Изучение патогенности аутоантител к различным участкам десмоглеина 3 в модели пузырчатки на животных тема диссертации и автореферата по ВАК РФ 14.00.36, кандидат биологических наук Коцарева, Ольга Дмитриевна

• Коцарева, Ольга Дмитриевна
• кандидат биологических наук
• 2007

Оглавление диссертации кандидат биологических наук Коцарева, Ольга Дмитриевна

ГЛАВА 1. ПАТ0ГЕНЕТР1ЧЕСКИЕ ОСНОВЫ ИСТИННОЙ ПУЗЫРЧАТКИ

1.1. Общая характеристика пузырчатки

1.2. Роль аутоантител в патогенезе пузырчатки

1.3.Мишени аутоантител при пузырчатке

1.4. Структура молекулы ДСГЗ

1.5. Гомология между ДСГЗ и другими членами семейства кадгеринов

1.6. Механизмы возникновения пузырчатки

1.7. Механизмы действия аутоантител при пузырчатке

1.8. Участие системы комплимента в процессе акантолиза

1.9. Клонирование гена dsg

1.10. Определение патогенных эпитопов ДСГЗ

1.11. Изучение Т-клеточного ответа на ДСГЗ

1.12. Гетерогенность антительного ответа при ВН

1.13 Связь между МНС гаплотипом и предрасположенностью кзаболеванию ВП

1.14. Возможное участие аутоантигенов, не относящихся к десмоглеинам впатогенезе ВН

1.15. Методы лечения пузырчатки

1.16. Анти-ДСП и ДСГЗ антитела у больных разными формамипемфигуса

1.17. Роль апоптоза в акантолизе

1.18. Модели пузырчатки на животных

1.19. Диагностика пузырчатки

1.20. Роль цитокинов в развитии акантолиза при пемфигусе

1.21. Нерспективные направления исследований

ГЛАВА 2. МАТЕРИАЛЫ И МЕТОДЫ 49РЕЗУЛЬТАТЫ СОБСТВЕННЫХ ИССЛЕДОВАНИЙ

ГЛАВА 3. ПОЛУЧЕНИЕ РЕКОМБИНАНТНЫХ БЕЖОВ НА ОСНОВЕДЕСМОГЛЕИНА ЧЕЛОВЕКА

3.1. Клонирование фрагментов reHadsg

3.2. Нолучение рекомбинантных белков Д1-2 и Д

ГЛАВА 4. ИЗУЧЕНИЕ НАТОГЕННОСТИ АНТИТЕЛ К БЕЛКАМ Д1-2 ИД1-5 В МОДЕЛЬНОЙ СИСТЕМЕ IN VITRO

4.1. Получение кроличьих антител на рекомбинантные белки Д1-2 иД

4.2. Анализ патогенности IgG различной специфичности

4.3. Оценка специфичности протективного действия антител к Д1-5,выделенных аффинной хроматографией

4.4. Оценка протективного действия антиидиотипических антител изсыворотки здоровых доноров

ГЛАВА 5. ИЗУЧЕНИЕ РОЛИ АКТИВАЦИИ ЭНДОТЕЛИЯ В ПАТОГЕНЕЗЕПУЗЫРЧАТКИ В МОДЕЛИ НА ЖИВОТНЫХ IN VIVO

5.1. Наличие антител к ДСГЗ не приводит к формированию заболевания умышей

5.2. Изучение роли активации эндотелия в патогенезе пузырчатки намышах in vivo

5.3. Изучение роли активации эндотелия в патогенезе пузырчатки накроликах in vivo 98ОБСУЖДЕНИЕ 99ВЫВОДЫ 106БЛАГОДАРНОСТИ

Введение диссертации (часть автореферата) на тему «Изучение патогенности аутоантител к различным участкам десмоглеина 3 в модели пузырчатки на животных»

ML бактерии Micrococcus Lysodeikticus

PBS фосфатный буфер

RT обратная транскриптаза

PVA антиген вульгарной пузырчатки pemphigus vulgaris antigen)

SDS додецилсульфат натрия

Th 1, Th2 хелперы 1, хелперы 2

ОГЛАВЛЕНИЕ

ВВЕДЕНИЕ.6

Заключение диссертации по теме «Аллергология и иммулология», Коцарева, Ольга Дмитриевна

ВЫВОДЫ

1. Проведено клонирование и экспрессия в бактериях E.coli участков гена десмоглеина 3, кодирующих внеклеточную часть молекулы и ее первые два домена.

2. Получены и охарактеризованы рекомбинантные белки Д1-5 и Д1-2, соответствующие внеклеточной части молекулы десмоглеина 3 и ее первым двум доменам.

3. Показано в модели in vitro на эксплантатах кожи неонатальных мышей, что антитела к Д1-5 блокируют акантолиз, вызванный патогенными аутоантителами к десмоглеину 3 из сывороток больных ВП.

4. Разработана модель пузырчатки in vivo на конвенционных взрослых мышах и кроликах.

5. Показано в модели на животных, что для индукции акантолиза эпидермиса кожи требуется наличие циркулирующих аутоантител к ДСГЗ и локальное воспаление кожи, которое и является триггером пузырчатки.

6. В модели пассивного переноса антител к Д1-2 на кроликах выявлено, что эффекторным звеном патогенеза являются аутоантитела, действие которых реализуется только в случае неспецифического воспаления кожи.

БЛАГОДАРНОСТИ

Автор приносит благодарность Кузину И.И. и Багаевой Л.В. за помощь в клонировании фрагмента гена dsg3 в плазмидном векторе pBluescript-SK(+), А.Н.Марченко и С.В.Беневоленскому за помощь в клонировании генных фрагментов dsg3 в плазмидном векторе рЕТ-22, М.А.Шевченко за помощь в постановке гель-электрофореза, А.А.Лысенко за помощь в иммунизации мышей, а также Т.В.Абрамовой (ВОНЦ, Москва) за подготовку гистологических препаратов.

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