Infliximab (anti-tumor necrosis factor alpha antibody): a novel, highly effective treatment of recalcitrant subcorneal pustular dermatosis (Sneddon-Wilkinson disease).
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Aged↗
Biomedical subjects
M Hertl
Publications and source records attributed to M Hertl.
[Hepatorenal syndrome].
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Diagnosis, Differential↗
Anticoagulation with hirudin for continuous veno-venous hemodialysis in liver transplantation.
Postoperative encephalopathy after orthotopic liver transplantation can be difficult to diagnose. We report a case of heparin-induced thrombocytopenia in a liver transplant patient who had seizures. Due to poor liver function the patient developed hepatorenal syndrome requiring continuous veno-venous hemodialysis (CVVHD). Initially we used heparin as the anticoagulant. After the diagnosis of heparin-induced thrombocytopenia (HIT) was made, we switched to r-hirudin. No serious side effects, e.g. bleeding or immune sensitization, were seen.
Adult↗
IgG, IgA and IgE autoantibodies against the ectodomain of desmoglein 3 in active pemphigus vulgaris.
BACKGROUND: IgG autoantibodies against desmoglein (Dsg) 3 play a key part in the pathogenesis of pemphigus vulgaris (PV), the most severe autoimmune bullous disorder. OBJECTIVES: To determine whether immunoglobulin isotypes other than IgG are detectable in the sera of patients with PV and whether a particular immunoglobulin subtype is associated with a distinct clinical phenotype of PV. METHODS: Sera from 41 patients with acute-onset, chronic active, and remittent PV disease with mucosal and cutaneous lesions were assayed against a baculovirus-expressed Dsg3 protein by immunoblot analysis. RESULTS: In acute-onset PV, Dsg3-reactive IgG1 was detected in nine of 15 (60%), IgG4 in 14 of 15 (93%), IgA in nine of 15 (60%) and IgE in two of 15 (13%) sera. In chronic active PV, Dsg3-reactive IgG1 was detected in 11 of 18 (61%), IgG4 in 16 of 18 (89%), IgA in 13 of 18 (72%) and IgE in two of 18 (11%) sera. In contrast, sera from patients with remittent PV disease contained only Dsg3-reactive IgG1 in six of eight (75%) and IgG4 in four of eight (50%) cases, but not Dsg3-reactive IgA or IgE. CONCLUSIONS: In extension of previous findings, our study demonstrates that, in addition to IgG autoantibodies, IgA and occasionally IgE autoantibodies reactive with Dsg3 are present in acute and chronic active PV. The detection of Dsg3-reactive autoantibodies of the IgG4, IgA and IgE subclasses in active PV provides additional evidence that PV is a T-helper 2-regulated autoimmune disorder.
Acute Disease↗
Effect of ursodeoxycholate in University of Wisconsin solution on long term preservation of rat livers.
OBJECTIVE: To find out whether the addition of ursodeoxycholate (UDC) to University of Wisconsin (UW) solution reduces injury during preservation of the liver. DESIGN: Controlled laboratory study. SETTING: University hospital, Germany. MATERIALS: Preserved livers from 12 rats. METHODS: Livers were flushed with 10 ml of ice-cold (0-1 degrees C) UW or iso-osmolar UW containing 5 mmol/l UDC. After preservation for 30 hours at 0-1 degrees C and 1 hour at 22 degrees C the livers were reperfused for 4 hours. Aspartate amino-transaminase, alanine aminotransferase, glutamate lactate dehydrogenase, and white blood cell (WBC) and platelet counts were measured during reperfusion. Bile flow and total bile salt secretion rate were also measured. RESULTS: Addition of UDC to UW reduced the release of liver enzymes, slightly increased platelet adherence, and reduced bile flow and bile salt secretion rate. CONCLUSION: The membrane-stabilising effect of UDC may explain the reduction in enzyme release. However, liver function, as expressed by bile salt secretion rate and bile flow was adversely affected.
