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Biomedical subjects

K M Leiferman

Publications and source records attributed to K M Leiferman.

At least 37 records · Page 2Linked to original sources
PubMed1997

Transmigration of eosinophils through basement membrane components in vitro: synergistic effects of platelet-activating factor and eosinophil-active cytokines.

Migration of eosinophils through the basement membrane barrier is an important step for their infiltration into tissues. To investigate the mechanism of transmigration, we used a chamber fitted with a Matrigel membrane as a model of the basement membrane. In this model, eosinophils treated with cytokines or chemotactic factors alone did not transmigrate from the upper to the lower chamber. However, platelet-activating factor (PAF) strongly induced transmigration of eosinophils stimulated by interleukin (IL)-5, indicating that both a cytokine and a chemotactic factor are required for eosinophil migration through Matrigel. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 also stimulated eosinophil transmigration in the presence of PAF. Of seven eosinophil chemotactic factors tested, leukotriene B4, C5a, RANTES, macrophage inflammatory protein-1alpha, and IL-8 did not induce significant eosinophil transmigration. Only PAF and eotaxin induced transmigration of eosinophils through Matrigel in the presence of IL-5; PAF was more potent than eotaxin at the optimal concentration. In contrast, PAF, eotaxin, and RANTES all potently induced migration of eosinophils through bare membrane in the absence of IL-5. Finally, eosinophil migration through Matrigel was markedly reduced by a combination of anti-CD18 and anti-CD29 monoclonal antibodies, suggesting that it is mediated by beta1- and beta2-integrin adhesion molecules. Our findings demonstrate that eosinophil transmigration through a basement membrane model requires both a specific chemoattractant, such as PAF, and an eosinophil-activating cytokine, such as IL-5. This synergistic effect is likely important in the tissue accumulation of activated eosinophils in allergic and other eosinophil-associated diseases.

Basement Membrane↗
PubMed1997

Migration of eosinophils through basement membrane components in vitro: role of matrix metalloproteinase-9.

In general, inflammatory cells cross basement membranes by producing proteinases. To investigate the role of proteinases in eosinophil basement membrane migration, we studied peripheral blood eosinophils in Matrigel-coated chemotaxis chambers. Electron microscopy showed degradation of the Matrigel layer when eosinophils, added to the upper chamber, transmigrated the membrane in the presence of both platelet-activating factor (PAF) in the lower chamber and interleukin (IL)-5 in both chambers. In the absence of either or both PAF and IL-5, no changes occurred in the Matrigel layer. Matrigel transmigration of eosinophils induced by PAF and IL-5 was inhibited by 1,10-phenanthroline, batimastat, 3,4-dichloroisocoumarin, chymostatin, and a neutralizing antibody for the matrix metalloproteinase (MMP)-9, indicating that serine proteinase(s) and MMP, specifically MMP-9, were involved in the transmigration of eosinophils through Matrigel. In contrast, eosinophil migration through a bare membrane was not affected by batimastat. Using gelatin zymography and immunoblotting, MMP-9 was detected in the migration upper chamber supernatant of the eosinophil transmigration assay and in the conditioned medium of eosinophils. Release of MMP-9 by eosinophils was increased by IL-5, PAF, or both, but the substrate-degrading activity of MMP-9 was increased only in the presence of both IL-5 and PAF, indicating that the releasing and activating mechanisms of MMP-9 are involved in eosinophil basement membrane migration. This study implicates MMP-9 in basement membrane migration of eosinophils and suggests its involvement in inflammatory diseases where tissue eosinophilia plays a role.

Basement Membrane↗
PubMed1996

Eosinophilic vasculitis in connective tissue disease.

