The Role of Dendritic Cells in Central Tolerance

Dendritic cells (DCs) play a significant role in establishing self-tolerance through their ability to present self-antigens to developing T cells in the thymus. DCs are predominantly localized in the medullary region of thymus and present a broad range of self-antigens, which include tissue-restricted antigens expressed and transferred from medullary thymic epithelial cells, circulating antigens directly captured by thymic DCs through coticomedullary junction blood vessels, and peripheral tissue antigens captured and transported by peripheral tissue DCs homing to the thymus. When antigen-presenting DCs make a high affinity interaction with antigen-specific thymocytes, this interaction drives the interacting thymocytes to death, a process often referred to as negative selection, which fundamentally blocks the self-reactive thymocytes from differentiating into mature T cells. Alternatively, the interacting thymocytes differentiate into the regulatory T (Treg) cells, a distinct T cell subset with potent immune suppressive activities. The specific mechanisms by which thymic DCs differentiate Treg cells have been proposed by several laboratories. Here, we review the literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation, and discusses its potential mechanisms and future directions.

Leucemia mieloide crónica en crisis: blástica bases moleculares y diagnóstico / Chronic myelogenous leukemia in blastic crisis: molecular basis and diagnostic

La leucemia mieloide crónica es una enfermedad con comportamiento bifásico o trifásico, 90 por ciento de los pacientes debuta en fase crónica, 50 por ciento asintomáticos al diagnóstico. Un porcentaje con enfermedad crónica desarrollan en tiempo variable una enfermedad más agresiva definida por un período intermedio y crisis blástica. Se diagnostica al encontrar más del 20 por ciento de blastos en médula ósea, 30 por ciento en sangre periférica o enfermedad extramedular. El pronóstico es pobre, al lograr respuesta completa, con una mediana de sobrevida de 3-12 meses, independiente del fenotipo. El 50 por ciento de los pacientes tendrán una mieloide, 25 por ciento linfoide y 25 por ciento fenotipo indiferenciado. Un grupo de expertos clínicos de Bogotá, Colombia, revisaron la mejor evidencia sobre diagnóstico y tratamiento. La información se obtuvo de búsquedas estructuradas y varios registros de experimentos clínicos en curso. Presentamos conclusiones y recomendaciones para la toma de decisiones basadas en la mejor evidencia.

Autoimmunity / 소아과

Self/non-self discrimination and unresponsiveness to self is the fundamental properties of the immune system. Self-tolerance is a state in which the individual is incapable of developing an immune response to an individual's own antigens and it underlies the ability to remain tolerant of individual's own tissue components. Several mechanisms have been postulated to explain the tolerant state. They can be broadly classified into two groups: central tolerance and peripheral tolerance. Several mechanisms exist, some of which are shared between T cells and B cells. In central tolerance, the recognition of self-antigen by lymphocytes in bone marrow or thymus during development is required, resulting in receptor editing (revision), clonal deletion, anergy or generation of regulatory T cells. Not all self-reactive B or T cells are centrally purged from the repertoire. Additional mechanisms of peripheral tolerance are required, such as anergy, suppression, deletion or clonal ignorance. Tolerance is antigen specific. Generating and maintaining the self-tolerance for T cells and B cells are complex. Failure of self-tolerance results in immune responses against self-antigens. Such reactions are called autoimmunity and may give rise to autoimmune diseases. Development of autoimmune disease is affected by properties of the genes of the individual and the environment, both infectious and non-infectious. The host's genes affect its susceptibility to autoimmunity and the environmental factors promote the activation of self-reactive lymphocytes, developing the autoimmunity. The changes in participating antigens (epitope spreading), cells, cytokines or other inflammatory mediators contribute to the progress from initial activation to a chronic state of autoimmune diseases.

Immune Tolerance in Murine Islet Transplantation Across HY Disparity

BACKGROUND: Minor histocompatibility HY antigen, as a transplantation antigen, has been known to cause graft rejection in MHC (major histocompatibility complex) matched donor-recipient. The aim of our study is to investigate the role of male antigen (HY) disparity on MHC matched pancreatic islet transplantation and to examine the mechanism of the immune reaction. METHODS: Pancreatic islets were isolated and purified by collagen digestion followed by Ficoll gradient. The isolated islets of male C57BL6/J were transplanted underneath the kidney capsule of syngeneic female mice rendered diabetic with streptozotocine. Blood glucose was monitored for the rejection of engrafted islets. After certain period of time, tail to flank skin transplantation was performed either on mouse transplanted with HY mismatched islets or on sham treated mouse. The rejection was monitored by scoring gross pathology of the engrafted skin. RESULTS: HY mismatched islets survived more than 300 days in 14 out of 15 mice. The acceptance of second party graft (male B6 islets) and the rejection of third party graft (male BALB/c islets) in these mice suggested the tolerance to islets with HY disparity. B6 Skin with HY disparity was rejected on day 25 +/- 7. However, HY mismatched skin transplanted on the mice tolerated to HY mismatched islets survived more than 240 days. Tetramer staining in these mice indicated the CTL recognizing MHC Db/Uty was not deleted or anergized. CONCLUSION: The islet transplantation across HY disparity induced tolerance to HY antigen in C57BL6 mouse, which in turn induced tolerance to HY mismatched skin, which otherwise would be rejected within 25 days. The MHC tetramer staining suggested the underlying mechanisms would not be clonal deletion or anergy.