Adenosine↗
Hydrophilic bile salts protect bile duct epithelium during cold preservation: a scanning electron microscopy study.
Prolonged graft preservation is associated with postoperative bile duct strictures after liver transplantation. We previously showed that hydrophilic bile salts mitigate bile duct preservation injury in a pig model. Because this injury occurs at the epithelial level, scanning electron microscopy was performed to further characterize this effect in vitro. Swine livers were harvested after the intravenous infusion of 1 of 3 solutions: saline (n = 7), tauroursodeoxycholate ([TUDC] hydrophilic; n = 4), or taurodeoxycholate ([TDC] hydrophobic; n = 4). Livers were perfused with University of Wisconsin solution. The bile ducts were flushed retrograde, and the liver was stored at 0 degrees C to 1 degrees C for 20 hours. Bile duct samples were obtained at the time of harvest and 8, 12, 16, and 20 hours thereafter. In saline-infused controls at time 0, the epithelium was intact and composed of uniform cuboidal cells covered with fine regular microvilli. There were no spaces between individual cells. After 8 to 12 hours of preservation, cells were more irregular in shape, with loss of cell-cell contact. The cell surfaces showed fewer microvilli. Surface erosions suggested loss of cell-wall integrity. TUDC was protective, evidenced by normal-appearing cells with uniform microvilli after 16 hours. In contrast, TDC accelerated the injury process, causing cell-surface erosions, blebs, and loss of microvilli as early as time 0. Scanning electron microscopy is an excellent tool to study injury to bile duct epithelium. This study supports the hypothesis that hydrophilic bile salts protect bile ducts during preservation. To determine whether treatment with hydrophilic bile salts can prevent postoperative stricture, in vivo transplantation studies are needed.
Animals↗
Immunologic mechanisms in hypersensitivity reactions to metal ions: an overview.
Metal ions such as Ni2+, Co2+, Cu2+, or Cr3+ are haptens with a high immunogenic potential, as contact dermatitis caused by ionic metals occurs in about 10-15% of the human population. Since alloys containing Ni2+, Co2+, and Cr3+ are components of implants in replacement surgery, dentures, orthodontic wires, and various other devices, adverse reactions to metal ions create serious problems in practical medicine as incompatibility reactions to metal-containing biomaterials. On the other hand, contact dermatitis to metal ions such as Ni2+ is a well-established model for studying the molecular mechanisms involved in the recognition of haptens by the immune system. Although many investigations have been performed to elucidate the molecular interactions causing contact hypersensitivity in man, many aspects remain to be clarified. This review will focus on the experimental data accumulated so far on the immunologic mechanisms responsible for the recognition of metal ions by T cells and eliciting adverse immune reactions causing contact dermatitis.
Cross Reactions↗
IgG, IgA and IgE autoantibodies against the ectodomain of BP180 in patients with bullous and cicatricial pemphigoid and linear IgA bullous dermatosis.
BACKGROUND: Bullous pemphigoid (BP), linear IgA bullous dermatosis (LABD) and cicatricial pemphigoid (CP) are clinically distinct autoimmune bullous skin diseases characterized by autoantibodies against components of the epidermal basement membrane. Like most patients with BP, a significant subgroup of patients with CP has circulating IgG specific for BP180, a transmembraneous protein of hemidesmosomes. Moreover, sera of patients with LABD contain IgA autoantibodies reactive with a 97/120-kDa protein, LABD antigen 1, which is highly homologous to the extracellular portion of BP180. OBJECTIVES: We aimed to determine whether, in these diseases, autoantibody reactivity to BP180 is restricted to distinct immunoglobulin subtypes. METHODS: Utilizing a baculovirus-encoded form of the ectodomain of BP180, sera from patients with BP (n = 10), CP (n = 9), LABD (n = 10) and normal human control sera (n = 10) were analysed by immunoblot for IgG, IgA and IgE reactivity against BP180. RESULTS: All of 10 BP sera displayed IgG, IgA and IgE reactivity with BP180. Six and seven of nine CP sera, respectively, contained IgG and IgA autoantibodies reactive with BP180, but none of nine sera contained BP180-specific IgE. Nine of 10 LABD sera contained IgA, and six of 10 IgG, which was reactive with BP180, but none of 10 sera showed IgE reactivity to BP180. CONCLUSIONS: The presence of IgG and IgA autoantibody responses to BP180 in patients with three clinically distinct autoimmune bullous diseases indicates that an autoimmune response to the same distinct adhesion protein may lead to different clinical manifestations. It is therefore conceivable that variable epitopes of BP180 are targeted by the different autoantibody isotypes, resulting in the distinct clinical pictures.