BACKGROUND: Neutrophilic and lymphocytic vascular inflammation is common in vasculitis associated with connective tissue disease (CTD). We recently identified eight patients with CTD and eosinophilic vasculitis. OBJECTIVE: The purpose of this study was to characterize a variant form of vasculitis in CTD with eosinophilic infiltration. METHODS: Of 98 CTD patients with cutaneous necrotizing vasculitis, eight were found with predominantly eosinophilic vascular infiltration. Nine CTD patients with cutaneous neutrophilic vasculitis were identified for comparison. Clinical and laboratory findings were reviewed and compared. Indirect immunofluorescence for eosinophil granule major basic protein (MBP), neutrophil elastase, and mast cell tryptase was performed on lesional tissue. MBP levels and eosinophil survival enhancing activity were assayed in sera from three patients. RESULTS: The patients with eosinophilic vasculitis had depressed serum complement levels and peripheral blood eosinophilia; MBP levels were elevated in serum and eosinophil survival was prolonged. Immunofluorescence of tissue showed marked angiocentric eosinophil MBP staining with peripheral neutrophil elastase staining; mast cell tryptase staining was notably absent. The patients with neutrophilic vasculitis were variably hypocomplementemic and did not have peripheral blood eosinophilia. Immunofluorescence showed marked angiocentric neutrophil elastase staining with scattered eosinophil MBP staining; mast cell tryptase staining showed normal mast cell numbers. CONCLUSION: Patients with eosinophilic vasculitis, CTD, and hypocomplementemia show vessel wall destruction in association with vessel wall deposition of cytotoxic eosinophil granule MBP, which suggests that eosinophils mediate vascular damage in this disease process. In addition, perivascular mast cells appear diminished, thereby suggesting that mast cell degranulation occurs.

Adult↗
PubMed1996

Eosinophils in allergy: role in disease, degranulation, and cytokines.

For over 100 years, the eosinophil has been associated with allergic disease. At present, eosinophils appear to be associated pathologically with asthma, atopic dermatitis, allergic rhinitis, eosinophilic gastroenteritis, and certain eye diseases. The effector functions of eosinophils appear to be derived primarily from release of lipid mediators and proteins, including cytokines and granule proteins. Eosinophil degranulation results in the release of several cytotoxic cationic granule proteins. Furthermore, release of cytokines by eosinophils and other cells involved in inflammation amplifies and regulates localized immune responses. Altogether, the eosinophil's capacity to release and be influenced by a variety of mediators, including the granule proteins and cytokines, implicates this cell in the pathology of inflammation and in the perpetuation of the inflammatory response.

Cell Degranulation↗
PubMed1996

Pachydermatous eosinophilic dermatitis.

We report three South African black teenage girls with extensive pruritic papular lesions arising on a pachydermatous base, resembling severe atopic dermatitis or onchodermatitis. All three had peculiar hypertrophic genital lesions and peripheral blood eosinophilia. Histological studies showed an eosinophil-rich lymphohistiocytic infiltrate and variable fibrosis. Extensive fibrillar extracellular deposition of eosinophil granule major basic protein was demonstrated by an indirect immunofluorescence technique. A beneficial therapeutic effect was obtained using dapsone, prednisolone and cetirizine. The term pachydermatous eosinophilic dermatitis is proposed and its position among other conditions characterized by peripheral blood and skin tissue eosinophilia, is discussed.

Adolescent↗
PubMed1996

Deposition of eosinophil granule proteins precedes blister formation in bullous pemphigoid. Comparison with neutrophil and mast cell granule proteins.

Eosinophils, neutrophils, and mast cells have all been implicated in the pathogenesis of bullous pemphigoid (BP). To comparatively characterize the involvement of these cells in BP, 10 lesional skin biopsy specimens were identified retrospectively and studied for tissue localization of eosinophil, neutrophil, and mast cell granule proteins. Subsequently, multiple skin biopsies of lesions in various developmental stages were obtained from 3 patients with untreated BP. Involved and uninvolved skin specimens were also obtained from 2 patients. Using indirect immunofluorescence, retrospectively identified lesions showed eosinophils and extracellular granule protein deposition prominently in areas of blistering. Evolving lesions showed eosinophil granule protein deposition in all stages but was most marked in early erythematous and prebullous (urticarial) lesions and was minimal in uninvolved skin. Vascular cell adhesion molecule-1, E-selectin, and P-selectin were detected on vessels and very late activation antigen-4 was detected on mononuclear cells and eosinophils by immunoperoxidase staining of lesions. Eosinophil granule proteins were increased in the peripheral blood, urine, and blister fluid. Blister fluids caused increased eosinophil survival that was inhibited by antibodies to interleukin-5 and interleukin-3. Although neutrophil and mast cell infiltration was observed, extracellular granule protein deposition from these cells was minimal except in two specimens. These results demonstrate that eosinophils infiltrate and deposit granule proteins early in the development of BP lesions, that eosinophil-activating cytokines are present in blister fluid, and that eosinophil-selective adhesion molecules are present. These studies strongly support a role for eosinophils in blister formation in BP.

