Liver health events: an indigenous community-led model to enhance HCV screening and linkage to care.

Despite high prevalence of hepatitis C virus (HCV), linkage to care and treatment for Indigenous people is low. In an Indigenous community in Saskatchewan, Canada a retrospective review identified 200 individuals (∼12% prevalence) had HCV antibodies though majority lacked ribonucleic acid (RNA) testing, and few received treatment despite availability of an effective cure. Following Indigenous oral traditions, focus group discussions were held with key community members and leadership. Participants emphasized the need for a community-based screening and treatment programme. A team of community members, peers and healthcare professionals developed a streamlined screening pathway termed 'liver health event' (LHE) to reduce stigma, reach undiagnosed, re-engage previously diagnosed, and ensure rapid linkage to care/treatment. LHEs began December 2016. Statistics were tracked for each event. As of July 2019, there were 10 LHEs with 540 participants, 227 hepatitis C tests and 346 FibroScans completed. This represented 294 unique individuals, of which 64.3% were tested, and of those, 40.8% were Ab positive. Among those positive for antibodies, 41.7% had active hepatitis C infections, and among these, 90% were linked to care, and 14 new positive individuals were identified. Following the success of LHEs, these were adapted and implemented in 10 other communities in this region, resulting in 17 additional LHEs. This intervention is reaching the undiagnosed and linking clients to care through a low-barrier and de-stigmatizing approach. It has facilitated collaboration, knowledge exchange and mentorship between Indigenous communities, significantly impacting health outcomes of Indigenous people in this region.

Individuals residing in geographically isolated Indigenous communities often face multiple barriers trying to access healthcare services in Saskatchewan Canada. Consequently, many individuals who have HCV antibody (Ab), often lack confirmatory RNA test and experience delays in linkage to HCV treatment. A collective decision was made by pertinent stakeholders including community members, peers, community healthcare staff, Chief and leadership to improve access to screening and linkage to HCV treatment in community. A streamlined HCV screening pathway referred to as LHEs was developed by an Indigenous community. Since implementation in December 2016, 10 LHEs were delivered in community, with 540 participant visits, 227 hepatitis C tests conducted, and 346 FibroScans completed. Out of 294 unique individuals who attended, 64.3% were tested, and of those, 40.8% were Ab positive. Among those positive for antibodies, 41.7% had active hepatitis C infections, and among these, 90% were linked to care, and 14 new positive individuals were identified. Following the success of the LHEs in reaching the undiagnosed, this screening pathway has been adapted and implemented in at least 10 additional Indigenous communities in Saskatchewan, Canada.

In-person learning low risk for COVID-19 acquisition: Findings from a population-based analysis of the 2020-2021 school year in Saskatchewan, Canada.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused substantial disruption to in-person learning, often interfering with the social and educational experience of children and youth across North America, and frequently impacting the greater community by limiting the ability of parents and caregivers to work outside the home. Real-world evidence related to the risk of COVID-19 transmission in school settings can help inform decisions around initiating, continuing, or suspending in-person learning. Methods: We analyzed routinely collected case-based surveillance data from Saskatchewan's electronic integrated public health system, Panorama, from the 2020-2021 school year, spanning various phases of the pandemic (including the Alpha variant wave), to better understand the risk of in-school transmission of COVID-19 in Saskatchewan schools. Results: The majority (over 80%) of school-associated COVID-19 infections were acquired outside the school setting. This finding suggests that the non-pharmaceutical measures in place (including masking, distancing, enhanced hygiene, and cohorting) worked to limit viral spread in schools. Conclusion: Implementation of such control measures may play an essential role in allowing children and youth to safely maintain in-person learning during the pandemic.

HIV outbreaks among people who inject drugs in Europe, North America, and Israel.

During 2011-16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks.

Characteristics of Gay, Bisexual and Other Men Who Have Sex With Men With Multiple Diagnoses of Infectious Syphilis in British Columbia, Canada, 2005-2014.

