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Mitrídates - ¿Desarrollando inmunidad al veneno?

Mitrídates - ¿Desarrollando inmunidad al veneno?


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Según la leyenda, Mitrídates investigó y examinó minuciosamente todas las toxinas conocidas y experimentó con posibles remedios utilizando prisioneros como conejillos de indias. Supuestamente, los esfuerzos de Mitrídates valieron la pena porque numerosos autores antiguos, incluido Plinio el Viejo, afirmaron que creó e ingirió regularmente un antídoto universal para todas las toxinas identificadas, y se conoció como mitridato (mithridatium).

Se dijo que estaba ingiriendo pequeñas cantidades de veneno para desarrollar inmunidad.

Ya sea veneno universal o ingiriendo cada tipo uno por uno, ¿es esto posible fortalecer su cuerpo para resistir o ser inmune al veneno / veneno / toxinas en general?


Bienvenido a SE. Editar: La respuesta está en dos partes basadas en el mecanismo de acción de la toxina. Cortesía: @David y @jamesqf

Inmunidad

Los glóbulos blancos en el cuerpo son responsables de reconocer péptidos propios o no propios y forman el compartimento adaptativo del sistema inmunológico. Los linfocitos B tienen un receptor que puede unirse a varios péptidos. Tras el reconocimiento de péptidos extraños en el cuerpo, estos atraviesan una reacción (hipermutación somática) para volverse más específicos del péptido extraño. También se diferencian en células plasmáticas que ahora pueden secretar otra proteína (anticuerpos) que neutraliza el péptido extraño.

Pequeñas cantidades, que no son letales, pero en concentración suficiente para impulsar la reacción de las células B, crean una "memoria" inmunológica. Esta memoria permite una respuesta más rápida al mismo péptido en comparación con la reacción. Esto permite que el cuerpo resista una mayor concentración de péptido tóxico, que de otro modo habría sido letal si se neutralizara.

Las vacunas funcionan según un principio muy cercano a este.

Homeostasis

Cada toxina interactúa con algún proceso biológico y la desequilibra. El cuerpo intenta activamente restablecer el equilibrio de alguna manera.

Por ejemplo, si se agota un ligando, el cuerpo puede aumentar la cantidad de receptores para contrarrestar el efecto y viceversa.

Al ingerir pequeñas cantidades de toxinas, el cuerpo puede ajustar el equilibrio en una cantidad muy pequeña a la vez, ajustando la concentración de ligandos o receptores relevantes.

Una vez más, la persona que ha pasado por este proceso puede soportar una dosis más alta de la toxina en comparación con una persona que no lo ha hecho.


Las 'superratas' desarrollan inmunidad genética a los venenos estándar

Un científico de la Universidad de Huddersfield ha alertado al Reino Unido sobre el creciente problema de las destructivas "superratas" inmunes al veneno convencional. Su investigación ha creado interés en todo el país, especialmente en el oeste de Inglaterra, donde podría ser que hasta el 75 por ciento de las ratas sean del tipo resistente.

El Dr. Dougie Clarke, director de Ciencias Biológicas de la Facultad de Ciencias Aplicadas de la Universidad de Huddersfield, dirige el Proyecto de mapeo de la resistencia a los rodenticidas en el Reino Unido. Toma muestras de ADN de cientos de ratas en todo el país para establecer qué regiones tienen la mayor prevalencia de ratas que tienen mutaciones genéticas que las protegen de los venenos para ratas más comúnmente utilizados.

El objetivo es encontrar qué partes del país tienen las mayores poblaciones de ratas con resistencia genética a los raticidas más utilizados: warfarina, bromadiolona y difenacoum. Estos son anticoagulantes que someten a las ratas a la muerte por hemorragia interna y se han utilizado ampliamente desde la década de 1950, pero poco después de su introducción, se descubrió que algunas ratas no se veían afectadas por estos venenos.

Después de que se supo por primera vez en la década de 1950 que algunas ratas podían resistir los venenos convencionales, el gobierno llevó a cabo una investigación. Pero tuvo que hacerlo mediante el laborioso método de atrapar ratas y realizar pruebas de alimentación en todo el animal. Esta investigación se interrumpió en la década de 1990, pero durante las dos últimas décadas ha aumentado el problema de la resistencia en las ratas.

Donde los animales prosperan, pueden propagar enfermedades, agotar los recursos alimenticios, roer cables eléctricos e incluso causar daños estructurales. Y debido a que sobrevivieron, sus descendientes tienen la misma resistencia. El resultado, dice el Dr. Clarke, es que si bien originalmente podría haber solo un pequeño porcentaje de ratas resistentes en ciertas áreas urbanas y rurales, ahora constituyen una proporción significativa de la población.

La prevalencia más alta se ha encontrado hasta ahora en ciertas áreas del sur de Inglaterra y West Country, donde más del 70% de los animales probados son del tipo "super" rata.

Esto significa que las poblaciones de las criaturas crecerán y podría haber una amenaza para la vida silvestre e incluso los gatos domésticos que cazan y devoran ratas cuyos cuerpos llevan el veneno al que se han vuelto resistentes.

Para combatir el problema existen venenos más fuertes, como brodifacoum y flocoumafen, que pueden usarse y han demostrado ser efectivos, incluso contra las llamadas superratas. Pero estos raticidas deben usarse en condiciones estrictamente controladas, bajo licencia del Ejecutivo de Salud y Seguridad. Por lo tanto, las autoridades locales, los operadores de control de plagas y los gigantes químicos que fabrican los venenos para ratas necesitan saber qué áreas del país están más fuertemente infestadas por ratas resistentes para que se pueda dar luz verde para usar las sustancias más poderosas.

"En un área, cada rata que analizamos era resistente y la infestación era tan mala que la compañía de control de plagas solicitó al Ejecutivo de Salud y Seguridad el uso de emergencia de los raticidas más fuertes y se eliminaron en dos semanas".

Como resultado del descubrimiento de las mutaciones genéticas que causan la resistencia, el Dr. Clarke y sus colegas se han embarcado en el nuevo e importante proyecto de investigación, financiado por una lista de empresas líderes en la industria europea de control de plagas (BASF, Bayer, Bell, Killgerm, PelGar , Syngenta), la Organización Británica de Control de Plagas y la Asociación Nacional de Técnicos en Plagas. En lugar de utilizar animales vivos, el estudio analiza la composición genética del animal para determinar si es resistente a los venenos convencionales utilizando tres centímetros de la punta de la cola de una rata.

El objetivo es probar al menos 600 animales y se espera que el proyecto se complete en 2013. La llegada del clima invernal, que roba a las ratas gran parte de su suministro natural de alimentos, acelerará el número de muestras enviadas a la Universidad de Laboratorios de Huddersfield.

El foco de la investigación está en una serie de puntos calientes en Gran Bretaña donde se sabe o se sospecha que predominan las ratas resistentes.

El término "superrata" es bastante apropiado, dice el Dr. Clarke. Las criaturas que no se ven afectadas por los venenos de rutina no se han vuelto resistentes debido a que su ADN muta como resultado de su exposición a los químicos rodenticidas. La escala de tiempo es demasiado corta para eso. En cambio, tienen una mutación genética natural que los protege de los venenos rodenticidas. Con el tiempo, en un área que se trata con estos venenos para el control de ratas con una población mixta de ratas `` normales '' susceptibles y las ratas `` súper '' genéticamente resistentes, la población se convertirá exclusivamente en el tipo de rata `` súper '' que transmite el gen de resistencia a su descendencia.

Cuando haya reunido más datos científicos, los hallazgos se publicarán, probablemente durante 2013. Pero mientras tanto, las noticias de su investigación han creado interés en todo el país, especialmente en el oeste de Inglaterra, donde podría ser que hasta el 75 por ciento de las ratas son del tipo resistente.


Algunos ratones se han vuelto inmunes al veneno a través de una evolución natural pero muy inusual

Los ratones son geniales (ver: ratones de alta resistencia, ratones con órganos artificiales cultivados en laboratorio, ratones de seguridad israelíes detectores de bombas) pero a veces simplemente no los quieres en tu apartamento / casa / panadería / cocina / estación de metro de Nueva York, por eso puede comprar warfarina, un veneno común para roedores. Sin embargo, algunos ratones han desarrollado inmunidad a ese veneno a través de medios muy inusuales: transferencia horizontal de genes, una especie de evolución a través de la hibridación que solo se había visto antes en microbios.

