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Competing Interests: None.

Background: Short-term airway stent placement (stent evaluation) has been employed to evaluate whether patients with excessive central airway collapse (ECAC) will benefit from tracheobronchoplasty. Although retrospective studies have explored the impact of stent placement on ECAC, prospective randomized controlled trials are absent., Methods: This was a randomized open-label trial comparing patients receiving airway stent placement and standard medical treatment (intervention group) versus standard medical treatment alone (control group) for ECAC. At baseline, patients' respiratory symptoms, self-reported measures, and functional capabilities were assessed. Follow-up evaluations occurred 7 to 14 days postintervention, with an option for the control group to crossover to stent placement. Follow-up evaluations were repeated in the crossover patients., Results: The study enrolled 17 patients in the control group [medical management (MM)] and 14 patients in the intervention group. At follow-up, 15 patients in the MM crossed over to the stent group, resulting in a total of 29 patients in the combined stent group (CSG). Subjectively (shortness of breath and cough), 45% of the CSG exhibited improvement with the intervention compared with just 12% in the MM. The modified St. George Respiratory Questionnaire score in the CSG improved significantly from 61.2 at baseline to 52.5 after stent placement (-8.7, P = 0.04). With intervention, the 6-minute walk test in CSG improved significantly from 364 meters to 398 meters (34 m, P < 0.01). The MM did not show a significant change in the St. George Respiratory Questionnaire score or 6-minute walk test distance., Conclusion: Short-term airway stent placement in patients with ECAC significantly improves respiratory symptoms, quality of life, and exercise capacity., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cone beam computed tomography (CBCT)-guided bronchoscopic sampling of peripheral pulmonary lesions (PPLs) is associated with superior diagnostic outcomes. However, the added value of a robotic-assisted bronchoscopy platform in CBCT-guided diagnostic procedures is unknown., Methods: We performed a retrospective review of 100 consecutive PPLs sampled using conventional flexible bronchoscopy under CBCT guidance (FB-CBCT) and 100 consecutive PPLs sampled using an electromagnetic navigation-guided robotic-assisted bronchoscopy platform under CBCT guidance (RB-CBCT). Patient demographics, PPL features, procedural characteristics, and procedural outcomes were compared between the 2 cohorts., Results: Patient and PPL characteristics were similar between the FB-CBCT and RB-CBCT cohorts, and there were no significant differences in diagnostic yield (88% vs. 90% for RB-CBCT, P=0.822) or incidence of complications between the 2 groups. As compared with FB-CBCT cases, RB-CBCT cases were significantly shorter (median 58 min vs. 92 min, P<0.0001) and used significantly less diagnostic radiation (median dose area product 5114 µGy•m2 vs. 8755 µGy•m2, P<0.0001)., Conclusion: CBCT-guided bronchoscopy with or without a robotic-assisted bronchoscopy platform is a safe and effective method for sampling PPLs, although the integration of a robotic-assisted platform was associated with significantly shorter procedure times and significantly less radiation exposure., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Oxygen Therapy Part 2: Indications and ToxicityWemple et al. continue their review of oxygen therapy, discussing the acute and chronic indications for oxygen and the delivery of supplemental oxygen (and its potential adverse effects and toxicity).

