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  • 1
    Keywords: CELLS ; EXPRESSION ; Germany ; DISEASE ; SITE ; DISTINCT ; GENE ; MOLECULES ; MICE ; ACTIVATION ; COMPLEX ; ARTHRITIS ; COMPLEXES ; IFN-GAMMA ; MARKER ; INDUCTION ; SKIN ; T cell activation ; T cells ; T-CELLS ; FLOW ; cytokines ; DELETION ; immunohistochemistry ; NUMBER ; PATHOGENESIS ; MOUSE MODEL ; INTERFERON ; INTERFERON-GAMMA ; human hair follicle ; T lymphocytes ; C3H/HEJ MICE ; FOLLICLE ; MAJOR HISTOCOMPATIBILITY COMPLEX ; AUTOIMMUNITY ; CYTOKINE ; HAIR FOLLICLE ; REQUIREMENT ; IMMUNE PRIVILEGE ; alopecia areata ; CD8(+) CELLS ; HAIR LOSS ; LOSSES ; lymph node ; LYMPH-NODE ; ONSET ; RESISTANT ; AA ; autoimmune disease ; regulatory T cells ; experimental animal models
    Abstract: Background: Alopecia areata (AA) is a T-cell mediated putative autoimmune disease of hair follicles, which can be transferred by CD4+ T cells. However, whether T-helper (Th) 1 or Th2 cytokines are predominant has not yet been defined. Methods: To elucidate the importance of Th1 cells in the pathogenesis of AA we investigated the functional role of interferon (IFN)-gamma in the experimental induction of AA. Results: AA was experimentally induced by grafting full-thickness skin from AA-affected C3H/HeJ mice on to C3H/HeJ mice with a targeted deletion of the Th1 cytokine IFN-gamma gene (IFN gamma(-/-)) and on to wild-type mice (IFN gamma(+/+)). Results: While 90% of wild-type mice developed AA, none of the IFN gamma(-/-) mice exhibited hair loss. Immunohistochemistry of skin sections revealed a dense perifollicular and intrafollicular infiltrate of CD4+ and CD8+ T cells in controls, while in IFN gamma(-/-) mice skin-infiltrating CD8+ T cells were absent and the number of CD4+ cells was significantly reduced. Aberrant expression of major histocompatibility complex class I and II molecules in the putative immune-privileged infrainfundibular site of the hair follicle was found to be weaker in AA-resistant IFN gamma(-/-) mice than in control mice with AA. Flow cytometry revealed that leucocytes of IFN gamma(-/-) mice did not respond to the transfer of AA-affected skin. As distinct from IFN gamma(+/+) mice, neither T-cell activation markers nor Th1 cytokines were upregulated in draining lymph node cells or skin-infiltrating leucocytes of AA-resistant IFN gamma(-/-) mice. However, there was no evidence for a shift towards a Th2 cytokine profile, nor for upregulation of regulatory T cells in IFN gamma(-/-) mice. Conclusions: IFN gamma(-/-) mice fail to activate Th1 cells in response to the transplanted (auto)antigens, which suggests an essential requirement for IFN-gamma-mediated Th1 activation in the induction of AA
    Type of Publication: Journal article published
    PubMed ID: 16911275
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; Germany ; THERAPY ; VITRO ; DISEASE ; DISEASES ; MICE ; ACTIVATION ; MECHANISM ; REDUCTION ; ANTIGEN ; DENDRITIC CELLS ; SKIN ; T cell activation ; T cells ; T-CELLS ; treatment ; MIGRATION ; RECRUITMENT ; ANTIGEN-PRESENTING CELLS ; C3H/HEJ MICE ; FOLLICLE ; SUBSET ; RE ; HAIR FOLLICLE ; LYMPHOID ORGANS ; REGULATORY T-CELLS ; DELAYED-TYPE HYPERSENSITIVITY ; RECOVERY ; HAIR LOSS ; lymph node ; LYMPH-NODE ; RELEVANCE ; AA ; autoimmune disease ; PROGRESS ; ACID DIBUTYLESTER SADBE ; ACTIVATED T-CELLS ; ATOPIC-DERMATITIS ; SKIN-ASSOCIATED CHEMOKINE
    Abstract: Long-lasting allergen treatment is the most efficient therapy in alopecia areata (AA). The underlying mechanism is unknown. We here asked whether treatment with a contact sensitizer influences leukocyte migration such that dendritic cell (DC) migration or the recruitment of activated T-cells towards the skin become hampered. Allergen treatment of AA mice was not accompanied by a decrease in skin- infiltrating leukocytes or draining lymph node cells (LNC). However, the distribution of leukocyte subsets was changed with a dominance of monocytes in the skin and a reduced percentage of DCs in draining nodes. Chemokine and chemokine receptor expression in skin and draining nodes was strikingly increased and LNC from untreated and allergen-treated AA mice showed high migratory activity in vitro and readily homed in draining nodes and skin after intravenous injection. However, FITC labelling of the skin and subcutaneous transfer of dye-labelled DC revealed that allergen treatment created a chemokine milieu severely hampering DC migration from the skin towards the draining node. An allergic eczema. Induced reduction in DC migration and antigen transfer could well contribute to insufficient T-cell activation and the recovery of hair follicle in AA and possibly be of relevance for other skin- related autoimmune diseases