Como se informa en la edición actual de Biología actual, se descubrió que los ratones de una panadería alemana no reaccionaban en absoluto al uso de una forma particularmente desagradable de warfarina, que suele ser un beso de muerte para nuestro amigo el ratón doméstico. Un análisis genético mostró que los ratones en esa cocina en realidad tenían una gran parte de ADN del ratón argelino, una especie separada (aunque estrechamente relacionada) del ratón doméstico que generalmente se encuentra alrededor de las costas arenosas occidentales del Mediterráneo.

El ratón argelino, como ve, es inmune a la warfarina y aparentemente ese gen también ayuda a controlar una deficiencia de vitamina K que tiene la dieta del ratón argelino y los humanos, con todos nuestros viajes y demás, introdujeron las dos especies, que normalmente no lo harían. han entrado en contacto entre sí. El ratón doméstico se crió con el ratón argelino y bam: super ratones domésticos inmunes al veneno.

Este tipo de evolución, en la que la hibridación produce una estructura genética beneficiosa, se denomina transferencia genética horizontal. Es muy diferente del estilo de evolución habitual, en el que las mutaciones beneficiosas se transmiten a la siguiente generación y, de hecho, nunca antes se había observado en ningún animal complejo. Hasta ahora, la transferencia horizontal de genes solo se ha visto en microbios, por lo que es bastante sorprendente verla en algo tan complejo y adorable como un ratón. Por supuesto, eso puede dificultar que los panaderos y los empleados de la MTA eliminen los roedores de sus negocios y / o estaciones de metro, pero los ratones probablemente estén contentos.


Tomando el control del reino

Alrededor del 116 a. C., Mitrídates salió de su escondite y se enfrentó a su madre. El joven rey sacó con éxito a su madre de su trono y la envió a prisión, donde finalmente murió. Durante su regencia, Laodicea había favorecido al hermano menor de Mitrídates, Mithridates Chrestus, tal vez porque era más maleable a su voluntad que su hermano mayor. Él también desapareció de la escena, posiblemente poco después del encarcelamiento de su madre. Una sugerencia es que Mitrídates hizo asesinar a su madre y a su hermano.

Con estos rivales fuera del camino, Mitrídates se convirtió en el único gobernante del Reino del Póntico.

Mitrídates comenzó entonces a ampliar su reino, como continuación de la política expansionista de su difunto padre. En 115/114 a. C., el joven rey cruzó el Mar Negro para intervenir en un conflicto que se estaba librando entre los asentamientos helenísticos de Crimea y sus vecinos escitas.

Un busto del rey del Ponto Mitrídates VI como Heracles. Mármol, época imperial romana (siglo I). ( CC BY 3.0 )

Como resultado de esto, los asentamientos helenísticos entregaron su independencia a Mitrídates a cambio de su protección. El siguiente objetivo de Mitrídates fue el vecino oriental de Ponto, Paflagonia, que ocupó en 108/107 a. C. con la ayuda de Nicomedes III Euergetes, el rey de Bitinia.

Aunque un emisario romano intentó que el rey paflagoniano, Astreodon, volviera a su trono, sus esfuerzos fueron en vano. En cambio, el hijo de Nicomedes fue colocado en el trono de Paphlagonian como rey títere.

En 104/103 a. C., Colchis (actual Georgia occidental) se agregó a los dominios de Mitrídates, y Mitrídates continuó expandiendo su reino. Es casi seguro que la toma de Paflagonia por Mitrídates y Nicomedes y las conquistas del primero no fueron vistas con el favor del Senado romano.

Mapa del Reino de Ponto, antes del reinado de Mitrídates VI (violeta oscuro), después de sus conquistas (violeta), sus conquistas en las primeras guerras de Mitrídatas (rosa) y el aliado de Ponto el Reino de Armenia (verde). ( Dominio publico )

Sin embargo, los romanos, hasta ese momento, no habían estado realmente interesados ​​en estos desarrollos. Esto se debió a ciertos factores, incluidas las guerras en las que ya estaba involucrada Roma, y ​​la distancia que separaba a Roma de Anatolia.


Mitrídates - ¿Desarrollando inmunidad al veneno? - biología

2) Esta capacidad de "atacar" una sustancia en particular se conoce como inmunidad y es el resultado de las actividades de un conjunto específico de células diferenciadas, llamadas colectivamente sistema inmunológico.

3) Cuando el material atacado es uno que no es dañino en sí mismo, de modo que los efectos secundarios del ataque inmune son más desagradables que los efectos directos del propio material, entonces nos referimos a las consecuencias del ataque inmune como un "alergia".
(Cuando alguien afirma que es "inmune a la hiedra venenosa", ¿qué quiere decir realmente?)

    Anemia perniciosa: se ataca la enzima que absorbe la vitamina B12
    Esclerosis múltiple: se ataca la vaina de mielina alrededor de los axones nerviosos
    Fiebre reumática: se ataca la matriz extracelular de las válvulas cardíacas.
    Lupus Eritematosis: el colágeno, el ADN y otros contenidos celulares son atacados
    Miastenia grave: los receptores de acetilcolina en las células musculares son atacados
    Esterilidad masculina después de las paperas: ¡los espermatozoides son atacados por primera vez en la pubertad!

5) Una parte importante de la inmunidad (la parte mejor entendida) es la síntesis y secreción en la sangre y otros fluidos de una clase de proteínas especiales llamadas "anticuerpos". También se denominan inmunoglobinas, porque forman parte de la fracción de proteínas sanguíneas llamadas globinas. Específicamente, forman el subconjunto de estos llamados gammaglobulinas.

6) Cada molécula de anticuerpo tiene 2 (o 10, en IgM) sitios de unión (análogos a los sitios activos mediante los cuales las enzimas se unen a sus sustratos químicos) mediante los cuales las moléculas de anticuerpo se unen de manera muy específica y muy estrecha a cualquier otra molécula que tenga exactamente el derecho. forma para encajar en este sitio de encuadernación. La molécula a la que se une un anticuerpo se llama su "antígeno". La aparente etimología de la palabra antígeno implica que la síntesis del anticuerpo es estimulada de alguna manera por el antígeno al que se unen sus sitios activos, pero esto no siempre es cierto. La palabra más nueva "epítopo" se refiere al sitio molecular al que se une un anticuerpo dado.

7) La especificidad de las moléculas de anticuerpo por su correspondiente epítopo de antígeno puede ser muy grande. Al igual que la especificidad de las enzimas por sus sustratos, la especificidad de la unión de anticuerpos resulta de un ajuste conformacional exacto entre las dos formas. Los biólogos experimentales a menudo aprovechan esta extrema especificidad para determinar las posiciones de ciertas moléculas dentro de las células. Los anticuerpos "contra" el antígeno de interés se obtienen, se toman prestados o se compran, y las sustancias químicas fluorescentes se unen covalentemente a estos anticuerpos para que su ubicación pueda observarse mediante "microscopía de inmunofluorescencia". Las pruebas de embarazo modernas también dependen de la especificidad de la unión de los anticuerpos a ciertas hormonas proteicas, al igual que los "ensayos radioinmunes" cuya precisión ha revolucionado la endocrinología.

8) Los anticuerpos son sintetizados por un tipo particular de glóbulo blanco llamado linfocito B (a menudo llamado simplemente células B). Cuando estos secretan, también se les llama "células plasmáticas".

9) (un dato clave) Cada linfocito B individual (y todas sus células hijas, cuando se divide) secretará moléculas de anticuerpos que tienen exactamente la misma especificidad de unión. Todas las moléculas de anticuerpos que esta célula y sus hermanas sintetizarán y secretarán tendrán exactamente los mismos sitios de unión de forma y se unirán a los mismos antígenos o epítopos. ¡Esta restricción de los clones de células B a una sola especificidad de unión es quizás el hecho más crucial sobre el mecanismo de nuestro sistema inmunológico! ¡Asegúrate de entender esto!

10) Los linfocitos B (o, mejor dicho, sus células precursoras) responden a la exposición a moléculas de "su" antígeno (aquel al que se unirán sus anticuerpos) aumentando el crecimiento y la división, así como aumentando la secreción de moléculas de anticuerpos. Este proceso de estimulación puede tardar varios días en producir suficientes anticuerpos para matar patógenos. De hecho, esta estimulación y respuesta es lo que ocurre durante los varios días que se necesitan para comenzar a recuperarse de una enfermedad infecciosa. Una vez que se ha producido la estimulación por parte de los antígenos de cierto patógeno, la cantidad de moléculas de anticuerpos y de linfocitos que los secretan permanecerá lo suficientemente alta como para evitar la reinfección por ese patógeno; a veces, esta protección durará el resto de su vida. Es por eso que solo contrae ciertas enfermedades una vez: por ejemplo, sarampión, paperas, varicela, polio.

