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PubMed1990

Spindle cell neoplasms of lymph nodes of probable reticulum cell lineage. True reticulum cell sarcoma?

Primary spindle cell neoplasms involving hematolymphoid organs are extremely rare. We present four cases of spindle cell neoplasms of unusual phenotype arising within lymph nodes. Two of the four cases showed morphologic and immunophenotypic features suggestive of interdigitating reticulum cell lineage; these cases expressed several macrophage antigens and S-100 protein but not CD1. The other two cases showed evidence suggestive of dendritic reticulum cell lineage. Both cases expressed HLA-DR, several macrophage antigens, complement receptors C3b and C3d; one case expressed R4/23; both showed the presence of desmosomes on ultrastructural examination. A germline configuration for the immunoglobulin heavy chain and beta-T--cell receptor genes was detected in all four cases. Of the two patients in the first group, one had local recurrence of tumor; the other died of widespread metastases. Of the two patients in the second group, both are alive and well at 12 and 27 months follow-up, respectively.

Adult↗
PubMedDate not supplied

The effect of C3 depletion on resistance of hamsters to infection with the yaws spirochete.

The role of complement in humoral-mediated resistance to frambesial infection (yaws) needs to be defined. The level of serum C3 was reduced shortly after infection of hamsters with Treponema pallidum subspecies pertenue. Five weeks after frambesial infection, the serum C3 level began to increase and by week 7 no difference was detected between infected and uninfected hamsters. When C3 was depleted in hamsters by injection of 20 units of cobra venom factor (CoVF), two alterations in host resistance to frambesial infection occurred. Depletion of C3 abrogated the ability of immune serum to confer complete protection on normal hamsters against infection with the yaws spirochete. In all hamsters receiving immune serum but not CoVF, lesions failed to develop and lymph nodes weighed significantly less (P less than or equal to 0.1) than those of controls. Furthermore, no treponemes were detected in the lymph nodes of passively immunized animals. Second, depletion of C3 increased the susceptibility of hamsters to frambesial infection. The onset and progression of frambesial lesions were enhanced as compared with frambesial-infected hamsters not treated with CoVF. Finally, CoVF treatment did not reduce the ability of frambesia-immune hamsters cured of disease with penicillin to resist reinfection. These results demonstrate that complement influences the pathogenesis of yaws.

Animals↗
PubMed1996

Prevention of hyperacute rejection by human decay accelerating factor in xenogeneic perfused working hearts.

As a potential source of organs for xenotransplantation, pigs that are transgenic for human decay accelerating factor (DAF) have been bred in order to overcome hyperacute rejection. We investigated the protective effect of human DAF in a porcine working heart model perfused by human blood. Hearts of normal landrace pits served as controls. The following parameters were measured: stroke work index, coronary flow and arteriovenous oxygen consumption, 6-keto prostaglandin F1alpha and prostaglandin E2 as markers of endothelial cell activation; creatine phosphokinase and lactate dehydrogenase for evaluation of the extent of myocardial damage; TNFalpha and IL-6 as markers of mononuclear cell activation. Histological and ultrastructural investigations from myocardial tissue sections were done at the end of perfusion. Human (h) DAF appeared to inhibit complement-mediated endothelial cell activation of transgenic pig hearts successfully. This was in contrast to landrace pig hearts, which had a sixfold increase of prostaglandin levels during perfusion with human blood. The cardiac weight increase during perfusion time due to interstitial edema tended to be less in the hDAF group. Myocardial damage was minimal in transgenic hearts, whereas normal pig hearts produced a threefold increase of creatine phosphokinase and lactate dehydrogenase levels. In these hearts, electron microscopy revealed single cell necrosis of myocytes and vacuolization of mitochondria with cristae rupture. According to the results obtained in the working heart model, the breeding of pigs that are transgenic for hDAF represents a promising step to making heart xenotransplantation a clinical reality in the future.

Acute Disease↗
PubMed1990

Expression from cloned DNA of biologically active glycoprotein C of herpes simplex virus type 1 in mammalian cells.

A DNA fragment of the herpes simplex virus type 1 genome encoding glycoprotein C (gC-1) has been cloned into different eukaryotic expression vectors for transient and stable expression of the glycoprotein in a number of cell lines. All of these expression vectors use a non-HSV promoter, such as the adenovirus major late promoter or murine leukemia virus long terminal repeat promoter to express gC-1 in COS and CHO cells or 3T3 cells. The gC-1 protein synthesized was fully glycosylated with both N- and O-linked oligosaccharides. Synthesis of the mature 120K gC-1 glycoprotein involved partially glycosylated 100K and 105K proteins and the non-glycosylated 70K protein as intermediate molecules. Immunofluorescence studies showed that the expressed gC-1 was localized intracellularly in the nuclear envelope as well as on the cell surface. The expressed gC-1 was biologically active and could act as a receptor for the complement component C3b in the absence of other HSV proteins.

