hypertension, allergic rhinitis, alcohol consumption, tumor stage, surgical approach, and recurrence were reviewed retrospectively. Specimens were investigated using polymerase chain reaction to detect HPV DNA (high-risk subtypes: 16, 18, 31, 33, 35, 52b, and 58; low-risk subtypes: 6 and 11). Seven patients (21.9%) experienced recurrence. HPV DNA was detected in five (15.6%) patients (high-risk subtypes, n = 2; low-risk subtypes, n = 3). Patients with recurrence of SNIP had a higher proportion of young adults and displayed higher rates of HPV infection, DM, and advanced tumor stage than those without recurrence. HPV infection, young adulthood, DM, and advanced tumor stage could be associated with a high recurrence rate, which suggests that patients with these risk factors could require close follow-up after surgery.

Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Improves Eating Behavior and Glycemic Control in Japanese Obese Type 2 Diabetic Patients.

We evaluated time-course changes and the relationship between eating behavior and glycemic profile during the treatment of 34 obese type 2 diabetic patients with the glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide. Changes in dietary habits were evaluated using the Japan Society for the Study of Obesity questionnaire. Semaglutide improved body weight and hemoglobin A1C (HbA1c) 3 and 6 months after treatment. In addition, semaglutide led to marked improvements in the total scores for eating behavior items on the questionnaire. In particular, changes in the scores regarding the sensation of hunger, food preference, eating style, regularity of eating habits and emotional eating behavior were significantly improved during semaglutide treatment. By contrast, there were no significant changes in the scores for the recognition of weight and constitution and external eating behavior. Furthermore, changes in the scores regarding the sensation of hunger and food preference were correlated with changes in HbA1c after semaglutide treatment. Multivariable regression analyses showed that the change in the sensation of hunger was related to HbA1c during treatment. In conclusion, the GLP1-RA semaglutide regulates eating behavior, and, in particular, the sensation of hunger is closely related to the improvement in HbA1c by semaglutide in obese patients with type 2 diabetes.

Adrenal Vein Sampling With Gadolinium Contrast Medium in a Patient With Florid Primary Aldosteronism and Iodine Allergy.

We describe a 35-year-old woman who was allergic to iodine contrast medium and was diagnosed with primary aldosteronism (PA) based on functional confirmatory tests. She was suspected to have unilateral PA because of marked hypertension, spontaneous hypokalemia, high plasma aldosterone, reduced plasma renin activity, and a right hypodense adrenal tumor. She wanted to become pregnant and requested adrenalectomy instead of medical treatment with mineralocorticoid receptor antagonists. Localization of PA by adrenal vein sampling (AVS) was necessary, but angiography with iodine contrast medium was not possible because of her allergy. AVS was performed using gadolinium contrast agent (gadoterate meglumine) instead of iodine, in combination with computed tomography angiography (CTA). In AVS, before and after adrenocorticotropin (ACTH) loading, 12 blood samples were drawn from the right adrenal vein, left adrenal central vein, left adrenal common duct, left and right renal veins, and the lower inferior vena cava with only 5 mL of gadolinium medium. There were no complications during AVS. Examination revealed an elevated aldosterone/cortisol ratio on the right side, lateralized ratio of 7.4, and contralateral ratio of 0.76; the patient was diagnosed with right unilateral PA. She underwent right adrenalectomy and showed improvements in aldosterone level from 312.4 pg/mL to 83.0 pg/mL, potassium from 3.0 mEq/L to 3.9 mEq/L, and systolic blood pressure from 138 mm Hg to 117 mm Hg. In PA patients with iodine allergy, AVS can be performed safely and precisely using gadolinium contrast combined with CTA.

Electronic structure and thermal conductance of the MASnI3/Bi2Te3 interface: a first-principles study.

To develop high-performance thermoelectric devices that can be created using printing technology, the interface of a composite material composed of MASnI3 and Bi2Te3, which individually show excellent thermoelectric performance, was studied based on first-principles calculations. The structural stability, electronic state, and interfacial thermal conductance of the interface between Bi2Te3 and MASnI3 were evaluated. Among the interface structure models, we found stable interface structures and revealed their specific electronic states. Around the Fermi energy, the interface structures with TeII and Bi terminations exhibited interface levels attributed to the overlapping electron densities for Bi2Te3 and MASnI3 at the interface. Calculation of the interfacial thermal conductance using the diffuse mismatch model suggested that construction of the interface between Bi2Te3 and MASnI3 could reduce the thermal conductivity. The obtained value was similar to the experimental value for the inorganic/organic interface.

Dopamine-Secreting Pheochromocytoma and Paraganglioma.

Predominantly or exclusively dopamine-secreting pheochromocytoma and paraganglioma are very rare. We report a 64-year-old woman with an adrenal incidentaloma. She was normotensive and had no symptoms of catecholamine excess. The 24-hour urine catecholamine level showed normal norepinephrine (122.9 µg/day), normal epinephrine (24.3 µg/day), and markedly elevated dopamine (148 212.4 µg/day). 123I-metaiodobenzylguanidine (MIBG) scintigraphy revealed tumor uptake. After α-blockade as preoperative management, she successfully underwent laparoscopic left adrenalectomy and was finally diagnosed with an exclusively dopamine-secreting pheochromocytoma. The tumor was histologically comprised of small polygonal cells with high cellularity and was immunohistochemically positive for all 3 catecholamine-synthesizing enzymes: tyrosine hydroxylase (very weak), dopamine ß-hydroxylase (heterogeneous), and phenylethanolamine N-methyltransferase (very weak). Electron microscopy revealed very few catecholamine-containing small vesicles with a few organelles, which reflected immature cells. No biochemical or imaging evidence of recurrence or metastasis were evident 1 year after the surgery. We conducted a literature search in the PubMed database. A total of 33 cases were collected. Our case had the second-highest 24-hour urinary dopamine excretion and was the first in which immunostaining for catecholamine synthase and electron microscopy were performed together. Histological findings in our case give a possible hypothesis that the mechanism underlying a dopamine-secreting pheochromocytoma is associated with immature catecholamine vesicles in which dopamine ß-hydroxylase is localized, thus resulting in inhibited conversion from dopamine to norepinephrine. We also discuss the reasons for the lack of catecholamine excess symptoms, whether preoperative management of α-blockade is needed, and the association between the prognosis and genetic mutation, with an extensive literature review.

Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice.

The extracellular matrix (ECM) is the basis for virtually all cellular processes and is also related to tumor metastasis. Fibronectin (FN), a major ECM macromolecule expressed by different cell types and also present in plasma, consists of multiple functional modules that bind to ECM-associated, plasma, and cell-surface proteins such as integrins and FN itself, thus ensuring its cell-adhesive and modulatory role. Here we show that FN constitutes an immune checkpoint. Thus, FN was identified as a physiological ligand for a tumor/leukemia/lymphoma- as well as autoimmune-associated checkpoint, ILT3/LILRB4 (B4, CD85k). Human B4 and the murine ortholog, gp49B, bound FN with sub-micromolar affinities as assessed by bio-layer interferometry. The major B4-binding site in FN was located at the N-terminal 30-kDa module (FN30), which is apart from the major integrin-binding site present at the middle of the molecule. Blockade of B4-FN binding such as with B4 antibodies or a recombinant FN30-Fc fusion protein paradoxically ameliorated autoimmune disease in lupus-prone BXSB/Yaa mice. The unexpected nature of the B4-FN checkpoint in autoimmunity is discussed, referring to its potential role in tumor immunity.