11) La "vacunación" se basa en estimular deliberadamente al cuerpo para que produzca más anticuerpos contra virus y bacterias patógenos. Esta estimulación generalmente se logra mediante una exposición deliberada del cuerpo a antígenos de estos organismos patógenos, en forma de antígenos aislados, patógenos muertos o incluso formas vivas pero debilitadas de los patógenos.

12) Se sabía en la antigüedad (lo menciona el historiador Thucidides) que las personas se vuelven insensibles a ciertas enfermedades por haberlas contraído una vez. En la década de 1700, Mary Montague introdujo en Inglaterra desde Turquía la idea de inocular deliberadamente a personas con casos leves de viruela. Más tarde, Edward Jenner defendió la práctica popular (¡entonces considerada por casi todos los médicos como una superstición!) De infectar deliberadamente a las personas con la enfermedad (leve) "viruela de las vacas", con el fin de inducir inmunidad a la (mucho más grave) enfermedad relacionada, viruela. (Observe cómo la palabra vacunación proviene de la raíz del idioma romance para "vaca", como en español "vaca", por lo tanto, vacunación = "cowification").

13) Entre los muchos logros del gran científico francés Louis Pasteur (más tarde en el siglo XIX) estuvo el desarrollo de procedimientos para aislar y debilitar deliberadamente los organismos patógenos para que luego puedan usarse para la vacunación. De lo contrario, este enfoque se limitaría solo a aquellas enfermedades en las que ya existe una forma relacionada, pero más débil, de la enfermedad. Básicamente, estaba buscando métodos para "hacer su propia viruela vacuna" para cualquier enfermedad determinada.

14) ¡La explicación mecanicista de la inmunidad en la que creía Pasteur y que, por tanto, motivó y guió su investigación, estaba completamente equivocada! Él creía que el cuerpo contenía varios oligoelementos que eran necesarios para el crecimiento y la supervivencia de cada organismo patógeno en particular, y que estos oligoelementos eran consumidos por estos organismos cuando tenía esa enfermedad en particular, creía que, por lo tanto, se volvía insensible a la enfermedad. porque entonces su cuerpo carece de suficientes oligoelementos para que los gérmenes vivan. (¡Observe cómo las teorías equivocadas a veces pueden hacer predicciones correctas y conducir a avances médicos!)

15) Más tarde se descubrió que la inyección con gérmenes muertos, e incluso solo con proteínas aisladas de ellos, puede (a veces) producir inmunidad. Un ejemplo de lo último es el uso de vacunas elaboradas a partir de toxinas proteicas tratadas con formaldehído de las bacterias del tétanos y la difteria ("toxoides"). Observe que el tipo de hipótesis de "agotamiento de oligoelementos" predeciría que solo los gérmenes vivos podrían producir inmunidad. Su desarrollo comenzó alrededor de 1900.

16) También se encontró que el suero aislado de una persona o animal ya vacunado podría producir algún grado de inmunidad cuando se inyecta (esto se llama "inmunidad pasiva" en contraposición a la "inmunidad activa" que resulta de producir sus propias moléculas de anticuerpos).

17) Poco después (primeras décadas del siglo XX) se comprendió que la razón por la que las transfusiones de sangre (que se habían probado durante muchos años) a menudo fallaban de manera tan catastrófica era que el cuerpo "atacaba" la sangre transfundida como si fueran gérmenes. Uno de los principales científicos involucrados en estos descubrimientos fue Karl Landsteiner (que era austríaco, pero llegó a Estados Unidos después de la Primera Guerra Mundial).

18) Debido a que la inmunidad a la sangre (de tipos distintos a la propia) no parecía requerir una exposición previa (transfusiones previas para "vacunarlo"), durante mucho tiempo se creyó que existían "anticuerpos naturales" que se sintetizan en grandes cantidades incluso sin cualquiera antes de la exposición a su antígeno. La verdadera explicación resultó ser que hay ciertas especies ubicuas de bacterias que tienen antígenos de superficie muy similares a los antígenos del grupo sanguíneo humano; es la exposición previa a estas bacterias lo que lo ha sensibilizado a los antígenos del grupo sanguíneo.

19) Hasta mucho después del cambio de siglo, se suponía que la capacidad de sintetizar anticuerpos contra cada antígeno en particular debía ser una capacidad heredada que nuestros antepasados ​​habían desarrollado por selección natural de la manera habitual, es decir, aquellos que carecían de la capacidad de producir los anticuerpos contra la enfermedad X tenderían a morir a causa de esa enfermedad, mientras que aquellos que tenían los genes para producir esos anticuerpos tenderían a sobrevivir, por lo que los genes para producir cada anticuerpo aumentarían en frecuencia en la población. Ésta es una forma de "mecanismo de selección" para la especificidad del anticuerpo. Esta suposición bastante razonable es implícitamente la base del final de H.G. Wells de su novela "La guerra de los mundos". Por cierto, el propio Wells realmente quería ser biólogo investigador, en lugar de novelista, y obtuvo un doctorado. en biología. A menudo se da la misma explicación para la mayor susceptibilidad de los indios americanos a las enfermedades europeas. ¿Alguna vez asumiste que era verdad?

20) El gran inmunólogo Paul Ehrlich propuso un tipo bastante diferente de mecanismo de selección. Esta era la teoría de la cadena lateral que sugería que las células del sistema inmunológico podrían comenzar con muchos miles de moléculas especiales ("cadenas laterales") en sus superficies. cada uno con una forma diferente y, por lo tanto, capaz de combinarse con un antígeno diferente cuando aparece un antígeno que se une a una de estas cadenas laterales, entonces esta unión de alguna manera estimularía a la célula para que produzca mucho más de ese tipo particular de cadena lateral, y Para dejar de fabricar los otros tipos, la idea era que las moléculas de anticuerpo fueran copias liberadas de esos tipos de cadenas laterales que las células habían sido estimuladas a hacer debido a la capacidad de estas cadenas laterales para unirse al antígeno. Esta idea presagió la hipótesis de selección clonal posterior de Jerne y Burnet, y tanto las similitudes como las diferencias entre las diferentes teorías merecen una cuidadosa reflexión.

21) Sin embargo, en la época de la Primera Guerra Mundial, Landsteiner descubrió que el cuerpo también puede producir anticuerpos contra sustancias químicas sintéticas muy artificiales. Debido a que no había ninguna posibilidad de que nuestros antepasados ​​pudieran haber estado expuestos a estos químicos (¡mucho menos de que su supervivencia y reproducción pudieran haber dependido de volverse inmunes a tales químicos!), Estas observaciones parecían probar (¡erróneamente!) Que las moléculas de anticuerpos debían de alguna manera "instruir" a nuestras células en cuanto a la forma que deberían tener los sitios de unión de anticuerpos (equivalente a hacer un guante que se ajuste a una mano específica, en lugar de encontrar uno en stock que encaje). Si vas a la zapatería y eliges unos zapatos que tienen el ajuste conformacional adecuado para tus pies, entonces ese es un mecanismo selectivo. Pero si la gente en la tienda tiene que medir sus pies y luego fabricar un zapato que le quede bien, entonces ese es un mecanismo de instrucción.

22) "Mecanismos" "instruccionales": se desarrollaron varios tipos de hipótesis para explicar cómo la misma secuencia de aminoácidos podría moldearse en muchas conformaciones alternativas diferentes. Una de esas teorías instructivas era que las moléculas de anticuerpo, durante su síntesis, podrían de alguna manera estar envueltas una muestra de molécula de antígeno, de modo que se amoldaran a su forma. Linus Pauling propuso tal teoría y publicó experimentos que la respaldan. Una vesión involucró el número relativamente grande de enlaces disulfuro en moléculas de anticuerpos: la idea era que las aproximadamente 10 cisteína Los grupos pueden unirse en muchas permutaciones alternativas diferentes, produciendo así muchos sitios de unión de antígenos diferentes (¿Puede calcular el número de formas posibles diferentes?)

23) Mucho más tarde, durante la década de 1960, se demostró que si desnaturaliza una molécula de anticuerpo (despliega la cadena de aminoácidos y rompe todos los enlaces disulfuro) y luego deja que la molécula se pliegue espontáneamente en el patrón que "quiera", entonces el sitio de unión de la molécula de anticuerpo resultante tendrá exactamente la misma especificidad de unión (especificidad de antígeno) que tenía antes de desnaturalizarse. Esto muestra que las especificidades de las moléculas de anticuerpos están determinadas por sus secuencias de aminoácidos a la inversa, los anticuerpos con diferentes especificidades tienen diferentes secuencias de aminoácidos.