    Type of Publication: Journal article published
    PubMed ID: 16675965
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  • 3
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; MODEL ; MODELS ; SYSTEM ; DISEASE ; microarray ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; ANTIGEN ; ANTIGENS ; AUTOIMMUNE-DISEASE ; DENDRITIC CELLS ; LYMPH-NODES ; mechanisms ; SKIN ; T-CELLS ; FLOW ; CYCLE ; SEQUENCE ; SUSCEPTIBILITY ; cytokines ; TARGET ; LYMPHOCYTES ; antigen presentation ; EPITOPE ; TARGETS ; rodent ; C3H/HEJ MICE ; DEBR MODEL ; FOLLICLE ; HAIR-FOLLICLES ; HUMAN SCALP EXPLANTS ; IN-VIVO DEPLETION ; inflammation,autoimmune disease,mouse model ; NONOBESE DIABETIC MICE ; TOPICAL IMMUNOTHERAPY
    Abstract: With our current view of alopecia areata as an autoimmune disease, it is probable that disease development in an individual is dependent on multiple genetic and environmental factors interacting in a complex system. Rodent models afford the opportunity to investigate alopecia areata development and to define the significance of the different factors involved. Recently, rodent model characterization has been conducted using flow cytometry, microarray analysis, and functional studies. From these a pattern of events in alopecia areata development has emerged. Although the preliminary activation events for the onset of alopecia areata remain unknown, the response of the immune system is characterized by antigen presentation and costimulation of lymphocytes in the lymph nodes and skin, a deficiency of CD4(+)/CD25(+) regulatory cells, and an action of activated lymphocytes on hair follicles via Fas/FasL signaling and cytokines. Thus, onset of disease may require appropriate (or inappropriate) expression of stimulatory antigens within the hair follicle, the breakdown of the putative hair follicle immune privilege, the presentation of antigens to the immune system, a failure of immune system regulation, and the ability of the activated immune system to disrupt anagen-stage hair follicles. Once the sequence of events is initiated, it may become a self-perpetuating cycle, with epitope spreading leading to a wider range of targets in chronic alopecia areata. Rodent model studies have provided significant insight into alopecia areata, but much more remains to be explained about the mechanisms of disease development
    Type of Publication: Journal article published
    PubMed ID: 14582670
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  • 4
    Keywords: CELLS ; EXPRESSION ; GROWTH-FACTOR ; tumor ; CELL ; Germany ; MOLECULES ; MICE ; ACTIVATION ; RESPONSES ; MECHANISM ; INDUCTION ; AUTOIMMUNE-DISEASE ; CONTRAST ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; treatment ; MOLECULE ; ACID ; NUMBER ; LYMPHOCYTES ; HIGH-LEVEL ; EFFECTOR ; C3H/HEJ MICE ; HUMAN SCALP EXPLANTS ; adhesion molecules,autoimmune disease,delayed type hypersensitivity,leucocyte recruitment ; ALLERGIC CONTACT-DERMATITIS ; GLYCINE-ASPARTIC ACID ; MONOCYTE CHEMOATTRACTANT PROTEIN-1 ; REGULATORY T-CELLS ; SQUARIC ACID DIBUTYLESTER ; VARIANT ISOFORM EXPRESSION