Adult↗
Frequency analysis of autoreactive T-helper 1 and 2 cells in bullous pemphigoid and pemphigus vulgaris by enzyme-linked immunospot assay.
BACKGROUND: Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are autoimmune bullous skin diseases mediated by autoantibodies against adhesion molecules of the skin. Previous studies have identified autoreactive T cells in patients with BP and PV, which may be critical in providing B-cell help for autoantibody production. OBJECTIVES: To evaluate the frequency of autoreactive T-helper (Th) 1 and Th2 cells in patients with BP (n = 7) or PV (n = 1) and in healthy controls (n = 11). METHODS: In an enzyme-linked immunospot (ELISPOT) assay, microtitre plates were coated with antihuman interleukin (IL)-5 IgG or antihuman interferon (IFN)-gamma IgG prior to culturing human peripheral blood lymphocytes (PBL) with BP180 or desmoglein (Dsg) 3 proteins for 7 days. Cytokine-producing autoreactive T cells were visualized as spot-forming units. RESULTS: One BP patient with extensive blisters had 5.1 +/- 1.5 (mean +/- SD) BP180-reactive Th1 cells and 2.9 +/- 1.5 Th2 cells per 105 PBL. In contrast, PBL from six BP patients in remission or on immunosuppressive therapy did not form IFN-gamma- or IL-5-producing spots per </= 5 x 105 PBL. The patient with oral PV had 4.7 +/- 2.4 Th1 cells and 3.0 +/- 0.4 Th2 cells per 105 PBL and a vigorous PBL response to Dsg3. In addition, three of 10 controls had BP180-reactive Th1 (2.7-13.8 per 105 PBL) and Th2 (0.3-1.8 per 105 PBL) cells and one control had 9.0 +/- 0.7 Th1 cells and 1.1 +/- 0.8 Th2 cells per 105 PBL, with reactivity to Dsg3. ELISPOT reactivity correlated with 3H-thymidine incorporation in six of seven patients and controls with autoreactive T-cell responses. CONCLUSIONS: The ELISPOT assay seems to be promising for the quantitative and qualitative analysis of autoreactive T-cell responses in BP and PV.
Autoimmunity↗
IgG autoantibodies from bullous pemphigoid patients recognize multiple antigenic reactive sites located predominantly within the B and C subdomains of the COOH-terminus of BP230.