Animals↗
PubMed1993

C3d,g deposits in inflammatory skin diseases: use of psoriatic skin as a model of cutaneous inflammation.

Recent studies in our laboratories have shown that human keratinocytes synthesize and secrete complement components including C3. Moreover, human keratinocyte-derived C3 is regarded as a potential source of C3d,g, a recently described constituent of the sublamina densa region of normal epidermal basement membrane. Additionally, human keratinocyte-derived C3 may also contribute to epidermal basement membrane deposits of C3 in autoimmune or inflammatory skin disorders. To further our understanding of the specificity and origin of epidermal basement membrane C3 deposits in normal and diseased skin, we have characterized in situ deposits of C3 and C3 cleavage fragments in various inflammatory skin diseases and utilized a skin equivalent model to assess the deposition of C3 cleavage fragments in neo-basement membrane of epidermal outgrowths from normal or diseased human skin. C3d,g reactivity was found to be greater in all samples of inflamed skin, and typically associated with C3c reactivity at these sites. No immunoglobulins or other complement components were detected. When lesional psoriatic skin rich in epidermal basement membrane C3c was used in our organ culture system, C3 incorporation within neo-basement membrane was observed. These results show that human keratinocyte-derived C3 may contribute to inflammatory reactions in skin as well as account for deposits of C3d,g in normal epidermal basement membrane.

Basement Membrane↗
PubMed1991

Selective inactivation of human neutrophil elastase by synthetic tannin.

Tannins of natural or synthetic origin are well-known adjuvants in topical anti-inflammatory therapy of skin diseases. In this study, the influence of synthetic tannin on neutrophil accumulation, enzyme release, and on the proinflammatory activity of neutrophil-derived enzymes was investigated. The results show that synthetic tannin (Tamol) specifically inhibits the neutrophil serine protease human leukocyte elastase (HLE) in an irreversible manner with a half-maximal inhibitory concentration (IC50) of 0.3 microgram/ml. Exogenous protein partially abolished the tannin-dependent HLE inhibition (IC50 of Tamol at 1% protein-concentration:1.0 microgram/ml). Synthetic tannin did not influence the activities of other neutrophil enzymes like Cathepsin G, beta-glucuronidase, and myeloperoxidase. The specificity of Tamol for HLE was further substantiated by the lack of inhibition of other serine proteases. Additionally, Tamol had no effect on f-met-leu-phe-induced neutrophil chemotaxis and did not alter enzyme degranulation of neutrophils in response to f-met-leu-phe and opsonized zymosan. We conclude from our results that the anti-inflammatory properties of synthetic tannin may at least in part be due to inactivation of the proinflammatory protease HLE.

Cell Degranulation↗
PubMed1995

Mechanism of human polymorphonuclear leukocyte adhesion to serum-treated corneocytes.

The accumulation of polymorphonuclear leukocytes (PMN) beneath the stratum corneum is a characteristic histopathologic finding in various aseptic pustular dermatoses. To elucidate the pathomechanism involved in this phenomenon, we investigated whether PMN also attach to a sheet of corneocytes in vitro. A 1-cm2 corneocyte sheet was attached to a sterile glass slide with double adhesive tape used for skin graft surgery before incubating with human serum. The PMN suspension then was applied to the sheet. Attached cells were stained with May-Grunwald-Giemsa and counted with a computer image analyzer. We quantitatively assessed PMN adhesion to the serum-treated corneocyte sheets, which was mediated by activation of the alternative complement pathway. Addition of either anti-CD18 or anti-CD11b antibody to the assay system resulted in a marked reduction of PMN adhesion. We also demonstrated immunohistochemically that iC3b was formed on the serum-treated corneocytes. These findings suggest that PMN attach to serum-treated corneocytes through an interaction of CR3 expressed on PMN with iC3b-coated corneocytes. In addition, we found that this adhesion was enhanced by activation of PMN with phorbol myristate acetate. From these results, we speculate that complement activation by corneocytes occurs in the cutaneous lesions of aseptic pustular dermatoses and that PMN can be stimulated by the interaction with iC3b-opsonized corneocytes as well as by chemotaxins, leading to damage of the surrounding epidermal keratinocytes.