24) Hasta finales de la década de 1950, todos los inmunólogos sensatos que asistían a la iglesia todavía creían con confianza en una u otra teorías instructivas de la especificidad de los anticuerpos (el antígeno debe "decirle" al cuerpo de alguna manera qué forma hacer los sitios de unión en la molécula del anticuerpo). Un joven temerario llamado Niels Jerne propuso un tipo de hipótesis explicativa muy diferente en la que la selección ocupa el lugar de la instrucción. Jerne llamó a su hipótesis revolucionaria la "teoría de la inmunidad por selección natural", pero fue rápidamente reemplazada por una modificación de esta teoría inventada por Burnet llamada "hipótesis de selección clonal". (¡Tenga en cuenta que Jerne estaba en el mismo laboratorio danés que Watson!)

25) Las ideas básicas de la hipótesis de selección clonal son las siguientes: A) Durante el desarrollo embrionario, cada animal individual (¡¡de alguna manera !!) genera muchos clones diferentes de linfocitos, cada uno de los cuales puede producir anticuerpos contra un antígeno diferente.
B) Cada linfocito produciría anticuerpos contra un solo antígeno en particular, y cuando este linfocito se divide, las células hijas continuarán teniendo la misma especificidad, produciendo solo anticuerpos contra su único antígeno elegido al azar.
C) Durante el desarrollo, la exposición de los linfocitos a "su" antígeno (al que se unirán sus anticuerpos) provocaría la muerte o inactivación de estos clones de linfocitos ("clones prohibidos"). Así es como el mecanismo explica la tolerancia a uno mismo.
D) Más adelante en la vida, los linfocitos responden a "sus" antígenos de manera opuesta, al ser estimulados para crecer, dividirse y secretar anticuerpos, produciendo así inmunidad.
E) La mayoría de los clones de linfocitos nunca estarían expuestos a "sus" antígenos (a los que se unirían sus anticuerpos) de modo que estos clones sobrevivieran en forma inactiva.

Por cierto, la versión original de Jerne de la teoría todavía estaba tan influenciada por el pensamiento instruccional que postulaba la generación y selección de clones de plantillas químicas (en lugar de clones de células sintetizadoras de anticuerpos) alrededor de las cuales supuestamente se moldearon las moléculas de anticuerpos. Es por eso que sería injusto pensar que Burnet ha "robado" la idea de Jerne (pero tenga en cuenta que los suecos le dieron el premio Nobel por esto a Burnet, no a Jerne, aunque lo consiguió mucho más tarde por otras teorías, incluida la suya " teoría de redes "). Como ha dicho Gore Vidal "Nunca subestimes el sentido del humor escandinavo".

26) La hipótesis de la selección clonal se probó experimentalmente inyectando antígenos en embriones y mostrando que el animal se volvió tolerante a esos antígenos. Por eso Peter Medawar compartió el premio Nobel con Burnet.

27) El mecanismo que genera toda esta diversidad de un millón de veces en los genes para las regiones de secuencia variable se ha llamado (algo irreverente) el "Generador de diversidad" (es decir, ¡G.O.D.!). Se predijo con seguridad que el descubridor de su mecanismo ganaría el Premio Nobel, y uno de los descubridores lo ganó en 1987 (Tonegawa). Los hipotéticos mecanismos propuestos eran divisibles en dos categorías principales, teorías de "línea germinal" y "línea somática", pero la verdadera respuesta resultó ser una extraña mezcla de ambas.

28) Fue muy difícil determinar las secuencias de aminoácidos de las moléculas de anticuerpos porque muchas moléculas de anticuerpos diferentes forman las gammaglobulinas de un individuo común. Era como intentar determinar la secuencia de aminoácidos de una colección completa de diferentes enzimas, todas mezcladas (ya que diferentes anticuerpos tienen diferentes secuencias de aminoácidos).
Este problema se solucionó utilizando "proteínas de Bence-Jones" en lugar de anticuerpos normales. Las proteínas de Bence-Jones se encuentran en altas concentraciones en la sangre y la orina de pacientes que padecen un cierto tipo de cáncer llamado "mieloma múltiple", este es un cáncer de los linfocitos B y las proteínas de Bence-Jones resultan ser fragmentos de moléculas de anticuerpos. . La ventaja es que para cualquier paciente con esta enfermedad, todas las proteínas de Bence-Jones tienen exactamente la misma secuencia de aminoácidos. Esto se debe a que todos los miles de millones de células B cancerosas en un paciente dado descienden de una sola célula B original que se transformó de manera cancerosa, y todas estas células B cancerosas secretan moléculas de anticuerpos con la misma secuencia de aminoácidos que esta original transformada. celda (aunque a menudo una forma defectuosa de esta secuencia original). En cierto sentido, las proteínas de Bence-Jones son los anticuerpos monoclonales originales. Estas proteínas de Bence-Jones se descubrieron alrededor de 1850, pero no se supo qué eran hasta mucho más tarde, en la década de 1960. También resulta posible inducir esta forma de cáncer en ciertas cepas de ratones ("Balb-C") inyectando aceite mineral en sus cavidades celómicas. (! * &?)

29) Estas y otras determinaciones de secuencias de aminoácidos mostraron que las moléculas de anticuerpo contienen algunas regiones en las que la secuencia es bastante diferente entre una molécula de anticuerpo y otra, estas se denominan regiones de secuencia variable. Pero la mayor parte de la molécula consta de regiones de secuencia constante en las que la secuencia de aminoácidos es la misma de un anticuerpo a otro (o de una proteína de Bence-Jones a otra). Se denominan regiones de secuencia constante. Como veremos más adelante, las regiones de secuencia variable constituyen el sitio de unión, mientras que la región de secuencia constante forma el resto de la molécula.

30) También resulta que hay varios tipos diferentes de moléculas de anticuerpos (llamadas inmunoglobina G, inmunoglobina M, etc., abreviadas como IgG, IgM, IgA, IgD e IgE). Cada uno de estos tiene regiones de secuencia constante algo diferentes. De hecho, cada uno de ellos consta de una combinación de diferentes moléculas de proteína: por ejemplo, cada molécula de IgG está formada por dos "cadenas pesadas" (cada una de aproximadamente 50.000 de peso molecular) y dos "cadenas ligeras" (cada una de aproximadamente 25.000 de peso molecular). . Cada cadena pesada tiene una región de secuencia constante de aproximadamente 300 aminoácidos y una región de secuencia variable de aproximadamente 100 aminoácidos. Cada cadena ligera tiene una región de secuencia constante de aproximadamente 100 aminoácidos y una región de secuencia variable de aproximadamente 100 aminoácidos. Las 4 cadenas están unidas por enlaces disulfuro.
Como habrás adivinado, el sitio de unión de la molécula de IgG está formado por la combinación de las regiones de secuencia variable de una cadena pesada y una cadena ligera. Cada molécula de IgG tiene dos de estos sitios de unión y ambos tienen la misma especificidad (se unen al mismo epítopo).

31) The IgM type of antibody molecule is even more complex, having 10 light chains and 10 heavy chains, with a total molecular weight of around 900,000. The structure is analogous to 5 IgG molecules combined together and they have 10 antigen binding sites instead of 2. When first exposed to an antigen, you at first synthesize mostly IgM, and then later you synthesize mostly IgG.
The other classes of immunoglobins (IgA, IgD and IgE) have 2 binding sites each.

32) Potential antigens will (usually!) not stimulate the immune system to synthesize antibodies unless the original antigens are parts of relatively large molecules (molecular weights of around 20,000 or more). Once the antibody molecules are made, however, they will bind perfectly well to antigens of low molecular weights (molecular weights as low as 100). An interesting example is the allergy which people sometimes develop to the antibiotic penicillin, even though it is a relatively small molecule the original sensitization to this compound depends on the fact that penicillin tends to bond covalently to proteins when attached to a protein, its effective molecular weight is then large enough to produce the needed stimulation of the immune system, although the antibody molecules which eventually result from this stimulation will also bind to individual penicillin molecules.
Thus, to immunize an animal against a small molecule, you usually need to combine the small molecule to some sufficiently big molecule. In addition, it is found that there are certain oily materials (called "adjuvants") which have the effect of increasing the sensitivity of the immune system to injected antigens, when they are injected mixed with the adjuvant.