BACKGROUND: Infectious syphilis has increased substantially over the past decade. Targeting limited public health resources toward subpopulations with multiple reinfections may have a large impact in reducing onward transmission within a community. METHODS: A chart review was conducted for individuals with 4 or more infectious syphilis diagnoses between 2005 and 2014 (the top 1% of all syphilis diagnoses in British Columbia, Canada). We characterized the sociodemographics, partner notification outcomes and social network. RESULTS: Between 2005 and 2014, there were 30 individuals with 4 or more syphilis diagnoses, accounting for 139 diagnoses. All were men who have sex with men and 29 (96%) were human immunodeficiency virus-positive. Of the 139 diagnoses, 65% occurred in the early latent stage of infection, 22% in the secondary stage, and 14% in the primary stage. The median number of sexual partners per diagnosis was 5 (range, 1-50). Among the 838 partners reported, 79% were notifiable, 53% were notified, and 23% were reported to be tested or treated. Sexual network mapping showed that almost half of the members of this group could be linked to one another either directly or indirectly via partners over 10 years. Social network mapping demonstrated high connectivity, with 4 venues associated with almost two thirds of the study population. CONCLUSIONS: The connectivity and recurrent diagnoses in this study population suggest potential benefits of targeted interventions to individuals with multiple diagnoses and their partners. Our study highlights the need for enhanced care, increased syphilis testing frequency, and exploring alternative preventative methods among individuals with syphilis rediagnoses to reduce syphilis incidence.

Remote sensing measurements of sea surface temperature as an indicator of Vibrio parahaemolyticus in oyster meat and human illnesses.

BACKGROUND: Vibrio parahaemolyticus (Vp) is a naturally occurring bacterium found in marine environments worldwide. It can cause gastrointestinal illness in humans, primarily through raw oyster consumption. Water temperatures, and potentially other environmental factors, play an important role in the growth and proliferation of Vp in the environment. Quantifying the relationships between environmental variables and indicators or incidence of Vp illness is valuable for public health surveillance to inform and enable suitable preventative measures. This study aimed to assess the relationship between environmental parameters and Vp in British Columbia (BC), Canada. METHODS: The study used Vp counts in oyster meat from 2002-2015 and laboratory confirmed Vp illnesses from 2011-2015 for the province of BC. The data were matched to environmental parameters from publicly available sources, including remote sensing measurements of nighttime sea surface temperature (SST) obtained from satellite readings at a spatial resolution of 1 km. Using three separate models, this paper assessed the relationship between (1) daily SST and Vp counts in oyster meat, (2) weekly mean Vp counts in oysters and weekly Vp illnesses, and (3) weekly mean SST and weekly Vp illnesses. The effects of salinity and chlorophyll a were also evaluated. Linear regression was used to quantify the relationship between SST and Vp, and piecewise regression was used to identify SST thresholds of concern. RESULTS: A total of 2327 oyster samples and 293 laboratory confirmed illnesses were included. In model 1, both SST and salinity were significant predictors of log(Vp) counts in oyster meat. In model 2, the mean log(Vp) count in oyster meat was a significant predictor of Vp illnesses. In model 3, weekly mean SST was a significant predictor of weekly Vp illnesses. The piecewise regression models identified a SST threshold of approximately 14oC for both model 1 and 3, indicating increased risk of Vp in oyster meat and Vp illnesses at higher temperatures. CONCLUSION: Monitoring of SST, particularly through readily accessible remote sensing data, could serve as a warning signal for Vp and help inform the introduction and cessation of preventative or control measures.

Identifying factors associated with changes in CD4(+) count in HIV-infected adults in Saskatoon, Saskatchewan.

OBJECTIVE: To assess the impact of clinical and social factors unique to HIV-infected adults in Saskatoon, Saskatchewan, regarding the rate of CD4(+) count change, and to identify factors associated with a risk of CD4(+) count decline. METHODS: A retrospective longitudinal cohort study from medical chart reviews at two clinics was conducted in Saskatoon. Univariate and multivariate linear mixed effects models were used to assess the impact of selected factors on CD4(+) count change. RESULTS: Four hundred eleven HIV-infected patients were identified from January 1, 2003 to November 30, 2011. Two hundred eighteen (53%) were male, mean (± SD) age was 35.6 ±10.1 years, 257 (70.8%) were First Nations or Métis, 312 (80.2%) were hepatitis C virus (HCV) coinfected and 300 (73.3%) had a history of injection drug use (IDU). In univariate models, age, ethnicity, HCV, IDU, antiretroviral therapy and social assistance were significant. Using ethnicity, HCV and IDU, three multivariate models (models 1, 2, 3) were built due to high correlation. First Nations or Métis ethnicity, HCV coinfection and a history of IDU were associated with significantly lower CD4(+) counts in multivariate models. Older age and social assistance were associated with significantly lower CD4(+) counts in models 1 and 3. Age was marginally significant in model 2 (P=0.055). Not prescribed antiretroviral therapy was associated with a significantly negative CD4(+) count slope in all multivariate models. CONCLUSION: The unique epidemiology of this HIV-infected population may be contributing to CD4(+) count change. Increased attention and resources focused on this high-risk population are needed to prevent disease progression and to improve overall health and quality of life.

