How has the study of the built environment changed the historiography of gender? This paper analyzes the shifts in the historiography of women and gender in late nineteenth- and early twentieth-century American history. It examines the evolution from a metaphorical concept of spheres to a more complex understanding of the interactions between space and gender. In the 1960s, feminist historians introduced the concept of ‘separate spheres’ as a way to understand the history of women in the nineteenth century. When historians, in the 1970s and 1980s, began to study actual spaces it became clear that the relationship of gender and space was more complex than the dichotomies of public and private, male and female, urban and suburban, which reinforced the idea of separate spheres. The study of actual spaces demonstrates that the boundaries of everyday life were more porous than those idealized by separate spheres and spaces. Further, scholars in the 1990s were able to show how the design, spatial arrangement, and décor of spaces contributed to the construction of masculinity and femininity in relation to each other.

C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, is primarily expressed on cells of the myeloid lineage, and to a lesser extent on endothelial cells and neurons in brain. Previous work demonstrated that a C5aR1 antagonist, PMX205, decreased amyloid pathology and suppressed cognitive deficits in Alzheimer disease (AD) mouse models. However, the cellular mechanisms of this protection have not been definitively demonstrated. Here, we show that C5a can induce neuronal cell death. Both pharmacologic and genetic data indicate that C5aR1 is required for the C5a-induced decrease of neuron MAP-2. Additionally, in the context of AD, we show that increased neuronal damage is caused by the addition of C5a to neurons treated with fAβ, and can be blocked by the C5aR1 antagonist, PMX53.To understand the role of microglial C5aR1 in an AD mouse model, CX3CR1GFP and CCR2RFP reporter mice were bred to C5aR1 sufficient and knockout wild type and Arctic mice. Microglia (GFP-positive, RFP-negative) and infiltrating monocytes (GFP and RFP-positive) were sorted for transcriptome analysis at 2, 5, 7 and 10 months of age. Immunohistochemical analysis showed no CCR2+ monocytes/macrophages near the plaques in the Arctic brain with or without C5aR1. RNA-seq analysis on microglia from these mice identified inflammation related genes as differentially expressed, with increased expression in the Arctic mice relative to wildtype and decreased expression in the Arctic/C5aR1KO relative to Arctic. In addition, phagosomal-lysosomal genes were increased in the Arctic mice and further increased in the Arctic/C5aR1KO mice. These data are consistent with a microglial polarization state in the absence of C5aR1 signaling with restricted induction of inflammatory genes and enhancement of degradation/clearance pathways and support the potential of this receptor as a novel therapeutic target for AD in humans.

M. tuberculosis has persisted as one of the most prevalent and deadly human pathogens in large part because of its ability to evade the host immune system. In addition to several cellular based evasion mechanisms have been described, the adaptive immune response to M. tuberculosis exhibits significantly delayed timing compared to most pathogens. As a result M. tuberculosis is able to grow unchecked, expanding >20,000-fold in the first 3 weeks in the lungs. The immune response that does develop only controls, but does not eliminate the infection, resulting in a chronic infection posing a constant threat to the host. Utilizing green fluorescent protein (GFP)-expressing M. tuberculosis we quantitated and characterized the infected cell subsets in the lungs determining that dendritic cells account for the largest percentage of infected cells after 2 weeks of infection and they transport a portion of the bacteria to the draining lymph node in a CCL19/CCL21-dependent manner. Incorporating the adoptive transfer of M. tuberculosis-specific transgenic CD4+ T cells into the studies demonstrated that CD4+ T cell activation in the draining lymph node is delayed until a threshold number of bacteria reached the lymph node. Impaired dendritic cell migration to the draining lymph node resulted in fewer bacteria and consequently delayed the adaptive immune response even further. One of the rate-limiting steps in the adaptive immune response to M. tuberculosis is the transport of bacteria by dendritic cells to the draining lymph node. Considering the rapid maturation of infected dendritic cells, we hypothesize that M. tuberculosis initially infects a non-migrating cell compartment and a round of bacteria growth and spread is necessary in order to infect sufficient numbers of dendritic cells to achieve transport of the threshold number of bacteria needed to initiate a T cell response. Lastly, we show that after the first 3 weeks of infection there is a significant decrease in the ability to stimulate Antigen 85B-specific T cells potentially contributing to the ability of M. tuberculosis to establish a chronic infection.

Deficiency in C1q, the recognition component of the classical complement cascade and a key opsonin involved in apoptotic cell clearance, leads to lupus-like autoimmune diseases characterized by auto-antibodies to self proteins and aberrant T and B cell activation. Studies have suggested that these pathological consequences may result from impaired clearance of apoptotic cells. To investigate how C1q may modulate inflammation resulting from diminished apoptotic cell clearance, I applied a novel system consisting entirely of primary human cells: human monocyte-derived macrophages (Mac) and dendritic cells (DC), ingesting autologous apoptotic human lymphocytes (C1q-polarized Mac; or C1q-polarized DC), and either autologous or allogeneic human T cells. This physiologically relevant experimental system enabled characterization of the C1q-polarized Mac or C1q-polarized DC functional phenotype and subsequent Mac and DC-mediated T cell activation, avoiding the caveats of other systems using either transformed cell lines or non-physiologic presentation of C1q. The results demonstrate that C1q influences intracellular signaling and gene expression of both secreted protein and cell surface receptors. That is, C1q-polarized Mac exhibited enhanced STAT1 phosphorylation that is correlated with attenuated NLRP3 inflammasome activation and sequential induction of type I IFN-s, IL-27, and IL-10 in LPS-stimulated Mac relative to Mac ingesting apoptotic lymphocytes alone. C1q-polarized DC also exhibited enhanced IL-27 expression relative to DC ingesting apoptotic lymphocytes without C1q. Under the same conditions C1q-polarized Mac showed suppressed induction of CD40 and enhanced expression of PD-L1 and PD-L2 expression while C1q-polarized DC exhibited reduced CD86 induction and elevated PD-L2 and CD39 expression relative to DC ingesting apoptotic cells alone. Finally, C1q-polarized Mac reduced allogeneic and autologous Th17 and Th1 subset proliferation, and initiated a trend towards increased regulatory T cell proliferation relative to Mac ingesting LAL alone. Moreover, relative to DC ingesting AC in the absence of C1q, C1q-polarized DC decreased autologous Th17 and Th1 proliferation. These data demonstrate that a functional consequence of C1q-polarized Mac and DC is the regulation of T effector cell activation, thereby "sculpting" the adaptive immune system to avoid autoimmunity while clearing dying cells. Importantly, these studies identify novel target pathways for therapeutic intervention in SLE and other inflammatory autoimmune diseases.