What Does the MacArthur Scale of Subjective Social Status Measure? Separating Economic Circumstances and Social Status to Predict Health.

BACKGROUND: Subjective socioeconomic status is robustly associated with many measures of health and well-being. The MacArthur Scale of Subjective Social Status (i.e., the MacArthur ladder) is the most widely used measure of this construct, but it remains unclear what exactly the MacArthur ladder measures. PURPOSE: The present research sought to explore the social and economic factors that underlie responses to the MacArthur ladder and its relationship to health. METHODS: We investigated this issue by examining the relationship between scores on the MacArthur ladder and measures of economic circumstances and noneconomic social status, as well as health and well-being measures, in healthy adults in the USA. RESULTS: In three studies (total N = 1,310) we found evidence that economic circumstances and social status are distinct constructs that have distinct associations with scores on the MacArthur ladder. We found that both factors exhibit distinct associations with measures of health and well-being and accounted for the association between the MacArthur ladder and each measure of health and well-being. CONCLUSIONS: Our findings suggest that the MacArthur ladder's robust predictive validity may result from the fact that it measures two factors-economic circumstances and social status-that are each independently associated with health outcomes. These findings provide a novel perspective on the large body of literature that uses the MacArthur ladder and suggests health researchers should do more to disentangle the social and economic aspects of subjective socioeconomic status.

Past research has found that people's subjective perception of their own socioeconomic status (SES) is associated with their health and well-being, even after controlling for traditional measures of SES such as income. But researchers still do not know why. One possibility is that subjective SES is simply a different measure of SES. Another is that it measures social status, separate from economic circumstances. We investigated this question using the MacArthur Scale of Subjective Social Status, which measures how people see their place in society. Across three studies using 1,300 adults in the USA, we found that the MacArthur Ladder measures two distinct factors: (i) economic circumstances, as measured by their income, education, housing, etc. and (ii) social status as measured by relative judgements of power, control, social influence, and their standing in their community and society. Both of these aspects of SES uniquely predict health and well-being. Our investigation demonstrates that the MacArthur ladder is good at predicting health outcomes because it measures both economic circumstances and social status. This new insight can help health researchers better understand the effects of social and economic factors on health, and to measure them more precisely.

Timing of valproic acid in acute lung injury: prevention is the best therapy?

BACKGROUND: Acute lung injury and respiratory distress syndrome is characterized by uncontrolled inflammation of the lungs after a severe inflammatory stimulus. We have previously demonstrated an ameliorated syndrome and improved survival in mice with early administration of valproic acid (VPA), a broad-spectrum histone deacetylase inhibitor, while studies in humans have shown no benefit when anti-inflammatories are administered late. The current study tested the hypothesis that early treatment would improve outcomes in our gram-negative pneumonia-induced acute lung injury. MATERIALS AND METHODS: Mice (C57BL/6) had 50 × 106 Escherichia coli (strain 19,138) instilled endotracheally and VPA (250 mg/kg) administered intraperitoneally 3, 4, 6, and 9 h (n = 12/group) later. Six hours after VPA administration, the animals were sacrificed, and bronchoalveolar lavage (BAL) fluid interleukin-6 (IL-6), tumor necrosis factor, neutrophils and macrophages as well as the E coli colony-forming units were quantified. Plasma IL-6 was also measured. A separate group of mice (n = 12/group) were followed prospectively for 7 days to assess survival. RESULTS: BAL IL-6 and tumor necrosis factor as well as plasma IL-6 were significantly lower in the animals administered VPA within 3 h (P < 0.05) but not when administered later (4, 6, 9 h). There was no difference in the BAL E coli colony-forming units, macrophage, or neutrophil numbers at any time point. Survival improved only when VPA was administered within 3 h. CONCLUSIONS: A narrow therapeutic window exists in this murine model of gram-negative pneumonia-induced acute lung injury and likely explains the lack of response in studies with late administration of anti-inflammatory therapies in clinical studies.

