Independent regulation of cutaneous lymphocyte-associated antigen expression and cytokine synthesis phenotype during human CD4+ memory T cell differentiation

Although considerable attention has been paid to the development of cytokine synthesis heterogeneity during memory T cell differentiation, little information is available on how this function is coregulated with homing receptor expression. The development of skin-homing, CD4+ memory T cells in the human provides an excellent model for such investigation, since 1) the skin supports both Th1- and Th2-predominant responses in different settings, and 2) the skin-homing capability of human memory T cells correlates with and appears to depend on expression of the skin-selective homing receptor cutaneous lymphocyte-associated Ag (CLA). In this study, we used multiparameter FACS analysis to examine expression of CLA vs IFN-gamma, IL-4, and IL-2 synthesis capabilities among fresh peripheral blood CD4+ memory T cells, and Th1 vs Th2 memory T cells generated in vitro from purified CD4+ naive precursors by cyclic activation in polarizing culture conditions. Among normal peripheral blood T cells, CLA expression was essentially identical among the IFN-gamma- vs IL-4-producing CD4+ memory subsets, clearly indicating the existence of in vivo mechanisms capable of producing both Th1 vs Th2 skin-homing T cells. In vitro differentiation of naive CD4+ T cells confirmed the independent regulation of CLA and all three cytokines examined, regulation that allowed differential production of IFN-gamma-, IL-4-, and IL-2-producing, CLA+ memory subsets. These studies also 1) demonstrated differences in regulatory factor activity depending on the differentiation status of the responding cell, and 2) revealed CLA expression to be much more rapidly reversible on established memory cells than cytokine synthesis capabilities.     

Evidence for superantigen involvement in skin homing of T cells in atopic dermatitis

The environmental factors that contribute to the homing of T cells in skin disease is unknown. The skin lesions of atopic dermatitis (AD) are frequently colonized with superantigen (SAg), producing strains of Staphylococcus aureus. In vitro, these superantigens have the capacity to activate and expand T cells expressing specific T cell receptor BV gene segments, and also to increase their skin homing capacity via upregulation of the skin homing receptor, cutaneous lymphocyte-associated antigen (CLA). These activities have been proposed to enhance the chronic cutaneous inflammation of AD, but an in vivo role for SAg has not been conclusively demonstrated. In this study, we sought direct evidence for in vivo SAg activity by comparing the SAg profiles of S. aureus cultured from the skin of AD subjects to the T cell receptor Vbeta repertoire of their skin homing (CLA+) T cells in peripheral blood. SAg secreting S. aureus strains were identified in six of 12 AD patients, and all of these subjects manifested significant SAg-appropriate Vbeta skewing within the CLA+ subsets of both their CD4+ and their CD8+ T cells. T cell receptor Vbeta skewing was not detectable among the overall CD4+ or CD8+ T cell subsets of these subjects, and was not present within the CLA+ T cell subsets of five patients with plaque psoriasis and 10 normal controls. T cell receptor BV genes from the presumptively SAg-expanded populations of skin homing T cells were cloned and sequenced from three subjects and, consistent with a SAg-driven effect, were found to be polyclonal. We conclude that SAg can contribute to AD pathogenesis by increasing the frequency of memory T cells able to migrate to and be activated within AD lesions.     

"Secondary" chondrosarcoma of the hand. Case report and review of the literature]

The expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin is important for the regulation of the leucocyte traffic into and in inflammatory dermatoses. ICAM-1, VCAM-1 and E-selectin were initially identified as cell-surface proteins, but recent evidence suggests that they also exist in a soluble form. The collection of human afferent lymph exclusively deriving from a selected skin area allows insight into local pathomechanisms as well as signal transmission in skin disorders. In the present study we measured the concentrations of the soluble adhesion molecules (sAM) sICAM-1, sVCAM-1 and sE-selectin in human skin lymph derived from normal untreated skin, irritant contact dermatitis (CD) and the induction and elicitation phases of allergic CD. The strong elicitation reactions of allergic CD produced an increase in sAM output to about three times the baseline values but in the weaker irritant CD we observed no increase at all. In the induction phase of allergic CD the concentrations during the first 9 days of the experiment remained unchanged, as in the lymph derived from normal untreated skin, but were slightly increased thereafter. To our knowledge, no in vivo data exist on the local involvement of sAM in irritant and allergic CD in humans. Our results provide evidence of increased concentrations of sAM mainly in strong allergic CD.     

