RESUMEN
Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation.
Asunto(s)
Trasplante de Médula Ósea/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Pulmón/inmunología , Linfocitos/inmunología , Macrófagos Alveolares/patología , Proteinosis Alveolar Pulmonar/inmunología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Interleucina-3/genética , Receptores de Interleucina/genética , Animales , Médula Ósea/patología , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/patología , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Humanos , Pulmón/patología , Linfocitos/patología , Ratones , Ratones Mutantes , Proteinosis Alveolar Pulmonar/genética , Proteinosis Alveolar Pulmonar/patología , Receptores de Interleucina-5RESUMEN
V(D)J rearrangement is the molecular mechanism by which an almost limitless number of unique immune receptors is generated. V(D)J rearrangement involves two DNA breaks and religations resulting in two DNA joints; coding and signal joints. If V(D)J recombination is impaired (as in murine SCID (C.B-17 mouse] or RAG [Recombinase Activating Genes) deficient mice), B lymphocyte and T lymphocyte development is blocked and severe immunodeficiency results. The first animal model of SCID was reported in Arabian foals in 1973. Recently we demonstrated that the mechanistic defect in SCID foals is V(D)J recombination. However, the impairment of V(D)J recombination in SCID foals is phenotypically distinct from SCID mice in that both signal and coding joint ligation are impaired. Furthermore, though equine SCID and murine SCID have definite phenotypic differences, both defects are likely to be the result of defective expression of the catalytic subunit of the DNA-dependent protein kinase.
Asunto(s)
Reordenamiento Génico/genética , Enfermedades de los Caballos/genética , Ratones SCID , Enfermedades de los Roedores/genética , Inmunodeficiencia Combinada Grave/veterinaria , Animales , Western Blotting/veterinaria , ADN/química , Electroforesis en Gel de Agar/veterinaria , Fibroblastos/química , Fibroblastos/inmunología , Regulación de la Expresión Génica , Reordenamiento Génico/inmunología , Enfermedades de los Caballos/inmunología , Caballos , Humanos , Región de Unión de la Inmunoglobulina/química , Región de Unión de la Inmunoglobulina/genética , Región de Unión de la Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Ratones , Reacción en Cadena de la Polimerasa/veterinaria , Proteínas Quinasas/análisis , Proteínas Quinasas/genética , Enfermedades de los Roedores/inmunología , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunologíaRESUMEN
IL-7 is a stromal cell-derived cytokine with a well-established physiologic role in lymphocyte biology. This report describes an unexpected role for IL-7 in the development of colitis in a T and B cell-deficient environment. Recombination-activating gene-2 (RAG-2)-deficient mice (RAG-2(-/-)) were exposed to and subsequently maintained a horizontally transmitted microbial flora that included Helicobacter hepaticus. These animals mounted a strong myeloid cell response and developed both systemic and local signs of a severe colitis. A striking infiltration of F4/80 and MHC class II-positive cells was seen in the colon and cecum of animals undergoing the disease. Mice mutant for both IL-7 and RAG-2 (IL-7/RAG-2(-/-)) that were colonized by the same flora showed no signs of myeloid responses or colitis, indicating that IL-7 plays a critical role in exacerbating a non-T cell/non-B cell-mediated chronic inflammatory response. Recombinant IL-10 protein therapy was able to prevent the occurrence of colitis in susceptible mice, suggesting a pivotal role for macrophages. The implications of a role for IL-7 in this disease model with respect to human inflammatory bowel disease are discussed.
Asunto(s)
Linfocitos B/patología , Colitis/genética , Colitis/inmunología , Interleucina-7/deficiencia , Interleucina-7/genética , Linfopenia/inmunología , Linfocitos T/patología , Animales , Animales Recién Nacidos , Movimiento Celular/inmunología , Colitis/prevención & control , Proteínas de Unión al ADN/genética , Eosinófilos/inmunología , Eosinófilos/patología , Células Epiteliales/inmunología , Células Epiteliales/patología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/prevención & control , Inmunidad Celular/genética , Interleucina-10/genética , Interleucina-10/uso terapéutico , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Linfopenia/genética , Linfopenia/patología , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Endogámicos , Ratones Noqueados , Proteínas Recombinantes/uso terapéuticoRESUMEN
V(D)J rearrangement is the molecular mechanism by which an almost infinite array of specific immune receptors are generated. Defects in this process result in profound immunodeficiency as is the case in the C.B-17 SCID mouse or in RAG-1 (recombination-activating gene 1) or RAG-2 deficient mice. It has recently become clear that the V(D)J recombinase most likely consists of both lymphoid-specific factors and ubiquitously expressed components of the DNA double-strand break repair pathway. The deficit in SCID mice is in a factor that is required for both of these pathways. In this report, we show that the factor defective in the autosomal recessive severe combined immunodeficiency of Arabian foals is required for (i) V(D)J recombination, (ii) resistance to ionizing radiation, and (iii) DNA-dependent protein kinase activity.