Bullous pemphigoid is a subepidermal bullous disorder characterized by an autoantibody response against the bullous pemphigoid antigen 230 (BP230) and the bullous pemphigoid antigen 180 (BP180), a cytoplasmic component and a transmembrane component, respectively, of hemidesmosomes. Although immunodominant sequences within the extracellular domain of BP180 have been identified, characterization of the antigenic sites on BP230 is still incomplete. To identify autoantibody-reactive sites on BP230 and to examine whether the targeted regions are contained within functionally important domains, recombinant fragments encompassing almost the entire BP230 were used to assess the reactivity of 25 bullous pemphigoid sera by immunoblotting. Our results demonstrate that (i) the region bearing the B and C subdomains of the COOH-terminus of BP230 contains immunodominant sequences recognized by the majority of bullous pemphigoid sera; (ii) additional autoantibody- reactive sites are present over extended regions of the NH2-terminal half of BP230 without evidence for antigenic cross-reactivity between the NH2- and COOH-termini of BP230; and, finally, (iii) autoantibodies reacting with the BP230 tail predominantly belong to the IgG4 and IgG1 subclasses, suggesting that both autoreactive TH2 and autoreactive TH1 cells regulate the autoantibody response to immunodominant sequences of BP230. As the COOH- terminus of BP230 mediates the attachment of keratin intermediate filaments to the hemidesmosomal plaque, whereas its NH2-terminus contains sequences important for its interaction with other constituents of hemidesmosomes, autoantibodies to BP230 might precipitate subepidermal blister formation and perpetuate the disease not only by eliciting an inflammatory reaction but also by interfering with the function of BP230 and thus the stability of hemidesmosomes.
Aged↗
Humoral and cellular autoimmunity in autoimmune bullous skin disorders.
Autoimmune bullous skin diseases, such as pemphigus vulgaris (PV) and bullous pemphigoid (BP), are severe, frequently life-threatening skin disorders. Immunologically, they are characterized by the presence of serum autoantibodies (auto-Ab) targeting distinct adhesion molecules of the epidermis or dermoepidermal basement membrane zone. Antibody (Ab) binding interferes with the adhesive function of these molecules, leading to detachment and subsequently blister formation. PV is the classical example of an Ab-mediated autoimmune disease affecting epidermal adhesion. Auto-Ab against the desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the pathogenesis of this disease, since the transfer of serum IgG Ab reactive with Dsg3 into newborn mice induces a bullous skin disease resembling PV. Autoreactive T cell responses to Dsg3 may be critical in the pathogenesis of PV because: (1) Ab production generally requires T cell help; (2) the involvement of CD4+ T lymphocytes in PV has been suggested by the strong association with distinct HLA class II alleles, and (3) T cell recognition of epitopes of Dsg3 may be crucial for the initiation and perpetuation of the production of Dsg3-specific auto-Ab by B cells. In PV and BP, autoreactive CD4+ T cells recognize distinct epitopes of the extracellular portions of Dsg3 and BP180 [BP antigen 2 (BPAG2) or type XVII collagen], respectively, and produce preferentially T helper type 2 (TH2) cytokines. Auto-Ab of the TH2-dependent IgG4 subtype are preferentially seen in the active stages of both PV and BP, while auto-Ab of the TH1-dependent IgG1 subclass are predominant during the chronic course of these disorders. These observations suggest that autoreactive TH2 cells may provide targets to specifically modulate the T cell-dependent production of pathogenic auto-Ab in these disorders.
Animals↗
Telomerase activity in neuroendocrine tumors.
INTRODUCTION: Neuroendocrine tumors span a rather heterogenic group of tumors, which differ in malignant potential. Very few is known about the tumorigenesis of neuroendocrine tumors. Telomeres seem to stabilize chromosomes and prevent DNA degradation and provide a signal of cellular senescence. During each cell cycle of replication, telomeres are progressively shortened. Non-diseased somatic cells, when the telomere length is reduced to a critical point, exit from the cell cycle and become senescent. In tumor cells, telomere shortening is prevented by the DNA-complex telomerase. Aim of this study was to evaluate the role of telomerase activity in the pathogenesis of neuroendocrine tumors and whether it can be a clinically useful marker for malignant potential. METHODS: Telomerase activity was determined in frozen tissue samples of 31 patients with neuroendocrine tumors by means of the "telomeric repeat amplification protocol" (TRAP)-assay. Classification of the tumors was done by the clinical course and histologic examination. There were 11 benign and 20 malignant neuroendocrine tumors. Telomerase activity was expressed as percentage of the positive control. RESULTS: 25 tumors had a telomerase activity between 0-5% of the positive control (group I), 5 tumors between 5-20% (group II) and 1 tumor over 20% (group II). We were not able to distinct malignant from benign tissue by means of the telomerase activity assay. There was no association with telomerase activity and clinicopathological parameters. CONCLUSIONS: The data indicate that telomerase activity does not seem to be associated with the tumorigenesis of neuroendocrine tumors and can therefore not be used as a suitable marker for malignancy.
