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Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity - enhanced secondary responses of innate immune cells after prior exposure - is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that in vivo , trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury. Ex vivo , C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output after training, which was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs - a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling, affecting cytokine production and metabolic reprogramming, and highlight a novel role for C3 in trained immunity.

The complement system is an evolutionarily conserved arm of innate immunity, which forms one of the first lines of host response to pathogens and assists in the clearance of debris. A deficiency in key activators/amplifiers of the cascade results in recurrent infection, whereas a deficiency in regulating the cascade predisposes to accelerated organ failure, as observed in colitis and transplant rejection. Given that there are over 60 proteins in this system, it has become an attractive target for immunotherapeutics, many of which are United States Food and Drug Administration-approved or in multiple phase 2/3 clinical trials. Moreover, there have been key advances in the last few years in the understanding of how the complement system operates locally in tissues, independent of its activities in circulation. In this review, we will put into perspective the abovementioned discoveries to optimally modulate the spatiotemporal nature of complement activation and regulation at mucosal surfaces., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for this currently hard-to-treat clinical entity that has several etiologies but a potentially focused mechanism.

Obesity and the metabolic syndrome are complex disorders resulting from multiple factors including genetics, diet, activity, inflammation, and gut microbes. Animal studies have identified roles for each of these, however the contribution(s) specifically attributed to the gut microbiota remain unclear, as studies have used combinations of genetically altered mice, high fat diet, and/or colonization of germ-free mice, which have an underdeveloped immune system. We investigated the role(s) of the gut microbiota driving obesity and inflammation independent of manipulations in diet and genetics in mice with fully developed immune systems. We demonstrate that the human obese gut microbiota alone was sufficient to drive weight gain, systemic, adipose tissue, and intestinal inflammation, but did not promote intestinal barrier leak. The obese microbiota induced gene expression promoting caloric uptake/harvest but was less effective at inducing genes associated with mucosal immune responses. Thus, the obese gut microbiota is sufficient to induce weight gain and inflammation.

Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2-dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS.