Aged↗
PubMed1995

Elevated levels of eosinophil major basic protein in the sera of patients with systemic sclerosis.

OBJECTIVE: To examine eosinophil activation, as reflected by evidence of eosinophil degranulation in the blood and affected tissues, in patients with diffuse and limited cutaneous forms of systemic sclerosis (SSc). METHODS: Levels of the eosinophil-derived major basic protein (MBP), a marker of eosinophil degranulation, were determined in sera from 46 SSc patients, from patients with rheumatoid arthritis and giant cell arteritis, and from healthy volunteers, and in bronchoalveolar lavage fluid from 4 SSc patients. Extracellular tissue deposition of MBP was evaluated in biopsy specimens from affected skin or lung of 11 SSc patients. RESULTS: Patients with diffuse cutaneous SSc (dcSSc) had elevated serum MBP levels compared with normal individuals (mean +/- SD 762 +/- 271 ng/ml versus 534 +/- 144 ng/ml; P = 0.0004). MBP levels were positively correlated with the extent of cutaneous involvement, and negatively correlated with pulmonary function and duration of disease (r = -0.20). By immunohistochemical analysis, modest extracellular MBP deposition could be demonstrated in involved skin in 7 of 10 biopsy specimens, and MBP staining was prominent in affected lung tissues in 2 patients. CONCLUSION: Eosinophil degranulation appears to be increased in some patients with dcSSc, as indicated by elevated serum levels of MBP and extracellular accumulation of MBP in the lung. Eosinophil granule proteins may contribute to the development of cutaneous and pulmonary fibrosis in SSc.

Adult↗
PubMed1995

Eosinophilic vasculitis syndrome: recurrent cutaneous eosinophilic necrotizing vasculitis.

We recently identified a syndrome of recurrent cutaneous eosinophilic vasculitis in three patients. These patients had in common widespread pruritic, erythematous, purpuric papules and angioedema of face and hands associated with peripheral blood eosinophilia. Eight skin biopsies from these three patients all showed necrotizing vasculitis of the small vessels of the skin, with exclusively eosinophilic infiltration and minimal or no leukocytoclasis. The disease followed a chronic course, with recurrent, itchy, swelling skin lesions and without evidence of systemic involvement over observation periods of 3, 17, and 23 years. The skin lesions responded promptly to systemic steroid treatment, but two patients required maintenance doses for control of the disease. Immunofluorescence studies showed marked deposition of the cytotoxic eosinophil granule major basic protein in the affected vessel walls. Eosinophil-active cytokine IL-5 was detected in the serum of one patient. Expression of the vascular cell adhesion molecule-1 for eosinophil adherence was detected on the endothelium of the affected vessels. Because this disease showed distinctive clinical manifestations and characteristic histopathological features, we believe it is a distinct entity and should be distinguished from other types of vasculitis.

Adolescent↗
PubMed1995

Hypereosinophilic syndrome.

The hypereosinophilic syndrome is a multisystem syndrome characterized by peripheral blood eosinophilia and eosinophil infiltration of bone marrow, heart, and other organs. The syndrome is associated with cardiac, hematological, pulmonary, neurological, and cutaneous involvement and, if untreated, has a high fatality rate. Criteria for the diagnosis of hypereosinophilic syndrome include (1) peripheral blood eosinophilia with eosinophil counts greater than 1,500/microL for at least 6 months; (2) no evidence of parasitic, allergic, or other known causes of eosinophilia; and (3) presumptive signs and symptoms of multiple organ involvement. Cutaneous manifestations occur commonly but are not diagnostic either clinically or histologically, although the presence of angioedema is a favorable prognostic sign. Because eosinophils are thought to mediate important pathogenic effects, treatment is aimed at controlling peripheral blood eosinophilia.

Humans↗
PubMed1995

Immunohistological comparison of granulated cell proteins in induced immediate urticarial dermographism and delayed pressure urticaria lesions.

