Properdin: emerging roles of a pattern-recognition molecule.

Complement is an innate immune system that is a first line of defense against pathogens and facilitates elimination of apoptotic and injured cells. During complement activation, the complement convertases are assembled on target surfaces and initiate their proteolytic activities, a process that marks targets for phagocytosis and/or lysis. The complement alternative activation pathway has been implicated in a number of autoimmune conditions including arthritis and age-related macular degeneration. Properdin, a plasma component that is also released by activated neutrophils, is critical in the stabilization of alternative pathway convertases. Recently, it has been shown that properdin is also a pattern-recognition molecule that binds to certain microbial surfaces, apoptotic cells, and necrotic cells. Once bound to a surface, properdin can direct convertase formation and target uptake. New studies are now focusing on a role for properdin in inflammatory and autoimmune diseases. This review examines the new properdin findings and their implications.

Complement receptor 1 is the human erythrocyte receptor for Plasmodium vivax erythrocyte binding protein.

The discovery that Africans were resistant to infection by Plasmodium vivax (P. vivax) led to the conclusion that P. vivax invasion relied on the P. vivax Duffy Binding Protein (PvDBP) interacting with the Duffy Antigen Receptor for Chemokines (DARC) expressed on erythrocytes. However, the recent reporting of P. vivax infections in DARC-negative Africans suggests that the parasite might use an alternate invasion pathway to infect DARC-negative reticulocytes. To identify the parasite ligands and erythrocyte receptors that enable P. vivax invasion of both DARC-positive and -negative erythrocytes, we expressed region II containing the Duffy Binding-Like (DBL) domain of P. vivax erythrocyte binding protein (PvEBP-RII) and verified that the DBL domain binds to both DARC-positive and -negative erythrocytes. Furthermore, an AVidity-based EXtracelluar Interaction Screening (AVEXIS) was used to identify the receptor for PvEBP among over 750 human cell surface receptor proteins, and this approach identified only Complement Receptor 1 (CR1, CD35, or C3b/C4b receptor) as a PvEBP receptor. CR1 is a well-known receptor for P. falciparum Reticulocyte binding protein Homology 4 (PfRh4) and is present on the surfaces of both reticulocytes and normocytes, but its expression decreases as erythrocytes age. Indeed, PvEBP-RII bound to a subpopulation of both reticulocytes and normocytes, and this binding was blocked by the addition of soluble CR1 recombinant protein, indicating that CR1 is the receptor of PvEBP. In addition, we found that the Long Homology Repeat A (LHR-A) subdomain of CR1 is the only subdomain responsible for mediating the interaction with PvEBP-RII.

Alternative pathway activation: Ever ancient and ever new.

Primitive underpinnings of the alternative pathway (AP), namely, a C3-like protein, likely arose more than a billion years ago. The development of an AP amplification loop, while greatly enhancing speed and potency, also presents a double-edged sword. Although critical to combat an infectious disease, it is also potentially destructive, particularly in a chronic disease process involving vital organs where scarring and reduction of regulatory function can occur. Furthermore, new knowledge is pointing to genetic factors involved in an increasing number of complement-related diseases such as age-related macular degeneration. However, even a normal functioning repertoire of complement components can drive cellular damage as a result of low-level complement activation over time. Thus, the modern human AP now faces a new challenge: cumulatively-driven tissue damage from chronic inflammatory processes that mediate cellular injury. The impact of ongoing low-level AP-enhanced complement activation in disease processes is just beginning to be appreciated and studied. However, the sheer numbers of individuals affected by chronic diseases emphasize the need for novel therapeutic agents capable of modulating the AP. The more we learn about this ancient system, the greater is the likelihood of developing fresh perspectives that could contribute to improved human health.

Mutations in atypical hemolytic uremic syndrome provide evidence for the role of calcium in complement factor I.

