Assuntos
Anafilaxia/induzido quimicamente , Antibacterianos/efeitos adversos , Ceftriaxona/efeitos adversos , Cefalosporinas/efeitos adversos , Hipersensibilidade a Drogas/imunologia , Hipersensibilidade Imediata/induzido quimicamente , Anafilaxia/imunologia , Antibacterianos/imunologia , Ceftriaxona/imunologia , Cefalosporinas/imunologia , Clindamicina/efeitos adversos , Clindamicina/imunologia , Reações Cruzadas/imunologia , Dexametasona/efeitos adversos , Dexametasona/imunologia , Humanos , Hipersensibilidade Imediata/imunologia , Masculino , Pessoa de Meia-Idade , Testes CutâneosRESUMO
Bronchiolitis obliterans is a small-airway obstructive lung disease for which immunologically mediated pathogenesis is supposed. Frequent association of bronchiolitis obliterans with paraneoplastic pemphigus is well known, but its association with other autoimmune bullous diseases has not been reported except for a case of anti-laminin-332-type mucous membrane pemphigoid in a patient with chronic graft-versus-host disease. We report a case of non-paraneoplastic autoimmune subepidermal bullous disease associated with fatal bronchiolitis obliterans in a patient without transplantation. Although the patient's serum contained immunoglobulin (Ig)A antibodies to the 180-kDa bullous pemphigoid antigen/type XVII collagen and IgG antibodies to laminin-332, diagnosis of either linear IgA bullous dermatosis or mucous membrane pemphigoid could not be made because of the failure to detect linear IgA deposition at the basement membrane zone by direct immunofluorescence and the lack of mucous membrane lesions. Physicians should be aware that autoimmune bullous diseases other than paraneoplastic pemphigus can also associate with this rare but potentially fatal lung disease.
Assuntos
Autoantígenos/imunologia , Bronquiolite Obliterante/complicações , Moléculas de Adesão Celular/imunologia , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/complicações , Insuficiência Respiratória/etiologia , Idoso , Antibacterianos/uso terapêutico , Autoanticorpos/sangue , Membrana Basal/metabolismo , Biópsia , Bronquiolite Obliterante/sangue , Evolução Fatal , Técnica Direta de Fluorescência para Anticorpo , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/metabolismo , Imunoglobulina G/sangue , Masculino , Minociclina/uso terapêutico , Niacinamida/uso terapêutico , Síndromes Paraneoplásicas/complicações , Penfigoide Bolhoso/tratamento farmacológico , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/patologia , Prednisolona/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Calinina , Colágeno Tipo XVIIRESUMO
Rejection of solid organ allografts is promoted by T cells. Recipient T cells can directly recognize intact allo-MHC molecules on donor cells and can also indirectly recognize processed donor-derived allo-peptides presented by recipient antigen-presenting cells in the context of self-MHC molecules. Although CD4(+) T cells primed through the indirect allorecognition pathway alone are sufficient to promote acute allograft rejection, it is unknown how they can mediate graft destruction without cognate recognition of donor cells. In this study, we analyzed the indirect effector mechanism of skin allograft rejection using a mouse model in which SCID recipients bearing MHC class II-deficient skin allografts were adoptively transferred with CD4(+) T cells. Histologically, entire graft necrosis was preceded by mononuclear cell infiltration in the graft epithelia with epithelial cell apoptosis, indicating cell-mediated cytotoxicity against donor cells as an effector mechanism. Beside CD4(+) T cells and macrophages, NK cells infiltrated in the rejecting grafts. Depletion of NK cells as well as blocking of the activating NK receptor NKG2D allowed prolonged survival of the grafts. Expression of NKG2D ligands was up-regulated in the rejecting grafts. These results suggest that NK cells activated through NKG2D contribute to the skin allograft rejection promoted by indirectly primed CD4(+) T cells.
Assuntos
Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Rejeição de Enxerto/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Transplante de Pele/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Anticorpos Bloqueadores/imunologia , Apresentação de Antígeno/genética , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Apresentação Cruzada , Feminino , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores Imunológicos/antagonistas & inibidores , Receptores de Células Matadoras Naturais , Transplante de Pele/patologia , Imunologia de Transplantes , Transplante HomólogoRESUMO
BACKGROUND: Mouse epidermis contains a population of gammadelta T cells, termed dendritic epidermal T cells (DETCs), which uniformly express the invariant Vgamma3 T cell receptor. Certain DETC lines were reported to respond to Gram-negative bacteria in the presence of immobilized anti-CD3 monoclonal antibody or to lipopolysaccharide (LPS) in the presence of B cell lines. OBJECTIVE: To determine whether DETCs express the primary signaling receptor for LPS, Toll-like receptor (TLR) 4-MD2. METHODS: We analyzed expression of TLR4-MD2 in three independent DETC lines as well as in freshly isolated DETCs. RESULTS: All DETC lines expressed TLR4 and MD2 transcripts and TLR4-MD2 protein complex intracellularly, but none expressed TLR4-MD2 on the cell surface. By immunoblotting, only the immature form of TLR4 protein was detected in the DETC lines. The DETC lines did not respond to LPS even in the presence of immobilized anti-CD3 monoclonal antibody. Freshly isolated DETCs and their fetal thymic precursors also lacked cell surface expression of TLR4-MD2, but a small subpopulation of dermal Vgamma3 T cells isolated from croton oil-painted skin expressed TLR4-MD2 on the cell surface. Similarly, Vgamma3 T cells emigrated from organ-cultured epidermis expressed cell surface TLR4-MD2. CONCLUSIONS: These results demonstrate that DETCs do not constitutively express cell surface TLR4-MD2, but TLR4-MD2 expression may be up-regulated when DETCs emigrate from epidermis during cutaneous inflammation.