Aurally and visually guided visual search in a virtual environment

BACKGROUND: Atopic dermatitis (AD) is characterized by skin infiltrates of leukocytes, such as lymphocytes and eosinophils. OBJECTIVE: To describe the mechanisms determining this inflammatory process, we have analyzed expression of adhesion molecules and their regulation on skin endothelial cells (ECs). METHODS: Expression of adhesion molecules on ECs was analyzed by immunohistochemistry by using Ulex europaeus agglutin 1 as a pan-endothelial marker. RESULTS: Vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin were not found in skin of nonatopic individuals, whereas expression of these surface molecules was observed in nonlesional skin of patients with AD and was even more pronounced in lesional skin or after epicutaneous application of aeroallergen. Induction of adhesion molecule expression was examined on both macrovascular ECs from human umbilical cord vein (HUVECs) and human microvascular ECs (HMEC-1) from skin. TNF-alpha very potently upregulated adhesion molecule expression in vitro on both EC cell types. To verify the in vivo relevance of TNF-alpha, we performed TNF-alpha staining in the skin. TNF-alpha was observed in the dermis of nonatopic skin, both in chymase-containing mast cells and CD68+ macrophages. The increase in the number of TNF-alpha-containing cells was concomitant with the increase in adhesion molecule expression in the skin of patients with AD. IL-4 is supposed to be important in atopic diseases because of its IgE- and VCAM-1-inducing properties. However, IL-4 addition failed to induce VCAM-1 expression on HMEC-1, although in the same set of experiments, a clear induction of VCAM-1 expression by IL-4 on HUVECs was demonstrated. Flow cytometry revealed the absence of 11-4 receptor alpha-chains on HMEC-1 and their presence on HUVECs. Immunohistochemistry examination on skin sections showed no binding of the IL-4R alpha-chain antibodies to ECs. CONCLUSION: We conclude that adhesion molecule expression is increased in the skin of patients with AD. Most probably, this increased expression is not a (direct) effect of IL-4 on skin endothelium, but other cytokines, such as TNF-alpha, might be responsible for this increased adhesion molecule expression. Continuous adhesion molecule expression may facilitate T-cell extravasation in a nonantigen-specific manner, thus explaining the presence of increased T-cell numbers in nonlesional skin of patients with AD.     

Ibuprofen inhibits pyrogen-dependent expression of VCAM-1 and ICAM-1 on human endothelial cells

Leukocyte adhesion and transmigration through the endothelial cell (EC) layer plays a crucial role in inflammation. IL-1 alpha and TNF alpha increase EC-adhesiveness for leukocytes by stimulating surface expression of ICAM-1 (intercellular adhesion molecule 1, CD54), VCAM-1 (vascular cell adhesion molecule 1, CD106) and E-selectin (CD62E). In this study, the effects of ibuprofen on IL-1 alpha and TNF alpha-induced expression of ICAM-1, VCAM-1 and E-selectin on cultured human umbilical vein EC (HUVEC) were analyzed. Exposure to IL-1 alpha or TNF alpha resulted in an increased expression of VCAM-1, ICAM-1, and E-selectin. Ibuprofen was identified as a potent inhibitor of IL-1 alpha and TNF alpha-induced surface expression of VCAM-1 and a less potent inhibitor of pyrogen-induced expression of ICAM-1, whereas no effect on E-selectin was found. The effects of ibuprofen on VCAM-1 expression were dose-dependent (IC50 [IL-1 alpha]: 0.5 mM; IC50 [TNF alpha]: 0.5 mM) and time-dependent with maximum responses observed after 18 h. Moreover, ibuprofen abrogated pyrogen-dependent adhesion of leukocytes to HUVEC. Ibuprofen also inhibited VCAM-1 mRNA expression in pyrogen activated EC. VCAM-1-downregulation on EC by ibuprofen may contribute to the anti-inflammatory actions of the drug.     