Background: Outcomes after lung retransplantation (LRT) remain inferior compared with primary lung transplantation (PLT). This study examined the impact of center volume on 1-year survival after LRT., Methods: Using the United Network for Organ Sharing database, the study abstracted patients undergoing PLT and LRT between January 2006 and December 2017, excluding combined heart-lung transplants and multiple retransplants. One-year survival rates after PLT and LRT were compared using propensity score matching. In the LRT cohort, multivariable Cox models with and without time-dependent coefficients were fitted to examine association between transplant center volume and 1-year survival. Center volume was categorized on the basis of inspection of restricted cubic splines., Results: A total of 20,675 recipients (PLT 19,853 [96.0%] vs LRT 822 [4.0%]) were included. One-year survival was lower for LRT recipients in the matched cohort (PLT 84.8% vs LRT 76.7%). There was steady improvement in 1-year survival after LRT (2006 to 2009 72.1% vs 2010 to 2013 76.6% vs 2014 to 2017 80.1%). Higher center volume was associated with better 1-year survival after LRT. This survival difference was noted in the initial 30 days after transplantation (intermediate vs low volume hazard ratio, 0.282 [95% confidence interval, 0.151 to 0.526]; high vs low volume hazard ratio, 0.406 [95% confidence interval, 0.224 to 0.737]), but it became insignificant after 30 days., Conclusions: Superior 1-year survival after LRT at higher-volume centers is predominantly the result of better 30-day outcomes. This finding suggests that LRT candidates may be referred to higher-volume centers for surgery., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Studies in lung transplantation have shown variable association between hospital volume and clinical outcomes. We aimed to identify the pattern of effect of hospital volume on individual patient survival after lung transplantation., Methods: We performed a retrospective analysis using the United Network for Organ Sharing national thoracic organ transplantation database. Adult patients who underwent lung transplantation between January 2013 and December 2017 were included. The association between mean annual center volume and 1-year overall survival was examined using restricted cubic splines in a random effects multivariable Cox model. The volume threshold for optimal 1-year overall survival was subsequently approximated by the maximum likelihood approach using segmented linear splines in the same model., Results: The study included 10,007 patients at 71 transplant centers. Median annual center volume was 22 cases (interquartile range, 10.6 to 38). A center volume threshold was identified at 33 cases per year (95% confidence interval, 28 to 37). Higher center volume, to 33 cases per year, was associated with better 1-year survival (hazard ratio 0.989, 95% confidence interval, 0.980 to 0.999 every additional case). Further increase in center volume above 33 cases per year showed no additional benefit (hazard ratio 1.000, 95% confidence interval, 0.996 to 1.003 every additional case). Twenty-three centers (32.4%) reached the volume threshold of 33 cases per year., Conclusions: One-year survival after lung transplantation improved with increasing center volume to as many as 33 cases per year. Low volume centers below the 33 cases per year threshold had large variations in their outcomes and had a higher risk of performing poorly, although many of them maintained good performance., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary embolism (PE) is unexpectedly detected in some donor lungs during organ procurement for lung transplantation. Anecdotally, such lungs are usually implanted; however, the impact of this finding on recipient outcomes remains unclear. We hypothesized that incidentally detected donor PE is associated with adverse short-term and long-term outcomes among lung transplant recipients., Methods: We analyzed a prospectively maintained database of all lung donors procured by a single surgeon and transplanted at our institution between 2009 and 2018. A standardized approach was used for all procurements and included antegrade and retrograde flush. Pulmonary embolism was defined as macroscopic thrombus seen in the pulmonary artery during the donor procurement operation., Results: A total of 501 consecutive lung procurements were performed during the study period. The incidence of donor PE was 4.4% (22 of 501). No organs were discarded owing to PE. Donors with PE were similar to donors without PE in baseline characteristics and Pao 2 . Recipients in the two groups were also similar. Pulmonary embolism was associated with a higher likelihood of acute cellular rejection grade 2 or more (10 of 22 [45.5%] vs 120 of 479 [25.1%], P = .03). Multivariable Cox modeling demonstrated an association between PE and the development of chronic lung allograft dysfunction (hazard ratio 2.02; 95% confidence interval, 1.23 to 3.30; P = .005)., Conclusions: Lungs from donors with incidentally detected PE may be associated with a higher incidence of recipient acute cellular rejection as well as reduced chronic lung allograft dysfunction-free survival. Surgeons must use caution when transplanting lungs with incidentally discovered PE. These preliminary findings warrant corroboration in larger data sets., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies in the field of organ transplantation have shown a possible association between nighttime surgery and adverse outcomes. We aim to determine the impact of nighttime lung transplantation on postoperative outcomes, long-term survival, and overall cost., Methods: We performed a single-center retrospective cohort analysis of adult lung transplant recipients who underwent transplantation between January 2006 and December 2017. Data were extracted from our institutional Lung Transplant Registry and Mid-America Transplant services database. Patients were classified into 2 strata, daytime (5 AM to 6 PM) and nighttime (6 PM to 5 AM), based on time of incision. Major postoperative adverse events, 5-year overall survival, and 5-year bronchiolitis obliterans syndrome-free survival were examined after propensity score matching. Additionally we compared overall cost of transplantation between nighttime and daytime groups., Results: Of the 740 patients included in this study, 549 (74.2%) underwent daytime transplantation and 191 (25.8%) underwent nighttime transplantation (NT). Propensity score matching yielded 187 matched pairs. NT was associated with a higher risk of having any major postoperative adverse event (adjusted odds ratio, 1.731; 95% confidence interval, 1.093-2.741; P = .019), decreased 5-year overall survival (adjusted hazard ratio, 1.798; 95% confidence interval, 1.079-2.995; P = .024), and decreased 5-year bronchiolitis obliterans syndrome-free survival (adjusted hazard ratio, 1.556; 95% confidence interval, 1.098-2.205; P = .013) in doubly robust multivariable analyses after propensity score matching. Overall cost for NT and daytime transplantation was similar., Conclusions: NT was associated with a higher risk of major postoperative adverse events, decreased 5-year overall survival, and decreased 5-year bronchiolitis obliterans syndrome-free survival. Our findings suggest potential benefits of delaying NT to daytime transplantation., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

