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J Haberstok

Publications and source records attributed to J Haberstok.

11 recordsLinked to original sources
PubMed2004

The role of antigen presenting cells at distinct anatomic sites: they accelerate and they slow down allergies.

It has been repeatedly demonstrated that allergic reactions are driven by the continuous flow of antigen uptake and presentation processes, which are perpetuated mainly by dendritic cells (DC). The ability of allergens to cause allergic inflammation is contingent upon the presence of an immunological milieu and microenvironment that either privileges Th2 responses or prohibits these reactions by the induction of contraregulatory anti-inflammatory activities of the immune system. In the light of recent developments it appears that DC have to manage two opposing tasks: on the one hand they can favor pro-inflammatory reactions and actively induce a T-cell response, yet on the other hand they serve an important function as 'silencers' in the immune system by sending out anti-inflammatory, tolerance inducing signals. This unique capacity of DC has opened several exciting possibilities for a role of DC in both - accelerating and slowing down allergic reactions. It is therefore a challenge to understand in which way DC subtypes located at distinct anatomic sites with frequent allergen exposure, such as the skin, the nasal mucosa, the respiratory tree or the mucosa of the intestinal tract can have an impact on mechanisms involved in tolerance induction or effective immunity.

Allergens↗
PubMed2001

In situ expression of the costimulatory molecules CD80 and CD86 on langerhans cells and inflammatory dendritic epidermal cells (IDEC) in atopic dermatitis.

The functional expression of costimulatory molecules on antigen-presenting cells may be a key event in the pathogenesis of atopic dermatitis (AD). Recently, the expression of CD86 (B7-2/B70) has been demonstrated on CD1a+ epidermal dendritic cells (DC) in AD lesions by immunohistological and functional analysis. Therefore, we sought to further characterize the in situ expression of costimulatory molecules on these cells, considering the two subpopulations of (1) CD1a+++/CD11b- Langerhans cells (LC) containing Birbeck granules and (2) CD1a+/CD11b+++ inflammatory dendritic epidermal cells (IDEC), devoid of Birbeck granules, from AD and other inflammatory skin diseases. Flow cytometry, skin mixed lymphocyte reactions (SMLR) and immunohistological analysis were performed, and showed that IDEC and not LC are the relevant cells expressing the costimulatory molecules CD80 and CD86 in situ. This expression varied with the underlying diagnosis, with AD showing the highest expression of both CD80 and CD86 in situ. Furthermore, the expression of CD80, CD86 and CD36 were significantly correlated. With short-term culture, both CD80 and CD86 were further upregulated on LC and IDEC. Finally, anti-CD86 antibody reduced the stimulatory activity of epidermal DC. These results indicate that costimulatory molecules on LC and IDEC might play a role in the pathogenesis of AD.

Antigens, CD↗
PubMed2001

Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease in which antigen-presenting epidermal dendritic cells (DCs), ie, Langerhans cells and the so-called inflammatory dendritic epidermal cells (IDECs) expressing the high-affinity receptor for IgE (FcepsilonRI) may play a significant pathophysiologic role. Therapeutic efficacy of the immunosuppressive macrolide tacrolimus (FK506) in AD has been demonstrated in clinical trials, but little is known of its mode of action. OBJECTIVE: The present study focused on the effects of topical tacrolimus treatment on epidermal CD1a+/FcepsilonRI+ DC populations in lesional AD. METHODS: Immunohistological analysis, epidermal DC phenotyping, and functional studies were performed on skin biopsy specimens from treated and untreated lesional skin of 10 patients with AD participating in a clinical trial with tacrolimus. RESULTS: Untreated lesional skin was characterized by a high proportion of CD1a+ cells, which was largely due to a high proportion of IDECs strongly expressing FcepsilonRI. Epidermal DCs isolated from untreated lesional skin exhibited high stimulatory activity toward autologous T cells, which was strongly reduced while clinical improvement was seen during application of tacrolimus. Concomitantly, a decreased FcepsilonRI expression was observed in both Langerhans cells and IDECs. Finally, topical tacrolimus led to a progressive decrease in the IDEC population within the pool of CD1a+ epidermal DCs and also to a decrease in their CD36 expression, which is indicative of lower local inflammation. CONCLUSION: Epidermal CD1a+ DCs may represent a target for topical tacrolimus in the treatment of AD.

Administration, Topical↗
PubMed2001

Standardized extracts from Chinese herbs induce IL-10 production in human monocyte-derived dendritic cells and alter their differentiation in vitro.