Urticarial dermographism and delayed pressure urticaria are two forms of physical urticaria which are well defined clinically and histologically. Previous studies have shown eosinophil granule protein deposition in urticarial reactions, including chronic urticaria, solar urticaria and delayed pressure urticaria. To evaluate and compare the involvement of granulated inflammatory cells in urticarial dermographism and delayed pressure urticaria, we studied sequential biopsies of induced lesions of urticarial dermographism and delayed pressure urticaria by indirect immunofluorescence, to detect eosinophil granule major basic protein (MBP) and neutrophil granule elastase. Biopsies from dermographic lesions at time 0, 5 min, 15 min, 2 h and 24 h, showed few infiltrating eosinophils, with minimal extracellular MBP deposition, and a few infiltrating neutrophils, with minimal neutrophil elastase deposition, throughout the evolution of the lesions. Sequential biopsies of delayed pressure urticaria at time 0, 20 min, 6, 12 and 24 h, showed eosinophil infiltration with extensive MBP deposition beginning at 20 min, and neutrophil infiltration with variable elastase deposition beginning at 20 min. Control tissue specimens from normal volunteers showed neutrophil infiltration and slight degranulation, but no eosinophil infiltration or degranulation. Comparison of urticarial dermographism with delayed pressure urticaria showed marked differences in the patterns of infiltration. Delayed pressure urticaria, with eosinophil and neutrophil degranulation, was strikingly similar to the IgE-mediated late phase reaction. In contrast, eosinophil and neutrophil involvement in urticarial dermographism was minimal. Considering the extent of eosinophil granule protein deposition and the biological activities of the eosinophil granule proteins, the findings in delayed pressure urticaria point to an important pathophysiological role of eosinophils in the disease.

Blood Proteins↗
PubMed1994

Human cutaneous allergic late-phase response is inhibited by soluble IL-1 receptor.

The late-phase allergic reaction (LPR) occurs 4 to 8 h after allergen exposure and probably causes the symptoms of chronic allergic disease. To determine the effects of soluble IL-1 receptor on the cutaneous LPR, we performed a prospective, randomized, double-blind, placebo-controlled study on 15 allergic subjects. Intradermal injections of allergen were placed on subjects' forearms, followed by immediate subcutaneous injections at the same site of either 1, 10, 25, 50, or 100 micrograms of rhu IL-1R to three subjects in each dosage group. Placebo was given to matched allergen-injected sites on the contralateral arm. Erythema, induration, and itching were recorded for each site. Sites were biopsied at 8 h for immunohistologic evaluations. Rhu IL-1R significantly reduced the clinical reaction at all concentrations. At 1 and 10 micrograms, measurements of LPR were significantly less (p < 0.05) than at placebo sites at several time points from 2 to 8 h. At higher concentrations, LPR was suppressed at rhu IL-1R and placebo sites, suggesting a systemic effect of rhu IL-1R. Histologic evaluation and indirect immunofluorescence for eosinophil granule major basic protein, neutrophil elastase, and mast cell tryptase showed no statistical differences between rhu IL-1R and placebo sites or among doses. IL-1 plays an important role in the generation of allergic LPR. While microgram quantities of rhu IL-1R inhibited the clinical signs and symptoms of LPR, its effects on the allergic inflammatory infiltrate are yet to be defined. In this short term trial, rhu IL-1R was neither immunogenic nor toxic.

Adult↗
PubMed1994

Assessment of eosinophil and neutrophil participation in atopic dermatitis: comparison with the IgE-mediated late-phase reaction.