Complement component C1q regulates macrophage expression of Mer tyrosine kinase to promote clearance of apoptotic cells.

Failure to efficiently clear apoptotic cells is linked to defects in development and the onset of autoimmunity. Complement component C1q is required for efficient engulfment of apoptotic cells in mice and humans; however, the molecular mechanisms leading to C1q-dependent engulfment are not fully understood. In this study, we used primary mouse macrophages to identify and characterize a novel molecular mechanism for macrophage-mediated C1q-dependent engulfment of apoptotic cells. We found that macrophage activation with C1q resulted in cycloheximide-sensitive enhanced engulfment, indicating a requirement for de novo protein synthesis. To investigate the cycloheximide-sensitive pathway, C1q-elicited macrophage transcripts were identified by microarray. C1q triggered the expression of Mer tyrosine kinase (Mer) and the Mer ligand growth arrest-specific 6: a receptor-ligand pair that mediates clearance of apoptotic cells. Full-length native C1q, and not the collagen-like tail or heat-denatured protein, stimulated Mer expression. This novel pathway is specific to C1q because mannose-binding lectin, a related collectin, failed to upregulate Mer expression and function. Soluble Mer-Fc fusion protein inhibited C1q-dependent engulfment of apoptotic cells, indicating a requirement for Mer. Moreover, Mer-deficient macrophages failed to respond to C1q with enhanced engulfment. Our results suggest that C1q elicits a macrophage phenotype specifically tailored for apoptotic cell clearance, and these data are consistent with the established requirement for C1q in prevention of autoimmunity.

Characterization of recovery, repair, and inflammatory processes following contusion spinal cord injury in old female rats: is age a limitation?

BACKGROUND: Although the incidence of spinal cord injury (SCI) is steadily rising in the elderly human population, few studies have investigated the effect of age in rodent models. Here, we investigated the effect of age in female rats on spontaneous recovery and repair after SCI. Young (3 months) and aged (18 months) female rats received a moderate contusion SCI at T9. Behavioral recovery was assessed, and immunohistocemical and stereological analyses performed. RESULTS: Aged rats demonstrated greater locomotor deficits compared to young, beginning at 7 days post-injury (dpi) and lasting through at least 28 dpi. Unbiased stereological analyses revealed a selective increase in percent lesion area and early (2 dpi) apoptotic cell death caudal to the injury epicenter in aged versus young rats. One potential mechanism for these differences in lesion pathogenesis is the inflammatory response; we therefore assessed humoral and cellular innate immune responses. No differences in either acute or chronic serum complement activity, or acute neutrophil infiltration, were observed between age groups. However, the number of microglia/macrophages present at the injury epicenter was increased by 50% in aged animals versus young. CONCLUSIONS: These data suggest that age affects recovery of locomotor function, lesion pathology, and microglia/macrophage response following SCI.

Membrane-associated CD93 regulates leukocyte migration and C1q-hemolytic activity during murine peritonitis.

CD93 is emerging as a novel regulator of inflammation; however, its molecular function is unknown. CD93 exists as a membrane-associated glycoprotein on the surface of cells involved in the inflammatory cascade, including endothelial and myeloid cells. A soluble form (sCD93) is detectable in blood and is elevated with inflammation. In this study, we demonstrate heightened susceptibility to thioglycollate-induced peritonitis in CD93(-/-) mice. CD93(-/-) mice showed a 1.6-1.8-fold increase in leukocyte infiltration during thioglycollate-induced peritonitis between 3 and 24 h that returned to wild type levels by 96 h. Impaired vascular integrity in CD93(-/-) mice during peritonitis was demonstrated using fluorescence multiphoton intravital microscopy; however, no differences in cytokine or chemokine levels were detected with Luminex Multiplex or ELISA analysis. C1q-hemolytic activity in CD93(-/-) mice was decreased by 22% at time zero and by 46% 3 h after thioglycollate injection, suggesting a defect in the classical complement pathway. Leukocyte recruitment and C1q-hemolytic activity was restored to wild type levels when CD93 was expressed on either hematopoietic cells or nonhematopoietic cells in bone marrow chimeric mice. However, elevated levels of sCD93 in inflammatory fluid were observed only when CD93 was expressed on nonhematopoietic cells. Because cell-associated CD93 was sufficient to restore a normal inflammatory response, these data suggest that cell-associated CD93, and not sCD93, regulates leukocyte recruitment and complement activation during murine peritonitis.