Induction of cutaneous lymphocyte-associated antigen expression by group A streptococcal antigens in psoriasis

The cutaneous lymphocyte-associated antigen (CLA) has been proposed as a homing receptor for the selective migration of memory T cells into the skin. To investigate the effect of group A streptococci (GAS) on the migration of T cells in psoriasis, CLA expression was assessed by double-staining for CD3 and the HECA-452 epitope on peripheral blood T cells from 13 patients with psoriasis, 10 patients with other inflammatory skin diseases and 12 normal controls before and after 7 days culture with a GAS sonicate, Candida albicans (control antigen) or medium. In addition, CLA+, and CLA-, CD3+ CD45RO+ subsets were isolated from individuals in each group and V beta 2 expression and proliferation to GAS studied. Mean CLA expression by freshly isolated T cells was almost identical in the three groups. After culture with GAS, T cells from the psoriatic patients and control showed a significant increase in mean percentage CLA+ expression compared to medium (P < 0.002, P < 0.05, respectively). This induction was inhibited by the addition of anti-IL-12 antibody. However, in psoriatic patients, but not in controls, the GAS-induced increase was significantly greater than that of C. albicans (P < 0.002) and was accompanied by a decrease in T cells positive for the peripheral lymph node homing receptor, L-selectin (P < 0.05). The percentage of V beta 2+ T cells was markedly higher in the CLA+ than in the CLA- T-cell subset in psoriatic patients (P < 0.01) and controls; both subsets proliferated to GAS, in each group. These findings suggest a differential modulation of specific tissue homing receptors on T cells by GAS in psoriasis.     

Adhesion of tumour-infiltrating lymphocytes to endothelium: a phenotypic and functional analysis

Efficacy of cancer immunotherapy with cultured tumour-infiltrating lymphocytes (TILs) depends upon infused TILs migrating into tumour-bearing tissue, in which they mediate an anti-tumour response. For TILs to enter a tumour, they must first bind to tumour endothelium, and this process depends on TILs expressing and regulating the function of relevant cell-surface receptors. We analysed the cell-surface phenotype and endothelial binding of TILs cultured from human melanoma and compared them with peripheral blood T cells and with allostimulated T cells cultured under similar conditions. Compared with peripheral blood T cells, TILs expressed high levels of five integrins, two other adhesion molecules, including the skin homing molecule CLA, and several activation markers and showed markedly enhanced integrin-mediated adhesion to a dermal microvascular endothelial cell line in vitro. Compared with the allostimulated T cells, TILs expressed higher levels of the cutaneous lymphocyte antigen (CLA), the adhesion molecule CD31 and the activation markers CD30 and CD69, but lower levels of several other adhesion and activation molecules. These phenotypic and functional properties of TILs should have complex effects on their migration in vivo. Expression of CLA, the skin homing receptor, may increase migration to melanoma (a skin cancer), whereas integrin activation may cause non-specific binding of TILs to other endothelium. Manipulation of the culture conditions in which TILs are expanded might result in a phenotype that is more conducive to selective tumour homing in vivo.     