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy. Genetic variants in complement proteins are found in ≈60% of patients. Of these patients, ≈15% carry mutations in complement factor I (CFI). Factor I (FI) is a multidomain serine protease that cleaves and thereby inactivates C3b and C4b in the presence of cofactor proteins. Crystal structures have shown that FI possesses 2 calcium-binding domains, low-density lipoprotein receptor class A (LDLRA) 1 and LDLRA2. Yet, the role of calcium in FI is unknown. We determined that 9 genetic variants identified in aHUS (N151S, G162D, G188A, V230E, A240G, G243R, C247G, A258T, and Q260D) cluster around the calcium-binding site of LDLRA1. Using site-directed mutagenesis, we established that the synthesis of all, except A258T, was impaired, implying defective protein folding, perhaps due to loss of calcium binding. To further explore this possibility, we generated 12 alanine mutants that coordinate with the calcium in LDLRA1 and LDLRA2 (K239A, D242A, I244A, D246A, D252A, E253A, Y276A, N279A, E281A, D283A, D289A, and D290A) and are expected to perturb calcium binding. Except for K239A and Y276A, none of the mutants was secreted. These observations suggest that calcium ions play key structural and functional roles in FI.

Functional analysis of rare genetic variants in complement factor I in advanced age-related macular degeneration.

Factor I (FI) is a serine protease inhibitor of the complement system. Heterozygous rare genetic variants in complement factor I (CFI) are associated with advanced age-related macular degeneration (AMD). The clinical impact of these variants is unknown since a majority have not been functionally characterized and are classified as 'variants of uncertain significance' (VUS). This study assessed the functional significance of VUS in CFI. Our previous cross-sectional study using a serum-based assay demonstrated that CFI variants in advanced AMD can be categorized into three types. Type 1 variants cause a quantitative deficiency of FI. Type 2 variants demonstrate a qualitative deficiency. However, Type 3 variants consist of VUS that are less dysfunctional than Types 1 and 2 but are not as biologically active as wild type (WT). In this study, we employed site-directed mutagenesis followed by expression of the recombinant variant and a comprehensive set of functional assays to characterize nine Type 3 variants that were identified in 37 individuals. Our studies establish that the expression of the recombinant protein compared with WT is reduced for R202I, Q217H, S221Y and G263V. Further, G362A and N536K, albeit expressed normally, have significantly less cofactor activity. These results led to re-categorization of CFI variants R202I, Q217H, S221Y and G263V as Type 1 variants and to reclassification of N536K and G362A as Type 2. The variants K441R, Q462H and I492L showed no functional defect and remained as Type 3. This study highlights the utility of an in-depth biochemical analysis in defining the pathologic and clinical implications of complement variants underlying AMD.

Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation.

TREX1 is an endoplasmic reticulum (ER)-associated negative regulator of innate immunity. TREX1 mutations are associated with autoimmune and autoinflammatory diseases. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to accumulate, but it is unknown how dominant frameshift (fs) mutations that encode DNase-active but mislocalized proteins cause disease. We found that the TREX1 C terminus suppressed immune activation by interacting with the ER oligosaccharyltransferase (OST) complex and stabilizing its catalytic integrity. C-terminal truncation of TREX1 by fs mutations dysregulated the OST complex, leading to free glycan release from dolichol carriers, as well as immune activation and autoantibody production. A connection between OST dysregulation and immune disorders was demonstrated in Trex1(-/-) mice, TREX1-V235fs patient lymphoblasts, and TREX1-V235fs knock-in mice. Inhibiting OST with aclacinomycin corrects the glycan and immune defects associated with Trex1 deficiency or fs mutation. This function of the TREX1 C terminus suggests a potential therapeutic option for TREX1-fs mutant-associated diseases.

At-Risk Drinking and Workplace Conditions among Latino Day Laborers.

Background: Latino Day Laborers (LDL) face a variety of factors which have been associated with at-risk drinking. The objective of this study was to assess the association of at-risk drinking with measures of work site conditions. Methods: Data from surveys conducted with 307 LDL in Houston, TX in 2015 were analyzed. Sociodemographic information and measures of exposures to hazardous products at the worksite, adverse working conditions, and work stressors were collected. Measures of positive working climate at the jobsite and a climate that promoted jobsite safety were also included. Participants were administered the Hazardous Use items from the Alcohol Use Disorders Identification Test of Consumption (AUDIT-C). Participants were classified as low-risk or at-risk drinkers based on AUDIT-C score. Logistic regression models were run to assess the associations of the sociodemographic and worksite related variables with drinking status. Results: One-hundred-five (34.2%) participants were classified as at-risk drinkers. At-risk drinking was associated with past-month income, being formerly married (compared to having never married), and lack of housing. At-risk drinking was also associated with measures of a positive working climate and a climate that promoted jobsite safety. Conclusions: One-third of our participants were classified as at-risk drinkers. At-risk drinking was associated with stressors in the form of lack of housing and no longer having a spouse but was also associated with increased income and with positive workplace factors. At-risk drinking was thus a function of both stressors and positive factors, including a positive work site.

Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses.

BACKGROUND: The pathogenesis of hereditary angioedema (HAE) type I and type II is linked to defective C1 esterase inhibitor (C1-INH) encoded by the SERPING1 gene. There are substantial variabilities in the clinical presentations of patients with HAE that are not directly correlated to the serum levels of C1-INH. The impact of SERPING1 variants on C1-INH expression, structure, and function is incompletely understood. OBJECTIVE: To investigate the influence of SERPING1 variants on the C1-INH expression, structure, and function of 20 patients with HAE from 14 families with no prior genetic diagnosis. METHODS: Patients underwent whole-exome sequencing (WES). If no variants were identified, whole-genome sequencing (WGS) was performed. Except for the frameshift and large deletions, each C1-INH variant was recombinantly produced and, if synthesized and secreted, was subjected to structural, oligosaccharide, and functional analyses. RESULTS: We identified 11 heterozygous variants in the SERPING1 gene, of which 5 were classified as pathogenic (E85Dfs∗63, N166Qfs∗91, K201Qfs∗56, P399A, and R466H) and 6 as variants of uncertain significance (C130W, I224S, N272del, K273del, L349F, and F471C). Three large heterozygous deletions were discovered through WGS. Our data indicate that C130W, N272del, P399A, and F471C are poorly synthesized, I224S prevents proper C1-INH folding, and K273del impairs C1-INH function by adding an additional oligosaccharide. Further evaluation suggests that compound variant P399A/L349F contributes to a more severe clinical phenotype. CONCLUSIONS: Our combined approach of WES and WGS uncovered SERPING1 gene alternations in each patient. The recombinant protein production followed by systematic antigenic, structural, and functional assessment facilitates the identification of underlying pathogenic mechanisms in HAE.

Group A Streptococcus Primary Peritonitis in Children, New Zealand.

Group A Streptococcus (GAS) primary peritonitis is a rare cause of pediatric acute abdomen (sudden onset of severe abdominal pain); only 26 pediatric cases have been reported in the English language literature since 1980. We discuss 20 additional cases of pediatric primary peritonitis caused by GAS among patients at Starship Children's Hospital, Auckland, New Zealand, during 2010-2022. We compare identified cases of GAS primary peritonitis to cases described in the existing pediatric literature. As rates of rates of invasive GAS increase globally, clinicians should be aware of this cause of unexplained pediatric acute abdomen.

Ex Vivo and In Vivo CD46 Receptor Utilization by Species D Human Adenovirus Serotype 26 (HAdV26).

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.

The Acquisition and Retention of Lumpy Skin Disease Virus by Blood-Feeding Insects Is Influenced by the Source of Virus, the Insect Body Part, and the Time since Feeding.