Ex vivo and in vivo evidence that cigarette smoke-exposed T regulatory cells impair host immunity against Mycobacterium tuberculosis.

Introduction: A strong epidemiologic link exists between cigarette smoke (CS) exposure and susceptibility to tuberculosis (TB). Macrophage and murine studies showed that CS and nicotine impair host-protective immune cells against Mycobacterium tuberculosis (MTB) infection. While CS and nicotine may activate T regulatory cells (Tregs), little is known about how CS may affect these immunosuppressive cells with MTB infection. Methods: We investigated whether CS-exposed Tregs could exacerbate MTB infection in co-culture with human macrophages and in recipient mice that underwent adoptive transfer of Tregs from donor CS-exposed mice. Results: We found that exposure of primary human Tregs to CS extract impaired the ability of unexposed human macrophages to control an MTB infection by inhibiting phagosome-lysosome fusion and autophagosome formation. Neutralizing CTLA-4 on the CS extract-exposed Tregs abrogated the impaired control of MTB infection in the macrophage and Treg co-cultures. In Foxp3+GFP+DTR+ (Thy1.2) mice depleted of endogenous Tregs, adoptive transfer of Tregs from donor CS-exposed B6.PL(Thy1.1) mice with subsequent MTB infection of the Thy1.2 mice resulted in a greater burden of MTB in the lungs and spleens than those that received Tregs from air-exposed mice. Mice that received Tregs from donor CS-exposed mice and infected with MTB had modest but significantly reduced numbers of interleukin-12-positive dendritic cells and interferon-gamma-positive CD4+ T cells in the lungs, and an increased number of total programmed cell death protein-1 (PD-1) positive CD4+ T cells in both the lungs and spleens. Discussion: Previous studies demonstrated that CS impairs macrophages and host-protective T effector cells in controlling MTB infection. We now show that CS-exposed Tregs can also impair control of MTB in co-culture with macrophages and in a murine model.

Ultrasound-Guided Injections of HYADD4 for Knee Osteoarthritis Improves Pain and Functional Outcomes at 3, 6, and 12 Months without Changes in Measured Synovial Fluid, Serum Collagen Biomarkers, or Most Synovial Fluid Biomarker Proteins at 3 Months.

BACKGROUND: Prior studies have demonstrated improved efficacy when intra-articular (IA) therapeutics are injected using ultrasound (US) guidance. The aim of this study was to determine if clinical improvement in pain and function after IA hyaluronic acid injections using US is associated with changes in SF volumes and biomarker proteins at 3 months. METHODS: 49 subjects with symptomatic knee OA, BMI < 40, and KL radiographic grade II or III participated. Subjects with adequate aspirated synovial fluid (SF) volumes received two US-guided IA-HA injections of HYADD4 (24 mg/3 mL) 7 days apart. Clinical evaluations at 3, 6, and 12 months included WOMAC, VAS, PCS scores, 6 MWD, and US-measured SF depth. SF and blood were collected at 3 months and analyzed for four serum OA biomarkers and fifteen SF proteins. RESULTS: Statistical differences were observed at 3, 6, and 12 months compared to baseline values, with improvements at 12 months for WOMAC scores (50%), VAS (54%), and PCS scores (24%). MMP10 levels were lower at 3 months without changes in SF volumes, serum levels of C2C, COMP, HA, CPII, or SF levels of IL-1 ra, IL-4, 6, 7, 8, 15, 18, ILGFBP-1, 3, and MMP 1, 2, 3, 8, 9. Baseline clinical features or SF biomarker protein levels did not predict responsiveness at 3 months. CONCLUSIONS: Clinical improvements were observed at 12 months using US needle guidance for IA HA, whereas only one SF protein biomarker protein was different at 3 months. Larger studies are needed to identify which SF biomarkers will predict which individual OA patients will receive the greatest benefit from IA therapeutics.