Immunopathologic study of the conjunctiva in patients with beh?et disease

PURPOSE: Even though conjunctiva is not primarily involved in patients with uveitis due to Beh?et disease, it may reflect the immunopathologic process when inflammation is induced by biopsy of conjunctiva, a phenomenon similar to the induced inflammation at skin pathergy sites. METHODS: Conjunctival biopsy specimens obtained 48 hours after a 2-mm biopsy of the epibulbar conjunctiva in 26 Turkish patients with inactive ocular Beh?et disease and 9 Turkish patients with inactive idiopathic uveitis were studied by immunoperoxidase using a panel of monoclonal antibodies: anti-CD1, -CD3, -CD4, -CD5, -CD14, -CD22, -CD25, and -CD67, HLA-DR, E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). RESULTS: Immunopathology of the conjunctival specimens obtained at the time of first biopsy was not significantly different between the Beh?et disease and the idiopathic uveitis groups. The second-biopsy specimens of the patients with Beh?et disease showed significantly greater numbers of T cells (CD3+, CD4+) and granulocytes (CD67+) as well as HLA-DR+ and ICAM-1+ cells in the substantia propria. Vascular endothelium of the conjunctiva in a patient with Beh?et disease had significantly more pronounced expression of the adhesion molecules, E-selectin, and ICAM-1. None of the conjunctival specimens in either group showed VCAM-1 positivity. CONCLUSIONS: These results show that a more intense antigen-independent inflammation develops with recruitment of both neutrophils and T lymphocytes of helper/ inducer phenotype in the conjunctiva of patients with Beh?et disease in response to surgical trauma. Increased expression of E-selectin and ICAM-1 in the conjunctiva of patients with Beh?et disease may suggest a critical role for these adhesion molecules in the initial events of inflammation.     

Neutralization of TNF by the antibody cA2 reveals differential regulation of adhesion molecule expression on TNF-activated endothelial cells

Upregulation of adhesion proteins plays an important role in mediating inflammation. The induction of adhesive molecules has been well studied, but the reversibility of their expression has not been well characterized. A neutralizing anti-TNF monoclonal antibody (cA2) was used to study the down regulation of TNF-induced E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on cultured human umbilical vein endothelial cells (HUVECs). Addition of cA2 following TNF stimulation of HUVECs enhanced the rate of E-selectin and VCAM-1 down-regulation from the cell surface and also reduced steady state E-selectin and VCAM-1 mRNA levels. The cA2-mediated disappearance of E-selectin, but not VCAM-1 protein was microtubule and not microfilament dependent. Neutralization of TNF only slightly reduced ICAM-1 cell surface levels following initial TNF stimulation, suggesting a slower turnover of ICAM-1 compared to E-selectin and VCAM-1. Microtubule inhibition during TNF stimulation partially inhibited E-selectin, VCAM-1 and ICAM-1 mRNA upregulation. VCAM-1 and ICAM-1 cell surface expression were similarly partially inhibited, however, E-selectin levels were unaffected, presumably due to the dual, opposing effect of inhibiting protein expression and inhibiting internalization. Microfilament inhibition during protein induction specifically inhibited the maximal expression of VCAM-1 protein and mRNA, without affecting E-selectin or ICAM-1. These data support the notion that E-selectin, VCAM-1, and ICAM-1 expression are differentially regulated on HUVECs and suggest that TNF neutralizing therapies may be effective because of their ability to reduce the levels of pre-existing adhesion proteins.     

Cell adhesion molecules--update

Cell adhesion molecules are glycoproteins expressed on the cell surface and play an important role in inflammatory as well as neoplastic diseases. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. The integrin family has eight subfamilies, designated as beta 1 through beta 8. The most widely studied subfamilies are beta 1 (CD29, very late activation [VLA] members), beta 2 (leukocyte integrins such as CD11a/CD18, CD11b/CD18, CD11c/CD18, and alpha d beta 2), beta 3 (CD61, cytoadhesions), and beta 7 (alpha 4 beta 7 and alpha E beta 7). The immunoglobulin superfamily includes leukocyte function antigen-2 (LFA-2 or CD2), leukocyte function antigen-3 (LFA-3 or CD58), intercellular adhesion molecules (ICAMs), vascular adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PE-CAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The selectin family includes E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L). Cadherins are major cell-cell adhesion molecules and include epithelial (E), placental (P), and neural (N) subclasses. The binding sites (ligands/receptors) are different for each of these cell adhesion molecules (e.g., ICAM binds to CD11/CD18; VCAM-1 binds to VLA-4). The specific cell adhesion molecules and their ligands that may be involved in pathologic conditions and potential therapeutic strategies by modulating the expression of these molecules will be discussed.     