BACKGROUND: The efficacy of traditional Chinese medicine (TCM) as a treatment for atopic dermatitis has been evaluated in clinical trials. Until now, the underlying mechanism of this treatment has remained completely elusive; this is particularly true of its putative effects on dendritic cells (DCs), which might play a pivotal role in the disease. OBJECTIVE: We investigated the influence of a standardized extract from 10 Chinese herbs that was successfully used in clinical trials on the generation of monocyte-derived DCs from atopic donors. METHODS: Detailed phenotypic and functional exploration of DCs generated in the presence of IL-4 and GM-CSF and treated with different concentrations of TCM or a placebo control was performed. RESULTS: TCM profoundly affected the morphology and phenotype of the developing DCs. They lost their typical dendritic morphology and decreased their expression of CD1a as well as the low-affinity IgE receptor CD23. Most importantly, TCM-exposed DCs exhibited a diminished stimulatory activity toward autologous antigen-specific and allogeneic T cells while secreting high amounts of IL-10. CONCLUSION: TCM induces immunopharmacologic alterations on DCs from atopic donors in vitro. These alterations might account, at least in part, for the therapeutic effect of this treatment in AD in vivo.

Dendritic Cells↗
PubMed2000

Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis.

UNLABELLED: Atopic dermatitis (AD) is a clinically characteristic, chronic inflammatory skin disease of unknown origin. IgE-mediated uptake and antigen focusing of environmental allergens by dendritic cells (DCs) is assumed to be a central immunopathogenetic event. A so-called intrinsic type of AD (IAD) has been delineated from the more common extrinsic AD (EAD) by normal serum IgE levels, negative RAST tests and negative immediate-type skin reactions towards environmental allergens. The recently characterized human autoantigen Hom S 1 has been proposed to play a part in the pathogenesis of IAD. OBJECTIVES: To compare clinical and laboratory data between patients with IAD and EAD, and to investigate potential differences in the inflammatory micromilieu of the epidermal compartment in IAD and EAD lesions. METHODS: Epidermal DC phenotyping, a recently validated technique based on the three-colour flow cytometric analysis of Langerhans cells and the so-called inflammatory dendritic epidermal cells from epidermal single-cell suspensions, was performed on samples from 69 patients with AD (seven with IAD and 62 with EAD) and 94 controls. RESULTS: Patients with EAD tended to have an earlier onset of disease but similar disease duration and family history of atopic diseases. Quantitative analysis of CD36 expression on DCs as a marker of inflammation, as well as the percentage of inflammatory dendritic epidermal cells in the CD1a+ epidermal DC pool, indicated a comparable disease activity in IAD and EAD. EAD was characterized by a significantly higher FcepsilonRI expression on the CD1a+ epidermal DCs than IAD. Using the FcepsilonRI/FcgammaRII expression ratio as a disease marker for AD, values for IAD fell below the diagnostic cut-off level of 1.5 for this ratio. CONCLUSIONS: While IAD is clinically similar to EAD, the inflammatory microenvironment in this condition seems different from classical EAD and can be distinguished by phenotyping of epidermal DCs.

Adolescent↗
PubMed1999

Effect of lactacidosis on cell volume and intracellular pH of astrocytes.

Acute traumatic or ischemic cerebral lesions are associated with tissue acidosis leading to cytotoxic brain edema, predominantly affecting astrocytes. Glial swelling from acidosis is believed to be the attempt of cells to maintain a physiological intracellular pH (pHi). However, this concept, potentially important for the development of new treatment strategies for cytotoxic brain edema, has not been validated experimentally. In the present study, cell volume and pHi of astrocytes were measured simultaneously in vitro. Exposure of suspended astrocytes to levels of acidosis found in vivo during ischemia and trauma (pH 6.8-6.2) led to a maximal increase in cell volume of 121.2% after 60 min (n = 5, p < 0.05) and to immediate intracellular acidification close to extracellular levels (pH 6.2, n = 5, p < 0.05). Inhibition of membrane transporters responsible for pHi regulation (0.1 mM amiloride for the Na+/H+ antiporter or 1 mM SITS for HCO3- -dependent transporters) inhibited cell swelling from acidosis but did not affect the profound intracellular acidification. In addition, acidosis-induced cell swelling and intracellular acidification were partly prevented by the addition of ZnCl2 (0.1 mM), an inhibitor of selective proton channels not yet described in astrocytes (n = 5, p < 0.05). In conclusion, these data demonstrate that glial swelling from acidosis is not a cellular response to defend the normal pHi, as had been thought. If these results obtained in vitro are transferable to in vivo conditions, the development of blood-brain barrier-permeable agents for the inhibition of acidosis-induced cytotoxic edema might be therapeutically useful, since they do not enhance intracellular acidosis and thus cell damage.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1996

Swelling, intracellular acidosis, and damage of glial cells.