To describe the infectious complications and interleukin-6 trajectories in mechanically ventilated patients with coronavirus disease 2019., Design: Retrospective cohort study., Setting: ICUs at Washington University-Barnes Jewish Hospital in St. Louis, MO., Participants: All consecutive patients admitted to the medical ICU and requiring mechanical ventilation from March 12, 2020, to April 21, 2020, were included., Interventions: Tocilizumab, an interleukin-6 receptor blocker, was prescribed at the discretion of the treating physicians to patients with a clinical picture compatible with cytokine release syndrome., Measurements: All the patients were followed to death or hospital discharge. Demographic and laboratory data were collected retrospectively from the electronic medical record. Interleukin-6 levels were measured at days 0, 3, 7, 14, and 21. Infections were divided into culture positive and culture negative (clinically suspected and treated). The main outcomes were infectious complications and interleukin-6 levels at different points in time., Results: Forty-three patients with respiratory failure secondary to coronavirus disease 2019 were on mechanical ventilation during the study period. Twenty-seven (68%) were male, and 31 (72.1%) were African-American. Median Charlson score was 2 (interquartile range, 0-4). Median Pao2/Fio2 was 171.5 (122-221) on the day of mechanical ventilation initiation, and 13 patients (30.2%) required vasopressors. C-reactive protein was 142.7 (97.7-213.7), d-dimer 1,621 (559-13,434), and Acute Physiology and Chronic Health Evaluation-II 11 (9-15). Interleukin-6 levels at admission were 61 pg/mL (interquartile range, 28.6-439 pg/mL). Patients treated with tocilizumab had higher levels of interleukin-6 at each measurement (days 0, 3, 7, 14, and 21) compared with patients receiving standard of care. Both groups reached peak interleukin-6 levels at day 7. Administration of tocilizumab was associated with a trend toward increased risk of infection., Conclusions: Interleukin-6 levels peak at day 7 in patients with severe coronavirus disease 2019 pneumonia requiring mechanical ventilation and follows a similar trajectory in patients with coronavirus disease 2019 pneumonia requiring mechanical ventilation irrespective of treatment with interleukin-6R blockers. Interleukin-6 levels continued to rise in nonsurvivors, in comparison with survivors, where the rise in interleukin-6 levels was followed by a decline., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

The life-saving benefits of organ transplantation can be thwarted by allograft dysfunction due to both infectious and sterile inflammation post-surgery. Sterile inflammation can occur after necrotic cell death due to the release of endogenous ligands [such as damage-associated molecular patterns (DAMPs) and alarmins], which perpetuate inflammation and ongoing cellular injury via various signaling cascades. Ischemia-reperfusion injury (IRI) is a significant contributor to sterile inflammation after organ transplantation and is associated with detrimental short- and long-term outcomes. While the vicious cycle of sterile inflammation and cellular injury is remarkably consistent amongst different organs and even species, we have begun understanding its mechanistic basis only over the last few decades. This understanding has resulted in the developments of novel, yet non-specific therapies for mitigating IRI-induced graft damage, albeit with moderate results. Thus, further understanding of the mechanisms underlying sterile inflammation after transplantation is critical for identifying personalized therapies to prevent or interrupt this vicious cycle and mitigating allograft dysfunction. In this review, we identify common and distinct pathways of post-transplant sterile inflammation across both heart and lung transplantation that can potentially be targeted.

BACKGROUNDThe complement system plays a key role in host defense but is activated by ischemia/reperfusion injury (IRI). Primary graft dysfunction (PGD) is a form of acute lung injury occurring predominantly due to IRI, which worsens survival after lung transplantation (LTx). Local complement activation is associated with acute lung injury, but whether it is more reflective of allograft injury compared with systemic activation remains unclear. We proposed that local complement activation would help identify those who develop PGD after LTx. We also aimed to identify which complement activation pathways are associated with PGD.METHODSWe performed a multicenter cohort study at the University of Pennsylvania and Washington University School of Medicine. Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA.RESULTSIn both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma.CONCLUSIONComplement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.FUNDINGThis research was supported by the NIH, American Lung Association, Children's Discovery Institute, Robert Wood Johnson Foundation, Cystic Fibrosis Foundation, Barnes-Jewish Hospital Foundation, Danish Heart Foundation, Danish Research Foundation of Independent Research, Svend Andersen Research Foundation, and Novo Nordisk Research Foundation.