Where and with whom does a brief social-belonging intervention promote progress in college?

A promising way to mitigate inequality is by addressing students' worries about belonging. But where and with whom is this social-belonging intervention effective? Here we report a team-science randomized controlled experiment with 26,911 students at 22 diverse institutions. Results showed that the social-belonging intervention, administered online before college (in under 30 minutes), increased the rate at which students completed the first year as full-time students, especially among students in groups that had historically progressed at lower rates. The college context also mattered: The intervention was effective only when students' groups were afforded opportunities to belong. This study develops methods for understanding how student identities and contexts interact with interventions. It also shows that a low-cost, scalable intervention generalizes its effects to 749 4-year institutions in the United States.

Assessing risk of vector transmission of Chagas disease through blood source analysis using LC-MS/MS for hemoglobin sequence identification.

Chagas disease is mainly transmitted by triatomine insect vectors that feed on vertebrate blood. The disease has complex domiciliary infestation patterns and parasite transmission dynamics, influenced by biological, ecological, and socioeconomic factors. In this context, feeding patterns have been used to understand vector movement and transmission risk. Recently, a new technique using Liquid chromatography tandem mass spectrometry (LC-MS/MS) targeting hemoglobin peptides has showed excellent results for understanding triatomines' feeding patterns. The aim of this study was to further develop the automated computational analysis pipeline for peptide sequence taxonomic identification, enhancing the ability to analyze large datasets data. We then used the enhanced pipeline to evaluate the feeding patterns of Triatoma dimidiata, along with domiciliary infestation risk variables, such as unkempt piles of firewood or construction material, cracks in bajareque and adobe walls and intradomiciliary animals. Our new python scripts were able to detect blood meal sources in 100% of the bugs analyzed and identified nine different species of blood meal sources. Human, chicken, and dog were the main blood sources found in 78.7%, 50.4% and 44.8% of the bugs, respectively. In addition, 14% of the bugs feeding on chicken and 15% of those feeding on dogs were captured in houses with no evidence of those animals being present. This suggests a high mobility among ecotopes and houses. Two of the three main blood sources, dog and chicken, were significantly (p < 0.05) affected by domiciliary infestation risk variables, including cracks in walls, construction material and birds sleeping in the intradomicile. This suggests that these variables are important for maintaining reproducing Triatoma dimidiata populations and that it is critical to mitigate these variables in all the houses of a village for effective control of these mobile vectors.

Brain-body pathways linking racism and health.

Racial disparities in health are a major public health problem in the United States, especially when comparing chronic disease morbidity and mortality for Black versus White Americans. These health disparities are primarily due to insidious anti-Black racism that permeates American history, current culture and institutions, and interpersonal interactions. But how does racism get under the skull and the skin to influence brain and bodily processes that impact the health of Black Americans? In the present article, we present a model describing the possible neural and inflammatory mechanisms linking racism and health. We hypothesize that racism influences neural activity and connectivity in the salience and default mode networks of the brain and disrupts interactions between these networks and the executive control network. This pattern of neural functioning in turn leads to greater sympathetic nervous system signaling, hypothalamic-pituitary-adrenal axis activation, and increased expression of genes involved in inflammation, ultimately leading to higher levels of proinflammatory cytokines in the body and brain. Over time, these neural and physiological responses can lead to chronic physical and mental health conditions, disrupt well-being, and cause premature mortality. Given that research in this area is underdeveloped to date, we emphasize opportunities for future research that are needed to build a comprehensive mechanistic understanding of the brain-body pathways linking anti-Black racism and health. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment.

