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Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.

Multivalent viral epitopes induce rapid, robust and T cell-independent humoral immune responses, but the biochemical basis for such potency remains incompletely understood. We take advantage of a set of liposomes of viral size engineered to display affinity mutants of the model antigen (Ag) hen egg lysozyme. Particulate Ag induces potent all-or-none B cell responses that are density dependent but affinity independent. Unlike soluble Ag, particulate Ag induces signal amplification downstream of the B cell receptor by selectively evading LYN-dependent inhibitory pathways and maximally activates NF-κB in a manner that mimics T cell help. Such signaling induces MYC expression and enables even low doses of particulate Ag to trigger robust B cell proliferation in vivo in the absence of adjuvant. We uncover a molecular basis for highly sensitive B cell responses to viral Ag display that is independent of encapsulated nucleic acids and is not merely accounted for by avidity and B cell receptor cross-linking.

Allergic immunity is orchestrated by group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells prominently arrayed at epithelial- and microbial-rich barriers. However, ILC2s and Th2 cells are also present in fibroblast-rich niches within the adventitial layer of larger vessels and similar boundary structures in sterile deep tissues, and it remains unclear whether they undergo dynamic repositioning during immune perturbations. Here, we used thick-section quantitative imaging to show that allergic inflammation drives invasion of lung and liver non-adventitial parenchyma by ILC2s and Th2 cells. However, during concurrent type 1 and type 2 mixed inflammation, IFNγ from broadly distributed type 1 lymphocytes directly blocked both ILC2 parenchymal trafficking and subsequent cell survival. ILC2 and Th2 cell confinement to adventitia limited mortality by the type 1 pathogen Listeria monocytogenes. Our results suggest that the topography of tissue lymphocyte subsets is tightly regulated to promote appropriately timed and balanced immunity.

B cell clones compete for entry into and dominance within germinal centers (GCs), where the highest-affinity B cell receptors (BCRs) are selected. However, diverse and low-affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesize that a negative feedback loop may operate within B cells to preferentially restrain high-affinity clones from monopolizing the early GC niche. Here, we report a role for the nuclear receptor NUR77/Nr4a1 in this process. We show that NUR77 expression scales with antigen stimulation and restrains B cell expansion. Although NUR77 is dispensable for regulating GC size when GCs are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. We propose that this is important to preserve early clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.

Antigen stimulation (signal 1) triggers B cell proliferation and primes B cells to recruit, engage and respond to T cell help (signal 2). Failure to receive signal 2 within a defined time window results in B cell apoptosis, yet the mechanisms that enforce dependence on co-stimulation are incompletely understood. Nr4a1-3 encode a small family of orphan nuclear receptors that are rapidly induced by B cell antigen receptor stimulation. Here, we show that Nr4a1 and Nr4a3 play partially redundant roles to restrain B cell responses to antigen in the absence of co-stimulation and do so, in part, by repressing the expression of BATF and, consequently, MYC. The NR4A family also restrains B cell access to T cell help by repressing expression of the T cell chemokines CCL3 and CCL4, as well as CD86 and ICAM1. Such NR4A-mediated regulation plays a role specifically under conditions of competition for limiting T cell help.

Abstract Background Community-based conservation (CBC) promotes the idea that long-term conservation success requires engaging with, and providing benefits for local communities. Though widespread, CBC projects are not always successful or free of controversy. With criticisms on all sides of the conservation debates, it is critical to have a better understanding of (1) whether CBC is an effective conservation tool, and (2) of the factors associated with the success or failure of CBC projects, and the scale at which these factors operate. Recent CBC reviews have typically examined only a single resource domain, have limited geographic scope, consider only one outcome, or ignore the nested nature of socioecological systems. To remedy these issues, we use a newly coded global comparative database of CBC projects identified by systematic review to evaluate success in four outcome domains (attitudes, behaviors, ecological, economic) and explore synergies and tradeoffs among these outcomes. We test hypotheses about how features of the national context (H-NC), project design (H-PD), and local community characteristics (H-CC) affect these four measures of success. Methods To add to a sample of 62 projects that we used from previous systematic reviews, we systematically searched the conservation literature using six terms in four online databases. To increase the number of projects for each country in order to conduct a multilevel analysis, we also conducted a secondary search using the Advancing Conservation in a Social Context online library. We coded projects for 65 pieces of information. We conducted bivariate analyses using two-dimensional contingency tables and proportional odds logistic regression and conducted multivariate analyses by fitting reduced form proportional odds logistic regression models that were selected using a forward stepwise AIC approach. Results The primary and secondary searches produced 74 new projects to go along with the 62 projects from previous reviews for a total of 136 projects. The analyses suggest that project design, particularly capacity building in local communities, is critical in generating success across all outcomes. In addition, some community characteristics, such as tenure regimes and supportive cultural beliefs and institutions, are important for some aspects of project success. Surprisingly, there is less evidence that national context systematically influences project outcomes. Conclusions Our study supports the idea that conservation projects should be carefully designed to be effective and that some characteristics of local communities can facilitate success. That well-designed projects can prevail over disadvantages relating to the pre-existing national and local context is encouraging. As the evidence base on CBC grows, it will be useful to repeat this analysis with additional search terms, and consider additional variables related to national context to further evaluate the role of broader socio-political and economic contexts.

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I. INTRODUCTION 141 II. TINKER AND ITS PROGENY 146 III. CIRCUIT COURTS TINKER WITH STUDENT SPEECH IN THE DIGITAL AGE 152 A. The Second Circuit Reasonable Foreseeability Approach 153 B. [...]

Access to sufficient financial resources is vital for effective biodiversity conservation. Although the importance of biodiversity conservation is widely recognized, lack of funding has been a significant impediment to achieving conservation goals. Yet, information on the allocation of conservation funding remains limited. This study addresses this gap by mapping conservation funding flows in Bhutan over the past four decades. We identified 249 projects totaling US$ 239.4 million allocated for biodiversity conservation in Bhutan from 1980 to 2019. Most of this funding derived from bilateral and multilateral aid agencies, with domestic trust fund and private foundations also contributing. Funding for projects with coupled conservation and development objectives and gender components was relatively high, particularly for funds allocated by multilateral and bilateral organizations. By contrast, domestic funding typically did not include development or gender components. Private foundations and domestic sources emphasized capacity development interventions. Despite relatively limited funding flows, the socio‐political context in Bhutan, which favors environmentally friendly practices, may have been key to the country's widely recognized conservation success. Evidence on trends and patterns in conservation finance, as presented here for Bhutan, can advance conservation science and practice by shedding new light on historical and current conservation priorities and helping inform future allocation. [ABSTRACT FROM AUTHOR]