As the pandemic has progressed, our understanding of hypoxemia in coronavirus disease 2019 (COVID-19) lung disease has become more nuanced, although much remains to be understood. In this article, we review ventilation-perfusion mismatching in COVID-19 and the evidence to support various biologic theories offered in explanation. In addition, the relationship between hypoxemia and other features of severe COVID-19 lung disease such as respiratory symptoms, radiographic abnormalities, and pulmonary mechanics is explored. Recognizing and understanding hypoxemia in COVID-19 lung disease remains essential for risk stratification, prognostication, and choice of appropriate treatments in severe COVID-19., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: Blood gas analyzers (BGA) aid medical decision-making. Their specified performance criteria are based on sea level conditions. However, millions of people are living at high altitude (HA) where the performance of BGAs is poorly characterized. We investigated the effect of exposure to 4,559 m on the reliability and robustness of two BGAs widely used at HA., Methods: In this prospective study arterial blood samples from 13 volunteers (2 female) with susceptibility to the development of high-altitude pulmonary edema were collected once near sea level at 423 m (nSL 423 ) and three times at high altitude (HA 4,559 ). Samples were measured in triplicate with the cartridge BGAs Rapidpoint 500 (SIE; Siemens Healthcare) and the ABL90 (RAD; Radiometer) to calculate coefficients of variation (CV) and intraclass correlation coefficients (ICC) within a mixed model., Results: At nSL 423 and HA 4,559 , 3% and 17% of all data were not reported with SIE, mainly due to clotting of the sample caused by delays because of the frequent automated calibration routines. No data were missing with RAD. ICCs were not significantly lower (mean (min-max) 0.87 (0.68-0.98) vs. 0.94 (0.84-1.00); p = 0.217) with SIE at nSL 423, but significantly lower at HA 4,559 (0.87 (0.49-1.00) vs. 0.99 (0.96-1.00); p = 0.025). All CVs, except that for arterial oxygen saturation at HA 4,559 ,were higher with SIE ., Conclusion: In this study, the reliability of RAD was superior to SIE at nSL 423 and HA 4,559 . In contrast to RAD, the performance of SIE declined at HA 4,559 . SIE was more prone to not reporting all variables, especially at HA 4559 ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

History, Physiology, and Evaluation of Oxygen TherapyOxygen is standard therapy for acute cardiopulmonary diseases, and long-term oxygen therapy is common in the outpatient setting. In part I of a two-part review, Wemple and colleagues discuss the physiology of tissue hypoxia, mechanisms of hypoxemia, and its clinical assessment.

Purpose: To evaluate findings after transbronchial lung cryobiopsy (TBLC) using intraprocedural cone-beam CT (CBCT) and follow-up chest CT examinations., Materials and Methods: A single-center, prospective cohort study was performed with 14 participants (mean age, 65 years ± 13 [SD]; eight male participants) undergoing CBCT-guided TBLC between August 2020 and February 2021 who underwent follow-up chest CT imaging. Intraprocedural CBCT and follow-up chest CT images were interpreted for changes compared with baseline CT images. Statistical analyses were performed using independent samples t test and analysis of variance., Results: A total of 62 biopsies were performed, with 48 in the field of view of CBCT immediately after biopsy. All 48 biopsy sites had evidence of postprocedural hemorrhage, and 17 (35%) had pneumatoceles at the biopsy site. Follow-up CT images showed resolution of these findings. Solid nodules developed at 18 of the 62 (29%) biopsy sites., Conclusion: Postbiopsy hemorrhage and pneumatoceles on intraprocedural CBCT images (which were clinically occult and resolved spontaneously) and new solid nodules on follow-up chest CT images were commonly observed after TBLC. These findings may help alleviate unnecessary follow-up imaging and tissue sampling. Keywords: Biopsy/Needle Aspiration, CT, Lungs, Lung Biopsy, Interventional Bronchoscopy© RSNA, 2023., Competing Interests: Disclosures of conflicts of interest: B.P.P. No relevant relationships. K.E.S. No relevant relationships. D.K.D. No relevant relationships. B.S. No relevant relationships. H.B. No relevant relationships. H.H.G. No relevant relationships., (© 2023 by the Radiological Society of North America, Inc.)

Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg ( P < 0.001) without a group difference ( P = 0.68). Arterial Po 2 fell to 36 ± 9 mmHg ( P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude ( P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%-100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m. NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.