Traumatic injury to the central nervous system results in the disruption of the blood brain/spinal barrier, followed by the invasion of cells and other components of the immune system that can aggravate injury and affect subsequent repair and regeneration. Although studies of chronic neuroinflammation in the injured spinal cord of animals are clinically relevant to most patients living with traumatic injury to the brain or spinal cord, very little is known about chronic neuroinflammation, though several studies have tested the role of neuroinflammation in the acute period after injury. The present study characterizes a novel cell preparation method that assesses, quickly and effectively, the changes in the principal immune cell types by flow cytometry in the injured spinal cord, daily for the first 10 days and periodically up to 180 days after spinal cord injury. These data quantitatively demonstrate a novel time-dependent multiphasic response of cellular inflammation in the spinal cord after spinal cord injury and are verified by quantitative stereology of immunolabelled spinal cord sections at selected time points. The early phase of cellular inflammation is comprised principally of neutrophils (peaking 1 day post-injury), macrophages/microglia (peaking 7 days post-injury) and T cells (peaking 9 days post-injury). The late phase of cellular inflammation was detected after 14 days post-injury, peaked after 60 days post-injury and remained detectable throughout 180 days post-injury for all three cell types. Furthermore, the late phase of cellular inflammation (14-180 days post-injury) did not coincide with either further improvements, or new decrements, in open-field locomotor function after spinal cord injury. However, blockade of chemoattractant C5a-mediated inflammation after 14 days post-injury reduced locomotor recovery and myelination in the injured spinal cord, suggesting that the late inflammatory response serves a reparative function. Together, these data provide new insight into cellular inflammation of spinal cord injury and identify a surprising and extended multiphasic response of cellular inflammation. Understanding the role of this multiphasic response in the pathophysiology of spinal cord injury could be critical for the design and implementation of rational therapeutic treatment strategies, including both cell-based and pharmacological interventions.

Cytokine signatures of end organ injury in COVID-19.

Increasing evidence has shown that Coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunologic response. We aimed to assess the differences in inflammatory cytokines in COVID-19 patients compared to contemporaneously hospitalized controls and then analyze the relationship between these cytokines and the development of Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI) and mortality. In this cohort study of hospitalized patients, done between March third, 2020 and April first, 2020 at a quaternary referral center in New York City we included adult hospitalized patients with COVID-19 and negative controls. Serum specimens were obtained on the first, second, and third hospital day and cytokines were measured by Luminex. Autopsies of nine cohort patients were examined. We identified 90 COVID-19 patients and 51 controls. Analysis of 48 inflammatory cytokines revealed upregulation of macrophage induced chemokines, T-cell related interleukines and stromal cell producing cytokines in COVID-19 patients compared to the controls. Moreover, distinctive cytokine signatures predicted the development of ARDS, AKI and mortality in COVID-19 patients. Specifically, macrophage-associated cytokines predicted ARDS, T cell immunity related cytokines predicted AKI and mortality was associated with cytokines of activated immune pathways, of which IL-13 was universally correlated with ARDS, AKI and mortality. Histopathological examination of the autopsies showed diffuse alveolar damage with significant mononuclear inflammatory cell infiltration. Additionally, the kidneys demonstrated glomerular sclerosis, tubulointerstitial lymphocyte infiltration and cortical and medullary atrophy. These patterns of cytokine expression offer insight into the pathogenesis of COVID-19 disease, its severity, and subsequent lung and kidney injury suggesting more targeted treatment strategies.

The Role of Subjective and Objective Social Status in the Generation of Envy.

Envy is a negative emotion experienced in response to another person's higher status. However, little is known about the composition of its most important element: status. The present research investigates the two main forms of social status (objective and subjective) in the generation of envy. In Study 1, participants recounted real-life situations when they felt envious; in Study 2 we examined whether the effect was the same in a controlled situation. We consistently found that those who were the most respected in the eyes of others were envied more than the richest ones. Furthermore, perceived deservingness of the superior other's success differentiated between benign and malicious envy. Although previous studies focused on material comparisons when investigating envy, our results indicate that envy is rather a subjective social status related emotion. Not material, but social advantage of the superior other causes the most painful envy and future studies should put more emphasis on this type of social comparison in envy research.