Assuntos
Membrana Celular/metabolismo , Dendritos/metabolismo , Células Epidérmicas , Glicoproteínas de Membrana/biossíntese , Receptores de Superfície Celular/biossíntese , Receptores Imunológicos/biossíntese , Pele/patologia , Linfócitos T/citologia , Regulação para Cima , Animais , Linhagem Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Dermatite/metabolismo , Epiderme/metabolismo , Feminino , Citometria de Fluxo , Immunoblotting , Inflamação , Lipopolissacarídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 4 Toll-LikeRESUMO
Epidermal keratinocytes secrete cytokines, chemokines, and anti-microbial peptides in response to various microbial pathogens and their components including lipopolysaccharide (LPS). To identify the receptor(s) involved in the anti-microbial responses of epidermal keratinocytes, we analyzed expression of CD14, Toll-like receptor 2 (TLR2), and TLR4 on cultured normal human epidermal keratinocytes (NHEK). Although CD14 and TLR2 mRNA were expressed in cultured NHEK, only TLR2 was detected on the cell surface. Cultured NHEK did not express TLR4 mRNA or protein. Commercial LPS preparations could stimulate epidermal keratinocytes to produce beta-defensin-2 and IL-8, and the LPS response was inhibited with mAb specific for TLR2, but not for CD14 or TLR4. Repurified LPS and lipid A did not stimulate epidermal keratinocytes, whereas peptidoglycan (PGN) from Gram-positive bacteria and yeast cell wall particle induced beta-defensin-2 and IL-8 production. Thus, cultured NHEK express functional TLR2, but not CD14 or TLR4, and the "LPS" response of epidermal keratinocytes shown in the previous studies might be mediated by TLR2-dependent recognition of non-LPS bacterial components contaminating in commercial LPS preparations. In the normal human skin, however, epidermal keratinocytes expressed both TLR2 and TLR4. Because TLR4 was induced in epidermal keratinocytes by in vitro stimulation with PGN from Gram-positive bacteria, constitutive expression of TLR4 on epidermal keratinocytes in vivo might also be induced by continuous recognition of the resident skin flora containing Gram-positive bacteria through TLR2.
Assuntos
Epiderme/metabolismo , Queratinócitos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Células Cultivadas , Células Epidérmicas , Epiderme/efeitos dos fármacos , Bactérias Gram-Positivas , Humanos , Queratinócitos/efeitos dos fármacos , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Peptidoglicano/farmacologia , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-LikeRESUMO
IL-2/IL-15Rbeta-deficient mice display impaired development of NK cells, NKT cells, and intraepithelial lymphocytes of the intestine and skin. To determine the role of survival signals mediated by IL-2/IL-15R in the development of these innate lymphocytes, we introduced a bcl-2 transgene into IL-2/IL-15Rbeta-deficient mice. Enforced expression of Bcl-2 restored the number of NK cells in IL-2/IL-15Rbeta-deficient mice, but the rescued NK cells showed no cytotoxic activity. The numbers of NKT cells and intestinal intraepithelial lymphocytes did not increase significantly, and skin intraepithelial lymphocytes remained undetectable in the bcl-2 transgenic IL-2/IL-15Rbeta-deficient mice. These results indicate an essential role of IL-2/IL-15R-mediated survival signals in the development of NK cells, but they also show that additional nonsurvival signals from IL-2/IL-15R are necessary for innate lymphocyte development.
Assuntos
Células Matadoras Naturais/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Interleucina-2/deficiência , Receptores de Interleucina-2/genética , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citotoxicidade Imunológica/genética , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-15/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Linfopenia/genética , Linfopenia/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Receptores de Interleucina-15 , Receptores de Interleucina-2/fisiologia , Pele/imunologia , Pele/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Transgenes/imunologiaRESUMO
Precursors for Thy-1(+) dendritic epidermal T cells (DETC) develop as Vgamma3(+) T cells in the fetal thymus and become distributed in the adult skin. DETC are variably distributed from site to site and from strain to strain. To elucidate the basis of strain variation, we first compared the density of DETC in the ear epidermis among different mouse strains. In the ear epidermis, we detected the highest level of DETC in C57BL/6 mice, intermediate levels in C3H and CBA/J mice, and the lowest levels in other strains including BALB/c and 129 mice. Although BALB/c and 129+Ter/Sv mice showed higher levels of DETC in the abdomen than in the ear, the levels were significantly lower than C57BL/6 mice. Furthermore, in neonatal abdominal epidermis we detected considerably lower numbers of DETC in BALB/c and 129+Ter/Sv mice than in C57BL/6 mice. In contrast, Vgamma3(+) DETC precursors in the fetal thymus are rather increased in 129+Ter/Sv mice. These results suggest that fewer DETC precursors are seeded in the neonatal skin of BALB/c and 129+Ter/Sv mice and that their expansion in the skin during neonatal to adult stages does not reach the levels in C57BL/6 mice.