Blood Physiological Phenomena↗
PubMed1992

Clinical, histologic, and immunofluorescent distinctions between subacute cutaneous lupus erythematosus and discoid lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) was originally described and distinguished from discoid lupus erythematosus (DLE) on the basis of clinical examination of the skin, but subsequent reports have questioned the concept of SCLE as a marker of a unique subset of LE patients. We classified 27 lupus patients, on the basis of cutaneous exam, as having discoid lupus skin lesions, subacute cutaneous skin lesions, or systemic lupus erythematosus (SLE) without DLE or SCLE lesions. Clinical features most characteristic of SCLE rather than DLE were superficial, non-indurated, non-scarring lesions, and photosensitivity, with lack of induration being the single most helpful finding. Histologic examination of lesional skin showed a relatively sparse, superficial infiltrate in SCLE and a denser, deeper infiltrate in DLE. A distinctive pattern of staining with direct immunofluorescence, particulate epidermal IgG deposition, was found in seven of seven SCLE patients (all anti-Ro/SSA positive) and none of the other patients. This distinctive pattern can be reproduced experimentally when anti-Ro/SSA autoantibodies are infused into human skin-grafted mice. Particulate dermal-epidermal junctional staining was the pattern seen in the patients who did not have SCLE. Clinically defining SCLE as a superficial inflammatory form of cutaneous lupus (i.e., considering lesions to be DLE if they are indurated) results in a meaningful segregation of SCLE and DLE patient groups. The epidermal IgG deposits unique to SCLE provide independent evidence that the clinical findings that were used to identify the patient groups actually identify distinctive cutaneous lupus subsets. The observation that antibodies are present in a different location in the skin in SCLE than in DLE indicates that SCLE and DLE are likely to have different pathomechanisms.

Antibodies, Antinuclear↗
PubMed1989

Defective expression of basement membrane-associated C3d,g in papulonodular basal cell carcinomas.

Recent studies in our laboratory have shown that C3d,g, a 41,000-Da fragment of the third component of complement, is present along the base of the lamina densa and in the sublamina densa region of normal human epidermal basement membrane, but absent from the skin of a patient with congenital C3 deficiency. In studies of human skin, papulonodular basal cell carcinomas have served as a useful model for the investigation of various basement membrane antigens and matrix proteins. To further investigate the presence of C3d,g within epidermal basement membrane as well as examine its relationship with other known basement membrane constituents, we have analyzed serial sections of ten papulonodular basal cell carcinomas by light and immunofluorescence microscopy. In these studies, C3d,g was either absent (N = 9) or minimumly detectable (N = 1) in tumor nest basement membranes. While bullous pemphigoid and KF-1 antigens were absent (N = 6 and N = 3, respectively) or significantly decreased (N = 4 and N = 7, respectively), epidermolysis bullosa acquisita antigen was routinely present though somewhat (N = 3) or moderately decreased (N = 3). Laminin and type IV collagen were expressed normally in all tumor nest basement membranes. All constituents, including C3d,g, were present in adjacent normal epidermal basement membrane of these tumor samples. This study has demonstrated antigenic alterations within each ultrastructural subregion of papulonodular basal cell carcinoma tumor nest basement membranes by identifying the virtual absence of C3d,g (sublamina densa) as well as a significant reduction in KF-1 (lamina densa) and bullous pemphigoid (lamina lucida) antigens. Moreover, the presence of laminin, type IV collagen, and epidermolysis bullosa acquisita antigen in tumor nest basement membranes suggests that these particular constituents neither cleave C3 nor act as essential binding sites for passive incorporation of this complement component in epidermal basement membrane. These studies give additional support to the hypothesis that C3d,g is a previously unrecognized constituent of normal epidermal basement membrane and does not represent passive incorporation of circulating C3 at this site in human skin.

Adult↗
PubMed1990

Studies of C3d,g in normal human epidermal basement membrane.

