Impacto de la deficiencia de C3 plasmático en la diferenciación y función leucocitaria
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2017
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06/07/2017
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Universidad Complutense de Madrid
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Abstract
El papel del complemento en la inmunobiología ha evolucionado notablemente desde que fue descrito inicialmente como un elemento clave de la inmunidad innata. Lejos de su visión tradicional como un simple elemento termolábil que complementaba la eliminación de microbios mediada por anticuerpos, hoy día el sistema de complemento es considerado como un puente entre la inmunidad innata y adaptativa1. De las más de 50 proteínas que lo componen, la proteína C3 es el eje central en el que convergen sus tres vías de activación y por ello, tiene un fuerte impacto en la regulación de la biología leucocitaria, especialmente en linfocitos T, B y células dendríticas (DC). Los antígenos solubles opsonizados por fragmentos plasmáticos de C3d(g) se unen a través de su receptor CD21 e inducen el reclutamiento de CD19 y CD81 para formar el co-receptor de linfocitos B, reduciendo significativamente el umbral de activación del receptor de linfocitos B2. El receptor CD21, también conocido como receptor de complemento 2, es expresado por células dendríticas foliculares que capturan antígenos opsonizados con C3d(g) en los centros germinales de los órganos linfoides secundarios, favoreciendo la maduración de la afinidad, el cambio de isotipo y la adquisición de memoria de linfocitos B naíf o primados3. A pesar de que hace años ya se apuntó a una síntesis extra-hepática del complemento, con el tiempo han ido creciendo las evidencias que respaldan su síntesis local por diferentes tipos leucocitarios4. De hecho, los recientes hallazgos que exponen la existencia de un sistema de activación de C3 intracelular diferente al conocido plasmático con importantes consecuencias para la homeostasis y función de los linfocitos T ponen de manifiesto el alcance de la influencia de C3 en mamíferos5. En este contexto se ha visto que tanto los linfocitos T como las DC sintetizan fragmentos de C3 que actúan de forma autocrina y paracrina, favoreciendo la función de presentación antigénica de las DC e induciendo funciones efectoras en los linfocitos T6...
The role of complement in immunobiology has greatly evolved since it was first described as a key element of innate immunity. Far from the traditional vision of complement as a simple heat-labile assistant in antibody-mediated killing of microbes, it is now recognized as a bridge between the innate and adaptive arms of immunity1. Among more than 50 proteins of the complement system, C3 is the central hub of the three complement pathways and thus has a strong impact in leucocyte biology, especially in T and B lymphocytes and in dendritic cells (DC). Soluble antigens containing the plasma C3 fragment C3d(g) due to opsonization will engage its receptor CD21 and induce the recruitment of CD19 and CD81 to form and trigger the B cell co-receptor, significantly lowering the activation threshold of B cell receptor signaling2. CD21, also known as complement receptor 2, is expressed on follicular dendritic cells which capture C3d(g)-opsonized antigens in the secondary lymphoid organs germinal centers, enhancing the affinity maturation, isotype switching and memory acquisition of naïve or primed human B cells3. Despite several years ago an extra-hepatic complement synthesis was described, increasing evidence have been accumulating supporting its local synthesis by different leukocyte types4. Indeed, the recent realization of an intracellular C3 activation system different from the extracellular with important consequences for T cell homeostasis and differentiation highlights the scope of C3 influences in mammals5. In this context, it has been shown that T lymphocytes as well as DC synthetize C3 fragments that act in an autocrine and paracrine manner, enhancing DC antigen presentation function and inducing T cell effector functions6. Therefore, plasma or intracellular C3 could be considered as T and B cell costimulators, but the relative contribution of their signals is not well characterized, and most of the studies that point to a specific role of complement fragments, especially regarding to B lymphocyte differentiation, are developed in mice. A better characterization would include the use of human samples, and more specifically, samples from plasma C3 deficient-patient’s samples, either primary —due to C3 mutations— or secondary — due to a deficiency in the regulator factor I, that leads to a plasma C3 consumption—. However, this deficiency is an extremely rare disease with very low prevalence and less than 50 cases reported, making it difficult to study...
The role of complement in immunobiology has greatly evolved since it was first described as a key element of innate immunity. Far from the traditional vision of complement as a simple heat-labile assistant in antibody-mediated killing of microbes, it is now recognized as a bridge between the innate and adaptive arms of immunity1. Among more than 50 proteins of the complement system, C3 is the central hub of the three complement pathways and thus has a strong impact in leucocyte biology, especially in T and B lymphocytes and in dendritic cells (DC). Soluble antigens containing the plasma C3 fragment C3d(g) due to opsonization will engage its receptor CD21 and induce the recruitment of CD19 and CD81 to form and trigger the B cell co-receptor, significantly lowering the activation threshold of B cell receptor signaling2. CD21, also known as complement receptor 2, is expressed on follicular dendritic cells which capture C3d(g)-opsonized antigens in the secondary lymphoid organs germinal centers, enhancing the affinity maturation, isotype switching and memory acquisition of naïve or primed human B cells3. Despite several years ago an extra-hepatic complement synthesis was described, increasing evidence have been accumulating supporting its local synthesis by different leukocyte types4. Indeed, the recent realization of an intracellular C3 activation system different from the extracellular with important consequences for T cell homeostasis and differentiation highlights the scope of C3 influences in mammals5. In this context, it has been shown that T lymphocytes as well as DC synthetize C3 fragments that act in an autocrine and paracrine manner, enhancing DC antigen presentation function and inducing T cell effector functions6. Therefore, plasma or intracellular C3 could be considered as T and B cell costimulators, but the relative contribution of their signals is not well characterized, and most of the studies that point to a specific role of complement fragments, especially regarding to B lymphocyte differentiation, are developed in mice. A better characterization would include the use of human samples, and more specifically, samples from plasma C3 deficient-patient’s samples, either primary —due to C3 mutations— or secondary — due to a deficiency in the regulator factor I, that leads to a plasma C3 consumption—. However, this deficiency is an extremely rare disease with very low prevalence and less than 50 cases reported, making it difficult to study...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Microbiología I, leída el 06/07/2017