El derecho "a no nacer" en el sistema jurídico costarricense / Right of not born in the juridical sistem in Costa Rican

Las técnicas de reproducción humana asistida, la biotecnología y la pericia médica actual nos tienen en capacidad de decidir cuando un niño nacerá con defectos congénitos. En tales casos se ha llegado a considerar el derecho a indemnizar a los niños (por medio de sus padres) por haber nacido así como consecuencia de una mala praxis médica. En este artículo se compararán otros ordenamientos jurídicos con el costarricense, el cual presenta una situación absolutamente peculiar, que hace aplicables y legales algunas "curiosas" situaciones, como el feto que es persona, pueda exigir el pago con la novedad no de la indemnización, sino del medio que usa. Palabras claves: Aborto, no nacer, feto, persona no nacida, mala praxis médica, indemnización, vida de la madre, vida del feto, obligación de matar.

Participation of the Bcl-2 and Fas molecules in experimental apoptosis of spleen B lymphocytes

Antecedentes. La homeostasis en el sistema inmune está basada en el equilibrio entre la generación de células y la muerte celular. Las fallas en los mecanismos para la eliminación de clonas B autoreactivas pueden contribuir a la generación de enfermedades autoinmunes: Objetivo. Estudiar la participación de Bcl-2 y Fas en la regulación de la muerte celular de linfocitos B. Métodos. Usamos dos cepas de ratones caracterizadas por tener mecanismos deficientes de apoptosis: 1) ratones transgénicos C57BL/6-Eµ-bcl-2-22 que expresan oncogen bcl-2 en las células B; 2) mutante C56BL/6-lpr/lpr que son incapaces de expresar una molécula Fas funcional. Ambas cepas desarrollan una enfermedad autoinmune similar al lupus eritematoso generalizado. Como control normal empleamos ratones de la cepa C57BL/6. Se indujo la apoptosis mediante tres diferentes tratamientos: dexametasona, choque térmico, y radicción. El número de células en apoptosis se midió con el método TUNEL. Resultados. Los porcientos (ñ DE) de células en apoptosis inducida fueron 13.5 ñ 2.6 por ciento; 6.0 ñ 1.9 por ciento, y 5.4 ñ 1.4 por ciento; para las cepas C57Bl/6, C57BL/6-lpr/lpryC57BL/6-Eµ-bcl-2-22 respectivamente. La mutación lpr fue más efectiva que el bcl-2 para inhibir la apoptosis inducida por radiación y por hipertermia pero lo contrario ocurrió en la apoptosis por dexametasona. Conclusión. Nuestros resultados muestran que mutación lpr y la sobre-expresión del oncogén bcl-2 confirmen resistencia a la apoptosis inducida por los tratamientos estudiados

Mecanismos gerais de tolerância imunológica e auto-imunidade / General mechanisms of immunologic tolerance and autoimmunity

A tolerância imunológica a antígenos próprios do organismo é um estado fisiológico, adquirido ao longo do desenvolvimento, envolvendo vários mecanismos, para preservar os tecidos do indivíduo. Ambos repertórios, de linfócitos T e B, sao tolerizados por mecanismos interconectados, que ocorrem em dois níveis: 1) órgaos linfóides primários (tolerância central), e 2) órgaos linfóides periféricos e sangue circulante (tolerância periférica). A deleçao, por apoptose, de clones Te B imaturos, em timo e medula óssea, respectivamente, constitui o principal mecanismo de tolerância, através da seleçao negativa de células com potencial de auto-reatividade. Este processo é influenciado por diversos fatores: grau de afinidade, pelo ligando, do receptor específico para o antígeno, dos linfócitos T e B; concentraçao e natureza do antígeno reconhecido; interaçao de co-receptores e de moléculas de adesao. A detecçao de clones T e B auto-reativos, no repertório periférico normal, confirma a possibilidade de escape à deleçao clonal. Por um lado, linfócitos maduros podem ser potencialmente auto-agressivos, e ainda tolerizados, em periferia, através de mecanismos descritos principalmente para o compartimento T: deleçao clonal, anergia clonal (ocupaçao do receptor, em ausência de co-estimulaçao) e imunossupressao (por células ou citocínas). Por outro lado, o conceito de auto-reatividade fisiológica é introduzido, para se diferenciar de doença auto-imune (auto-reatividade patológica). As doenças auto-imunes se desenvolvem por falhas na manutençao da tolerância, cujas causas sao múltiplas: terreno genético individual, sobretudo genes que regulam a apresentaçao e reconhecimento antigênicos, e fatores ambientais (dieta, infecçoes virais ou bacterianas).