Expression of L-selectin on peripheral memory CD4+ T cells in atopic diseases

L-selectin is one of the adhesion molecules, which is known as a leukocyte homing receptor. L-selectin contributes labile rolling adhesion of leukocytes on the blood vessel wall. To elucidate characteristics of L-selectin expression on peripheral CD4+ lymphocytes in atopic diseases, flow cytometric analysis was performed. Subjects were 7 patients with atopic asthma (BA), 10 with atopic dermatitis (AD), 9 with allergic rhinitis (AR) and 10 normal adults (control). Peripheral lymphocytes in all subjects were three-color-analyzed using monoclonal antibodies. As a result, compared with the control group. BA and AD showed significantly higher proportions of L-selectin-positive memory CD4+ T cells (BA 64.0%; AD 62.0%; AR 50.9%; Control 38.0%), and significantly lower proportions of L-selectin-negative memory CD4+ T cells (BA 18.3%; AD 11.6%; AR 21.1%; Control 29.2%), respectively (reported percentages represent average values for each subject group). As previously reported. L-selectin-positive memory CD4+ T cells produce mainly Th2-type cytokines (Kanegane et al., 1996); Given these results, the present study suggests that increased Th2-like cells express L-selectin for extravasation in the process of local infiltration in atopic diseases.     

A comparative phenotypical analysis of rheumatoid nodules and rheumatoid synovium with special reference to adhesion molecules and activation markers

OBJECTIVES: (1) To analyse the in situ expression of adhesion molecules in rheumatoid nodules. (2) To compare the endothelial expression of adhesion molecules in synovial tissue and subcutaneous nodules obtained from the same patients. (3) To compare the expression of adhesion molecules and activation markers on T cell lines from nodules and synovium. METHODS: (1) Immunohistochemical analysis by APAAP technique of E selectin, CD44, ICAM-1, PECAM-1, and VCAM-1 was performed on 10 rheumatoid nodules from seven patients with rheumatoid arthritis (RA); nodules and synovium were simultaneously analysed from three patients. (2) T cell lines were generated from RA nodules (n = 7) and synovium (n = 7) by interleukin 2 expansion, and subsequently characterised by flow cytometry for surface expression of alpha E beta 7, alpha 4 beta 7, CD44, L selectin, LFA-1a, PECAM-1, and CD30. RESULTS: (1) In rheumatoid nodules, the palisading layer strongly stains for ICAM-1 and PECAM-1, but less pronounced for CD44. VCAM-1 staining was usually negative. ICAM-1 is upregulated in the vessels surrounding the central zone of fibrinoid necrosis. The immunohistological picture in different nodules derived from the same patient was similar. (2) The endothelial expression of adhesion molecules is comparable in RA nodules and synovium on an individual level, except for E selectin, which is overexpressed in nodule endothelium. (3) T cell lines from nodules and synovium display similar adhesion molecule profiles. However, the expression of CD30, a T cell activation marker linked with Th2 subsets, is higher in nodules compared with synovium. CONCLUSION: These data support a recirculation hypothesis of T cells between articular and extra-articular manifestations in RA, although the activation state of the T cells in each of these localisations may differ.     