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19-related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that (a) coronaviruses activate multiple complement pathways; (b) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.

Factors contributing to donor-specific HLA antibody (DSA) development after lung transplantation have not been systematically evaluated. We hypothesized that the isolation of Pseudomonas aeruginosa in respiratory specimens would increase the risk of DSA development. Our objective was to determine the risk of DSA development associated with the isolation of Pseudomonas aeruginosa after lung transplantation. We conducted a single-center retrospective cohort study of primary lung transplant recipients and examined risk factors for DSA development using Cox regression models. Of 460 recipients, 205 (45%) developed DSA; the majority developed Class II DSA (n = 175, 85%), and 145 of 205 (71%) developed DSA to HLA-DQ alleles. Univariate time-dependent analyses revealed that isolation of Pseudomonas from respiratory specimens, acute cellular rejection, and lymphocytic bronchiolitis are associated with an increased risk of DSA development. In multivariable analyses, Pseudomonas isolation, acute cellular rejection, and lymphocytic bronchiolitis remained independent risk factors for DSA development. Additionally, there was a direct association between the number of positive Pseudomonas cultures and the risk of DSA development. Our findings suggest that pro-inflammatory events including acute cellular rejection, lymphocytic bronchiolitis, and Pseudomonas isolation after transplantation are associated with an increased risk of DSA development., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Discovery of a C3(H 2 O) uptake pathway has led to renewed interest in this alternative pathway triggering form of C3 in human biospecimens. Previously, a quantifiable method to measure C3(H 2 O), not confounded by other complement activation products, was unavailable. Herein, we describe a sensitive and specific ELISA for C3(H 2 O). We initially utilized this assay to determine baseline C3(H 2 O) levels in healthy human fluids and to define optimal sample storage and handling conditions. We detected ~500 ng/ml of C3(H 2 O) in fresh serum and plasma, a value substantially lower than what was predicted based on previous studies with purified C3 preparations. After a single freeze-thaw cycle, the C3(H 2 O) concentration increased 3- to 4-fold (~2,000 ng/ml). Subsequent freeze-thaw cycles had a lesser impact on C3(H 2 O) generation. Further, we found that storage of human sera or plasma samples at 4°C for up to 22 h did not generate additional C3(H 2 O). To determine the potential use of C3(H 2 O) as a biomarker, we evaluated specimens from patients with inflammatory-driven diseases. C3(H 2 O) concentrations were moderately increased (1.5- to 2-fold) at baseline in sera from active systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients compared to healthy controls. In addition, upon challenge with multiple freeze-thaw cycles or incubation at 22 or 37°C, C3(H 2 O) generation was significantly enhanced in SLE and RA patients' sera. In bronchoalveolar lavage fluid from lung-transplant recipients, we noted a substantial increase in C3(H 2 O) within 3 months of acute antibody-mediated rejection. In conclusion, we have established an ELISA for assessing C3(H 2 O) as a diagnostic and prognostic biomarker in human diseases.

The complement system provides host defense against pathogens and environmental stress. C3, the central component of complement, is present in the blood and increases in BAL fluid after injury. We recently discovered that C3 is taken up by certain cell types and cleaved intracellularly to C3a and C3b. C3a is required for CD4 + T-cell survival. These observations made us question whether complement operates at environmental interfaces, particularly in the respiratory tract. We found that airway epithelial cells (AECs, represented by both primary human tracheobronchial cells and BEAS-2B [cell line]) cultured in C3-free media were unique from other cell types in that they contained large intracellular stores of de novo synthesized C3. A fraction of this protein reduced ("storage form") but the remainder did not, consistent with it being pro-C3 ("precursor form"). These two forms of intracellular C3 were absent in CRISPR knockout-induced C3-deficient AECs and decreased with the use of C3 siRNA, indicating endogenous generation. Proinflammatory cytokine exposure increased both stored and secreted forms of C3. Furthermore, AECs took up C3 from exogenous sources, which mitigated stress-associated cell death (e.g., from oxidative stress or starvation). C3 stores were notably increased within AECs in lung tissues from individuals with different end-stage lung diseases. Thus, at-risk cells furnish C3 through biosynthesis and/or uptake to increase locally available C3 during inflammation, while intracellularly, these stores protect against certain inducers of cell death. These results establish the relevance of intracellular C3 to airway epithelial biology and suggest novel pathways for complement-mediated host protection in the airway.

