Genetic associations with brain microbleeds: Systematic review and meta-analyses.

OBJECTIVE: We performed a systematic review and meta-analyses to assess the evidence for genetic associations with brain microbleeds (BMBs). METHODS: We sought all published studies of the association between any genetic polymorphism and BMBs studied in a total of >100 people. We critically appraised studies, and calculated pooled odds ratios (ORs) using the generic inverse variance fixed effects method. We used I² and χ² statistics to assess heterogeneity, and fail-safe N estimates to assess the robustness of our results. RESULTS: Only the APOE ε2/3/4 polymorphism had been studied in >100 people (10 studies, 7,351 participants). Compared with people with the ε3/ε3 genotype, carriers of the ε4 allele (ε4+) were statistically significantly more likely to have BMBs in any location (ε4+ vs ε3/ε3: pooled OR 1.22, 95% confidence interval [CI] 1.05-1.41, p = 0.01). For strictly lobar BMBs, this association appeared slightly stronger (ε4+ vs ε3/ε3: pooled OR 1.35, 95% CI 1.10-1.66, p = 0.005). The association of ε4+ genotypes with strictly lobar BMBs was reasonably robust to potential publication and reporting biases. CONCLUSIONS: Given the known associations of APOE alleles with lobar intracerebral hemorrhage and cerebral amyloid angiopathy, these findings support the concept that strictly lobar BMBs may be an imaging biomarker of cerebral amyloid angiopathy.

Feeding by the tick, Ixodes scapularis, causes CD4(+) T cells responding to cognate antigen to develop the capacity to express IL-4.

Effects of tick feeding on an early antigen-specific T cell response were studied by monitoring a clonotypic population of adoptively transferred T cell receptor (TCR) transgenic CD4 cells responding to a tick-associated antigen. When recipient mice were infested with pathogen-free Ixodes scapularis nymphs several days prior to T cell transfer and intradermal injection of soluble cognate antigen at the feeding site, the clonotypic CD4 cells gained the ability to express the Th2 effector cytokine IL-4. Notably, this effect was not only observed in BALB/c mice predisposed towards developing Th2 responses but also in B10.D2 mice predisposed towards Th1 responsiveness. Furthermore, tick feeding was able to superimpose IL-4 expression potential onto a strong Th1 response (indicated by robust IFN-gamma expression potential) elicited by immunization with a vaccinia virus expressing the cognate antigen. The magnitude to which tick feeding was able to programme IL-4 expression potential in CD4 cells was partially reduced in mice that had been previously exposed to pathogen-free tick nymphs 6 weeks earlier, as well as when the nymphs were infected with Borrelia burgdorferi. Intradermal injection of salivary gland extract programmed IL-4 expression potential similar to that of tick infestation, suggesting that IL-4 programming activity is contained within tick saliva.

Tick modulation of the in-vitro expression of adhesion molecules by skin-derived endothelial cells.

As a tick feeds, its saliva induces innate and acquired immune responses in the host, including leucocyte infiltration into the bite site. Tick salivary glands produce molecules, however, that counteract many host defences against blood feeding. The effects of salivary-gland extracts (SGE) of Dermacentor andersoni and Ixodes scapularis on the expression of various adhesion molecules [E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)] by the sEND.1 cell line (which is based on cells from the subcutaneous tissue of mice) have now been investigated in vitro. The effects were found to differ with the tick species. The SGE of D. andersoni significantly down-regulated the expression of ICAM-1, whereas a similar extract prepared from I. scapularis significantly reduced the expression of P-selectin and VCAM-1. Tick salivary proteins therefore appear to have direct effects on adhesion-molecule expression, in addition to their previously established roles in down-regulating the pro-inflammatory cytokines that activate endothelial cells. It remains unclear exactly how the reduction of adhesion-molecule expression in the host's endothelial cells benefits the feeding tick but it may alter leucocyte migration to the bite site and/or reduce antigen presentation by the endothelial cells. It may also modulate the interactions between the host's leucocytes and any tick-borne pathogens, during initial infection of the endothelium.

Murine extramedullary erythropoiesis induced by tick infestation.

Tick saliva contains molecules that modulate the haemostasis, pain/itch responses, wound healing and immune defences of the host. Using BALB/c mice that were each infested with 10 nymphs of Dermacentor andersoni Stiles (Acari: Ixodidae), an attempt has now been made to determine the influence of tick infestation on the expression of leucocyte adhesion molecules in the host. The ticks became fully engorged by the fourth to sixth day of infestation. On the fourth day of infestation, the results of flow cytometry indicated that 2% of the host's splenocytes were expressing high levels of CD49 (alpha4 integrin of VLA-4) and low levels of CD11a (alphaL subunit of the integrin LFA-1). By the eighth day of infestation, 30% of the hosts' splenocytes had this phenotype and were negative for the lineage markers CD3e (T-lymphocytes), DX5 (natural-killer cells of a BALB/c lineage), B220 (B-lymphocytes), CD11b (monocytes/macrophages, granulocytes, natural-killer cells, activated T-lymphocytes, and B-1 cells) and CD11c (myeloid and splenic dendritic cells). Histological examination of the spleens from infested mice revealed disruption of the white-pulp/red-pulp demarcations and the presence of a large number of basophilic normoblasts. The CD11a(lo) population of splenocytes from the tick-infested mice was positive for TER-119 but negative for CD3, B220, CD11b and Gr, confirming that the splenocytes were members of the erythroid lineage. These results indicate that, within 8 days of their initiation, the tick infestations induced extramedullary erythropoiesis in the spleens of their murine hosts.