    Abstract: The acute phase of alopecia areata (AA) is characterized by an increase in CD44v3(+) and CD44v10(+) skin-infiltrating leucocytes (SkIL). Induction of a contact eczema, one of the therapeutic options in AA, can be mitigated strongly by a blockade of CD44v10. The observation that induction of a delayed type hypersensitivity (DTH) reaction abrogates an autoimmune reaction, where both responses apparently use similar effector mechanisms, is surprising and prompted us to search for the underlying mechanisms. AA-affected C3H/HeJ mice were treated with the contact sensitizer SADBE (squaric acid dibutylester) and leucocyte subpopulations and their activation state was evaluated in SkIL and draining lymph nodes. AA-affected mice exhibited an increased number of SkIL with a predominance of T lymphocytes. After treatment with the contact sensitizer SADBE recovery of SkIL was reduced and monocytes predominated. However, a significantly increased number of leucocytes was recovered from draining lymph nodes. Draining lymph node cells from untreated and treated AA mice exhibited all signs of recent activation with high-level expression of co-stimulatory and accessory molecules and an increased percentage of CD44v3(+) and CD44v10(+) leucocytes. In contrast, SkIL of SADBE-treated AA mice contained relatively few activated T cells and reduced numbers of CD44v3(+) and CD44v10(+) cells. Thus, the activation state and the distribution of leucocyte subsets in SADBE-treated AA mice are consistent with a blockade of leucocyte extravasation. Accordingly, the therapeutic effect of long-term SADBE treatment may rely on impaired leucocyte traffic
    Type of Publication: Journal article published
    PubMed ID: 15008971
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; FACTOR RECEPTOR ; Germany ; MODELS ; DISEASE ; MICE ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; MARKER ; REDUCTION ; INDUCTION ; SKIN ; T-CELLS ; FREQUENCY ; SUSCEPTIBILITY ; cytokines ; DELETION ; MOUSE ; resistance ; MARKERS ; PATHOGENESIS ; LYMPHOCYTES ; RECRUITMENT ; INVOLVEMENT ; T-LYMPHOCYTES ; GROWTH-FACTOR-BETA ; RECEPTORS ; IL-2 ; INTERFERON-GAMMA ; inflammation ; INTERLEUKIN-2 ; FACTOR-BETA ; FACTOR RECEPTORS ; INFILTRATION ; targeted ; hair ; development ; DELAYED-TYPE HYPERSENSITIVITY ; LEVEL ; NECROSIS-FACTOR ; alopecia areata ; CD8(+) CELLS ; experimental mouse model ; HAIR LOSS ; interieukin-2 ; TUMOR NECROSIS FACTOR
    Abstract: Alopecia areata (AA) is an autoimmune hair loss disease, that can be transferred between C3H/HeJ mice by skin grafting. We explored whether AA susceptibility is influenced by the availability of interleukin (IL)-2, a cytokine with leukocyte activating and regulatory properties. Mice heterozygous for a targeted deletion of IL-2 from the histocompatible C3.129P2(B6)-II2(tm1Hor) substrain, that produce reduced levels of IL-2, were examined for AA development after grafting skin from AA-affected C3H/HeJ mice. After grafting, nine of 19 (47%) heterozygous IL-2(+/-) versus 16 of 18 (88%) IL-2(+/+) wild-type littermates developed AA. Although dense follicular leukocyte infiltrates were apparent in AA affected wild-type mice, AA-developing IL-2(+/-) littermates had a reduced leukocyte infiltration, and AA-resistant IL-2 mice had no inflammation. Lymph node cell analysis revealed a reduction in leukocyte activation markers in AA-developing IL-2(+/-) mice. IL-2(+/-) mice presented with low level expression of cytokines (IL-4, IL-10, interferon-gamma, transforming growth factor-beta), upregulation of tumor necrosis factor receptors, and increased leukocyte apoptosis susceptibility independent of AA expression. In the skin, CD4(+) cells and monocytes were reduced; activation markers were not upregulated and very few CD44v3(+) or CD44v10(+) leukocytes were recovered. Taken together, our data suggest that AA resistance of IL-2(+/-) mice is because of the failure of activated leukocyte recruitment, thus pointing toward an involvement of IL-2 in AA pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 16297194
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; BLOOD ; CELL ; Germany ; MODEL ; DEATH ; DISEASE ; PATIENT ; ACTIVATION ; LIGAND ; MECHANISM ; ANTIGEN ; AUTOIMMUNE-DISEASE ; mechanisms ; SKIN ; T cell ; T cell activation ; T cells ; T-CELL ; T-CELLS ; treatment ; immunohistochemistry ; CELL-DEATH ; NUMBER ; LINE ; LYMPHOCYTES ; CD8(+) ; PERIPHERAL-BLOOD ; FAS-LIGAND ; BIOPSY ; C3H/HEJ MICE ; DEBR MODEL ; FOLLICLE ; IN-VIVO DEPLETION ; TOPICAL IMMUNOTHERAPY ; CD44 ; INCREASE ; FAS ; HAIR FOLLICLE ; hair ; SQUARIC ACID DIBUTYLESTER ; DELAYED-TYPE HYPERSENSITIVITY ; HAIR-GROWTH ; PHASE ; RECOVERY ; alopecia areata ; lymph node ; LYMPH-NODE ; RESISTANT ; RELEVANCE ; AA ; autoimmune disease ; peripheral blood ; REPLACEMENT ; CONTACT ; ALOPECIA-AREATA ; BIOPSIES ; diphenycyclopropenone ; HUMAN T-LYMPHOCYTES ; perifollicular lymphocytes ; TUNEL