Recent studies in our laboratory have demonstrated that polyclonal as well as monoclonal antibodies directed against C3d,g, a specific 41,000-Da fragment of the third component of complement, bind normal human epidermal basement membrane in a continuous pattern. No such reactivity is present within dermal microvascular basement membranes. By direct immunofluorescence microscopy, anti-human C3d,g antibodies bind the base of the cleavage plane in 1 M NaCl split human skin. By immunoelectron microscopy, anti-human C3d,g reactivity is found along the base of the lamina densa and in the sublamina densa region. Control antibodies directed against human C3, C3c, C5, IgG, IgA, or IgM do not bind normal human epidermal basement membrane or identify in situ deposits of immune complexes in multiple samples of normal human skin that are all positive for C3d,g. Preabsorption of monoclonal or polyclonal anti-human C3d,g antibodies with purified human C3d completely blocks these reagents' epidermal basement membrane reactivity. Studies of skin samples from a patient with congenital C3 deficiency reveal that anti-human C3d,g antibodies do not bind this subject's epidermal basement membrane. Moreover, in vitro treatment of this patient's skin with normal serum, aged serum containing C3d,g, purified human C3, or zymosan-serum reaction mixtures does not restore epidermal basement membrane anti-human C3d,g binding. Studies of other primate tissues demonstrate that C3d,g is not restricted to basement membranes of stratified squamous epithelia as it is also present within renal tubule and glomerular basement membranes. While a recent study has demonstrated that C3d binds laminin in vitro, our investigations show a difference in both the regional and ultrastructural distribution of laminin and C3d,g in normal human skin. Furthermore, C3d,g is absent from laminin-rich basement membranes of papulonodular basal cell carcinomas. These findings suggest that C3d,g is not passively incorporated within selected epithelial basement membranes but rather is a previously unrecognized normal constituent. Basement membrane-associated C3d,g may play a role in adhesive interactions between leukocytes and matrix proteins. Moreover, a C3d,g binding site(s) in selected epithelial basement membranes may account for the accumulation of C3 containing immune complexes in such tissues.

Animals↗
PubMed2005

Inhibition of monocyte-derived dendritic cell differentiation and interleukin-12 production by complement iC3b via a mitogen-activated protein kinase signalling pathway.

We have previously demonstrated that iC3b is deposited at the dermal-epidermal junction of the skin following ultraviolet (UV) exposure and that it plays a role in UV-induced immunosuppression and antigenic tolerance. In vitro, iC3b differentially regulates monocyte production of interleukin-10 (IL-10) and IL-12. Additionally, iC3b arrests monocytic cell differentiation into CD1c-expressing dendritic cell (DC) precursors. The present study addresses mitogen-activated protein kinase (MAPK) signalling following the cross-linking of CR3 by its ligand iC3b with regard to monocyte differentiation and cytokine regulation. Sheep erythrocytes were coated with IgM alone (EA) or iC3b (EAiC3b) to allow for CR3 cross-linking onto monocytes. EAiC3b increased the phosphorylation (p) of extracellular signal-regulated kinase (ERK) MAPK in fresh human monocyte, particularly in monocyte-derived DC (MDDC) that were differentiated by means of GM-CSF (1000 U/ml) and IL-4 (200 U/ml) for 2 days before iC3b exposure for an additional 24 h (P=0.034, n=3). CD1a expression, induced by GM-CSF and IL-4, was inhibited by iC3b (EAiC3b vs. EA, P=0.012, n=4). Conversely, the inhibition of ERK by the specific inhibitor (PD98059), but not the p-38 inhibitor SB203580, restored CD1a expression (P=0.011, n=4) in iC3b-stimulated MDDC. Concordantly, the inhibition of ERK during iC3b exposure fully reversed the inhibition of IL-12p70 induction in MDDC by 95% (P<0.01, n=4) and decreased IL-10 production. Taken together, our data demonstrate that iC3b interferes with MDDC differentiation and IL-12 and IL-10 production is mediated via an ERK MAPK-dependent mechanism. Thus, ERK MAPK inhibition may represent a therapeutic strategy for preventing monocytic precursor diversion away from DC differentiation when monocytes enter injured tissues in which iC3b is generated, such as UV-exposed skin.

Animals↗
PubMed1979

Predominance of T lymphocytes in the dermal infiltrate of atopic dermatitis.

Tissue sections from diseased skin of sixteen patients with atopic dermatitis were investigated with haematoxylin-eosin and toluidine-blue staining, with direct immunofluorescence staining using FITC-conjugated antisera against IgG F(ab')2 and IgM, and with the indirect immunofluorescence method utilizing specific rabbit anti-human T lymphocyte antiserum with FITC-conjugated goat anti-rabbit Ig antiserum as the second layer. Furthermore, cryostat sections were investigated in a closed chamber immune adherence method using aminoethylisothiouronium bromide (AET) treated sheep red blood cells to detect E receptors on T lymphocytes, and with various types of coated sheep red blood cells to detect cells with IgG Fc receptors and complement factor C3b receptors. All sections presented dermal perivascular infiltrates of mononuclear cells as judged by haematoxylin-eosin staining. Staining with toluidine-blue demonstrated varying numbers of mast-cells, but in no case pathological increased number. The majority of the infiltrating cells presented rim-like membrane fluorescence with the anti-T antiserum, and the AET treated sheep red blood cells (SRBC) adhered to the infiltrates, thus indicating a predominance of T lymphocytes in the skin infiltrates of atopic dermatitis.

