Maklumat

42.2C: Kekebalan Medium Sel - Biologi


Kekebalan yang dimediasi sel melibatkan sel T sitotoksik yang mengenali sel yang dijangkiti dan membawa kemusnahannya.

Objektif Pembelajaran

  • Ringkaskan tindak balas imun yang dimediasi sel

Perkara utama

  • Setelah patogen memasuki sel, ia tidak lagi dapat dikesan oleh tindak balas imun humoral; sebaliknya, tindak balas imun yang dimediasi sel mesti diambil alih untuk membunuh sel yang dijangkiti sebelum dapat membiarkan virus atau bakteria mereplikasi dan menyebar.
  • Sel T mengenali sel yang dijangkiti dengan berinteraksi dengan antigen yang terdapat pada molekul MHC II mereka; sebelum sel T dapat melakukannya, ia mesti diaktifkan melalui interaksi dengan antigen yang menghadirkan sel, atau APC.
  • Sekali sel T sitotoksik (TC) diaktifkan, ia akan mengklon dirinya sendiri, menghasilkan banyak TC sel dengan reseptor yang betul; beberapa bahagian sel aktif dan akan membantu memusnahkan sel yang dijangkiti, sementara yang lain adalah sel memori yang tidak aktif yang akan menghasilkan T yang lebih aktifC sel sekiranya jangkitan kembali.
  • Sel T pembantu (TH sel) juga membantu kekebalan yang dimediasi sel dengan melepaskan molekul isyarat yang dikenali sebagai sitokin yang dapat merekrut sel pembunuh semula jadi dan fagosit untuk memusnahkan sel yang dijangkiti dan mengaktifkan TC sel; mereka tidak secara langsung memusnahkan patogen.

Syarat Utama

  • sel T sitotoksik: subkumpulan limfosit (sel darah putih) yang mampu menyebabkan kematian kepada sel-sel somatik atau tumor yang dijangkiti; bahagian imuniti sel
  • sitokin: mana-mana pelbagai protein pengawal kecil yang mengatur sel-sel sistem imun; mereka dibebaskan setelah mengikat PRR ke PAMPS

Sel T

Sama seperti tindak balas imun humoral mempunyai sel B yang menjadi perantara tindak balasnya, tindak balas imun selular mempunyai sel T, yang mengenali sel yang dijangkiti dan memusnahkannya sebelum patogen di dalamnya dapat mereplikasi dan menyebar untuk menjangkiti sel lain. Tidak seperti sel B, limfosit T (sel T) tidak dapat mengenali patogen tanpa bantuan. Pertama, sel pembentang antigen (APC, seperti sel dendritik atau makrofag) mengesan, menelan (melalui fagositosis dalam kes makrofag atau dengan kemasukan patogen dengan sendirinya dalam hal sel dendritik), dan mencerna patogen menjadi ratusan atau ribuan pecahan antigen. Fragmen ini kemudian diangkut ke permukaan APC, di mana ia disajikan pada protein yang dikenali sebagai Major Histocompatibility Complexes class II (MHC II, lihat). Sel-sel T diaktifkan ke arah antigen tertentu setelah mereka bertemu dipaparkan pada MHC II. Selepas virus atau bakteria memasuki sel, ia tidak lagi dapat dikesan oleh tindak balas imun humoral. Sebaliknya, tindak balas imun selular mesti diambil alih. Untuk melakukannya, sel T akan diaktifkan dengan berinteraksi dengan antigen sel yang dijangkiti atau virus yang terdapat pada MHC II APC.

Sel T sitotoksik memediasi satu bahagian tindak balas imun selular

Terdapat dua jenis sel T utama: limfosit T pembantu (THdan limfosit T sitotoksik (TC). The TH limfosit berfungsi secara tidak langsung untuk memberitahu sel-sel imun lain mengenai potensi patogen, sementara sel T sitotoksik (TC) adalah komponen utama dari sistem imun adaptif yang dimediasi sel yang menyerang dan memusnahkan sel yang dijangkiti. TC sel sangat penting dalam melindungi dari jangkitan virus kerana virus mereplikasi di dalam sel di mana mereka terlindung dari kontak ekstraselular dengan antibodi yang beredar. Setelah diaktifkan, TC mencipta klon sel yang besar dengan satu set reseptor permukaan sel tertentu, serupa dengan percambahan sel B yang diaktifkan. Seperti sel B, klon merangkumi T aktifC sel dan memori tidak aktif TC sel. T aktif yang dihasilkanC sel kemudian mengenal pasti sel inang yang dijangkiti.