Lumpy skin disease virus (LSDV) is a poxvirus that causes severe systemic disease in cattle and is spread by mechanical arthropod-borne transmission. This study quantified the acquisition and retention of LSDV by four species of Diptera (Stomoxys calcitrans, Aedes aegypti, Culex quinquefasciatus, and Culicoides nubeculosus) from cutaneous lesions, normal skin, and blood from a clinically affected animal. The acquisition and retention of LSDV by Ae. aegypti from an artificial membrane feeding system was also examined. Mathematical models of the data were generated to identify the parameters which influence insect acquisition and retention of LSDV. For all four insect species, the probability of acquiring LSDV was substantially greater when feeding on a lesion compared with feeding on normal skin or blood from a clinically affected animal. After feeding on a skin lesion LSDV was retained on the proboscis for a similar length of time (around 9 days) for all four species and for a shorter time in the rest of the body, ranging from 2.2 to 6.4 days. Acquisition and retention of LSDV by Ae. aegypti after feeding on an artificial membrane feeding system that contained a high titer of LSDV was comparable to feeding on a skin lesion on a clinically affected animal, supporting the use of this laboratory model as a replacement for some animal studies. This work reveals that the cutaneous lesions of LSD provide the high-titer source required for acquisition of the virus by insects, thereby enabling the mechanical vector-borne transmission. IMPORTANCE Lumpy skin disease virus (LSDV) is a high consequence pathogen of cattle that is rapidly expanding its geographical boundaries into new regions such as Europe and Asia. This expansion is promoted by the mechanical transmission of the virus via hematogenous arthropods. This study quantifies the acquisition and retention of LSDV by four species of blood-feeding insects and reveals that the cutaneous lesions of LSD provide the high titer virus source necessary for virus acquisition by the insects. An artificial membrane feeding system containing a high titer of LSDV was shown to be comparable to a skin lesion on a clinically affected animal when used as a virus source. This promotes the use of these laboratory-based systems as replacements for some animal studies. Overall, this work advances our understanding of the mechanical vector-borne transmission of LSDV and provides evidence to support the design of more effective disease control programmes.

The complement system and human autoimmune diseases.

Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis.

Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study.

OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia. DESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls. SETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven. POPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts. METHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type. MAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations. RESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V. CONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.

Treatment outcome of metastasis to the pituitary gland: a case series of 21 patients with pathological diagnosis.

OBJECTIVE: The aim of this study was to report the treatment course of histologically confirmed metastases to the pituitary gland (pituitary metastasis). METHODS: The Mayo data explorer was used to find patients with pituitary metastasis. Twenty-one patients were identified between the years 2001 and 2021, and their data were retrospectively collected. RESULTS: The most common primary cancer origin was lung in men (45%) and breast in women (33%). The median age was 66 years (IQR 56-68 years). Patients presented with headache (67% [14/21]), vision problems (86% [18/21]), anterior hypopituitarism (71% [15/21]), and arginine vasopressin deficiency (38% [8/21]). Pituitary metastases were found before the diagnosis of the primary cancer in 5 patients (24%). The mean ± SD tumor size was 2.0 ± 0.7 cm, and 90% (19/21) presented as a solitary pituitary mass with no other intracranial metastatic lesions. Common radiological features were pituitary stalk thickening (90% [19/21]), cavernous sinus involvement (71% [15/21]), and constriction at the diaphragma sellae (52% [11/21]). Transsphenoidal surgery was performed in 20 patients, and subtotal resection was most frequently attained (76% [16/21]). Fourteen patients (67%) had adjuvant radiation therapy, and 15 patients (71%) were treated with systemic therapy. The median time from surgery to the initiation of radiation therapy was 16 days (IQR 11-21 days), and that from surgery to the initiation of systemic therapy was 5.0 months (IQR 1.5-14 months). During management, headaches improved in 57% (8/14) and vision problems improved in 61% (11/18) of cases; new hypopituitarism occurred in 5 patients. Six patients developed recurrence, and the median progression-free survival was 24 months (95% CI 5.4-43 months). After recurrence, 1 patient with adenoid cystic carcinoma was treated with rescue radiotherapy twice, and 4 patients responded well to systemic therapy. The median overall survival (OS) was 25 months (95% CI 7.1-43 months). The mean OS was better in patients with neuroendocrine lung tumor (261 months) and papillary thyroid carcinoma (80 months) and worse in patients with small cell lung cancer (4 months) and unknown origin (5 months). CONCLUSIONS: Surgery with or without adjuvant radiotherapy is effective for mass reduction, rapid symptomatic improvement of vision and headaches, and definitive diagnosis. Even after local tumor control failure, some patients still benefit from radiation and/or systemic therapy.

Development and refinement of a corner-based injury prevention programme for Latino day labourers.