33) When the immune system fails (or refuses!) to make antibodies against a certain antigen, this is called "tolerance" (or "immune tolerance"). Our day-to-day survival depends upon this refusal of our immune systems to attack the many thousands of potential antigens which are normal parts of our bodies. Failure of this self-tolerance in the case of even just one or a few of our normal constituent molecules results in autoimmune diseases, some of which were listed above: many are fatal.
One consequence of self-tolerance is that it can be difficult or impossible to stimulate animals to make antibodies against proteins which happen to be evolutionarily conservative, such as actin. The mechanism of self-tolerance remains one of the least understood aspects of immunity. A tendency to take tolerance for granted has long characterized the study of immunity.

    Question for class discussion: How could you try to explain self-tolerance in terms of either the original evolutionary selection type of explanation for immunity (#19 above), or in terms of the later instructional type of explanation (#22 above).

34) Monoclonal antibodies are made by growing clones of antibody-synthesizing lymphocytes in culture. Since the antibodies made by each lymphocyte and its mitotic progeny all have exactly the same amino acid sequence in their variable sequence regions, they all have exactly the same specificity. So you can get lots and lots of antibody molecules all of which have exactly the same specificity (exactly the same shaped binding sites). The essential trick was to fuse cancerous lymphocytes (immortal, fast-growing) with normal lymphocytes (slow-growing, but antibody synthesizing) one then selects progeny cells which both grow rapidly and secrete antibody molecules. Quite recently, people have isolated antibody genes and transformed them into bacteria.

35) The differences between B lymphocytes and T lymphocytes: It has been discovered that the effector cells of the immune system fall into two distinct categories. The cells that actually secrete the antibodies are B lymphocytes (or "B cells"), responsible for "humoral immunity". The "T cells", on the other hand, do not secrete antibodies but some of them produce equivalently specific binding proteins on their surface membranes ("called T cell receptors") that serve the analogous purpose in selectively killing cells that have antigens on their surfaces to which these reecptors will bind. This killing process has a degree of specificity approximately equivalent to that of antibody binding and is the central part of "cellular immunity".
In addition, there are other sub-classes of T cells whose functions are to control the activities of the B cells -sometimes by assisting in their sensitization to antigens, sometimes by stimulating them and sometimes by inhibiting them. T cells can function without B cells, but the B cell part of the immune system becomes non-functional if deprived of T cells. It is for this reason that people born without the B cell part of the immune system can survive much better than those born without the T cell part and it is also why the disease AIDS, which selectively kills a sub-class of T cell needed for the activation of killer T cells as well as B cells, results in the loss of both humoral and cellular immunity (and was the first evidence of helper T cells).
In general, one can say that resistance to bacterial infection is primarily the result of B cell (humoral) immunity, while resistance to viruses, fungi, protozoa and cancer are primarily the job of the T cell (cellular) immunity. The T cell system is supposed to have evolved first.

36) Graft rejection is believed to be largely due to the activities of T cells attacking the graft tissue, as opposed to being a result of the effects of antibodies. Likewise, the unpleasant effects of poison ivy are (supposedly) due to T cells: somehow the plant's toxin ("urushiol") changes exposed skin cells in such a way that T cells regard them as alien and therefore "reject" the skin cells as they would a graft. More needs to be known about this interesting phenomenon, and such knowledge may prove very useful not only for the treatment of poison ivy poisoning itself but also potentially for the deliberate use of this and comparable toxins to induce the rejection of cancerous cells.

37) There is a theory of "Immune Surveillance" according to which cancers actually arise much more frequently than we realize but that nearly all of them are killed off by the immune system before they can do any harm. This theory was originally proposed by none other than the well-known medical essayist Lewis Thomas and was very popular for several years before becoming somewhat passe. The most relevant supporting evidence is the much higher frequency of cancers which is observed in people whose immune systems are somehow suppressed (for example, by anti-rejection drugs following organ transplants, as well as in AIDS victims). Although this is exactly what the theory predicts, an alternative explanation is that the immune system is protecting us from cancer causing viruses and (perhaps) chemicals, rather than from already-transformed cells.

    Second set of questions for class discussion: How to use the immune system to reject cancer cells, even though they are part of the body itself. Actually, it is not unusual for a person's immune system to attack cancer cells. That may be the cause of many thousands of "spontaneous" cures of what had seemed incurable cancers? Much research has and is being focused on the possibility of stimulating immune attacks specifically on cancer cells, without attacking normal cells.
    a) But if the cancer cells are part of your body, why shouldn't your body be tolerant to them?
    b) And if cancer cells are often attacked by T-cells and antibodies, what does this imply about cancer cell antigens?
    c) How might the immune system be made more likely to attack "self" cancer cells?
    d) How might you try to increase the sensitivity of cancer cells to immune attack?
    e) Suppose that there were forms of uncontrolled cell growth in which the immune system always did successfully attack and destroy the abnormal cells: would such a disease be classified as a form of cancer?

39) It is believed that differentiation of B cells depends upon transient residence in some glandular organ (which thus serves the inductive maturation function equivalent to that served by the thymus for the T cells). In the case of birds, it was proven experimentally (although inadvertently) that this function is served by a diverticulum from their hindguts that is called the "Bursa of Fabricius". If this organ is prevented from developing then the resulting bird is unable to make antibodies because it has no B cells. In fact, the term "B" cells is derived from b in "bursa". Curiously, however, this organ is peculiar to birds and is not found in mammals so presumably some other organ serves the same function in mammals, possibly it might be the appendix, or the "Peyer's Patches", or the bone marrow itself, but no one knows. There is a widespread hope that the name of the organ responsible will happen to start with the letter B!
Animals lacking B cells cannot make antibodies, of course. This weakens, but does not eliminate their immune resistance to disease. Their T cells can still fight off many pathogens, as well as reject grafts, even without the help of B cells. In contrast, animals that lack the T cell part of the immune system have little or no immune capacity, even to make antibodies. This was once a puzzle but the explanation seems to be that the stimulation of the B cells to make antibodies depends on the B cells' interactions with certain kinds of ("helper") T cells. Of course, this is also what is believed to to be that basis of immune deficiency in AIDS.

40) The mechanism of the "Generator of Diversity": (G. O. D. as it was called)

The following is a list of some of the alternative hypothetical mechanisms that were seriously considered as possible explanations for how you get the genes coding for a million-plus different variable sequence regions (do you remember which one(s) turned out to be correct?):

A) There could simply be a million different antibody genes (i.e. in the eggs and sperm), each individual gene identical in the part coding for the constant sequence region, but each different (and unique) in the part coding for the variable sequence region.

B) The genome could contain a million different genes for just the variable sequence regions, with one of these being chosen at random (in each lymphocyte clone) and somehow spliced onto the gene for one of the different classes of constant sequence regions.

C) There could be a very, very high rate of somatic mutation in the part of the antibody gene that codes for the variable sequence region..

D) There might not actually be gene for the variable sequence region, at least not in the germ line cells or in cell types other than lymphocytes. Instead, as part of the differentiation, there might be some mechanism for random addition of nucleotides. The net result would be equivalent to the high rate of somatic mutation.

E) There might be only two different genes for the variable sequence region during the differentiation of lymphocytes, a process of genetic crossing-over (equivalent to that known to occur in meiosis) might occur between these two original variable sequence regions of DNA, even though these regions differed greatly in base sequence. Such crossing-over between genes of very different base sequences would thus generate many, many new sequences (although with certain predictable patterns of either/or regularity you might want to think about what sort of regularity this ought to have been!)

F) Different clones of lympocytes might have different populations of special t-RNAs with specificities different from those of the usual genetic code.

G) There might be some kinds of special base-altering enzymes that would act on the variable sequence regions of the m-RNAs coding for antibody molecules (with each lympocyte clone having a special set of such enzymes).

H) The variable sequence region of each the different antibody gene might be spliced together out of 2 or 3 randomly selected fragments from series of 4 - 100 (or so) alternative fragment sequences (perhaps something along the lines of "one from column A, one from column B,would you like a potato or rice. and which kind of dressing on your salad: French, thousand island. ).

Do you see why some types of theories (such as A and B) were sometimes called "germ line theories", to contrast them from other types of theories (such as C and D) that were called "somatic line theories"?

    Third set of questions for class discussion: Pretend that you don't already know which one of the 9 theories above turned out to be true (or maybe you don't have to pretend?), and discuss how each of the following sets of facts could be used to argue for or against these 9 alternatives.

(alpha) Mutations had been found that corresponded to amino acid substitutions in the constant sequence regions of the antibody molecules, and these mapped genetically in a simple Mendelian fashion, as if located at a single site on a particular chromosome

(beta) The total amount of DNA in a mammal genome would be barely adequate to code for several million different proteins of the molecular weight of the immunoglobins.