Adolescent↗
PubMed1983

Effect of house dust mite on serum complement activation and total haemolytic activity in vitro in normal subjects and in patients with bronchial asthma.

House dust mite (Dermatophagoides farinae) has been shown to activate the complement system in vitro by both the classical and alternative pathways in normal serum and in two groups of (skin test positive and skin test negative) patients with bronchial asthma. The activation was dose dependent in the lower range of allergen concentrations. Skin test positive asthmatic subjects showed the maximum activation. Skin test negative patients had activation between skin test positive patients and normal subjects. However, at the higher allergen concentration normal serum and bronchial asthma patients showed similar results.

Asthma↗
PubMed2005

Reduced iC3b-mediated phagocytotic capacity of pulmonary neutrophils in cystic fibrosis.

Cystic fibrosis (CF) is characterized by a neutrophil-dominated chronic inflammation of the airways with persistent infections. In order to investigate whether neutrophils contribute to an inadequacy in the pulmonary defence mechanism, the phagocytic activity of pulmonary and peripheral blood neutrophils from CF and non-CF respiratory patients were compared. Neutrophils were isolated from both the blood and bronchoalveolar lavage fluid of 21 patients with CF (12 male, 9 female; mean age 7.5 years, range 0.25-16.4 years) and 17 non-CF subjects (9 male, 8 female; mean age 5.4 years, range 0.2-13.1 years). The ex vivo phagocytic rate of normal pulmonary neutrophils to internalize zymosan particles opsonized with iC3b was faster than that of circulating neutrophils (P < 0.05), but the maximum capacity (9 particles/cell) was similar. In contrast, pulmonary neutrophils from patients with CF had a lower phagocytic capacity than circulating neutrophils either from the same patients or from normal subjects. This deficiency could not be attributed to (i) the cell surface density of CR3 (CD18/CD11b) receptors, which were not significantly different between the other groups (ii) the signalling ability of the CR3 receptors, using cytosolic free Ca(2+) signalling as the receptor activity read-out or (iii) a decrease in cellular ATP concentration. As CFTR was not detectable on neutrophils from any source by either histochemistry or Western blotting, it was concluded that the reduced phagocytic capacity was not the direct result of a CFTR mutation, but was attributed to a failure of neutrophil phagocytic priming during translocation into the CF lung.

Adenosine Triphosphate↗
PubMed1987

Characterization of a lectin in human plasma analogous to bovine conglutinin.

The structural characteristics of a human plasma protein analogous to bovine conglutinin were studied. The protein was previously found to bind to complement-reacted IgG in a calcium-dependent and N-acetyl-D-glucosamine-inhibitable manner and it further shows cross-reactivity with anti-bovine conglutinin antibody. By gel permeation chromatography the conglutinin activity in human plasma was localized to fractions containing proteins of Mr at around 700,000. The conglutinin was localized by one ELISA for antigen determinants and by another for biological activity. When analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) under non-reducing conditions these fractions were shown to contain proteins of about 300,000. When human conglutinin-like protein, partially purified by affinity chromatography, was analysed unreduced by SDS-PAGE followed by western blotting, the cross-reacting anti-bovine conglutinin antibody bound to a protein with an Mr of 330,000. When the sample was reduced and alkylated before electrophoresis a band of 66,000 was immunostained. The 330,000 and 66,000 proteins were shown to be collagenase sensitive. 125I-iC3b was seen to bind to the 330,000 band when incubated with western blots of partially purified human conglutinin.

Animals↗
PubMed1991

Human follicular dendritic cells: isolation and characteristics in situ and in suspension.

Follicular dendritic cells (FDC) in human tonsils, either in situ in follicular germinal centres or isolated from tissue, were characterized by immunohistochemical, enzyme cytochemical and electron microscopical methods. Using polyclonal and monoclonal antibodies, expression of DRC-1, Ki-M4, HLA-DR, CR1, C1q antigens, a macrophage marker, and surface IgG and IgM were found on isolated FDC and on FDC in situ. None of these reagents proved to be specific for FDC, e.g. the FDC-directed antibodies DRC-1 and Ki-M4 labelled B lymphocytes in cytofluorography. Enzyme cytochemical staining revealed activities of non-specific esterase, acid alpha-naphthylacetate esterase and ATPase in germinal centres and in freshly isolated FDC. Immunohistochemistry demonstrated a weak expression of CD4 by a fraction of isolated FDC, which was confirmed by two-colour immuno-staining and immuno-electron microscopy.

5'-Nucleotidase↗