Identification of childhood vaccine providers in Maryland

Chronic inflammation seems to play a major role in skin and muscle cell damage in dermatomyositis. Adhesion molecules and their ligands are fundamental in regulating inflammation. We have carried out an immunohistochemical analysis of different activation-inducible adhesion markers in 15 biopsy specimens from dermatomyositis skin lesions. Consistent findings were the increased expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, inflammatory cells and focally grouped keratinocytes in contact with subepidermal inflammatory infiltrates. Immunoreactivity for vascular cell adhesion molecule-1 (VCAM-1) was predominant on endothelial cells of the upper reticular dermis and dermal stellate-shaped cells. E-selectin (endothelial leukocyte adhesion molecule-1) immunoreactivity was less extensive, detected mostly on segments of vessels of the papillary dermis and upper reticular dermis, and sometimes independent of inflammation. This pattern of adhesion molecule expression is similar to that described in other immunemediated dermatoses. The up-regulation of the adhesion molecules appears to play a role in the development and perpetuation of dermatomyositis skin lesions.     

Differential expression of ICAM-1 and LFA-1 versus L-selectin and VCAM-1 in autoimmune insulitis of NOD mice and association with both Th1- and Th2-type infiltrates

The infiltration of pancreatic islets by mononuclear cells is the hallmark of the development of insulin dependent diabetes mellitus (IDDM) in the NOD mouse, an animal model for human IDDM. The aim, of this study was to correlate adhesion molecule expression with the degree of islet infiltration and to compare Th1- and Th2-driven islet inflammation. Cryostat sections of NOD mouse pancreata before and after diabetes development were analysed by semiquantitative immunohistochemistry. NOD mouse islets did not show the expression of ICAM-1, LFA-1, L-selectin and VCAM-1 prior to infiltration by mononuclear cells. Furthermore, islets with early stage insulitis (grade 1, periinsular location of small infiltrates) still were devoid of adhesion molecule expression. ICAM-1 and LFA-1 were first demonstrable in islets with strong periinsular infiltrates (insulitis grade 2) while L-selectin and VCAM-1 were only seen in islets with mild or strong intraislet infiltration (grade 3-4). Adhesion molecules were demonstrable in areas of macrophage and T-lymphocyte infiltrates but not in adjacent endocrine islet tissue. Islets of all infiltration stages contained Th2 lymphocytes (positive for IL-4). Substantial numbers of Th1 cells (positive for IFN-gamma, TNF-alpha, IL-2 and/or IL-2 receptor) were observed only after acceleration of diabetes development by a single injection of cyclophosphamide (250 mg/kg i.p.). Interestingly, the adhesion molecule expression pattern in islets with "Th1' versus "Th2 insulitis' was not different. In conclusion, the expression of adhesion molecules in islets during the development of autoimmune diabetes does not precede mononuclear infiltration but probably occurs in response to the activation of initial small infiltrates. ICAM-1 and LFA-1 expression is seen prior to L-selectin and VCAM-1. However, adhesion molecule expression during Th1 versus Th2 cell infiltration is very similar, suggesting similar adhesion molecule requirements of the two Th subsets.     

Regulation of beta-chemokine mRNA expression in adult rat astrocytes by lipopolysaccharide, proinflammatory and immunoregulatory cytokines

Methotrexate (MTX) is one of the most widely prescribed drugs in the treatment of rheumatoid arthritis (RA). The mechanism by which MTX exerts its anti-rheumatic effect has not yet been defined. The aim of the present study was to investigate the effect of MTX treatment (7.5-15 mg/week) on synovial tissue in RA. For this purpose, synovial biopsies were taken from 11 RA patients before and 16 weeks after initiation of MTX therapy. Immunohistochemistry was performed using monoclonal antibodies (MAb) specific for CD3, CD4, CD8, CD22, CD25, CD38, CD68, MAb67, Ki67, interferon gamma (IFN-gamma), interleukin (IL)-1alpha, IL-1beta, tumour necrosis factor alpha (TNF-alpha), E-selectin, ICAM-1 and VCAM-1. All parameters for disease activity improved during the period of treatment. Immunohistochemical analysis revealed a statistically significant decrease in scores for CD3, CD8, CD38, CD68, Ki67, IL-1beta, TNF-alpha and the adhesion molecules E-selectin and VCAM-1. The observed decrease in synovial scores for inflammatory cells, monokines and adhesion molecules suggests that the anti-inflammatory effect of MTX is, in part, dependent on a reduction in monokine-inducible vascular adhesion molecules and subsequent reduction of cell traffic into joints.     

Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells

Polarized Th1 and Th2 cells differentially express adhesion molecules and chemokine receptors, endowing these cells with distinct tissue homing capabilities. Here we report that, in contrast to other chemokine receptors, the expression of CCR4 and CCR8 on Th2 cells is transiently increased following TCR and CD28 engagement. IL-4 is not required for this activation-induced up-regulation of CCR4 and CCR8. In accordance with receptor expression, the response of Th2 cells to I-309 (CCR8 ligand) and thymus- and activation-regulated chemokine (CCR4 and CCR8 ligand) is enhanced upon activation. Moreover, activated Th1 cells up-regulate CCR4 expression and functional responsiveness to thymus- and activation-regulated chemokine. Analysis of polarized subsets of CD8+ T cells reveals a similar pattern of chemokine receptor expression and modulation of responsiveness. Taken together, these findings suggest that an up-regulation of CCR4 and CCR8 following Ag encounter may contribute to the proper positioning of activated T cells within sites of antigenic challenge and/or specialized areas of lymphoid tissues.     

P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues

When activated, T helper cells differentiate into one of two subsets, Th1 and Th2, characterized by distinct profiles of cytokine production. Th1 cells activate pro-inflammatory effector mechanisms involved in protection and autoimmunity, whereas Th2 cells induce humoral and allergic responses and downregulate local inflammation. Apart from differences in the repertoire of cytokines, no phenotypic attributes are established that distinguish the two subsets. Here we show that Th1 cells, but not Th2 cells, are able to bind to P-selectin and E-selectin. Moreover, only Th1 cells can efficiently enter inflamed sites in Th1-dominated models, such as sensitized skin or arthritic joints, but not in a Th2-dominated allergic response. Immigration of Th1 cells into inflamed skin can be blocked by antibodies against P- and E-selectin. These results provide evidence for adhesion mechanisms to distinguish between the two T helper subsets and mediate their differential trafficking. They indicate that selective recruitment is an additional level of regulation for both effector function profile and character of a local immune response.     

Soluble adhesion molecules in patients with pre-eclampsia

Plasma concentrations of the circulating adhesion molecules ICAM-1 (CD54), VCAM-1 (CD106) were determined in 31 women with pre-eclampsia, 9 women with HELLP syndrome, and 13 women with transient pregnancy induced hypertension (PIH). Data were compared with a control group of 157 healthy pregnant women of the same gestational age. Furthermore, concentrations of circulating E-selectin (CD62E), P-selectin (CD62P), and PECAM-1 (CD31) were determined in a subpopulation of 17 women with pre-eclampsia. Plasma concentrations of circulating ICAM-1, VCAM-1, E-selectin, and PECAM-1 were significantly elevated in women with pre-eclampsia compared to healthy control pregnant women. Circulating ICAM-1 and VCAM-1 levels were also significantly elevated in the pre-eclampsia group compared to women with PIH. Concentrations of circulating P-selectin varied strongly in all experimental groups (SD > 70% of the mean), most likely reflecting various degrees of thrombocyte degranulation in the individual samples. Finally, longitudinal profiles of cICAM-1 and cVCAM-1 concentrations were determined in 123 healthy pregnant women between the 16th and the 42nd week of gestation. This analysis identified cICAM-1 and cVCAM-1 as tightly regulated plasma parameters that varied in a small concentration range. Concentrations of cICAM-1 and cVCAM-1 did not vary during pregnancy and the determined concentrations corresponded to the reported reference levels of nonpregnant individuals.