OBJECTIF: Évaluer les répercussions des facteurs cliniques et sociaux propres aux adultes infectés par le VIH de Saskatoon, en Saskatchewan, sur le taux de modifications de la numération de CD4+ et déterminer les facteurs associés à un risque de diminution de la numération de CD4+. MÉTHODOLOGIE: Les chercheurs ont réalisé une étude de cohorte longitudinale rétrospective des dossiers médicaux de deux cliniques de Saskatoon. Ils ont utilisé les modèles linéaires à effets mixtes univariés et multivariés pour évaluer les répercussions de certains facteurs associés aux modifications de la numération de CD4+. RÉSULTATS: Les chercheurs ont repéré 411 patients infectés par le VIH entre le 1er janvier 2003 et le 30 novembre 2011. Deux cent dix-huit d'entre eux (53 %) étaient de sexe masculin et avaient un âge moyen (± ÉT) de 35,6 ans ±10,1 ans, 257 (70,8 %) étaient Métis ou originaires des Premières nations, 312 (80,2 %) étaient co-infectés par le virus de l'hépatite C (VHC) et 300 (73,3 %) avaient des antécédents de consommation de drogues par injection (CDI). Dans les modèles univariés, l'âge, l'ethnie, le VHC, la CDI, l'antirétrovirothérapie et l'aide sociale étaient déterminants. À l'aide de l'ethnie, du VHC et de la CDI, les chercheurs ont formé trois modèles multivariés (modèles 1, 2, 3) en raison de leur forte corrélation. Le fait d'être Métis ou originaire des Premières nations, d'être co-infecté par le VHC et d'avoir des antécédents de CDI s'associait à des numérations de CD4+ beaucoup plus faibles dans les modèles multivariés. Le fait d'être plus âgé et de recevoir de l'aide sociale s'associait à une numération beaucoup plus faible de CD4+ dans les modèles 1 et 3. L'âge était légèrement significatif dans le modèle 2 (P=0,055). Dans tous les modèles multivariés, l'antirétrovirothérapie ne s'associait jamais à une pente négative de la numération de CD4+. CONCLUSION: L'épidémiologie unique de cette population infectée par le VIH contribue peut-être à une modification de la numération de CD4+. Il faudra se pencher sur ces patients à haut risque et y injecter plus de ressources pour prévenir l'évolution de leur maladie et améliorer leur santé et leur qualité de vie globales.

Low pertussis toxin antibody levels in two regional cohorts of Canadian pregnant women.

Infants under 6 months of age are at greatest risk of mortality and severe morbidity from pertussis disease. Interventions that increase pertussis protection in newborns are therefore a clear public health imperative. The objective of this study was to assess maternal pertussis toxin antibody (anti-PT) level as a potential source of mother-to-child transfer of pertussis-associated antibodies that may reduce neonatal risk of pertussis disease. Anti-PT level was assessed in a 2013 cohort of pregnant women from two regions in two Canadian provinces, British Columbia and Nova Scotia. Basic demographics, health, and pertussis immunization history were collected, along with blood specimens. Anti-PT levels were compared for self-reported vaccination status and prior pertussis disease. To assess secular trend, a parallel analysis was also undertaken, using anonymized residual sera from a 1996-1997 cohort of pregnant women in British Columbia. A total of 169 pregnant women participated in the study - 50 from Nova Scotia and 119 from British Columbia. The mean and median age of participants from both sites was 31 years of age (range 16-42 years). The lower limit of quantification of the anti-PT assay was 10 ELISA units per milliliter (EU/ml). Overall, 59% of women had anti-PT levels less than 10 EU/ml and anti-PT level did not differ with time since last self-reported pertussis vaccination (χ(2)(2)=3.166, p=0.205). Among a 1996-1997 cohort of pregnant women in British Columbia, 101 of 200 (51%) had anti-PT levels less than 10 EU/ml. Our study found that most pregnant women in two geographically disparate health regions in Canada have low residual anti-PT levels, may be vulnerable to pertussis infection themselves, and would unlikely be a source of passive ante- or postnatal transfer of anti-PT to their newborn.

Process monitoring of an HIV treatment as prevention program in British Columbia, Canada.