(gamma) The binding site of antibodies is formed along the zone of contact between the variable sequence of the heavy chain and the variable sequence of the light chain.

(delta) As a given animal responds to a particular antigen, it first makes mostly IgM antibodies against it, but later shifts to making mostly IgG antibodies with the same specificity. This occurs at the single cell level, in the sense of individual B-cells shifting from secreting IgM antibodies secreting IgG molecules (i.e. as if keeping the same variable sequence region, but shifting to a different constant sequence region).

(epsilon) Variable sequence regions from different myeloma clones were found to differ much more in some parts ("hypervariable regions") than in the rest.

(zeta) Except in the hypervariable regions, the amino acid sequence of variable regions from antibodies from different myeloma clones tended to fall into patterns in which each site was occupied by either of only 2 (or sometimes of only 3, or 4) different alternative amino acids. For example, at site #22, you might have valines in the antibodies from 8 of 14 myeloma clones, and leucines in the antibodies from the other 6 clones. Likewise, sequence of amino acids tend to be steroetyped, alternating between one particular sequence and another.

(eta) X-ray diffraction crystallography of antibody molecules shows that the variable sequences of both heavy and light chains consistently fold into beta pleated sheet patterns that are very similar to one another (even for antibodies against different antigens) except at the binding site itself (which is small relative to the whole variable sequence regions).

41) Histocompatibility antigens: A graft of tissue from one person to another (unless the two are identical twins) will almost always result in the "rejection" of the grafted cells by the immune system of the host, which attacks them much as if they were pathogens. Much research has been devoted to identifying which particular antigens are most responsible for this immune rejection of grafts (analogous to the A and B antigens, rhesus factors, etc. that are responsible for the analogous rejection of blood transfusions). A whole technology if "tissue typing" has been developed, analogous to the typing of blood. Unfortunately, it has turned out that there are a great many more different variable forms of genes which govern the graft rejection this means that the probability of finding a "match" between two individuals is enormously lower than is the case with blood. Imagine that instead of just having antigens A and B, our blood had A, B, C, . X, Y, and Z antigens, a difference in any one of which would result in an immune reaction.
Research on graft rejection has been concentrated in mice and humans. Ironically, this work began with grafts of cancers from one mouse to another as Medawar once wrote, "people started out thinking that they were using immunology to study cancer, but it turned out that they were really using cancer to study immunology"! Although there are many different molecules at the cell surface, and differences in any of these can potentially stimulate and be the targets of some degree of immune attack, it turned out that there are a few special classes of cell surface molecules which stimulate the immune system much more strongly than any others. These are called histocompatibility antigens, although the term has come to be confined specifically to those coded for by genes located in a cluster called the major histocompatibility locus. They have been most intensivily studied in mice, where they are called the H-2 antigens the equivalents in humans are called the HLA antigens.
In most species (in mice and humans, for example but not in Syrian hampsters) there are many alternative forms of these genes, thus reducing the chances of any 2 people being compatible and this situation is made still worse by the presence of multiple genetic loci in each set of chromosomes, so that each person has several different forms of the antigen, a situation which almost seems fiendishly designed to make tissue and organ grafting nearly impossible. Presumably there is no evolutionary selection pressure against the acceptance of tissue grafts (although some would answer that such selection pressures might have existed in some ancestral invertebrates, such as sea squirts or sponges). We therefore need to ask what functions these antigens have, of which graft rejection is an unfortunate by-product.
The answer was suggested by the structures of the major histocompatibility antigens themselves, which are very similar to antibody molecules and even have antigen binding sites that hold 10-20 amino acid peptides! It is now thought that their normal function is as a sort of molecular "holder" for the purpose of "presenting" partially digested fragments of potential antigen molecules to other cells of the immune system. This is part of the cell-cell signalling system by which the specificity of antibody-antibody binding is ascertained. Thus, when these holder molecules are themselves alien, the immune system responds with special diligence and ferocity.

    A) Why do most species have so many variant genetic forms in the population? B) Why is the possession of certain ones of these variant forms correlated with greatly increased probabilities of certain autoimmune diseases? C) Why are the genes for different forms of these antigens so closely linked to one another and to other genes which regulate the activity of the immune system, such as those for several lymphokines?

43) The activities of the various kinds of T and B cells are controlled by feedback cycles, many of which involve sending signals from one cell to another. The signaling mechanisms can be divided into two categories, those that involve direct contacts between cell surface molecules, and those that are accomplished by hormone-like proteins that are secreted by one cell and reach others by diffusion. These proteins are called "lymphokines", and around a dozen have been identified. Interferon is one of the best known (one should rather say, "the interferons" since there are 3 main kinds). The artificial synthesis of interferons and other lymphokines has been accomplished by cloning the genes for them into bacteria this is a very active area of pharmaceutical research because of the prospect of being able to control and manipulate the activities of the immune system. Interferons and several other lymphokines are now being used as experimental treatments for cancer, following more conventional chemotherapy. Unfortunately, the interferons produce the same side effects as having the flu fever, headache, aching joints, etc.! When you have the flu, your body is stimulated to produce lots of interferon, which is a large part of what makes you feel so bad.

44) A radically selectionist hypothesis about learning and the brain: You might be interested to know that Gerald Edelman, who shared the Nobel Prize for work on the molecular structures of antibodies, and later discovered new kinds of cell-cell adhesion proteins, has now moved on to neurophysiology. He has proposed a new and exciting hypothesis to explain how people learn new skills. He calls this new theory "Neural Darwinism" and has written a book with that title. His proposal is reminiscent of Jerne's and Burnet's, the basic idea being that the brain initially generates a large number of different neural wiring circuits (sort of like computer chips, or maybe pocket calculators) made with many different randomly-chosen wiring patterns, so that each circuit differs in capabilities. Edelman's idea is that these circuits play approximately the same role as the lymphocyte clones. Learning is then supposed to be selective, in the sense that each different circuit gets "tried out" to see which ones produce desirable consequences. The circuits that produce bad results are discarded or destroyed, while those that yield good results are kept and reduplicated. This may sound impractical or crazy, but so did clonal selection, at first. Do you think neurophysiology could now undergo a revolutionary paradigm switch from instructionism to selectionism?
There are some interesting parallels to Socrates' theory that education was a process of recalling of forgotten information, probably from previous reincarnations!! This notion was the original motivation for his famous "Socratic method" of teaching, although few people realize this.
Past thinking about learning has nearly all what one might call "instructionist", going back to John Locke's metaphor of the mind as "Tabula Rasa", Latin for "blank slate", on which experience writes things into your memory. Piaget's ideas also seem very "instructionist" to me. Learning is assumed to be a matter of putting something into the brain, or of creating something new there, as opposed to picking and choosing between different things that are already there (or differentially strengthening and weakening pre-existing patterns). On the other hand, Noam Chomsky, (MIT professor) revolutionized linguistics by providing strong evidence that babies and young children could not possibly learn correct grammar as rapidly as they do (i.e. having heard as few spoken sentences as they have) unless some kind of very abstract grammatical rules were already genetically programmed into the brain at birth (sort of like the ROM chip in a Macintosh computer!). Note that there would have to be one set of abstract rules for all languages. Several people have tried unsuccessfully to deduce what these rules might be. The great British zoologist J. Z. Young had previously proposed theories comparable to Edelman's "neural darwinism" based on many years of experiments on behavior and learning in captive octopuses!! Science moves along strange paths!

    Fourth set of questions for class discussion: What do you think goes on in your brain when you learn a new concept? Do you suppose that it's more like a multiple choice test, a true-false test, or a fill-in-the-blank? Are some people really smarter than others? Is it that smarter people have learned more that they can learn more or perhaps that they are faster or otherwise more skillful at learning? If Edelman were right, what would I.Q. be, at cellular and molecular levels?

1) Do you see why it is essential that each clone of B lymphocytes should make antibodies against only one single antigen (i.e. that all the antibodies made by a given clone should have exactly the same amino-acid sequences in their variable sequence regions)? Suppose that each lymphocyte clone made two different antibodies, with binding specificities for two different antigens. What would be some of the undesireable consequences of having some lymphocyte clones make more than one antibody? Would there be any advantages?

2) Mass epidemics of smallpox and other diseases decimated the native populations of the Americas soon after Columbus' voyages (and a comparable epidemic of syphilis occurred in Europe ). The usual explanation is that the natives had not "evolved immunity" to the germs. Is this consistent with current theories of immunity, or does it seem to reflect older assumptions? Discuss what the true explanation might be, whether this might require some further "revolution" in our theories, and what sorts of experiments or observations might be relevant to the question.