Background: Systemic arterial gas embolism (SAGE) is a rare yet serious and underrecognized complication of bronchoscopic procedures. A recent case of presumed SAGE after transbronchial needle aspiration prompted a systematic literature review of SAGE after biopsy procedures during flexible bronchoscopy., Methods: We performed a systematic database search for case reports and case series pertaining to SAGE after bronchoscopic lung biopsy; reports or series involving only bronchoscopic laser therapy or argon plasma coagulation (APC) were excluded. Patient data were extracted directly from published reports., Results: A total of 29 unique patient reports were assessed for patient demographics, specifics of the procedure, clinical manifestations, diagnostic findings, and clinical outcomes. Cases of SAGE occurred after multiple types of bronchoscopic biopsy and under both positive and negative pressure ventilation. The most common clinical findings were neurologic, followed by cardiac manifestations; temporal patterns included acute onset of cardiac or neurologic emergencies immediately after biopsy, or delayed awakening post-procedure. There was a high mortality rate among cases (28%), with residual neurologic deficits also common (24%)., Discussion: SAGE is an underrecognized but severe adverse effect of bronchoscopic lung biopsy, which often presents with acute coronary or cerebral ischemia or delayed awakening from sedation. It is important for all physicians who perform bronchoscopic biopsies to be aware of the clinical manifestations and therapeutic management of SAGE in order to mitigate morbidity and mortality among patients undergoing these procedures., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jtd-21-717). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

The pathophysiology of acute respiratory distress syndrome (ARDS) is marked by inflammation-mediated disruptions in alveolar-capillary permeability, edema formation, reduced alveolar clearance and collapse/derecruitment, reduced compliance, increased pulmonary vascular resistance, and resulting gas exchange abnormalities due to shunting and ventilation-perfusion mismatch. Mechanical ventilation, especially in the setting of regional disease heterogeneity, can propagate ventilator-associated injury patterns including barotrauma/volutrauma and atelectrauma. Lung injury due to the novel coronavirus SARS-CoV-2 resembles other causes of ARDS, though its initial clinical characteristics may include more profound hypoxemia and loss of dyspnea perception with less radiologically-evident lung injury, a pattern not described previously in ARDS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Decreased oxygen saturation (SO 2 ) at high altitude is associated with potentially life-threatening diseases, e.g., high-altitude pulmonary edema. Wearable devices that allow continuous monitoring of peripheral oxygen saturation (SpO 2 ), such as the Garmin Fēnix ® 5X Plus (GAR), might provide early detection to prevent hypoxia-induced diseases. We therefore aimed to validate GAR-derived SpO 2 readings at 4559 m. SpO 2 was measured with GAR and the medically certified Covidien Nellcor SpO 2 monitor (COV) at six time points in 13 healthy lowlanders after a rapid ascent from 1130 m to 4559 m. Arterial blood gas (ABG) analysis served as the criterion measure and was conducted at four of the six time points with the Radiometer ABL 90 Flex. Validity was assessed by intraclass correlation coefficients (ICCs), mean absolute percentage error (MAPE), and Bland-Altman plots. Mean (±SD) SO 2 , including all time points at 4559 m, was 85.2 ± 6.2% with GAR, 81.0 ± 9.4% with COV, and 75.0 ± 9.5% with ABG. Validity of GAR was low, as indicated by the ICC (0.549), the MAPE (9.77%), the mean SO 2 difference (7.0%), and the wide limits of agreement (-6.5; 20.5%) vs. ABG. Validity of COV was good, as indicated by the ICC (0.883), the MAPE (6.15%), and the mean SO 2 difference (0.1%) vs. ABG. The GAR device demonstrated poor validity and cannot be recommended for monitoring SpO 2 at high altitude.

The ongoing coronavirus disease (COVID-19) pandemic has been unprecedented on many levels, not least of which are the challenges in understanding the pathophysiology of these new critically ill patients. One widely reported phenomenon is that of a profoundly hypoxemic patient with minimal to no dyspnea out of proportion to the extent of radiographic abnormality and change in lung compliance. This apparently unique presentation, sometimes called "happy hypoxemia or hypoxia" but better described as "silent hypoxemia," has led to the speculation of underlying pathophysiological differences between COVID-19 lung injury and acute respiratory distress syndrome (ARDS) from other causes. We explore three proposed distinctive features of COVID-19 that likely bear on the genesis of silent hypoxemia, including differences in lung compliance, pulmonary vascular responses to hypoxia, and nervous system sensing and response to hypoxemia. In the context of known principles of respiratory physiology and neurobiology, we discuss whether these particular findings are due to direct viral effects or, equally plausible, are within the spectrum of typical ARDS pathophysiology and the wide range of hypoxic ventilatory and pulmonary vascular responses and dyspnea perception in healthy people. Comparisons between lung injury patterns in COVID-19 and other causes of ARDS are clouded by the extent and severity of this pandemic, which may underlie the description of "new" phenotypes, although our ability to confirm these phenotypes by more invasive and longitudinal studies is limited. However, given the uncertainty about anything unique in the pathophysiology of COVID-19 lung injury, there are no compelling pathophysiological reasons at present to support a therapeutic approach for these patients that is different from the proven standards of care in ARDS.