BACKGROUND: In light of accumulated scientific evidence of the secondary preventive benefits of antiretroviral therapy, a growing number of jurisdictions worldwide have formally started to implement HIV Treatment as Prevention (TasP) programs. To date, no gold standard for TasP program monitoring has been described. Here, we describe the design and methods applied to TasP program process monitoring in British Columbia (BC), Canada. METHODS: Monitoring indicators were selected through a collaborative and iterative process by an interdisciplinary team including representatives from all 5 regional health authorities, the BC Centre for Disease Control (BCCDC), and the BC Centre for Excellence in HIV/AIDS (BC-CfE). An initial set of 36 proposed indicators were considered for inclusion. These were ranked on the basis of 8 criteria: data quality, validity, scientific evidence, informative power of the indicator, feasibility, confidentiality, accuracy, and administrative requirement. The consolidated list of indicators was included in the final monitoring report, which was executed using linked population-level data. RESULTS: A total of 13 monitoring indicators were included in the BC TasP Monitoring Report. Where appropriate, indicators were stratified by subgroups of interest, including HIV risk group and demographic characteristics. Six Monitoring Reports are generated quarterly: 1 for each of the regional health authorities and a consolidated provincial report. CONCLUSIONS: We have developed a comprehensive TasP process monitoring strategy using evidence-based HIV indicators derived from linked population-level data. Standardized longitudinal monitoring of TasP program initiatives is essential to optimize individual and public health outcomes and to enhance program efficiencies.

Adverse events following immunization: evaluating an enhanced nursing role for PHNs.

Maintaining confidence in vaccine safety is critical to successful public health immunization programs. Surveillance and assessment of adverse events following immunization (AEFIs) are important for maintaining vaccine safety. The authors describe the evaluation of an initiative at Fraser Health Authority designed to enhance the role of a communicable disease nurse coordinator (CDNC) in assessing AEFI reports, in collaboration with a designated medical health officer (MHO) as required, and providing recommendations to clients and immunization providers. Previously, only MHOs performed this role. This evaluation project demonstrates this initiative's feasibility and provides a roadmap for health authorities interested in pursuing a similar model. MHOs, public health nurses and public health management expressed satisfaction with the process and the quality of the CDNC's recommendations. There was no statistically significant difference in median turnaround time for AEFI reporting date and date of recommendation, indicating this work is completed in as timely a manner by the CDNC as by the MHO. This role provides opportunity for professional growth, facilitates nursing practice to full scope, enables acquisition of specialized knowledge and provides a platform to share nursing expertise at a provincial level.

Effectiveness of home visiting programs on child outcomes: a systematic review.

BACKGROUND: The effectiveness of paraprofessional home-visitations on improving the circumstances of disadvantaged families is unclear. The purpose of this paper is to systematically review the effectiveness of paraprofessional home-visiting programs on developmental and health outcomes of young children from disadvantaged families. METHODS: A comprehensive search of electronic databases (e.g., CINAHL PLUS, Cochrane, EMBASE, MEDLINE) from 1990 through May 2012 was supplemented by reference lists to search for relevant studies. Through the use of reliable tools, studies were assessed in duplicate. English language studies of paraprofessional home-visiting programs assessing specific outcomes for children (0-6 years) from disadvantaged families were eligible for inclusion in the review. Data extraction included the characteristics of the participants, intervention, outcomes and quality of the studies. RESULTS: Studies that scored 13 or greater out of a total of 15 on the validity tool (n = 21) are the focus of this review. All studies are randomized controlled trials and most were conducted in the United States. Significant improvements to the development and health of young children as a result of a home-visiting program are noted for particular groups. These include: (a) prevention of child abuse in some cases, particularly when the intervention is initiated prenatally; (b) developmental benefits in relation to cognition and problem behaviours, and less consistently with language skills; and (c) reduced incidence of low birth weights and health problems in older children, and increased incidence of appropriate weight gain in early childhood. However, overall home-visiting programs are limited in improving the lives of socially high-risk children who live in disadvantaged families. CONCLUSIONS: Home visitation by paraprofessionals is an intervention that holds promise for socially high-risk families with young children. Initiating the intervention prenatally and increasing the number of visits improves development and health outcomes for particular groups of children. Future studies should consider what dose of the intervention is most beneficial and address retention issues.

HIV disease progression to CD4 count <200 cells/µL and death in Saskatoon, Saskatchewan.