TC sel berusaha mengenal pasti dan memusnahkan sel yang dijangkiti dengan mencetuskan apoptosis (kematian sel yang diprogramkan) sebelum patogen dapat mereplikasi dan melarikan diri, sehingga menghentikan perkembangan jangkitan intraselular. Untuk mengenali sel yang hendak dikejar, TC mengenali antigen yang terdapat pada kompleks MHC I, yang terdapat pada semua sel nukleasi. Kompleks MHC I menunjukkan pembacaan protein intraselular semasa di dalam sel dan akan menunjukkan antigen patogen jika patogen terdapat di dalam sel. TC sel juga menyokong limfosit NK untuk memusnahkan barah awal.

Sitokin yang dikeluarkan oleh TH sel merekrut sel NK dan fagosit

Sitokin adalah molekul isyarat yang dirembeskan oleh TH sel sebagai tindak balas kepada sel yang dijangkiti patogen; mereka merangsang sel pembunuh semula jadi dan fagosit seperti makrofag. Fagosit kemudian akan menyelubungi sel yang dijangkiti dan memusnahkannya. Sitokin juga terlibat dalam merangsang TC sel, meningkatkan keupayaan mereka untuk mengenal pasti dan memusnahkan sel dan tumor yang dijangkiti. Ringkasan bagaimana tindak balas imun humoral dan sel yang diaktifkan muncul dalam sel B sel dan TC sel secara kolektif disebut sel efektor kerana mereka terlibat dalam "mempengaruhi" (membawa) tindak balas imun membunuh patogen dan sel inang yang dijangkiti.


Pemakanan dan imunologi: dari klinik ke biologi selular dan kembali lagi

Diet dan kekebalan telah diketahui saling berkaitan selama berabad-abad. Dalam 30 tahun terakhir kajian sistematik telah mengesahkan bahawa kekurangan nutrien mengganggu tindak balas imun dan membawa kepada jangkitan teruk yang sering mengakibatkan peningkatan kematian, terutama pada kanak-kanak. Kekurangan zat makanan bertenaga protein mengakibatkan pengurangan bilangan dan fungsi sel-T, sel fagosit dan tindak balas antibodi imunoglobulin A. Di samping itu, tahap banyak komponen pelengkap dikurangkan. Penemuan yang serupa telah dilaporkan untuk kekurangan zat makanan individu seperti mineral surih dan vitamin, terutamanya Zn, Fe, Se, vitamin A, B6, C dan E. Sebagai contoh, kekurangan Zn dikaitkan dengan penurunan mendalam imuniti sel-sel seperti sebagai tindak balas rangsangan limfosit, penurunan sel CD4 +: CD8 +, dan penurunan kemotaksis fagosit. Di samping itu, tahap thymulin, yang merupakan hormon yang bergantung kepada Zn, menurun dengan ketara. Penggunaan suplemen nutrien, secara tunggal atau bersama, merangsang tindak balas imun dan boleh mengakibatkan jangkitan yang lebih sedikit, terutama pada orang tua, bayi dengan berat badan lahir rendah dan pesakit yang mengalami kekurangan gizi di hospital. Interaksi antara pemakanan dan sistem imun adalah kepentingan kesihatan klinikal, praktikal dan kesihatan awam.


Kekebalan Medium Sel (Dengan Rajah)

Walaupun imuniti humoral melindungi tubuh daripada agen patogen ekstraselular dan antigen larut seperti toksin, imuniti sel-sel diarahkan terhadap patogen intraselular. Sel-sel badan yang dijangkiti dikenali oleh sel-sel imun dan musnah.

Sel badan yang tidak normal, seperti sel barah, diakui sebagai bukan diri kerana adanya antigen khusus tumor di permukaannya dan dimusnahkan oleh sistem imun yang dimediasi sel. Begitu juga, sel dan tisu yang dipindahkan menjadi sasaran serangan imuniti jenis ini.

Imuniti sel-sel disebabkan oleh aktiviti limfosit T, sama seperti imuniti humoral disebabkan oleh aktiviti limfosit B, walaupun sel-sel sistem imun lain juga terlibat.

(i) T-Limfosit (Sel-T):

Sel T, seperti juga sel B, berasal dari sel stem limfopoietik. Prekursor sel-T berkembang biak, membezakan dan matang pada kelenjar timus. Di dalam kelenjar timus, mereka biasanya dipanggil timosit. Pada kelenjar timus, timosit berkembang biak dalam jumlah besar dan dibezakan, tetapi sebahagian besarnya dihilangkan oleh apoptosis.

