Analysis of the putative role of CR1 in Alzheimer’s disease: Genetic association, expression and function

Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer's disease (AD). Recent large genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the C3b/C4b receptor (CR1 or CD35) that are associated with late onset AD. Here, anti-CR1 antibodies (Abs) directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1) regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved

Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens

The human membrane cofactor protein (MCP, CD46) is a central component of the innate immune system. CD46 protects autologous cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. Recent data show that CD46 also plays a role in mediating acquired immune responses, and in triggering autophagy. In addition to these physiologic functions, a significant number of pathogens, including select adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria, use CD46 as a cell attachment receptor. We have determined the crystal structure of the extracellular region of CD46 in complex with the human adenovirus type 11 fiber knob. Extracellular CD46 comprises four short consensus repeats (SCR1-SCR4) that form an elongated structure resembling a hockey stick, with a long shaft and a short blade. Domains SCR1, SCR2 and SCR3 are arranged in a nearly linear fashion. Unexpectedly, however, the structure reveals a profound bend between domains SCR3 and SCR4, which has implications for the interactions with ligands as well as the orientation of the protein at the cell surface. This bend can be attributed to an insertion of five hydrophobic residues in a SCR3 surface loop. Residues in this loop have been implicated in interactions with complement, indicating that the bend participates in binding to C3b and C4b. The structure provides an accurate framework for mapping all known ligand binding sites onto the surface of CD46, thereby advancing an understanding of how CD46 acts as a receptor for pathogens and physiologic ligands of the immune system

When Sex Work Becomes Your Everything

In Peru, there are few studies on male sex workers (MSWs), and existing studies explore limited subgroups or offer limited information about MSWs' perspectives. This study provides in-depth perspectives from 40 MSWs who work in downtown Lima (Cercado) and in surrounding urban neighborhoods (non-Cercado) through interviews on their identities, lives, and HIV/STI (sexually transmitted infection) risks and vulnerabilities. Findings are that entry into sex work links economy and affection, particularly among Cercado MSWs. Continued sex work cements this link, making it difficult to exit sex work and establish goals. Ties between economics and affections influence MSWs' perceived HIV/STI risks, vulnerabilities, and prevention practices. Although Cercado MSWs report higher HIV/STI risks and vulnerabilities than non-Cercado peers, they report fewer prevention practices given inability to buy condoms and acceptance of client offers of higher payment, especially clients they feel affection for. MSWs need support to strengthen their self-perceptions and define and pursue their goals in order to improve their HIV/STI prevention practices, health, and well-being

Pobreza e HIV/AIDS: aspectos antropológicos e sociológicos Poverty and HIV/AIDS: anthropological and sociological aspects

A partir da perspectiva das várias epidemias de HIV/AIDS que coexistem em mesmo espaço, bem como dos dados epidemiológicos do Brasil, acredita-se serem observáveis as variações já descritas alhures - feminilização, pauperização, juvenilização e interiorização - como resultado das profundas desigualdades da sociedade brasileira. Foram examinadas as contribuições de três vertentes de análise dos aspectos sócio-econômicos da AIDS: 1) pesquisas e teorias sociológicas a respeito do impacto da reestruturação econômica e transformação social global recentes e sua relação com a saúde pública; 2) literatura transcultural e transnacional em antropologia e sociologia dedicada aos fatores estruturais que conformam o curso da epidemia em diferentes conjunturas; e 3) corpo de pesquisas antropológicas e sociológicas concernentes aos efeitos sinérgicos do HIV/AIDS, exclusão social, e problemas sociais associados nos bolsões de extrema pobreza encontrados nas grandes cidades de países centrais. Conclui-se que as políticas de prevenção do HIV/AIDS devem abordar, de forma integrada, as várias dimensões que determinam as diferenciadas vulnerabilidades à epidemia, dependendo, portanto, de transformações sociais substantivas.<br>Focusing on the HIV/AIDS epidemic as a summation of several epidemics coexisting in the same space and drawing on Brazilian epidemiological data, we argue that the epidemic there shows variations already described elsewhere, such as feminization, pauperization, juvenization and interiorization, as a result of the deep inequalities characteristic of Brazilian society. We then examine the contributions of three bodies of sociological and anthropological literature related to HIV/AIDS: 1) sociological research and theory on the impact of recent global economic restructuring and social transformation, and its relationship to public health issues; 2) the cross-cultural and cross-national anthropological and sociological literature on structural factors shaping the course of the epidemic in different settings; and 3) the body of anthropological and sociological research on the synergistic effects of HIV/AIDS, social exclusion, and related social problems in pockets of extreme poverty in the large cities of core countries. We conclude that prevention policies for HIV/AIDS should deal comprehensively with diverse dimensions that determine differential vulnerabilities to the epidemic, thus requiring substantial social transformations