We hypothesized that repeated IgE-mediated late-phase reactions are critical in the pathogenesis of atopic dermatitis (AD). Prior studies have shown that extracellular deposition of eosinophil granule major basic protein (MBP) occurs in lesional AD skin, despite a paucity of infiltrating eosinophils, and that deposition of both neutrophil and eosinophil granule proteins occurs in the IgE-mediated late-phase reaction. We evaluated the participation of both eosinophil and neutrophil granule proteins in AD. Cutaneous biopsy specimens and serum and urine samples were obtained from 22 patients with AD. Lesional tissue was examined by means of immunofluorescence for neutrophil elastase and lactoferrin and for eosinophil granule MBP, eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP). Serum levels of elastase, MBP, EDN, and ECP and urine levels of MBP, EDN, and ECP were measured. Marked extracellular deposition of at least one of the eosinophil granule proteins was present in the dermis of 15 of the 22 AD skin specimens, but minimal or no extracellular neutrophil elastase or lactoferrin deposition was observed in any specimens. Serum and urine levels of MBP, EDN, and ECP in the patients were elevated when compared with those of normal controls, whereas serum levels of neutrophil elastase were not elevated. Serum MPB levels correlated with extent of body surface involvement. These results suggest that eosinophil degranulation occurs in AD but that neutrophil degranulation does not. Although eosinophil degranulation is prominent in both the late-phase reaction and in AD, the lack of neutrophil degranulation in AD demonstrates differences in the inflammatory reactions.

Adolescent↗
PubMed1994

The effect of immunotherapy on the cutaneous late phase response to antigen.

BACKGROUND: This study used the skin chamber model to evaluate prospectively the effect of immunotherapy (IT) on the cutaneous early and late phase response (LPR) to epicutaneous antigen challenge. METHODS: Nine subjects with allergic rhinitis were studied at three time points: before starting IT, after 3 months of IT, and after 6 months of IT. Skin chamber histamine content was measured hourly for 12 hours, and cell counts performed hourly during hours 6 to 12. An intradermal skin test was placed, and the reaction was measured hourly for 12 hours. Skin biopsy specimens were obtained 8 hours after intradermal placement and evaluated for cellular infiltrate and major basic protein deposition. Serum antigen-specific IgG and IgE levels were measured at each time point to confirm physiologic effect of IT. RESULTS: Six months of IT significantly (p < 0.05) decreased both early and LPR skin test reactivity and skin chamber histamine for hours 1 to 3, 4 to 6, and 9 to 12. Skin chamber LPR cellular influx decreased significantly (p < 0.05) for neutrophils only. Decrease in LPR histamine after 6 months of IT was significantly correlated with both decrease in mononuclear cells (R2 = 0.817, p = 0.002) and decrease in neutrophils (R2 = 0.813, p = 0.009). Also significantly correlated were decrease in LPR skin test reactivity, with percent change in skin chamber mononuclear cells (R2 = 0.800, p = 0.009) and decrease in early skin test reactivity (R2 = 0.675, p = 0.01). Biopsy specimens showed no consistent change in either dermal cellular infiltrate or deposition of major basic protein. CONCLUSION: IT significantly attenuates cutaneous histamine release and skin test reactivity and is accompanied by a decrease in skin chamber LPR neutrophil influx without significantly altering the dermal infiltrate at 8 hours.

Adult↗
PubMed1994

Eosinophil granule proteins inhibit substance P-induced histamine release from human skin mast cells.

We have investigated the activity of the four principal cationic proteins of the eosinophil granules, major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil-derived neurotoxin, and eosinophil cationic protein on histamine release from human skin mast cells. These four cationic proteins, over the concentration range of 10 to 200 micrograms/ml, did not induce significant histamine release, nor did they prime anti-IgE-induced histamine release from human skin mast cells significantly. However, a brief incubation (15 minutes) of two of the four principal eosinophil granule proteins, MBP and EPO, at concentrations of 50 to 200 micrograms/ml, caused a significant concentration-related inhibition of histamine release induced by 30 mumol/L substance P. The concentrations producing 50% inhibition for MBP and EPO on substance P-induced histamine release were 30 micrograms/ml and 100 micrograms/ml, respectively. This inhibitory effect appears to be a direct effect of these proteins on skin mast cells because purified (78% to 85%) skin mast cells displayed a similar response to MBP and EPO (n = 4). Also, when skin mast cells were incubated with 100 micrograms/ml MBP and EPO for 15 minutes and washed twice before activation by substance P, the inhibitory effect was not altered. These two proteins also inhibited histamine release induced by 10 micrograms/ml compound 48/80. These results suggest that MBP and EPO affect the same binding site(s) on skin mast cells as those of substance.