Adult↗
Tauroursodeoxycholate ameliorates reperfusion injury after pig liver transplantation.
Reperfusion injury is a serious problem after clinical liver transplantation, often leading to dys- or even non-function of grafts. The present study was designed to determine whether the hydrophilic bile salt tauroursodeoxycholate (TUDC), known to be hepatoprotective in cholestatic liver disease, mitigates reperfusion injury in an in vivo pig liver transplantation model. Liver transplantation was performed in 12 pigs after a preservation time of 8 h. TUDC was administered to donor and recipient animals, and saline to controls. Blood was drawn at different time points for determination of liver enzymes. Bile samples were collected, and bile flow (BF), and bile salt secretion rate (BSSR) determined. Samples of liver tissue and bile ducts were taken for assessment by light and electron microscopy. Liver enzymes were significantly lower in the TUDC group. BF and BSSR were significantly higher. Microscopy revealed better preservation of bile duct architecture of the TUDC-infused animals. We can conclude that infusions of TUDC in pig livers ameliorate reperfusion injury in vivo. The molecular basis for this finding may be the membrane stabilizing effect of TUDC. Further studies are warranted to clarify its effect.
Animals↗
In vivo protection of the pig liver against ischemia/reperfusion injury by tauroursodeoxycholate.
INTRODUCTION: Tauroursodeoxycholate (TUDC) is used routinely in the treatment of cholestatic liver disease. The present study was designed to determine whether it would mitigate ischemia/reperfusion injury in an in vivo pig liver-transplantation model. METHODS: Transplantation was performed in 12 animals after a preservation time of 8 h. In the control group (n=6), 0.9% saline was infused into the donor. In the experimental group (n=6), TUDC was given intravenously at a rate of 2 micromol/kg body weight per minute. In the recipient, infusion was started at the time of reperfusion; saline was infused for 400 min in the control group, TUDC for the same duration at a rate of 0.2 micromol/kg body weight per minute in the experimental group. Blood was drawn for determination of liver enzymes. Bile samples were collected and bile flow (BF) and bile salt secretion rate (BSSR) were determined. RESULTS: One-week survival was 92% and not different among groups. Liver enzymes were lower in the TUDC group than the saline group. Prior to TUDC infusion in the donor animals, there were no differences in BF and BSSR. After infusion of TUDC, BF and BSSR were highly significantly different than the control group. DISCUSSION: Infusion of TUDC in pig livers protects against ischemia/reperfusion injury in vivo. This might be due to the membrane-stabilizing effect of TUDC. Preconditioning of liver grafts with TUDC could potentially lead to improved liver function post-transplantation.
Analysis of Variance↗
Childhood bullous pemphigoid associated with IgA antibodies against BP180 or BP230 antigens.
Linear IgA bullous dermatosis (LABD) comprises a heterogeneous group of subepidermal blistering disorders characterized by in situ bound IgA antibodies in epidermal basement membrane. We report three children presenting clinical and immunopathological features characteristic of LABD. By immunoblotting, the three patients' sera contained IgA antibodies that reacted against the bullous pemphigoid (BP) antigen 180 and or BP230, molecular markers for BP. In addition, IgG antibodies directed against the ectodomain of BP180 were detected by an enzyme-linked immunosorbent assay using a eukaryotic recombinant form of BP180. Consistent with recent studies suggesting that the LABD antigen 1, the predominant autoantigen of LABD, is either a proteolytic product of BP180 or an isoform of the BP180 gene, our findings indicate that a subset of children with features of LABD have a distinct form of BP associated with an IgA response.