The creation of dedicated sepsis guidelines and their broad dissemination over the past 2 decades have contributed to significant improvements in sepsis care. These successes have spurred the creation of bundled care mandates by major healthcare payers, such as the Center for Medicare and Medicaid Services. However, despite the likely benefits of guideline-directed sepsis bundles, mandated treatments in sepsis may lead to unintended consequences as the standard of care in sepsis improves. In particular, the heterogeneous spectrum of presentation and disease severity in sepsis, as well as the complexity surrounding the benefits of specific interventions in sepsis, argues for an individualized and titrated approach to interventions: an approach generally not afforded by care mandates. In this review, we review the risks and benefits of mandated care for sepsis, with particular emphasis on the potential adverse consequences of common bundle components such as early empiric antibiotics, weight-based fluid administration, and serum lactate monitoring. Unlike guideline-directed care, mandated care in sepsis precludes providers from tailoring treatments to heterogeneous clinical scenarios and may lead to unintended harms for individual patients., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The stress of high altitude alters vascular permeability, which may be related to structural changes in the endothelial glycocalyx. We aimed to study these changes by measuring plasma concentrations of several glycocalyx components upon exposure to high altitude. Methods: Plasma collected from 17 subjects at low altitude (423 m) and at three time points (7, 20, and 44 hours) after rapid ascent to high altitude (4559 m) were evaluated for concentrations of three glycocalyx components: syndecan-1, intercellular adhesion molecule-1 (ICAM-1), and heparan sulfate. Vital signs and echocardiographic measurement of systolic pulmonary artery pressure (sPAP) and cardiac output were also obtained at low and high altitudes. Results: Mean age of the study population was 35.5 ± 11.2 years with a body mass index of 22.7 ± 2.5 kg/m 2 . Concentrations of ICAM-1 and heparan sulfate increased from baseline to 7 hours after arrival at high altitude; the ICAM-1 rise persisted at 20 hours. Syndecan-1 concentrations were increased only at 44 hours. Increased ICAM-1 concentrations correlated with sPAP and peripheral edema. Elevations in heparan sulfate appeared to correlate with acute mountain sickness (AMS). Conclusions: Levels of circulating glycocalyx components increase after exposure to high altitude and may correlate with AMS. Measuring plasma concentrations of various glycocalyx components could serve as a useful tool for further evaluation of vascular endothelial injury and repair in illness at high altitude.

