Justin Roake

Dendritic cells (DC) in nonlymphoid organs can internalize and process foreign antigens before migrating to secondary lymphoid tissues to initiate primary immune responses. However, there is little information on which stimuli promote migration of DC from the tissues. Systemic administration of lipopolysaccharide (LPS), which induces in vivo production of cytokines, led to a reduction in the numbers of major histocompatibility complex class II-positive (Ia+) leukocytes in mouse hearts and kidneys: > 95% of DC were depleted 1-3 d after injection of 50 micrograms LPS. Several lines of evidence indicated that this response was due to migration of DC rather than loss of Ia expression or cytotoxic effects. In skin of treated mice, the number of Ia+ epidermal Langerhans' cells (LC) was reduced, and "cords" of Ia+ leukocytes became evident in the dermis. The latter cells expressed little NLDC145 and may have originated from recruited or resident DC progenitors. Systemic administration of recombinant tumor necrosis factor (rhTNF)-alpha resulted in a decrease in numbers of Ia+ cells in heart and kidney and of epidermal LC, and it also induced dermal cords. Administration of a rh-interleukin (IL)-1 resulted in a decrease in Ia+ cells only in renal medulla, appeared to activate a subset of epidermal LC, and induced dermal cords. Similar microgram doses of rhIL-2 had no obvious effect. Treatment with a neutralizing anti-TNF antiserum before LPS administration inhibited the depletion of LC from skin but not from heart or kidney. Therefore, TNF-alpha and IL-1 alpha may promote DC migration from nonlymphoid tissues and may have differential effects on different DC populations, but it is unclear whether they act on DC directly or indirectly (e.g., via other cytokines).

RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Dendritic cells (DC) are thought to be distributed throughout lymphoid and most nonlymphoid tissues. Single cell suspensions were prepared from mouse hearts and kidneys. Subsets of MHC class II-positive (Ia+) leukocytes from both sources expressed markers such as CDw32 Fc receptors, F4/80, and complement receptor type 3 (CD11b/CD18). The capacity of these cells to initiate primary in vitro immune responses was assessed using oxidative mitogenesis and allogeneic mixed leukocyte responses. After fractionation by density centrifugation, cell sorting, immunomagnetic bead separation, or cell panning, the stimulatory activity of kidney cell suspensions was found to reside in the low density, Ia+ leukocyte fractions after overnight culture (day 1). In contrast, freshly isolated (day 0) cells had considerably less or no activity in these assays. However, depletion of Ia+ or CD45+ cells on day 0 followed by overnight culture removed the stimulatory activity on day 1. Therefore, day 0 kidney cells contain Ia+ leukocytes that can acquire or up-regulate their stimulatory activity during overnight culture. Similar observations were made for cells isolated from hearts, except that a population of uncharacterized nonleukocytes with stimulatory activity was detected on day 0 but not day 1. The phagocytic capacity of the leukocytes was then examined. Subsets of Ia+ cells phagocytosed zymosan, as shown by two-color flow cytometry and other immunofluorescence studies, and the zymosan-positive cells from kidney were able to initiate primary responses. Overall, these data demonstrate the existence of DC in kidneys and hearts, and suggest that in situ these cells resemble immature rather than mature DC.