Objective: Latino day labourers (LDLs) in the USA are at increased risk for non-fatal and fatal occupational injuries, which are compounded by stressors that include wage theft, job insecurity and discrimination. This paper describes the development and refinement of Vales+Tú (You are Worthy of More), an injury prevention programme currently being evaluated as part of a cluster randomised trial in which health promotion is taken directly to the 'corners' (e.g. street corners, home improvement store parking lots, and public parks) where workers gather to seek employment. Design: Vales+Tú comprises two corner-based intervention approaches, group problem-solving (small group discussions) and brief motivational interviewing (one-on-one dialogue), that aim to activate LDL agency to control their safety and that of their peers. Setting: Corners in Houston, Texas, where LDLs seek employment. Method: Intervention Mapping informed the refinement of Vales+Tú for the current trial. We provide a narrative review of the development process based on needs assessment and formative development activities (surveys, focus group discussions and pilot tests). Results: In addition to documenting the need for LDL injury prevention, with 20.2%-41.6% of Houston-based LDLs surveyed between 2013-2014 and 2019 reporting a severe work-related injury in the past year, we describe key facets of the Vales+Tú corner-based intervention approaches - including their theoretical basis and LDL-centred activities, as well as enhancements made informed by formative evaluation. Conclusion: The community-engaged development process of Vales+Tú resulted in two practical intervention approaches that can be adopted by worker centres and other organisations to promote LDL worker safety.

Quantifying and Modeling the Acquisition and Retention of Lumpy Skin Disease Virus by Hematophagus Insects Reveals Clinically but Not Subclinically Affected Cattle Are Promoters of Viral Transmission and Key Targets for Control of Disease Outbreaks.

Lumpy skin disease virus (LSDV) is a vector-transmitted poxvirus that causes disease in cattle. Vector species involved in LSDV transmission and their ability to acquire and transmit the virus are poorly characterized. Using a highly representative bovine experimental model of lumpy skin disease, we fed four model vector species (Aedes aegypti, Culex quinquefasciatus, Stomoxys calcitrans, and Culicoides nubeculosus) on LSDV-inoculated cattle in order to examine their acquisition and retention of LSDV. Subclinical disease was a more common outcome than clinical disease in the inoculated cattle. Importantly, the probability of vectors acquiring LSDV from a subclinical animal (0.006) was very low compared with that from a clinical animal (0.23), meaning an insect feeding on a subclinical animal was 97% less likely to acquire LSDV than one feeding on a clinical animal. All four potential vector species studied acquired LSDV from the host at a similar rate, but Aedes aegypti and Stomoxys calcitrans retained the virus for a longer time, up to 8 days. There was no evidence of virus replication in the vector, consistent with mechanical rather than biological transmission. The parameters obtained in this study were combined with data from studies of LSDV transmission and vector life history parameters to determine the basic reproduction number of LSDV in cattle mediated by each of the model species. This reproduction number was highest for Stomoxys calcitrans (19.1), followed by C. nubeculosus (7.1) and Ae. aegypti (2.4), indicating that these three species are potentially efficient transmitters of LSDV; this information can be used to inform LSD control programs.IMPORTANCE Lumpy skin disease virus (LSDV) causes a severe systemic disease characterized by cutaneous nodules in cattle. LSDV is a rapidly emerging pathogen, having spread since 2012 into Europe and Russia and across Asia. The vector-borne nature of LSDV transmission is believed to have promoted this rapid geographic spread of the virus; however, a lack of quantitative evidence about LSDV transmission has hampered effective control of the disease during the current epidemic. Our research shows subclinical cattle play little part in virus transmission relative to clinical cattle and reveals a low probability of virus acquisition by insects at the preclinical stage. We have also calculated the reproductive number of different insect species, therefore identifying efficient transmitters of LSDV. This information is of utmost importance, as it will help to define epidemiological control measures during LSDV epidemics and of particular consequence in resource-poor regions where LSD vaccination may be less than adequate.

Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells.

In this study we demonstrate a new form of immunoregulation: engagement on CD4(+) T cells of the complement regulator CD46 promoted the effector potential of T helper type 1 cells (T(H)1 cells), but as interleukin 2 (IL-2) accumulated, it switched cells toward a regulatory phenotype, attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 after interaction of the CD46 tail with the serine-threonine kinase SPAK. Activated CD4(+) T cells produced CD46 ligands, and blocking CD46 inhibited IL-10 production. Furthermore, CD4(+) T cells in rheumatoid arthritis failed to switch, consequently producing excessive interferon-gamma (IFN-gamma). Finally, gammadelta T cells, which rarely produce IL-10, expressed an alternative CD46 isoform and were unable to switch. Nonetheless, coengagement of T cell antigen receptor (TCR) gammadelta and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.

Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.

Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While "tonic" intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.

Surgical management of sacral schwannomas: a 21-year mayo clinic experience and comparative literature analysis.

INTRODUCTION: Sacral and presacral schwannomas are rare, accounting for a minority of spinal schwannomas. We present our institution's experience surgically treating spinal schwannomas and compare it to the literature. METHODS: Data were collected for 27 patients treated surgically for sacral or presacral schwannoma between 1997 and 2018 at all Mayo Clinic locations and 93 patients in the literature. Kaplan-Meier disease-free survival analysis was conducted. Unpaired two-sample t tests and Fisher's exact tests assessed statistical significance between groups. RESULTS: Our patients and those in the literature experienced a similar age at diagnosis (49.9 y/o. vs 43.4 y/o., respectively). Most of our patients (59.3%) reported full recovery from symptoms, while a minority reported partial recovery (33.3%) and no recovery (11.1%). A smaller percentage in the literature experienced full recovery (31.9%) and partial recovery (29.8%) but also no recovery (1.1%). Our patients experienced fewer complications (14.8% versus 25.5%). Disease-free survival curves for all patients showed no significant variation in progression by extent of resection of schwannoma (log-rank P = 0.26). No lesion progression was associated with full or partial symptom improvement (p = 0.044), and female patients were more likely to undergo resection via a posterior approach (p = 0.042). CONCLUSION: Outcomes of patients with sacral or presacral schwannomas vary based on patient demographics, tumor characteristics, symptoms, and surgical treatment. Among the range of symptoms experienced by these patients, the most common is pain. Prognosis improves and overall survival is high when the surgical approach towards sacral schwannomas is prepared and executed appropriately.

Vales+Tú: a cluster-randomized pilot study to reduce workplace injuries among US Latino day laborers.

Latino day laborers (LDL) are a vulnerable population of workers facing considerable risk for occupational injury. Under the guidance of our Community Advisory Board, we developed and tested the feasibility, acceptability and preliminary effects of Vales+Tú (You Are Worth More), a workplace injury risk-reduction program implemented by promotores on street-corners where LDL seek employment. The program was informed by theoretical perspectives emphasizing individual and group agency and self-determination. A pilot three-arm cluster-randomized community trial was conducted among 75 LDL. The intervention arms consisted of an individualized Brief Motivational Interview, a Group Problem Solving activity and a standard of care control (OSHA safety cards). We met our study goal of 25 LDL per intervention arm, and contacted 88% of participants post intervention. Participants evaluated the interventions favorably. At post-test, the Brief Motivational Interview group reported significant reductions in exposure to workplace hazards and increases in risk-reduction practices. The Group Problem Solving participants showed significant reductions in exposure to hazards (t-test -4.16, p < 0.001). Both intervention groups increased their reliance on corner peers, a measure of social support. Standard of care participants increased in self-efficacy to work safely. Overall, the only significant different between the three study conditions was in self-efficacy. These findings provide evidence of the feasibility and acceptability of Vales+Tú and show preliminary program efficacy. A large-scale replication trial will permit a more formal modeling of the study findings. Clinical Trial Registration (ClinicalTrials.gov): NCT04378348.

This pilot-randomized trial tested the feasibility and initial efficacy of an injury risk-reduction program among Latino day laborers (LDL). The study tested two alternative interventions consisting of a Brief Motivational Interview (Individual) and a Group Problem Solving (Group) conditions that were compared with a Standard-of-Care control group receiving safety cards. We then tested the extent to which the study conditions reduced exposure to workplace hazards and increased safety practices at work. Results indicate that intervening at day labor corners is a feasible intervention strategy acceptable to these immigrant workers. Initial results also indicate that there were multiple within-group significant differences in risk reduction, mostly in the individual condition, and that there was one significant between-group difference in safety self-efficacy at post-test. A larger more rigorous trial can further test the stability of these results and determine the extent to which these intervention approaches can reduce the risk for injury that LDL confront at work.