Discovery and Development of the Oral Complement Factor D Inhibitor Danicopan (ACH-4471).

Complement plays a vital role in our innate immune defense against invasive microorganisms. Excessive complement activation or insufficient control of activation on host cells, however, is associated with several chronic disorders. Essential to the activation and amplification of the Alternative Pathway (AP) of complement, Complement Factor D (CFD) is a specific serine protease that cleaves its unique substrate, Complement Factor B (CFB) in complex with an activated form of complement component 3 (C3), to generate the AP C3 convertases C3(H2O)Bb and C3bBb. These convertases comprise a central component in eliciting effector responses following AP activation, and they also enable a powerful amplification loop for both the Classical Pathway (CP) and Lectin Pathway (LP) of complement. Because CFD is not required for the activation of either the CP or LP, selective CFD inhibition presents a favorable therapeutic approach to modulating complement activity that leaves intact the effector functions following CP and LP activation and thus poses a lower risk of bacterial infection than other complement-directed approaches. This review provides an update on inhibitors of CFD, which have evolved from irreversible small molecules that demonstrate poor selectivity to reversible small molecules and monoclonal antibodies that demonstrate exceptional selectivity and potency. The reversible small-molecule inhibitor danicopan.

Complement C6 deficiency exacerbates pathophysiology after spinal cord injury.

Historically, the membrane attack complex, composed of complement components C5b-9, has been connected to lytic cell death and implicated in secondary injury after a CNS insult. However, studies to date have utilized either non-littermate control rat models, or mouse models that lack significant C5b-9 activity. To investigate what role C5b-9 plays in spinal cord injury and recovery, we generated littermate PVG C6 wildtype and deficient rats and tested functional and histological recovery after moderate contusion injury using the Infinite Horizon Impactor. We compare the effect of C6 deficiency on recovery of locomotor function and histological injury parameters in PVG rats under two conditions: (1) animals maintained as separate C6 WT and C6-D homozygous colonies; and (2) establishment of a heterozygous colony to generate C6 WT and C6-D littermate controls. The results suggest that maintenance of separate homozygous colonies is inadequate for testing the effect of C6 deficiency on locomotor and histological recovery after SCI, and highlight the importance of using littermate controls in studies involving genetic manipulation of the complement cascade.

Histone Deacetylase 7 Inhibition in a Murine Model of Gram-Negative Pneumonia-Induced Acute Lung Injury.

BACKGROUND: Pulmonary infections remain the most common cause of Acute Respiratory Distress Syndrome (ARDS), a pulmonary inflammatory disease with high mortality, for which no targeted therapy currently exists. We have previously demonstrated an ameliorated syndrome with early, broad spectrum Histone Deacetylase (HDAC) inhibition in a murine model of gram-negative pneumonia-induced Acute Lung Injury (ALI), the underlying pulmonary pathologic phenotype leading to ARDS. With the current project we aim to determine if selective inhibition of a specific HDAC leads to a similar pro-survival phenotype, potentially pointing to a future therapeutic target. METHODS: C57Bl/6 mice underwent endotracheal instillation of 30×10Escherichia coli (strain 19138) versus saline (n = 24). Half the infected mice were administered Trichostatin A (TSA) 30 min later. All animals were sacrificed 6 h later for tissue sampling and HDAC quantification, while another set of animals (n = 24) was followed to determine survival. Experiments were repeated with selective siRNA inhibition of the HDAC demonstrating the greatest inhibition versus scrambled siRNA (n = 24). RESULTS: TSA significantly ameliorated the inflammatory phenotype and improved survival in infected-ALI mice, and HDAC7 was the HDAC with the greatest transcription and protein translation suppression. Similar results were obtained with selective HDAC7 siRNA inhibition compared with scrambled siRNA. CONCLUSION: HDAC7 appears to play a key role in the inflammatory response that leads to ALI after gram-negative pneumonia in mice.

Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury.