Antibodies, Anti-Idiotypic↗
IgG autoantibodies from bullous pemphigoid (BP) patients bind antigenic sites on both the extracellular and the intracellular domains of the BP antigen 180.
Bullous pemphigoid (BP) and gestational pemphigoid (PG) are subepidermal blistering disorders associated with autoantibodies directed against two components of hemidesmosomes: the BP antigen 180 (BP180) and the BP antigen 230 (BP230). Autoantibodies against the extracellular domain (ECD) of BP180 are thought to play an initiatory role in subepidermal blister formation. To characterize the targeted antigenic sites on BP180, we have assessed the reactivity of sera from BP and PG patients against eukaryotic recombinant proteins encompassing various portions of the ECD and the intracellular domain (ICD) of BP180. Twenty-two of 22 (100%) BP sera that immunoblotted BP180 in keratinocyte extracts, bound a mutant form consisting of the entire ECD of BP180, whereas only three of these 22 sera (14%) reacted against the ECD of BP180 lacking the NC16A membrane proximal region. Thirteen out of the 22 (59%) BP sera recognized the ICD of BP180. Circulating IgG from a representative BP patient that was affinity purified against the ECD of BP180 did not bind the ICD when reblotted, indicating that there was no antigenic cross-reactivity between the ECD and the ICD of BP180. Reactivity against the ICD of BP180 was further ascertained by immunofluorescence microscopy studies showing that nine of the 22 (41%) BP sera stained COS-7 cells expressing the ICD of BP180. Using deletion mutants of the ICD of BP180, the majority of the sera was found to recognize the central region of the ICD of BP180. Specifically, an immunodominant region was localized to an 87-amino acid segment located towards the NH2-terminus of BP180. In contrast to BP sera, five of six (83%) PG sera contained IgG that recognized exclusively the NC16A region, whereas none bound to the ICD of BP180. Together, the results indicate that in BP, autoantibody reactivity to BP180 is not exclusively restricted to the NC16A region, but that additional antigenic determinants exist on the ICD of BP180. The observed heterogeneous immune response against BP180 might reflect intramolecular epitope spreading. Because the ICD ofBP180 harbors functionally important regions, it is possible that autoantibodies against the ICD of BP180 have pathogenic significance for the progression of the disease.
Adult↗
Analysis of the T cells that are potentially involved in autoantibody production in pemphigus vulgaris.
Pemphigus vulgaris (PV) is a classical example of an antibody-mediated autoimmune disease of the skin. Direct evidence exists that autoantibodies against the desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the pathogenesis of this disease. The transfer of serum IgG antibodies reactive with Dsg3 into newborn mice induces a bullous skin disease resembling PV. Autoreactive T cell responses to Dsg3 may be critical in the pathogenesis of PV because 1) antibody production generally requires T cell help, 2) the involvement of CD4+ T lymphocytes in PV has been suggested by the strong association with distinct HLA class II alleles, and 3) T cell recognition of epitopes of Dsg3 may be crucial for the initiation and perpetuation of the production of Dsg3-specific autoantibodies by B cells. We and others have identified autoreactive T cells recognizing distinct epitopes of the extracellular portion of Dsg3 in PV patients. These autoreactive CD4+ T cells preferentially produced TH2 cytokines such as IL-4, and IL-10. Autoantibodies of the TH2-dependent IgG4 subtype are preferentially seen in active stages of PV disease, while autoantibodies of the TH1-dependent IgG1 subclass are predominant upon remission of PV. Healthy individuals who carried HLA class II alleles similar or identical to those found to be highly prevalent in PV also developed autoreactive T cell responses to Dsg3. Autoreactive T cells from PV patients produced both TH1 and TH2 cytokines; autoreactive T cells from normals produced TH0 cytokines. These observations suggest that Dsg3-specific T cells may provide targets to eventually modulate the T cell-dependent production of pathogenic autoantibodies in PV.
Alleles↗