Pemilihan sedemikian berdasarkan kemampuan sel-T untuk mengikat antigen diri. Sel T yang masih hidup adalah sel yang mengikat protein MHC dengan lemah. Sel-sel ini kemudian berhijrah melalui aliran darah ke organ limfoid sekunder, seperti kelenjar getah bening dan limpa. Tetapi sebelum mereka meninggalkan timus, setiap sel-T memperoleh akseptor khusus untuk penentu antigenik.

Ini dipanggil akseptor sel T (TCR). Juga, semasa pembezaan dalam timus, sel-T memperoleh protein permukaan CD4 atau CD8 yang memberikan kelakuan fungsinya (lihat Gambar 10.13). Sel-T menjumpai antigen untuk pertama kalinya dalam tisu limfoid sekunder dan pemilihan klonal berlaku, seperti yang berlaku juga pada sel-sel B.

Terdapat dua jenis fungsi sel T yang utama iaitu sel T-helper (Th) dan sel T sitotoksik (CTL). Kedua-dua jenis ini dibezakan dengan memiliki protein permukaan yang berbeza, iaitu. Protein CD4 pada TH-cells dan protein CD8 pada CTL. Selain dua jenis utama ini, terdapat dua jenis lain. Ini adalah sel T hipersensitiviti tertunda (TD) yang juga mempunyai protein CD8, dan sel-sel penekan (Ts) yang mempunyai protein CD4.

Fungsi utama imuniti sel-sel adalah untuk membunuh sel tubuh yang dijangkiti. Fungsi ini dijalankan oleh CTL. Sebaliknya, TH-sel membantu pengaktifan sel lain. Fungsi Ts dan TD sel kurang dikenali.

CTL mengikat dengan bantuan protein CD8 ke sel tubuh yang dijangkiti yang menyatakan penentu antigenik yang tertanam dalam protein MHC Kelas I. CTL mengenali penentu antigenik dengan bantuan TCR kognitifnya, sementara CD8 mengikat protein MHC Kelas I. Sebaliknya, TH-cell mengikat dengan TCRnya ke sel pembentang antigen, seperti makrofag atau sel dendritik atau sel B yang mengekspresikan penentu antigenik yang tertanam dalam protein MHC Kelas II. Dalam kes ini, protein CD4 TH-cell mengikat protein MHC.

Dalam CTL dan TH-cell, pengiktirafan penentu antigenik dibuat oleh TCR kognitif mereka dan pengikatannya stabil oleh protein CD8 dan CD4, masing-masing. Sebagai tambahan kepada CD8 dan CD4, protein permukaan lain terlibat dalam pengikatan berkesan dengan sel sasarannya.

(ii) Reseptor Sel T (TCR):

Sama seperti setiap sel B mempunyai reseptor antigen tertentu, begitu juga setiap sel T - tanpa mengira jenisnya - mempunyai reseptor, yang disebut reseptor sel T (TCR) yang dapat mengenali dan mengikat penentu antigenik tertentu. TCR dapat mengenali penentu antigenik hanya jika dikomplekskan dengan protein MHC. Sebaliknya, sel B, di mana antigen-reseptor adalah molekul Ig satu kelas atau yang lain, dapat mengenali antigen bebas terikat sel dan bebas.

TCR adalah heterodimer yang terdiri daripada dua rantai polipeptida, α dan β, yang mempunyai berat molekul masing-masing 50 dan 39 kilo Dalton. Kedua-dua rantai itu saling bersatu dengan ikatan disulfida dan kedua-duanya disambungkan ke membran sel-T. Setiap rantai mempunyai domain berubah-ubah dan domain tetap. Domain berubah dari rantai α dan β membentuk TCR tapak pengikat antigen. Oleh itu, dilihat bahawa TCR menyerupai molekul Ig dalam banyak aspek dan sebenarnya ia tergolong dalam keluarga super imunoglobulin. Pada masa yang sama, TCR berbeza dalam beberapa aspek dari Ig.

Sebagai contoh, TCR selalu dilekatkan pada membran sel-T, dan tidak pernah didapati bebas dalam plasma atau cecair badan seperti Ig. Sekali lagi, TCR hanya dapat berinteraksi dengan antigen yang dikomplekskan dengan protein MHC sel sasaran, sedangkan molekul Ig dapat bertindak balas dengan antigen terikat sel atau bebas.