3) To what extent have the various theories of immunity conformed to Karl Popper's ideas about the best hypotheses being those that are most susceptible to disproof? Can you suggest some examples in which immunological theories now believed to be correct would once have actually seemed to have been conclusively disproven?

4) To what extent does the intellectual history of immunology conform to Thomas Kuhn's ideas? What were the different "revolutions" that occurred in this field, and what were the alternative "paradigms" that replaced one other? In particular, can you trace a "swing of the pendulum" back and forth between instructional and selectionist types of theories.

5) It has been said that "Any complicated phenomenonon has to be invented before anyone can discover it. Unless you have already considered the possible existence of a phenomenon, then how will you be able to recognize it even if you see it.?" Do you think that this is generally true in science? To what extent do you think that it may be true in daily life, in general? Can you give some examples, either from the history of immunololgy or from some other field, where this assertion seems to you to be true, or where it seems to be untrue? Do you think that maybe it tends to be more true of complex phenomena? If so, then how complicated does a phenomenon have to be before this statement becomes true?

6) Can you give some examples, either from immunology or from some other field, in which erroneous theories nevertheless made correct predictions.

    (a) immunity to diseases from which one has recovered.
    (b) allergy.
    (c) "immunity" to such things as poison ivy.
    (d) "immunity" to poisons which one has been exposed to repeatedly
    (as in the ancient story of King Mithridates, and in one of the Peter Wimsey murder mysteries).
    (e) reactions to blood transfusions.
    (g) graft rejection.
    (h) rejection of grafts of cancers from one animal to another.
    (i) occasional spontaneous recoveries from cancer.
    (j) accumulation of proteins in the urine of some lymphoma patients.
    (k) autoimmune diseases.
    (l) correlation of immunodeficiency syndromes with calcium imbalances.
    (m) failure of hair development in immunodeficient mice.

Another unsolved problem is how to use the immune system to kill cancer cells specifically. Because cancer cells are merely behaviorally-abnormal versions of your own cells, you should expect every animal to be just as self-tolerant to its own cancer cells as it is to all of its other cells. In fact, however, there is often evidence of immune attacks on tumors many cases of "spontaneous" remissions of cancer in humans seem to result from some activity of the immune system in addition, much medical research has been devoted to stimulating the immune system to attack cancer cells.
Injection of cytokines, more specifically interferons, following cancer chemotherapy, has been tried experimentally for about the past ten years, but with mostly disappointing (i.e. no) results.

In the specific cases of B-cell and T-cell lymphomas (almost? all Non-Hodgkin's lymphomas fall into one or the other of these categories), it is to be expected that all of the cancerous cells in a given patient will be members of a single original clone, so that their antibodies (in the case of B-cells) or their T-cell receptors (in the case of T-cells) will have binding sites of a given amino acid sequence and shape. Perhaps you can imagine cures based on inducting other cells of the immune system could to attack specifically any cells having surface molecules shaped like these binding sites (i.e. the binding sites specific to that particular person's lymphoma cells). Reading between the lines of some of the newspaper stories about former Chancellor Hooker's attempted "experimental treatment at Johns Hopkins" may have been based on this general approach. Newspapers strive to exclude factual information that some of its readers would not understand better nobody should know the facts than have some of the readers receive information they are not educated enough to understand?

A special class of T-lymphocytes is needed to stimulate the function of B-cells and other T cell. These "helper T-cells" are selectively killed by the AIDS virus, thereby weakening the whole immune system to the degree that the person dies of bacteria, fungi or other pathogens to which everyone is normally immune. Preventing this, or re-establishing helper T-cells, or perhaps substituting for their functions (in some other way stimulating B & T-cell function) are all possible ways of curing AIDS.

The specific enzyme(s) that serves to recombine the V(D)J sequences is called RAG. It is an important question when and where the genes for the RAG enzyme are expressed.

There have been reports that the RAG genes are expressed (=the messenger RNAs transcribed & the proteins made) only during the early development of B-cell and T-cells.

There have also been reports that RAG may be expressed in certain cells of the developing brain!

It has been controversial to what extent RAG genes may be expressed (& V(D)J recombination occur?) later in life in B cells as part of their response to exposure to their antigen! There is a report in this week's Nature that GFP (Green Fluorescent Protein) - RAG fusion genes are expressed in B-cells after antigen presentation. Copies of that paper will be handed out in the next class.


Is poison immunity actually attainable by poisoning the body repeatedly?

Sometimes, but it depends upon the poison/toxin/venom and how you define immune. That's exactly the process which is often used to produce snake antivenom. People will inject horses with small doses and build up a tolerance, then harvest their blood for the antibodies. Those horses are effectively immune to a normal snakebite. You could argue that a large enough dose would still be lethal so it's not complete immunity, but for practical purposes it is. I have run into stories of at least one person doing this to himself intentionally.

But you aren't going to be able to build up a resistance to mercury, for instance, because your body can't produce antibodies against it.

Your last sentence is a key point. Some poison will simply accumulate and eventually kill you.

That remind me of a quote, 'it's not the poison that kills you it's the dose'

The term for administrating sub-lethal amounts of a poison with the purpose of building up tolerance is called mithridatism. In practice it entails a lot of risk and is only effective against certain types of poisons, mostly those that are biologically complex that the liver metabolizes. Essentially this method is conditioning the liver to ramp up enzyme production. This doesn't give you immunity to the poison only increases the amount you have built up tolerance to. Where as poisons like heavy metals will not be metabolized and accumulate, this method will not be effective against these types of poisons.

Origin of the term is interesting, referring to Mithradates of Pontus

The Third Mithridatic War began in 75 BC, and ended with Mithridates’ final defeat and death in 63 BC. Following Mithridates’ defeat, he fled to his territories to the north of the Black Sea, where he faced a rebellion by his son. Cornered, Mithridates decided to take his own life. The following account is taken from Cassius Dio,

“Mithridates had tried to make away with himself, and after first removing his wives and remaining children by poison, he had swallowed all that was left yet neither by that means nor by the sword he was able to perish by his own hands. For the poison, although deadly, did not prevail over him, since he had inured his constitution to it, taking precautionary antidotes in large doses every day and the force of the sword blow was lessened on account of the weakness of his hand, caused by his age and present misfortunes, and as a result of taking the poison, whatever it was. When, therefore, he failed to take his life through his own efforts and seemed to linger beyond the proper time, those whom he had sent against his son fell upon him and hastened his end with their swords and spears."


Mithridatism is the practice of protecting oneself against a poison by gradually self-administering non-lethal amounts. The word is derived from Mithridates VI, the King of Pontus, who so feared being poisoned that he regularly ingested small doses, aiming to develop immunity.

So by that logic, if vaccines are poison, one should be able to protect themselves by getting immunizations!

Yes this is literally how vaccines for the most part work

Then if im not mistaken tried to kill himself with poison and it failed because of his immunity

Just chiming in to say that Mithridates did in fact succeed at attaining poison immunity. At great feasts he would dump poison on his food as a publicity stunt. To prove the poison was lethal he would then force a slave to eat it (dying soon after and proving how poisonous it was) then chow down in front of everyone like it wasn't anything. Many thought he was some kind of black magician king.

He as I remember, had to get a slave to chop his head off, the many bottles of poison wouldn't work, his kingdom was falling into enemy hands, he wasnt going down like that.

The book about him, “The Poison King,” is super fascinating. Apparently, he hatched a plot to have all of his subjects rise up en masse and murder any Roman settlers in their territory.

He managed to get the word out maintaining complete secrecy, and on the appointed day, the populace rose and slaughtered them. Tens of thousands died.

My favorite anecdote from that book was when he fed his ducks poison flowers, which they could tolerate, and then served them up at a feast, wiping out the whole guest list because the meat had absorbed so much toxins.

Not necessarily the first genocide,the first recorded genocide.

I just knew this would be here.

I’m reading a book called “Rubicon” right now and the author has just finished setting the table for his bigger confrontations with the Roman Republic. He mentioned the poison thing, too.

I first learned of Mithridates in a classic poem everyone should know:

Terence, This is Stupid Stuff

'Terence, this is stupid stuff: You eat your victuals fast enough There can't be much amiss, 'tis clear, To see the rate you drink your beer. But oh, good Lord, the verse you make, It gives a chap the belly-ache. The cow, the old cow, she is dead It sleeps well, the horned head: We poor lads, 'tis our turn now To hear such tunes as killed the cow. Pretty friendship 'tis to rhyme Your friends to death before their time Moping melancholy mad: Come, pipe a tune to dance to, lad.'