    Abstract: Alopecia areata (AA) is a T cell-mediated autoimmune disease that can be treated with the contact sensitizer diphenylcyclopropenone (DCP). Peripheral blood leukocytes from AA patients are relatively resistant 6 apoptosis which might be due to decreased Fas Ligand (FasL) expression, or to an increase in CD44v7 expression. Moreover it has been suggested in a murine model of AA that contact allergen treatment might interfere with the emigration of Langerhans cells into the draining lymph node, thus hampering autoreactive T-cell activation. To assess whether and which of these mechanisms is of clinical relevance, immunohistochemistry was performed in scalp biopsies of successfully DCP-treated AA patients in the early phase of hair regrowth. In line with recent studies in a murine model of AA, there was no evidence that DCP treatment would interfere with extravasation and skin homing of activated leukocytes. Perifollicular infiltrates of DCP-treated as compared to untreated AA patients actually showed an increased number of perifollicular CD8(+) and CD1a(+) cells. Furthermore, the expression of CD44 and CD49d, which are of major importance in leukocyte extravasation, was even increased in DCP-treated as compared to AA patient infiltrates. The same accounted for the skin homing receptor CD44v10. When we evaluated the leukocyte subpopulations in DCP-treated as compared to untreated AA patients' skin biopsies, there was an undue increase in CD1a(+) cells, that could well be indicative of hampering of the emigration of antigen presenting cells (APC) by allergen treatment. Most importantly, the number of perifollicular TUNEL- and FasL-positive cells was strikingly increased, whereas the number of CD44v7(+) cells remained unaltered. Taken together, this study provides strong evidence that long term treatment with a contact sensitizer allows for the recovery of hair follicle by driving autoreactive T cells into activation-induced cell death. In addition the replacement with newly activated autoreactive T-cells might be impaired due to a DCP-mediated hindrance of APC emigration
    Type of Publication: Journal article published
    PubMed ID: 17101475
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  • 7
    Keywords: Germany ; human ; DIAGNOSIS ; DISEASE ; GENE ; AUTOIMMUNE-DISEASE ; SKIN ; T cells ; antibodies ; antibody ; STAGE ; immunohistochemistry ; HEALTH ; HUMANS ; MUTATION ; MUTATIONS ; Jun ; POLYMERASE-CHAIN-REACTION ; CHAIN-REACTION ; BIOPSY ; FOLLICLE ; ORIGIN ; molecular ; CHAIN ; PERSISTENT ; CHILDHOOD ; HAIR FOLLICLE ; polymerase chain reaction ; methods ; technique ; HAIR LOSS ; LOSSES ; female ; ONSET ; autoimmune disease ; animal ; ENGLAND ; serology ; ALOPECIA-AREATA ; BIOPSIES ; ATRICHIA ; HUMAN HAIRLESS GENE ; ISTHMUS ; MURAL FOLLICULITIS ; PAPULAR LESIONS ; rhesus macaque
    Abstract: Background A 14-year-old female rhesus monkey (Macaca mulatta) of Chinese origin has been suffering from alopecia universalis since childhood. Methods Recently, the health status of the animal was recorded comprehensively by detailed clinical examination including hematology and serology supplemented by histological and immunohistochemical investigations of skin biopsies and molecular biological techniques to clarify the causes of the persistent hair loss. Results and conclusions The hairless gene (hr) nonsense mutation was ruled out by polymerase chain reaction and by sequencing of the corresponding gene. Histological examinations revealed a prominent chronic lymphocytic perifolliculitis and folliculitis affecting anagen stage hair follicles as well as miniaturized hair follicles. Immunohistochemistry using the antibodies CD3, CD20 and CD4 confirmed the diagnosis of a T-cell-mediated autoimmune disease resembling alopecia areata universalis in humans
    Type of Publication: Journal article published
    PubMed ID: 17517086
