Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.

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e Bacillus cereus, aseptically isolated from potato tubers, were screened for cereulide production and for toxicity on human and other mammalian cells. The cereulide-producing isolates grew slowly, the colonies remained small (ϳ1 mm), tested negative for starch hydrolysis, and varied in productivity from 1 to 100 ng of cereulide mg (wet weight) ؊1 (ϳ0.01 to 1 ng per 10 5 CFU). By DNA-fingerprint analysis, the isolates matched B. cereus F5881/94, connected to human food-borne illness, but were distinct from cereulide-producing endophytes of spruce tree (Picea abies). Exposure to cell extracts (1 to 10 g of bacterial biomass ml ؊1 ) and to purified cereulide (0.4 to 7 ng ml ؊1 ) from the potato isolates caused mitochondrial depolarization (loss of ⌬⌿m) in human peripheral blood mononuclear cells (PBMC) and keratinocytes (HaCaT), porcine spermatozoa and kidney tubular epithelial cells (PK-15), murine fibroblasts (L-929), and pancreatic insulin-producing cells (MIN-6). Cereulide (10 to 20 ng ml ؊1 ) exposed pancreatic islets (MIN-6) disintegrated into small pyknotic cells, followed by necrotic death. Necrotic death in other test cells was observed only after a 2-log-higher exposure. Exposure to 30 to 60 ng of cereulide ml ؊1 induced K ؉ translocation in intact, live PBMC, keratinocytes, and sperm cells within seconds of exposure, depleting 2 to 10% of the cellular K ؉ stores within 10 min. The ability of cereulide to transfer K ؉ ions across biological membranes may benefit the producer bacterium in K ؉ -deficient environments such as extracellular spaces inside plant tissue but is a pathogenic trait when in contact with mammalian cells. C ereulide, the emetic toxin of Bacillus cereus, is most likely responsible for the severe cases of illness connected to the consumption of food contaminated with B. cereus (1-9). Cereulideproducing B. cereus isolates are frequently reported in processed foods, implicated (3-16) or not implicated (17-21) with foodborne illness, but appear infrequently in farming or natural outdoor environments (22-26).B. cereus is known to occur in the rhizomicrobiota and endophytic community of plants, as well as in root vegetables, including potato (27), but these habitats have not been searched for cereulide producers (28). The extracellular spaces of plants, as well as natural waters, including soil water, contain Ͻ1 mM K ϩ ions, whereas the concentration of K ϩ in the interior of the cytoplasmic space of plant cells, as well as in bacteria, is Ͼ100 mM (29, 30). Bacteria living in the extracellular spaces of the tuber of a crop plant must thus compete for K ϩ ions with its plant host and with other bacteria inside the crop plant.Cereulide is known to be a heat-stable cyclic depsipeptide (6, 31, 32) with high affinity and selectivity for sequestering K ϩ ions from a low-potassium environment (33-35). We recently found (36) that an endophytic, cereulide-producing Bacillus cereus strain (37) from Picea abies (Norway spruce), had a competitive advantage against nonproducers in potassium-deficient (Ͻ...

Pneumococcal pili have been shown to influence pneumococcal colonization, disease development, and the inflammatory response in mice. The role of the pilus-associated RrgA adhesin in pneumococcal interactions with murine and human macrophages was investigated. Expression of pili with RrgA enhanced the uptake of pneumococci by murine and human macrophages that was abolished by antibodies to complement receptor 3 (CR3) and not seen in CR3-deficient macrophages. Recombinant RrgA, but not pilus subunit RrgC, promoted CR3-mediated phagocytosis of coated beads by murine and human macrophages. Flow cytometry showed that purified CR3 binds pneumococcal cells expressing RrgA, and purified RrgA was shown to interact with CR3 and its I domain. In vivo, RrgA facilitated spread of pneumococci from the upper airways and peritoneal cavity to the bloodstream. Earlier onset of septicemia and more rapidly progressing disease was observed in wild-type mice compared to CR3-deficient mice challenged intranasally or intraperitoneally with pneumococci. Motility assays and time-lapse video microscopy showed that pneumococcal stimulation of macrophage motility required RrgA and CR3. These findings, together with the observed RrgA-dependent increase of intracellular survivors up to 10 h following macrophage infection, suggest that RrgA-CR3-mediated phagocytosis promotes systemic pneumococcal spread from local sites.

Intercellular adhesion molecule‐4 (ICAM‐4, LW blood group antigen), a member of the immunoglobulin superfamily expressed on red cells, has been reported to bind to CD11a/CD18 and CD11b/CD18 leukocyte integrins. The location of the ICAM‐4 binding sites on CD11a/CD18 and CD11b/CD18 are not known. CD11/CD18 integrin I domains have been found to act as major binding sites for physiological ligands and a negatively charged glutamic acid in ICAMs is considered important for binding. ICAM‐4 lacks such a residue, which is replaced by an arginine. However, we demonstrate here that ICAM‐4 in red cells and transfected fibroblasts interacts specifically with the I domains of CD11a/CD18 and CD11b/CD18 integrins. The binding was inhibited by anti‐I domain and anti‐ICAM‐4 antibodies and it was dependent on divalent cations. Interestingly, ICAM‐4 negative red cells were still able to bind to the CD11b/CD18 I domain but the binding of these cells to the CD11a/CD18 I domain was clearly reduced. Using a solid phase assay, we were able to show that isolated I domains directly and specifically bind to purified recombinant ICAM‐4 in a cation dependent manner. Competition experiments indicated that the binding sites in ICAM‐4 for the CD11a and CD11b I domains are different. However, the ICAM‐4 binding region in both I domains seems to overlap with the regions recognized by the ICAM‐1 and ICAM‐2. Thus we have established that the I domains contain an ICAM‐4 binding region in CD11a/CD18 and CD11b/CD18 leukocyte integrins.