Cerebral ischemia and severe head injury among others are associated with a limited availability of oxygen, leading to cell catabolism as well as anaerobic glycolysis. Resulting metabolites, such as arachidonic- and lactic acid, can be expected to leak into perifocal brain areas, contributing there to cytotoxic swelling and damage of neurons and glia. Since elucidation of mechanisms underlying cell swelling and damage in the brain is difficult in vivo, respective investigations were carried out in vitro using suspended glial cells. Thereby, effects of arachidonic acid (AA) and of lactacidosis on glial cell volume, intracellular pH (pHi), and cell damage were analyzed utilizing flow cytometry. AA led to an immediate, dose dependent swelling and intracellular acidosis of glial cells. A concentration of 0.1 mM increased cell volume to 110% of control and decreased pHi to 7.05. Whereas glial swelling was permanent, pHi recovered to baseline after 90 min. Cell viability of 90% remained unchanged after addition of AA up to 0.1 mM, while at 0.5 mM it was significantly decreasing. Glial swelling from AA was nearly completely inhibited by the aminosteroid U-74389F or by using a Na(+)-free suspension medium for the experiment. Acidification of the medium to pH 6.8 or 6.2 led to a cell volume of 110% or 120% of control without affecting cell viability. The cells were not capable to defend their normal pHi during lactacidosis of the suspension medium but became acidotic as well. Addition of amiloride or utilization of Na(+)-free medium inhibited cell swelling from lactacidosis, while intracellular acidosis was even more pronounced. The results indicate that AA as well as acidosis are potent mediators of glial swelling and damage at levels found under pathophysiological conditions in the brain in vivo. Whereas intracellular acidification caused by AA was reversible, glial cells were unable to regulate their pHi during maintenance of extracellular acidosis. Concerning the mechanisms of glial swelling by AA, the production of oxygen- and lipid radicals might play a major role in the swelling process. The results indicate a role of the Na+/H(+)-antiporter in acidosis-induced glial swelling, whereas the exchanger has a limited significance for maintenance of pHi. As seen, the final pathway of glial swelling from both, AA and lactacidosis, requires a net influx of Na(+)-ions, probably together with Cl-ions, and osmotically obliged water.

Acid-Base Equilibrium↗
PubMed1996

New insights in the structure and biology of the high affinity receptor for IgE (Fc epsilon RI) on human epidermal Langerhans cells.

The recent structural and functional analysis of the high affinity receptor for IgE (Fc epsilon RI) expressed on human epidermal Langerhans cells (LC) revealed new aspects of the biology of this structure. In contrast to basophils and mast cells where this receptor seems to be expressed constitutively at a constant level, the expression of Fc epsilon RI on LC varies on the donor and the inflammatory environment of the cells and lacks the classical beta-chain. This also implies functional differences most probably related to the expression level. Although the signalling pathway seems to be similar to that of basophils or mast cells, LC from individuals with atopic dermatitis are fully activated by receptor ligation while LC from normal individuals fail to exhibit calcium mobilization under the same conditions. Finally, LC from normal and atopic individuals use Fc epsilon RI to maximize antigen uptake via specific IgE and subsequent presentation to T cells. Thus, Fc epsilon RI expressed on LC differs in terms of structure and function from that expressed on effector cells of anaphylaxis.

Antigen Presentation↗
PubMed1994

[Swelling and damage to nerves and glial cells by acidosis].

OBJECTIVE: Development of acidosis is a prominent pathophysiological factor in acute cerebral disorders, such as ischaemia or severe brain trauma. The impairment of the acid-base state in brain parenchyma among others is involved in the development of brain oedema, eventually leading to irreversible damage of neurons and glial cells. In the present study the pathophysiological role of acidosis for cytotoxic cell swelling and damage of glial and neuronal cells was investigated in vitro under conditions found in the ischaemic penumbra in vivo--the still viable perifocal border zone surrounding an infarct with elevated interstitial K(+)- and H(+)-concentrations. Assessment of cell swelling by acidosis was combined with experiments on underlying mechanisms as a basis for therapeutical interventions to inhibit cytotoxic brain oedema in vivo. METHODS: C6 glioma cells, astrocytes from primary culture, as well as Neuro-2A cells were cultivated, harvested and suspended as single cells under continuous control of pH, pO2, and temperature according to a standard procedure. Cell volume and cell viability were quantified by flow cytometry. Acidosis was induced by isotonic sulfuric- or lactic acid, respectively. RESULTS: Acidification of the medium led to cell swelling once pH fell below 7.0. Cell viability, however, was not affected by the increasing acidosis down to pH 6.2, while pH 5.6 or below was associated with cell death dependent on the duration of exposure. Acidosis-induced cell swelling was attenuated or completely inhibited by blocking of ion exchange mechanisms, such as the Na+/H(+)-antiporter, or elimination of Na+ ions from the medium. CONCLUSION: The present results provide new information on the nature of cytotoxic cell swelling and damage in central nervous system by acidosis under consideration of underlying mechanisms. Accordingly, acidosis-induced cell swelling is attributable to activation of ion exchange mechanisms, such as the Na+/H(+)- and Cl-/HCO3(-)-antiporter, in order to maintain a normal cellular acid-base state. This compensation process, however, is associated with the loss of cell volume control by net uptake of osmotic active solutes. Consequently, cell swelling occurring under these conditions is a result of regulatory mechanisms to defend homoeostasis rather than a consequence of cytotoxic cell damage. If cell swelling is inhibited by appropriate treatment, care should be exercised not to enhance the vulnerability of the nerve and glial cells.

Acid-Base Equilibrium↗