Blood Proteins↗
PubMed1994

Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is an autoimmune subepidermal blistering disease that may be associated with drug exposure. OBJECTIVE: Our purpose was to compare the clinical, pathologic, and immunofluorescence findings in drug-induced LABD with those in the idiopathic type. METHODS: Six patients with an acute drug eruption were identified who had linear IgA deposition at the basement membrane zone (BMZ). Lesional tissue was examined by brightfield microscopy, and perilesional tissue was examined by direct immunofluorescence (DIF). The presence of circulating BMZ antibody was assayed by indirect immunofluorescence (IIF) on monkey esophagus (ME) and salt-split human skin (SS). RESULTS: Histopathologic examination showed subepidermal bullae with varying numbers of inflammatory cells. DIF showed linear IgA at the BMZ; three of the patients also had weak deposition of C3 at the BMZ. Serum from five patients was studied by IIF. One patient had circulating IgA BMZ antibodies in a titer of 1:80 on ME, localized to the dermal side on SS. All patients were free of lesions within 5 weeks after discontinuation of the drug. CONCLUSION: Drug-induced LABD is a self-limited eruption characterized by linear deposition of IgA without IgG at the BMZ. Most patients lack circulating antibodies. The distribution of lesions and the course of the disease differ from those of idiopathic LABD.

Aged↗
PubMed1994

Bullous morphea: clinical, pathologic, and immunopathologic evaluation of thirteen cases.

BACKGROUND: Bullous morphea is a rare disease. Its pathogenesis is unknown. OBJECTIVE: We evaluated bullous morphea clinically, pathologically, and immunopathologically and investigated the role of spirochetes and eosinophils in its pathogenesis. METHODS: The clinical and pathologic findings from 13 patients with bullous morphea were reviewed. Tissue sections were studied with the Elias-Bosma stain for spirochetes and indirect immunofluorescence for eosinophil granule major basic protein. RESULTS: Bullae were found in all forms of morphea; the lower extremities were the most common sites of involvement. Lymphatic dilatation was found in 77% of the patients. Deposition of major basic protein was found in 60% of cases studied. There was no evidence of spirochetes in any of the specimens examined with the Elias-Bosma stain. CONCLUSION: Our results suggest that the pathogenesis of bullous morphea is related to lymphatic dilatation as well as release of major basic protein from eosinophils in some patients. We found no association between spirochetes and bullous morphea.

Adult↗
PubMed1994

Recurrent cutaneous necrotizing eosinophilic vasculitis. A novel eosinophil-mediated syndrome.

BACKGROUND AND DESIGN: Review of skin biopsy specimens showing necrotizing vasculitis revealed three patients with small dermal vessel eosinophilic vasculitis and common clinical features characterized by glucocorticoid responsive pruritic erythematous, purpuric papules and angioedema associated with peripheral blood eosinophilia. Indirect immunofluorescent localization of eosinophil granule proteins, neutrophil granule proteins, and mast cell tryptase, electron-microscopic evaluation and immunoperoxidase staining for vascular cell adhesion molecule type 1, intercellular adhesion molecule type I, endothelial-leukocyte adhesion molecule type 1, and very-late activation antigen type 4 were performed. Eosinophil-active cytokines in serum were evaluated by an eosinophil survival assay. OBSERVATIONS: Eight skin biopsy specimens from the three patients all showed small-vessel necrotizing vasculitis with exclusive eosinophil infiltration. Ultrastructural study demonstrated degenerating eosinophils and eosinophil granules in proximity to damaged endothelium. The affected small vessels showed marked deposition of the toxic eosinophil granule major basic protein in the vessel walls and expression of vascular cell adhesion molecule type 1 and intercellular adhesion molecule type 1 on the endothelium with adherence of very-late activation antigen type 4-positive eosinophils; E-selectin staining was negative. The presence of interleukin 5 in serum available from one patient was detected by an eosinophil survival assay. CONCLUSIONS: We studied three patients whose cutaneous lesions showed small-vessel eosinophilic vasculitis and who presented with recurrent glucocorticoid-responsive pruritic purpuric papules and angioedema. The presence of eosinophil-active cytokines in serum and the expression of vascular cell adhesion molecule type 1 on the endothelium of affected vessels may contribute to the selective adherence and localization of activate eosinophils. Subsequent release of cytotoxic proteins such as major basic protein may result in destruction of the endothelium in this unique syndrome.

Adolescent↗