An intracellular complement system (ICS) has recently been described in immune and nonimmune human cells. This system can be activated in a convertase-independent manner from intracellular stores of the complement component C3. The source of these stores has not been rigorously investigated. In the present study, Western blotting identified a band corresponding to C3 in freshly isolated human peripheral blood cells that was absent in corresponding cell lines. One difference between native cells and cell lines was the time absent from a fluid-phase complement source; therefore, we hypothesized that loading C3 from plasma was a route of establishing intracellular C3 stores. We found that many types of human cells specifically internalized C3(H2O), the hydrolytic product of C3, and not native C3, from the extracellular milieu. Uptake was rapid, saturable, and sensitive to competition with unlabeled C3(H2O), indicating a specific mechanism of loading. Under steady-state conditions, approximately 80% of incorporated C3(H2O) was returned to the extracellular space. These studies identify an ICS recycling pathway for C3(H2O). The loaded C3(H2O) represents a source of C3a, and its uptake altered the cytokine profile of activated CD4+ T cells. Importantly, these results indicate that the impact of soluble plasma factors should be considered when performing in vitro studies assessing cellular immune function.

The advent of biologic agents has provided a more specific and targeted approach to the treatment of various hematological malignancies and other autoimmune disorders. Such biologic agents have been relatively well tolerated with fewer adverse events reported as compared with many other chemotherapeutic agents. Rituximab is a monoclonal antibody to the B-cell marker CD20 and is a common biologic agent widely used for the treatment of B-cell lymphoma, lymphoproliferative disorders, and inflammatory conditions that are refractory to conventional treatment, including rheumatoid arthritis and some vasculitides. However, through randomized controlled trials and post-marketing surveillance, an increasing number of serious adverse events are being associated with the use of rituximab, often leading to or complicating an intensive care unit admission. The purpose of this review is to focus on the severe complications that are associated with the use of rituximab and that require critical care. Management and prevention strategies for the most common complications along with some examples of its uses within the critical care setting are also discussed.

Context: An intensive care unit (ICU) admission of a patient causes considerable stress among relatives. Whether this impact differs among populations with differing sociocultural factors is unknown., Aims: The aim was to compare the psychological impact of an ICU admission on relatives of patients in an American and Indian public hospital., Settings and Design: A cross-sectional study was carried out in ICUs of two tertiary care hospitals, one each in major metropolitan cities in the USA and India., Materials and Methods: A total of 90 relatives visiting patients were verbally administered a questionnaire between 48 hours and 72 hours of ICU admission that included the Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory-II (BDI-II) and Impact of Events Scale-Revised (IES-R) for post-traumatic stress response., Statistical Analysis: Statistical analysis was done using the Mann-Whitney and chi-square tests., Results: Relatives in the Indian ICU had more anxiety symptoms (median HADS-A score 11 [inter-quartile range 9-13] vs. 4 [1.5-6] in the American cohort; P<0.0001), more depression symptoms (BDI-II score 14 [8.5-19] vs. 6 [1.5-10.5], P<0.0001) but a comparable post-traumatic stress response (IES-R score>30). 55% of all relatives had an incongruous perception regarding "change in the patient's condition" compared to the objective change in severity of illness. "Change in worry" was incongruous compared to the perception of improvement of the patient's condition in 78% of relatives., Conclusions: Relatives of patients in the Indian ICU had greater anxiety and depression symptoms compared to those in the American cohort, and had significant differences in factors that may be associated with this psychological impact. Both groups showed substantial discordance between the perceived and objective change in severity of illness.

Optic nerve involvement is a rare side effect of isoniazid (INH) and has not been described in children. We describe this adverse reaction in a 10-year-old boy, who was treated for tuberculous meningitis. The patient showed almost complete resolution following withdrawal of INH and administration of pyridoxine and steroids.