Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins1. While the proteins so targeted represent a tiny fraction of the airborne proteins humans are exposed to, allergenicity is a quite public phenomenon—the same proteins typically behave as aeroallergens across the human population. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental mechanistic question that remains largely unanswered. The major house dust mite allergen, Der p 2, has structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR)4 signalling complex2–4. Here we show that Der p 2 has functional homology as well, facilitating signalling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signalling in the absence of MD-2. Mirroring this, airway sensitization and challenge with Der p 2 led to experimental allergic asthma in wild type and MD-2-deficient, but not TLR4-deficient, mice. Our results suggest that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. The fact that other members of the MD-2-like lipid binding family are allergens, and that a majority of defined major allergens are thought to be lipid-binding proteins5, suggests that intrinsic adjuvant activity by such proteins and their accompanying lipid cargo may have some generality as a mechanism underlying the phenomenon of allergenicity.

We examined the bactericidal activity of polymorphonuclear leukocytes (PMN) against an invasive wild-type strain of Shigella flexneri (M90T) and a plasmid-cured noninvasive derivative (BS176). Both Shigella strains, as well as a rough strain of Escherichia coli, were killed with similar efficiencies by intact inflammatory PMN in room air and under N 2 (i.e., killing was O 2 independent). Bacterial killing by PMN extracts was substantially inhibited by antibodies to the bactericidal/permeability-increasing protein (BPI). Whereas wild-type Shigella escapes from the phagosome to the cytoplasm in epithelial cells and macrophages, wild-type Shigella was trapped in the phagolysosome of PMN as visualized by electron microscopy. The efficient killing of Shigella by PMN suggests that these inflammatory cells may not only contribute initially to the severe tissue damage characteristic of shigellosis but also ultimately participate in clearance and resolution of infection.

Fibrinogen-dependent interactions of Staphylococcus aureus are believed to contribute to bacterial virulence by promoting bacterial attachment to fibrinogen-coated surfaces and inducing the formation of bacterial clumps that are likely resistant to phagocytosis. Although S. aureus produces several fibrinogen-binding proteins, the cell wall-associated protein clumping factor (encoded by clfA) appears to be most important in bacterial interactions with immobilized or soluble purified fibrinogen. We have compared bacterial clumping in several strains of S. aureus, including isogenic ClfA+ and ClfA− Newman strains, in the presence of purified rabbit fibrinogen, human plasma, and inflammatory fluid and examined the effect of clumping on bacterial sensitivity to mammalian group IIA phospholipase A2 (PLA2). This enzyme is the major extracellular bactericidal agent in inflammatory fluid active against S. aureus. Both ClfA-dependent and ClfA-independent bacterial clumping was observed, depending on the source and fibrinogen content of the biological fluid. In each case, clumping only partially reduced the antibacterial activity of PLA2, suggesting that this extracellular enzyme can substantially penetrate dense bacterial clumps. Bacterial clumps could be dispersed by added proteases, restoring full antibacterial activity to PLA2. Thus, the extracellular mobilization of group IIA PLA2 during inflammation may provide a mechanism by which the host can control the proliferation and survival of S. aureus even after bacterial clumping.

The bactericidal potency toward complement-resistant Escherichia coli of bactericidal/permeability-increasing protein (BPI) released from polymorphonuclear leukocytes (PMNs) in glycogen-induced inflammatory peritoneal exudates of rabbits is dependent on synergy with extracellular p15s. This synergy depends on the high molar ratio of p15s to BPI in the extracellular fluid (∼50:1), which greatly exceeds the intracellular ratio (∼5:1). To explore the possible basis of the greater accumulation of p15s in inflammatory fluid, we examined the subcellular localization of BPI and p15 in PMNs. Immunogold electron microscopy confirmed the storage of BPI in primary granules and showed that p15s are stored in secondary granules. Reverse-transcription polymerase chain reaction of density-fractionated rabbit bone marrow cells verified that p15s are expressed later than BPI during myeloid differentiation. As the inflammatory response evolves, p15 mRNA appears earlier in blood and exudate cells than mRNA for BPI, consistent with release of progressively less mature precursors from bone marrow. Finally, Ca2+-ionophore–mediated exocytosis of p15s occurs more readily than release of BPI. We therefore propose that localization of a synergistic partner of BPI (p15s) in more readily released secondary granules allows the neutrophil to mobilize potent BPI-dependent antibacterial activity extracellularly without significant depletion of intracellular BPI stores.

The Gram-negative pathogen Neisseria meningitidis, is one of the leading causes of bacterial meningitis worldwide (1). The host range for this organism is restricted to humans, where it colonizes the mucosal epithelium of the upper airway. It occasionally disseminates causing invasive disease (sepsis, disseminated intravascular coagulation [DIC], meningitis). Epidemic meningococcal meningitis is a major health problem, most notably in sub-Saharan Africa. In 1999, an outbreak of meningococcal disease spread across Guinea-Bissau, a region that is part of what is commonly called the African meningitis belt (2). There were 2,169 reported cases and 404 deaths resulting from meningococcal disease in this outbreak from Jan. 1 to April 5, 1999. Also in 1999, there were reported outbreaks in Sudan (22,000 cases and 1,600 deaths) Rwanda (29 cases and 11 deaths), Angola (253 cases and 147 deaths), Ethiopia (126 cases and 4 deaths) and Senegal (2,709 cases and 372 deaths) (2). According to the World Health Organization (WHO), each year approx 500,000 cases of meningitis and 50,000 deaths are attributable to N. meningitidis worldwide. In the United States, meningococcal disease is less common, although small outbreaks are reported each year (3).