Although studies have suggested a role for the complement system in the pathophysiology of spinal cord injury (SCI), that role remains poorly defined. Additionally, the relative contribution of individual complement pathways in SCI is unknown. Our initial studies revealed that systemic complement activation was strongly influenced by genetic background and gender. Thus, to investigate the role of the classical complement pathway in contusion-induced SCI, male C1q knock-out (KO) and wild-type (WT) mice on a complement sufficient background (BUB) received a mild-moderate T9 contusion injury with the Infinite Horizon impactor. BUB C1q KO mice exhibited greater locomotor recovery compared with BUB WT mice (p<0.05). Improved recovery observed in BUB C1q KO mice was also associated with decreased threshold for withdrawal from a mild stimulus using von Frey filament testing. Surprisingly, quantification of microglia/macrophages (F4/80) by FACS analysis showed that BUB C1q KO mice exhibited a significantly greater percentage of macrophages in the spinal cord compared with BUB WT mice 3 d post-injury (p<0.05). However, this increased macrophage response appeared to be transient as stereological assessment of spinal cord tissue obtained 28 d post-injury revealed no difference in F4/80-positive cells between groups. Stereological assessment of spinal cord tissue showed that BUB C1q KO mice had reduced lesion volume and an increase in tissue sparing compared with BUB WT mice (p<0.05). Together, these data suggest that initiation of the classical complement pathway via C1q is detrimental to recovery after SCI.

Anti-Factor H Antibody Reactivity in Young Adults Vaccinated with a Meningococcal Serogroup B Vaccine Containing Factor H Binding Protein.

Meningococcal serogroup B (MenB) vaccines contain recombinant factor H binding protein (FHbp), which can complex with complement factor H (CFH) and thereby risk eliciting anti-FH autoantibodies. While anti-FH antibodies can be present in sera of healthy persons, the antibodies are implicated in autoimmune atypical hemolytic uremic syndrome and C3 glomerulopathies. We immunized 120 students with a MenB vaccine (Bexsero). By enzyme-linked immunosorbent assay (ELISA), there were small increases in serum anti-FH levels at 3 weeks postvaccination (geometric mean optical density at 405 nm [OD405], 0.54 versus 0.51 preimmunization, P ≤ 0.003 for each schedule tested). There was a similar small increase in anti-FH antibody levels in a second historical MenB study of 20 adults with stored paired preimmunization and postimmunization sera (P = 0.007) but not in three other studies of 57 adults immunized with other meningococcal vaccines that did not contain recombinant FHbp (P = 0.17, 0.84, and 0.60, respectively). Thus, humans vaccinated with MenB-4C develop small increases in serum anti-FH antibody reactivity. Although not likely to be clinically important, the data indicate a host response to FH. In the prospective MenB study, three subjects (2.5%) developed higher anti-FH titers postimmunization. The elevated titers returned to baseline within 3 to 4 months, and none of the subjects reported adverse events during the follow-up. Although anti-FH antibodies can decrease FH function, the postimmunization sera with high anti-FH antibody levels did not impair serum FH function as measured using a hemolytic assay. Thus, while additional studies are warranted, there is no evidence that the anti-FH antibodies elicited by MenB-4C are likely to cause anti-FH-mediated autoimmune disorders. (This study has been registered at ClinicalTrials.gov under registration no. NCT02583412.)IMPORTANCE Meningococci are bacteria that cause sepsis and meningitis. Meningococcal species are subdivided into serogroups on the basis of different sugar capsules. Vaccines that target serogroup A, C, Y, and W capsules are safe and highly effective. New serogroup B (MenB) vaccines target a bacterial protein that can bind to a blood protein called complement factor H (FH). While serogroup B vaccines appear to be safe and effective, there is a theoretical risk that immunization with a bacterial protein that binds host FH might elicit anti-FH autoantibodies. Autoantibodies to FH have been detected in healthy persons but in rare cases can cause certain autoimmune diseases. We found small and/or transient increases in serum antibody to FH after MenB immunization. While no serious adverse events were reported in the subjects with elevated anti-FH titers, since onset of autoimmune disease is a rare event and may occur months or years after vaccination, additional, larger studies are warranted.

Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury.

BACKGROUND: The complement system has been suggested to affect injury or disease of the central nervous system (CNS) by regulating numerous physiological events and pathways. The activation of complement following traumatic CNS injury can also result in the formation and deposition of C5b-9 membrane attack complex (C5b-9/MAC), causing cell lysis or sublytic effects on vital CNS cells. Although complement proteins derived from serum/blood-brain barrier breakdown can contribute to injury or disease, infiltrating immune cells may represent an important local source of complement after injury. As the first immune cells to infiltrate the CNS within hours post-injury, polymorphonuclear leukocytes (PMNs) may affect injury through mechanisms associated with complement-mediated events. However, the expression/association of both early and terminal complement proteins by PMNs has not been fully characterized in vitro, and has not observed previously in vivo after traumatic spinal cord injury (SCI). METHOD: We investigated the expression of complement mRNAs using rt-PCR and the presence of complement proteins associated with PMNs using immunofluroescence and quantitative flow cytometry. RESULTS: Stimulated or unstimulated PMNs expressed mRNAs encoding for C1q, C3, and C4, but not C5, C6, C7 or C9 in culture. Complement protein C1q or C3 was also detected in less than 30% of cultured PMNs. In contrast, over 70% of PMNs that infiltrated the injured spinal cord were associated with C1q, C3, C7 and C5b-9/MAC 3 days post-SCI. The localization/association of C7 or C5b-9/MAC with infiltrating PMNs in the injured spinal cord suggests the incorporation or internalization of C7 or C5b-9/MAC bound cellular debris by infiltrating PMNs because C7 and C5b-9/MAC were mostly localized to granular vesicles within PMNs at the spinal cord epicenter region. Furthermore, PMN presence in the injured spinal cord was observed for many weeks post-SCI, suggesting that this infiltrating cell population could chronically affect complement-mediated events and SCI pathogenesis after trauma. CONCLUSION: Data presented here provide the first characterization of early and terminal complement proteins associated with PMNs in vitro and in vivo after SCI. Data also suggest a role for PMNs in the local internalization or deliverance of complement and complement activation in the post-SCI environment.

Valproic acid mitigates the inflammatory response and prevents acute respiratory distress syndrome in a murine model of Escherichia coli pneumonia at the expense of bacterial clearance.

BACKGROUND: Histone deacetylase inhibitors (HDACI) are members of a family of epigenetic modifying agents with broad anti-inflammatory properties. These anti-inflammatory properties may have important therapeutic implications in acute respiratory distress syndrome (ARDS). However, administration of HDACI may create an immunosuppressive environment conducive to bacterial growth. Accordingly, the aim of the current study is to investigate the effect of HDACI valproic acid (VPA) on host inflammatory response and bacterial burden in a murine model of Escherichia coli pneumonia-induced ARDS. METHODS: ARDS was induced in male C57BL6 mice (n = 24) by endotracheal instillation of 3 × 10 E. coli. VPA (250 mg/kg) was administered 30 minutes after E. coli instillation in the intervention group. Blood samples were collected at 3 and 6 hours, and animals were sacrificed at 6 hours. Bronchoalveolar lavage (BAL) was performed, and tissue specimens were harvested. Cytokine levels were measured in blood and BAL, and so was transalveolar protein transit. Cell counts and colony forming units were quantified in BAL fluid. RESULTS: VPA reduced neutrophil influx into the lungs and local tissue destruction through decreased myeloperoxidase activity. It also ameliorated the pulmonary and systemic inflammatory response. This led to greater bacterial proliferation in the pulmonary parenchyma. CONCLUSION: Administration of VPA in a clinically relevant bacterial model of murine ARDS mitigates the host inflammatory response, essentially preventing ARDS, but creates an immunosuppressive environment that favors bacterial overgrowth.