OBJECTIVE: To characterize and identify determinants of HIV disease progression among a predominantly injection drug use (IDU) HIV population in the highly active antiretroviral therapy era. METHODS: The present retrospective study was based on 343 HIV patients diagnosed from 2005 to 2010 from two clinics in Saskatoon, Saskatchewan. Disease progression was defined as the time from diagnosis to immunological AIDS (CD4 count <200 cells/µL) and death. Uni- and multivariable Cox proportional hazards models were used. RESULTS: Of the 343 patients, 79% had a history of IDU, 77% were hepatitis C virus (HCV) coinfected and 67% were of Aboriginal descent. The one-year and three-year immunological AIDS-free probabilities were 78% and 53%, respectively. The one-year and three-year survival probabilities were 97% and 88%, respectively. Multicollinearity among IDU, HCV and ethnicity was observed and, thus, separate models were built. HCV coinfection (HR 2.9 [95% CI 1.2 to 6.9]) was a significant predictor of progression to immunological AIDS when controlling for baseline CD4 counts, treatment, age at diagnosis and year of diagnosis. For survival, only treatment use was a significant predictor (HR 0.34 [95% CI 0.1 to 0.8]). HCV coinfection was marginally significant (P=0.067). CONCLUSION: Baseline CD4 count, HCV coinfection, year of diagnosis and treatment use were significant predictors of disease progression. This highlights the importance of early treatment and the need for targeted interventions for these particularly vulnerable populations to slow disease progression.

OBJECTIF: Caractériser et établir les déterminants de la progression du VIH dans une population atteinte du VIH surtout composée d'utilisateurs de drogues injectables (UDI) à une époque d'antirétrovirothérapie très active. MÉTHODOLOGIE: La présente étude rétrospective s'est fondée sur 343 patients atteints du VIH diagnostiqués entre 2005 et 2010 dans deux cliniques de Saskatoon, en Saskatchewan. La progression de la maladie était définie comme le moment du diagnostic jusqu'à l'apparition du sida immunologique (numération de CD4 inférieure à 200 cellules/µL), puis jusqu'au décès. Les chercheurs ont utilisé le modèle univariable et multivariable de risques proportionnels de Cox. RÉSULTATS: Sur les 343 patients, 79 % avaient déjà été UDI, 77 % étaient co-infectés par le virus de l'hépatite C (VHC) et 67 % étaient d'origine autochtone. La probabilité de non-apparition de sida immunologique au bout d'un an et de trois ans correspondait à 78 % et à 53 %, respectivement. La probabilité de survie au bout d'un an et de trois ans s'élevait à 97 % et à 88 %, respectivement. Les chercheurs ont observé une multicolinéarité entre les UDI, le VHC et l'ethnie et ont donc préparé des modèles différents. La co-infection par le VHC (RC 2,9 [95 % IC 1,2 à 6,9]) était un prédicteur important de progression en sida immunologique lorsqu'on contrôlait l'effet de la numération de CD4 de référence, du traitement, de l'âge au diagnostic et de l'année de diagnostic. Seule l'utilisation du traitement était une prédicteur important de la survie (RC 0,34 [95 % IC 0,1 à 0,8]). La co-infection par le VHC avait peu d'importance (P=0,067). CONCLUSION: La numération de CD4 de référence, la co-infection par le VHC, l'année de diagnostic et l'utilisation d'un traitement étaient des prédicteurs importants de progression de la maladie. Ces constatations font ressortir l'importance d'un traitement rapide et la nécessité de procéder à des interventions ciblées pour ces populations particulièrement vulnérables afin de ralentir la progression de la maladie.

The determinants of chronic bronchitis in Aboriginal children and youth.

BACKGROUND: There is limited knowledge concerning chronic bronchitis (CB) in Canadian Aboriginal peoples. OBJECTIVE: To determine the prevalence (crude and adjusted) of CB and its associated risk factors in Canadian Aboriginal children and youth six to 14 years of age. METHODS: Data from the cross-sectional Aboriginal Peoples Survey were analyzed in the present study. Logistic regression analysis was used to determine risk factors influencing the prevalence of CB among Aboriginal children and youth. The balanced repeated replication method was used to compute standard errors of regression coefficients to account for clustering inherent in the study design. The outcome of interest was based on the question: "Have you been told by a doctor, nurse or other health professional that you have chronic bronchitis?" Demographics, environment and population characteristics (predisposing and enabling resources) were tested for an association with CB. RESULTS: The prevalence of CB was 3.1% for boys and 2.8% for girls. Other significant risk factors of CB were age (OR 1.38 [95% CI 1.24 to 1.52] for 12 to 14 year olds versus six to eight year olds), income (OR 2.28 [95% CI 2.02 to 2.59] for income category <$25,000/year versus ≥$85,000/year), allergies (OR 1.96 [95% CI 1.78 to 2.16] for having allergies versus no allergies), asthma (OR 7.61 [ 95% CI 6.91 to 8.37] for having asthma versus no asthma) and location of residence (rural/urban and geographical location). A significant two-way interaction between sex and body mass index indicated that the relationship between the prevalence of CB and body mass index was modified by sex. DISCUSSION: The prevalence of CB was related to well-known risk factors among adults, including older age and lower annual income.

