Opsonized streptococcal cell walls cross-link human leukocytes and erythrocytes by complement receptors.

Serum-opsonized group A streptococcal cell walls, consisting of peptidoglycan-polysaccharide polymers (PG-APS), induced monolayers of human neutrophils, monocytes, and eosinophils to aggregate. When erythrocytes were present in the incubation medium, they also were associated with the leukocyte aggregates. By immunofluorescence staining, PG-APS was localized at the site of cell-to-cell contact. By scanning electron microscopy the cells appeared to adhere to one another by surface contact; filopodia often acted as connectors, particularly in leukocyte-erythrocyte interaction. Cellular binding of PG-APS and aggregation were dependent upon C3 fixation. No aggregation was observed when heat-inactivated serum was used as an opsonin. In contrast to peptidoglycan, an activator of the alternative complement pathway, the group-specific polysaccharide moiety of PG-APS induced no cellular aggregation. Rosette formation was observed in suspensions when neutrophils were incubated with erythrocytes coated with C3b-opsonized PG-APS. Cell monolayers bound serum-opsonized PG-APS, but aggregation was observed only when serum was present in the incubation medium. Similar results were obtained with C5-deficient serum. No aggregation was observed with heat-inactivated serum or bovine serum albumin. A heat-labile serum component(s) appears to be required to elicit leukocyte aggregation. It is suggested that C3 fixed to PG-APS acts as a bridge to link cells together in clusters as a result of common recognition of C3 by leukocyte and erythrocyte complement receptors

Neutral proteases of human polymorphonuclear granulocytes: putative mediators of pulmonary damage.

Tissue proteolytic enzymes are currently believed to be critical to the pathogenesis of panacinar emphysema. Polymorphonuclear leukocytes (Polys) have several enzymes including elastase and cathepsin G in their azurophil granules. They have collagenase in their specific granules. We have found that this collagenase is doubly latent. It has the lysosomal type of latency that depends on the impermeability of the unit membrane that surrounds each specific granule. In addition it has a latency that is converted to activity by proteolytic enzymes. The cathepsin G of the azurophil granule is a potent activator of this latent collagenase once the collagenase is released from its membrane dependent latency. Thus latency of enzymes, the nature of the latency and accessibility of the latent enzymes to activating mechanisms must all be taken into account in any analysis of their contribution to pathogenesis of local lung disease. Equally important is that fact that polys are not a prominent cellular component of normal lung. Polys must be attracted to the lung by chemotactic peptides. These peptides must be released by the interaction of inflammatory stimuli, such as smoke particles, with complement components or they must be provided by other sources. The hypothesis that lung damage in panacinar emphysema is mediated by polys and their proteases is attractive and suggestive evidence supporting this is available. However, more evidence that takes into full account the cell biology of the proteases any poly turnover in the lung are needed to extend the hypothesis and to form a rational basis for therapeutic and prophylactic measures

Transient Increase in Cyclic AMP Localized to Macrophage Phagosomes

Cyclic AMP (cAMP) regulates many biological processes and cellular functions. The importance of spatially localized intracellular gradients of cAMP is increasingly appreciated. Previous work in macrophages has shown that cAMP is produced during phagocytosis and that elevated cAMP levels suppress host defense functions, including generation of proinflammatory mediators, phagocytosis and killing. However, the spatial and kinetic characteristics of cAMP generation in phagocytosing macrophages have yet to be examined. Using a Förster resonance energy transfer (FRET)-based cAMP biosensor, we measured the generation of cAMP in live macrophages. We detected no difference in bulk intracellular cAMP levels between resting cells and cells actively phagocytosing IgG-opsonized particles. However, analysis with the biosensor revealed a rapid decrease in FRET signal corresponding to a transient burst of cAMP production localized to the forming phagosome. cAMP levels returned to baseline after the particle was internalized. These studies indicate that localized increases in cAMP accompany phagosome formation and provide a framework for a more complete understanding of how cAMP regulates macrophage host defense functions

Anti-neutrophil cytoplasmic antibodies:Current diagnostic and pathophysiological potential