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; IN-VIVO ; THERAPY ; VITRO ; VIVO ; SUPPORT ; POPULATION ; PROTEIN ; MICE ; ACTIVATION ; NITRIC-OXIDE ; IFN-GAMMA ; REDUCTION ; INDUCTION ; CD8(+) T-CELLS ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; DOWN-REGULATION ; PHOSPHORYLATION ; cytokines ; NO ; DECREASE ; EFFICIENT ; CD8(+) ; sensitization ; chemokine ; protein expression ; HIGH-LEVEL ; EFFECTOR ; Bcl-2 ; C3H/HEJ MICE ; EFFECTOR-CELLS ; ANTIGEN RECEPTOR ; CYTOKINE ; RE ; THERAPIES ; HAIR FOLLICLE ; regulation ; IMMUNE SUPPRESSION ; cell proliferation ; chemokines ; LEVEL ; SUPPRESSOR ; USA ; LYMPH-NODE ; in vivo ; immunology ; regulatory T cells ; spleen ; EXPANSION ; CONTACT ; ALOPECIA-AREATA ; DOMINANCE
    Abstract: Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4(+)CD25(high) lymph node cells from mice repeatedly treated with a contact sensitizer. This obviously is a consequence of a dominance of freshly activated cells as compared with regulatory CD4(+)D25(+) T cells. Instead, a population of Gr1(+)D11b(+) cells was significantly increased in skin and spleen of AA mice repeatedly treated with a contact sensitizer. Gr-1(+)11b(+) spleen cells mostly expressed CD31. Expression of several proinflammatory cytokines as well as of the IFN-gamma receptor and the TNF receptor I were increased. Particularly in the skin, Gr-1(+) cells expressed several chemokines and CCR8 at high levels. Gr-1(+)CD11b(+) cells most potently suppressed AA effector cell proliferation in vitro and promoted partial hair regrowth in vivo. When cocultured with CD4(+) or CD8(+) cells from AA mice, the Gr-1(+)CD11b(+) cells secreted high levels of NO. However, possibly due to high level Bcl-2 protein expression in AA T cells, apoptosis induction remained unaltered. Instead, zeta-chain expression was strongly down-regulated, which was accompanied by a decrease in ZAP70 and ERK1/2 phosphorylation. Thus, a chronic eczema supports the expansion and activation of myeloid suppressor cells that, via zeta-chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo
    Type of Publication: Journal article published
    PubMed ID: 17911592
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  • 9
    Keywords: APOPTOSIS ; EXPRESSION ; CELL ; THERAPY ; DISEASE ; MICE ; SKIN ; signal transduction ; LYMPHOCYTES ; ALPHA-INDUCED APOPTOSIS ; TOLL-LIKE RECEPTORS ; C3H/HEJ MICE ; AUTOIMMUNITY ; IMMUNE-SYSTEM ; HAIR LOSS ; ALOPECIA-AREATA ; myeloid-derived suppressor cells ; MEMBRANE PERMEABILIZATION ; CHRONIC CONTACT ECZEMA ; Delayed type hypersensitivity
    Abstract: Mild but efficient treatments of autoimmune diseases are urgently required. One such therapy, long-term maintenance of chronic delayed type hypersensitivity, has been described for alopecia areata (AA), a hair follicle-affecting autoimmune disease. The molecular mechanisms underlying the therapeutic efficacy are unknown, but may involve myeloid-derived suppressor cells (MDSCs). AA-affected mice were treated with squaric acid dibutyl ester (SADBE). The immunoreactivity of SADBE-treated AA lymphocytes and of AA lymphocytes co-cultured with SADBE-induced MDSCs was analyzed. The curative effect of SADBE was abolished by all-transretinoic acid, which drives MDSCs into differentiation, confirming a central role for MDSCs in therapeutic SADBE treatment. SADBE and SADBE-induced MDSCs strongly interfered with sustained autoreactive T-cell proliferation in response to AA skin lysate (autoantigen), which was accompanied by weak zeta-chain down-regulation and strongly impaired Lck activation. In contrast, activation of the mitochondrial apoptosis pathway and blockade of the anti-apoptotic PI3K/Akt pathway by SADBE-induced MDSCs did not require T-cell receptor engagement. Apoptosis induction correlated with high TNF-alpha expression in SADBE-induced MDSCs and elevated TNFRI levels in AA lymphocytes. SADBE-induced MDSCs interfere with persisting autoreactive T-cell proliferation and promote apoptosis of these T cells, which qualifies MDSCs induced and maintained by chronic delayed type hypersensitivity reactions as promising therapeutics in organ-related autoimmune diseases
    Type of Publication: Journal article published
    PubMed ID: 21728175
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  • 10
    Keywords: CYTOKINE ; cytokines ; PATHOGENESIS ; IFN-GAMMA ; ALOPECIA
    Type of Publication: Meeting abstract published
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