Prognostication in sepsis is limited by disease heterogeneity, and measures to risk-stratify patients in the proximal phases of care lack simplicity and accuracy. Hyperlactatemia and vasopressor dependence are easily identifiable risk factors for poor outcomes. This study compares incidence and hospital outcomes in sepsis based on initial serum lactate level and vasopressor use in the emergency department (ED). In a retrospective analysis of a prospectively identified dual-center ED registry, patients with sepsis were categorized by ED vasopressor use and initial serum lactate level. Vasopressor-dependent patients were categorized as dysoxic shock (lactate >4.0 mmol/L) and vasoplegic shock (≤4.0 mmol/L). Patients not requiring vasopressors were categorized as cryptic shock major (lactate >4.0 mmol/L), cryptic shock minor (>2.0 and ≤4.0 mmol/L), and sepsis without lactate elevation (≤2.0 mmol/L). Of 446 patients included, 4.9% (n = 22) presented in dysoxic shock, 11.7% (n = 52) in vasoplegic shock, 12.1% (n = 54) in cryptic shock major, 30.9% (n = 138) in cryptic shock minor, and 40.4% (n = 180) in sepsis without lactate elevation. Group mortality rates at 28 days were 50.0, 21.1, 18.5, 12.3, and 7.2%, respectively. After adjusting for potential confounders, odds ratios for mortality at 28 days were 15.1 for dysoxic shock, 3.6 for vasoplegic shock, 3.8 for cryptic shock major, and 1.9 for cryptic shock minor, when compared to sepsis without lactate elevation. Lactate elevation is associated with increased mortality in both vasopressor dependent and normotensive infected patients presenting to the emergency department (ED). Cryptic shock mortality (normotension + lactate >4 mmol/L) is equivalent to vasoplegic shock mortality (vasopressor requirement + lactate <4 mmol/L) in our population. The odds of normotensive, infected patients decompensating is three to fourfold higher with hyperlactemia. The proposed Sepsis-3 definitions exclude an entire group of high-risk ED patients. A simple classification in the ED by vasopressor requirement and initial lactate level may identify high-risk subgroups of sepsis. This study may inform prognostication and triage decisions in the proximal phases of care.

Patients suffering from chronic mountain sickness (CMS) have excessive erythrocytosis. Low -level cobalt toxicity as a likely contributor has been demonstrated in some subjects. We performed a randomized, placebo controlled clinical trial in Cerro de Pasco, Peru (4380m), where 84 participants with a hematocrit (HCT) ≥65% and CMS score>6, were assigned to four treatment groups of placebo, acetazolamide (ACZ, which stimulates respiration), N-acetylcysteine (NAC, an antioxidant that chelates cobalt) and combination of ACZ and NAC for 6 weeks. The primary outcome was change in hematocrit and secondary outcomes were changes in PaO 2 , PaCO 2 , CMS score, and serum and urine cobalt concentrations. The mean (±SD) hematocrit, CMS score and serum cobalt concentrations were 69±4%, 9.8±2.4 and 0.24±0.15μg/l, respectively for the 66 participants. The ACZ arm had a relative reduction in HCT of 6.6% vs. 2.7% (p=0.048) and the CMS score fell by 34.9% vs. 14.8% (p=0.014) compared to placebo, while the reduction in PaCO 2 was 10.5% vs. an increase of 0.6% (p=0.003), with a relative increase in PaO 2 of 13.6% vs. 3.0%. NAC reduced CMS score compared to placebo (relative reduction of 34.0% vs. 14.8%, p=0.017), while changes in other parameters failed to reach statistical significance. The combination of ACZ and NAC was no better than ACZ alone. No changes in serum and urine cobalt concentrations were seen within any treatment arms. ACZ reduced polycythemia and CMS score, while NAC improved CMS score without significantly lowering hematocrit. Only a small proportion of subjects had cobalt toxicity, which may relate to the closing of contaminated water sources and several other environmental protection measures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Lactate clearance has been implicated as a predictor of mortality among emergency department (ED) patients with severe sepsis or septic shock. We aimed to validate prior studies showing that lactate clearance during the ED stay is associated with decreased mortality., Methods: Retrospective dual-centered cross-sectional study using patients identified in the Yale-New Haven Hospital Emergency Medicine sepsis registry with severe sepsis or septic shock who had initial lactate levels measured in the ED and upon arrival (<24 hours) to the hospital floor. Lactate clearance was calculated as percent of serum lactate change from ED to floor measurement. We compared mortality and hospital interventions between patients who cleared lactate and those who did not., Results: 207 patients (110 male; 63.17±17.9 years) were included. Two reviewers extracted data with 95% agreement. One hundred thirty-six patients (65.7%) had severe sepsis and 71 patients (34.3%) had septic shock. There were 171 patients in the clearance group and 36 patients in the non-clearance group. The 28-day mortality rates were 15.2% in the lactate clearance group and 36.1% in the non-clearance group (p<0.01). Vasopressor support was initiated more often in the non-clearance group (61.1%) than in the clearance group (36.8%, p<0.01) and mechanical ventilation was used in 66.7% of the non-clearance group and 36.3% of the clearance group (p=0.001)., Conclusion: Patients who do not clear their lactate in the ED have significantly higher mortality than those with decreasing lactate levels. Our results are confirmatory of other literature supporting that lactate clearance may be used to stratify mortality-risk among patients with severe sepsis or septic shock.