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by rapid deterioration of renal function occurring within days or weeks together with signs of glomerulonephritis, that is, proteinuria and hematuria with cellular casts. The syndrome is, in many cases, histopathologically manifested as fibrinoid necrosis of the capillary wall with extracapillary proliferation and crescent formation [1]. This so-called necrotizing crescentic glomerulonephritis (NCGN) is seen in 5 to 15% of renal biopsies in most series [1–3]. Although it is infrequent, the importance of the condition is illustrated by the fact that most cases of NCGN, if left untreated, develop renal failure within days or weeks [1]. Based on immunohistopathology NCGN can be subdivided into three distinct categories. The first one, occurring in 2 to 20% of the cases and characterized by linear staining of the glomerular capillary wall for immunoglobulin and complement, has classically been described as anti-glomerular basement membrane (GBM) disease. It is associated with autoantibodies to structural antigens of the GBM, in particular to the first globular noncollagen domain of collagen type IV [4]. The antibodies are considered of pathogenetic significance. The second category, comprising 15 to 50% of cases, is characterized by granular deposits of immunoglobulin and complement suggesting that immune complexes are pathogenetically involved. This type occurs in conjunction with systemic autoimmune diseases such as lupus erythematosus, in cases of post-infectious glomerulonephritis, IgA nephropathy or Henoch-Schönlein purpura, or as an idiopathic variety. The third group of NCGN, occurring in 40 to 80%, demonstrates only a few or no immune deposits and is designated as pauci-immune NCGN [1–3, 5, 6]. Pauci-immune NCGN occurs as part of Wegener's granulomatosis (WG) or related conditions, or without systemic vasculitis (idiopathic NCGN). The pathophysiology of this pauci-immune type of NCGN has not been elucidated. Within the last decade, however, it has been recognized that the condition is associated with autoantibodies to cytoplasmic components of neutrophils (anti-neutrophil cytoplasmic antibodies or ANCA).ANCA were first described in 1982 by Davies et al in a few patients with segmental necrotizing glomerulonephritis [7]. Only in 1985 did it become apparent that ANCA are a sensitive and specific marker for Wegener's granulomatosis (WG) [8]. Later on, ANCA were described in patients with microscopic polyarteritis [9]. Falk and Jennette, in 1988, showed that ANCA are also associated with the idiopathic form of pauci-immune NCGN [10]. These data have now been confirmed by many groups and support the view that ANCA-associated glomerulonephritis and vasculitis is, indeed, a distinct disease category. A number of studies, in addition, have suggested that ANCA are involved in the pathophysiology of the aforementioned disorders. As ANCA, however, have recently also been detected in a wide range of inflammatory and infectious conditions, a critical reappraisal of the diagnostic significance of ANCA-testing seems justified.In this review we will evaluate the current state of ANCA-testing as well as elaborate on the pathophysiological role of the autoantibodies in necrotizing glomerulonephritis and vasculitis. Data presented recently at the Fifth International Workshop on ANCA, held in Cambridge, United Kingdom, will be included [11]. As such, it adds to previous reviews on ANCA that were published following the Second [12], Third [13], and Fourth [14] Workshops on ANCA

Feminine Imperial Ideals in the Caesares of Suetonius

The dissertation examines Suetonius' ideals of feminine conduct by exploring the behaviors he lauds or censures in imperial women. The approach comes from scholarship on the biographer's practice of evaluating of his male subjects against a consistent ideal. This study argues that Suetonius applies the same method to imperial women. His tendency to speak of women in standardized rubrics (ancestry, marriage, the birth of children) suggests that he has a fixed notion of model feminine behavior, one that values women for being wives and mothers. Chapter 1 argues that because Suetonius' Lives center on male subjects, his picture of women is fragmented at best. The biographer uses this fragmentation to manipulate his female characters. Livia, for instance, is cast as a "good" wife in the Augustus, but as a "bad" mother in the Tiberius. Suetonius' often inconsistent drawing of women reveals that he uses them primarily to elucidate certain aspects of their associated men. Having a "good" wife, mother, or sister reflects well on an emperor, while having a "bad" one reveals his lack of authority. Chapter 2 explores the role of mother. Atia serves as the "good," silent type and Livia and Agrippina the Younger the "bad," meddling type. Chapter 3 investigates the role of wife. Livia exemplifies the "good," loyal wife who is not politically active, while Agrippina the Younger illustrates the "bad," sexually manipulative wife who murders her husband to advance her son. Chapter 4 looks at members of the wider imperial family, noting that Suetonius writes more about sexually promiscuous women, such as Drusilla and Julia, than those women, like Domitilla the Younger, who followed social norms by marrying and bearing children. As a result, the Caesares are slanted towards negative portrayals of women. Chapter 5 "reassembles" the fragmented picture of women. The small role that Suetonius writes for Poppaea reveals his independence from Tacitus. The biographer's portrayal of Livia and Agrippina subverts ideals espoused on imperial coins and statues. Overall, the most important role for women in the Caesares is that of mother. By focusing on his portrayal of women, this study also sheds light on Suetonius' use of rhetoric and stereotypes.Dissertatio