Why, if 'tis dancing you would be, There's brisker pipes than poetry. Say, for what were hop-yards meant, Or why was Burton built on Trent? Oh many a peer of England brews Livelier liquor than the Muse, And malt does more than Milton can To justify God's ways to man. Ale, man, ale's the stuff to drink For fellows whom it hurts to think: Look into the pewter pot To see the world as the world's not. And faith, 'tis pleasant till 'tis past: The mischief is that 'twill not last. Oh I have been to Ludlow fair And left my necktie God knows where, And carried half way home, or near, Pints and quarts of Ludlow beer: Then the world seemed none so bad, And I myself a sterling lad And down in lovely muck I've lain, Happy till I woke again. Then I saw the morning sky: Heigho, the tale was all a lie The world, it was the old world yet, I was I, my things were wet, And nothing now remained to do But begin the game anew.

Therefore, since the world has still Much good, but much less good than ill, And while the sun and moon endure Luck's a chance, but trouble's sure, Iɽ face it as a wise man would, And train for ill and not for good. 'Tis true, the stuff I bring for sale Is not so brisk a brew as ale: Out of a stem that scored the hand I wrung it in a weary land. But take it: if the smack is sour, The better for the embittered hour It should do good to heart and head When your soul is in my soul's stead And I will friend you, if I may, In the dark and cloudy day.

There was a king reigned in the East: There, when kings will sit to feast, They get their fill before they think With poisoned meat and poisoned drink. He gathered all the springs to birth From the many-venomed earth First a little, thence to more, He sampled all her killing store And easy, smiling, seasoned sound, Sate the king when healths went round. They put arsenic in his meat And stared aghast to watch him eat They poured strychnine in his cup And shook to see him drink it up: They shook, they stared as white's their shirt: Them it was their poison hurt.


Symptoms of COVID-19 Vaccine Damage

Many of the symptoms now being reported are suggestive of neurological damage. They have severe dyskinesia (impairment of voluntary movement), ataxia (lack of muscle control) and intermittent or chronic seizures. Many cases detailed in personal videos on social media are quite shocking.

Equally shocking is that these videos are quickly removed by the social media platforms, ostensibly for violating some term of service. It’s hard to fathom how a personal experience can be considered “false information.”

“What is causing this is the neuroinflammation,” Mikovits says. “It’s the brain on fire. You’re going to see tics, you’re going to see Parkinsonian disease, you’re going to see ALS, you’re going to see things like this developing at extremely rapid rates, and it’s inflammation of the brain.”

Side effects are also suggestive of a dysregulated innate immune response and a disrupted endocannabinoid system, which acts as a dimmer switch on your immune system.

“We see mast cell activation syndromes (MCAS). The clinical symptoms are going to be the inflammatory diseases. We hear everybody calling it ‘long haul COVID’ — the extreme, profound, crippling fatigue, the inability to produce energy from your mitochondria.

It’s not long haul COVID. It’s exactly what it always was — myalgic encephalomyelitis, inflammation of the brain and the spinal cord. What they’re intentionally doing is killing off [certain] populations, which they previously injured.”

Another common side effect from the vaccine we’re seeing is allergic reactions, including anaphylactic shock. A likely culprit in this is PEG, which an estimated 70% of Americans are allergic to. “These instantaneous effects are almost certainly the PEG and that lipid nano particle, the toxic particle that’s being injected,” Mikovits says.

In the longer term, she suspects we’ll see a significant uptick in migraines, tics, Parkinson’s disease, microvascular disorders, different cancers, including prostate cancer, severe pain syndromes like fibromyalgia and rheumatoid arthritis, bladder problems, kidney disease, psychosis, neurodegenerative diseases such as Lou Gehrig’s disease (ALS) and sleep disorders, including narcolepsy. In young children, autism-like symptoms are likely to develop as well, she thinks.


Allergic Contact Dermatitis

Dermatitis is an inflammation of the skin. If the allergy which causes the dermatitis is a response to something which came into contact with the skin, it is called dermatitis de contacto alérgica. In addition to poison ivy, other things which contact the skin such as clothing, shampoo, jewelry, make-up, and deodorants can also cause allergic contact dermatitis. Allergic dermatitis can also be caused from within, as when a skin rash develops because of something we ate.

An extensive list of substances causing allergic contact dermatitis has been provided by Truett.


What poisons can I safely take to build immunity to toxic substances? Does eating poison ivy build resistance to allergic reaction?

Dear Cecil:

I'd like to become resistant to one or more toxic substances by gradually increasing my intake of them over time. Unfortunately, many poisons build up in the body, usually in fatty tissue, until the concentration is lethal. Cecil, which poisons can I safely take in increasing quantities to build a resistance?

The Dread Pirate RobertsI've just been through my first-ever bout with poison ivy. Walking around with a bright red bumpy face has encouraged people to tell me of their remedies, but the strangest thing I heard was from two different people who told me that they'd eaten poison ivy to build up a resistance to it. Do people really do this? James Nelli, Columbus, Ohio

I’m seeing a problem right off the bat here, DPR, which is your use of the word “safely.” Deliberately exposing yourself to incrementally greater doses of poison (sometimes called mithridatization, after King Mithridates VI of Pontus, who reputedly pursued such a regimen) isn’t something that can really be done safely, any more than one can safely undertake to jump a nitro-burning funny car over a row of buses. Maybe you’ll make it, but the enterprise has a fair bit of risk built in.

To a limited extent, it is possible to build up a tolerance to certain poisonous metals. Metallothioneins are proteins produced in the body that, among other things, seem to bond to ions of dangerous elements like arsenic and cadmium and so help to minimize organ damage and other serious ill effects. While there’s no way to become immune to such poisons, chronic exposure to them may — I repeat, may — stimulate the body into upping its metallothionein output, thus allowing one to take on greater quantities of the toxic stuff before starting to get really sick.

Something along these lines might have been going on in the case of the famed arsenic eaters of Upper Styria, Austria. In the mid-1800s word got out to the wider world that a considerable percentage of Styrian peasants were ingesting potentially lethal quantities of arsenic (a by-product of the ore smelting going on thereabouts) on a regular basis, essentially as a health tonic — they believed it improved their breathing and complexion and helped them maintain a robust body weight. Many scientists scoffed, but academics familiar with the region vouched for the phenomenon. Fritz Pregl, a professor at the University of Graz, assured an American colleague in 1927 that arsenic eating was for real and remained common in Styria as of that time. The most popular delivery method, apparently, was to spread shavings of arsenic trioxide on a hunk of bread.

Some animal venoms may lend themselves to the mithridatic process as well. Several maverick herpetologists have reportedly developed partial immunity to various kinds of snakebite by injecting themselves with venom over a period of years the most famous of these is Bill Haast, for decades the proprietor of the Florida tourist attraction called the Miami Serpentarium (he still runs a venom lab under the name) and the survivor of something like 170 poisonous bites.

There’s a degree of self-selection in effect here, though. The people who embark on a long-term program of venom exposure aren’t, I’m guessing, the kind of people who first write to someone like me to ask if it’s a good idea. If you don’t already have a garage full of deadly reptiles from which you extract venom regularly, my suspicion is you’re not destined to get involved in any kind of venom-shooting scene.

But if you’re determined to become resistant to something unpleasant, you could always start with poison ivy. The active ingredient in poison ivy (as well as in poison oak and sumac) is the chemical urushiol, a nasty and persistent oil contained in almost every part of the plant contact with this stuff produces a serious allergic reaction in about 85 percent of the populace.

And as difficult as it may be to imagine doing, James, outdoors types have long advocated eating poison ivy leaves, in small amounts, as a way of building up one’s urushiol tolerance Euell Gibbons recommends the practice in his foraging guide Stalking the Wild Asparagus. Does it work? Dermatological testing says yes — ingesting urushiol made subjects less likely to break out in a rash following skin contact. The benefits decrease fairly quickly over time, so you have to keep up with it, and one noted side effect is pruritus ani, also known as itchy ass syndrome. You can also develop urushiol resistance via injections, or through occupational exposure — the oil is a key ingredient in traditional Japanese lacquer.

Minimizing your reaction to poison ivy doesn’t have quite the same dramatic flair as rendering yourself immune to actual poison, true, but it may prove more useful. El aumento de los niveles de CO2 en la atmósfera, dicen los investigadores, puede hacer que la hiedra venenosa se haga más grande y más virulenta en un futuro cercano, solo otro beneficio adicional divertido del calentamiento global.


Ver el vídeo: Starkes Rizin-Gift: Patient ist immun gegen das tödliche Gift (Octubre 2022).