Nitric oxide (NO) is a potent vasodilator in terrestrial vertebrates, but whether vascular endothelial-derived NO plays a role in vascular regulation in fish remains controversial. To explore this issue, a study was made of spiny dogfish sharks (Squalus acanthias) in normoxia and acute hypoxia (60 min exposure to seawater equilibrated with 3% oxygen) with various agents known to alter NO metabolism or availability. In normoxia, nitroprusside (a NO donor) reduced blood pressure by 20%, establishing that vascular smooth muscle responds to NO. L-arginine, the substrate for NO synthase, had no hemodynamic effect. Acetylcholine, which stimulates endothelial NO and prostaglandin production in mammals, reduced blood pressure, but also caused marked bradycardia. L-NAME, an inhibitor of all NO synthases, caused a small 10% rise in blood pressure, but cell-free hemoglobin (a potent NO scavenger and hypertensive agent in mammals) had no effect. Acute hypoxia caused a 15% fall in blood pressure, which was blocked by L-NAME and cell-free hemoglobin. Serum nitrite, a marker of NO production, rose with hypoxia, but not with L-NAME. Results suggest that NO is not an endothelial-derived vasodilator in the normoxic elasmobranch. The hypertensive effect of L-NAME may represent inhibition of NO production in the CNS and nerves regulating blood pressure. In acute hypoxia, there is a rapid up-regulation of vascular NO production that appears to be responsible for hypoxic vasodilation.

B7-1 is a co-stimulatory molecule that signals T-cells that recognize antigen to proliferate and differentiate into effector T-cells. The same cell must present antigen and express co-stimulatory molecules, such as B7-1, to activate naive T-cells. Thus, tissues that do not express co-stimulatory molecules would not be expected to induce immune responses, while expression of a co-stimulator on tissue cells may convert them into effective antigen-presenting cells and induce autoimmunity. To test this, transgenic mice have been generated that express B7-1 on the beta-cells of the pancreatic islets of Langerhans. On a B6 genetic background, B7-1 expression on beta-cells does not predispose to diabetes. B6 mice are resistant to diabetes. However, when B7-1 is expressed on the beta-cells of B6 mice backcrossed once to the genetically susceptible NOD strain, the onset of diabetes is accelerated and the autoimmune attack intensified. This illustrates that B7-1 is a very potent co-stimulatory molecule in vivo and that its presence on the surface of tissue cells can potentiate the autoimmune process.

The non-obese diabetic (NOD) mouse spontaneously develops an insulin-dependent diabetes mellitus that resembles human type I diabetes. This disease can be transferred by purified T cells or cloned T cell lines, implicating an autoimmune T cell attack on the pancreatic beta cells of the islets of Langerhans. As all T cell responses involve recognition of peptides bound to MHC molecules displayed at the cell surface, we have examined self peptides binding to the MHC molecules on spleen cells of the NOD mouse. Peptides eluted from the MHC class I molecule Kd have sequences that conform to known motifs for peptides binding this molecule in other strains of mice. The NOD mouse expresses the unique MHC class II molecule I-Ag7. Peptides eluted from I-Ag7 have sequences that implicate an acidic residue in the C terminus of the peptide as important for binding. The role of this residue in binding has been confirmed by direct peptide-binding analysis. This C-terminal acidic amino acid may interact with an arginine residue in the MHC class II alpha-chain that is exposed when beta-chain residue 57 is mutated to serine, or to the unique beta-chain residue histidine 56. These data may provide valuable insights into the nature of autoantigenic peptides presented by NOD mouse MHC molecules by defining the nature of I-Ag7-peptide binding.