Protective role of complement C5a in an experimental model of Staphylococcus aureus bacteremia.

The complement system is a key component of the innate immune response. Here, we have examined the role of complement anaphylatoxin C5a in an experimental model of Staphylococcus aureus bacteremia. Our data provide compelling evidence for a protective role of C5a during staphylococcal bloodstream infection.

Both FcgammaRIV and FcgammaRIII are essential receptors mediating type II and type III autoimmune responses via FcRgamma-LAT-dependent generation of C5a.

FcgammaRIV is a relatively new IgG Fc receptor (FcgammaR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FcgammaRIII, complement and IgG2 subclasses remains uncertain. Here we define FcgammaRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FcgammaRIV and FcgammaRIII is critical to mediate certain type II/III autoimmune responses. FcgammaRIII-deficient mice display compensatory enhanced FcgammaRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased FcgammaRIV alone is not sufficient to trigger these diseases in the absence of FcgammaRIII. Importantly, however, blockade of FcgammaRIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that FcgammaRIII and FcgammaRIV are each essential to trigger an FcRgamma-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FcgammaRIII and FcgammaRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FcgammaR and C5a anaphylatoxin receptor activation to generate inflammation.

STIM1 is essential for Fcgamma receptor activation and autoimmune inflammation.

Fcgamma receptors (FcgammaRs) on mononuclear phagocytes trigger autoantibody and immune complex-induced diseases through coupling the self-reactive immunoglobulin G (IgG) response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcRgamma-based activation is critical in the pathogenesis of these diseases, although the contribution of FcgammaR-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum-resident calcium sensor, STIM1, cannot activate FcgammaR-induced Ca(2+) entry and phagocytosis. As a direct consequence, STIM1 deficiency results in resistance to experimental immune thrombocytopenia and anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis. These results establish STIM1 as a novel and essential component of FcgammaR activation and also indicate that inhibition of STIM1-dependent signaling might become a new strategy to prevent or treat IgG-dependent immunologic diseases.

Phosphoinositide 3-kinases gamma and delta, linkers of coordinate C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation.

Fcgamma receptors (FcgammaR) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in IC-induced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3Kgamma abrogates C5aR signaling that is crucial for FcgammaR-mediated activation of lung macrophages. Thus, in PI3Kgamma(-/-) mice, IgG IC-induced FcgammaR regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3Kgamma(-/-) mice but was impaired in PI3Kdelta(-/-) mice. Consequently, class IA PI3Kdelta deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3Kgamma and PI3Kdelta coordinate the inflammatory effects of C5aR and FcgammaR and define PI3Kdelta as a novel and essential element of FcgammaR signaling in the generation of C5a in IC disease.

Characterization of the murine IgG Fc receptor III and IIB gene promoters: a single two-nucleotide difference determines their inverse responsiveness to C5a.

The two low affinity IgG Fc receptors (FcgammaR), FcgammaRIII and FcgammaRIIB, are coexpressed on myeloid effector cells, and their genes, as reported here, are positively and negatively regulated by both C5a and interferon-gamma through different signaling mechanisms. Two 48- and 43-bp sequences (C5a-inductive region (CIR) and C5a-suppressive region (CSR)) in the FcgammaRIII and FcgammaRIIB 5'-flanking regions that are necessary for C5a induction and suppression, respectively, are defined. Sequence analysis of the CIR and CSR, which localize apart from the interferon-gamma-responsive regions in each gene, revealed the presence of a novel element that differs by two nucleotides between FcgammaRIII and FcgammaRIIB. Mutation analysis of the CIR and CSR showed that this small difference determines inverse responsiveness in an FcgammaR gene context-dependent manner. Our study suggests that C5a uses similar DNA motifs (defined as GTGAXXTCCA) in both pathways of transcriptional induction and suppression of FcgammaRIII and FcgammaRIIB.

Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice.

Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody-induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcgamma receptors (FcgammaRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcgammaR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcgammaRI and FcgammaRIII, anti-erythrocyte antibody-induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcgammaR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a--produced by and acting on FcgammaR--and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.