Struktur TCR ditunjukkan dalam Rajah 10.41:

(iii) Kepelbagaian Sel T:

Oleh kerana satu sel-T tertentu dapat mengenali hanya satu penentu antigenik tertentu, jumlah populasi sel-T semestinya mewakili sejumlah besar klon sel-sel ini. Kepelbagaian sel-T disebabkan oleh reseptor sel-T. Mekanisme asas untuk mewujudkan kepelbagaian ini serupa dengan yang menyebabkan kepelbagaian antibodi. Sama seperti rantai H- dan L molekul Ig, rantai α- dan β-TCR mengandungi domain yang berbeza.

Setiap domain ini dikodkan oleh beberapa segmen DNA di garis kuman. Terdapat kira-kira satu juta rantai β yang berbeza dan 25 rantai α yang berbeza, menghasilkan sekitar 25 x 10 6 TCR yang berbeza. Rantai-α dibuat dari domain V, J dan C, dan rantai-P mempunyai domain V, D, J dan C. Gen yang mengkodkan domain polipeptida ini terletak di kromosom manusia 7 (untuk rantai α) dan kromosom 14 (untuk rantai β).

Kumpulan gen untuk dua rantai ditunjukkan dalam Rajah 10.42:

Seperti kes imunoglobulin & # 8217s, penyusunan semula gen dengan pemilihan rawak segmen DNA satu segmen V, satu segmen J dan segmen C menyebabkan pembentukan gen untuk rantai α. Sekiranya rantai β, terdapat satu domain D tambahan yang dikodkan oleh dua segmen DNA, D1 dan D2. Dapat dilihat bahawa gen yang mengawal rantai-β tersebar (tidak berpaut).

Penyusunan semula gen TCR bermula sejurus selepas prekursor (sel stem limfopoetik) memasuki kelenjar timus. Kepelbagaian timbul terutamanya melalui penggabungan somatik secara rawak dari segmen DNA V, J, D dan C dalam kes rantai β, dan segmen V, J dan C dalam kes rantai α. Tetapi kepelbagaian yang lebih jauh juga ditambahkan oleh penggabungan yang tidak tepat (kepelbagaian persilangan), seperti yang telah dijelaskan dalam kes kepelbagaian antibodi.

Setelah polipeptida TCR disintesis, mereka dinyatakan sebagai TCR pada permukaan timosit. Sel-T yang mengikat kuat protein MHC (antigen diri) dihilangkan dengan kematian sel yang diprogramkan (apoptosis). Sel-T yang masih hidup (kurang dari 5% daripada jumlah thimosit yang dihasilkan dari sel-sel induk) yang mengikat lemah pada antigen diri kemudian keluar dari timus sebagai sel yang berkebolehan imun.

(iv) Pengaktifan Sel-T:

Kekebalan yang dimediasi sel, juga dikenal sebagai imuniti sel, memberikan perlindungan terhadap patogen intraselular, kebanyakannya virus, tetapi juga beberapa bakteria dan kulat yang dapat tumbuh di dalam sel tubuh yang dijangkiti. Sel-T yang berpotensi imuniti memusnahkan sel-sel yang dijangkiti, sehingga membuat patogen terbuka untuk diserang oleh antibodi.

Peranan utama dalam membunuh sel tubuh yang dijangkiti dimainkan oleh sel T sitotoksik (CTL) tetapi untuk melakukannya, CTL perlu diaktifkan. Dalam proses pengaktifan ini, TH sel terlibat secara aktif. Sebaliknya, TH-kel sendiri harus diaktifkan untuk menjalankan peranannya dalam pengaktifan sel lain, termasuk CTL.

Peranan TH-sel dalam pengaktifan sel-B, seperti juga telah dilihat bagaimana TH-sel sendiri diaktifkan sebelum berinteraksi dengan sel-B (lihat Gambar 10.28 dan Gambar 10.29). Sekarang mari kita kaji bagaimana pengaktifan CTL berlaku dengan bantuan sel TH.

Patogen yang masuk ke dalam badan pertama kali dicabar oleh sel-sel fagosit sistem pertahanan bawaan. Sel-sel ini, seperti makrofag dan sel dendritik menelan patogen dan mencernanya dengan enzim hidrolitiknya. Peptida yang dihasilkan berasal dari protein mikroba yang menjangkiti bertindak sebagai penentu antigenik dan ini tertanam dalam matriks protein MHC Kelas I dan dinyatakan di permukaan fagosit.

Fagosit kini menjadi sel antigen-present (APC) dan mereka berpindah ke tisu limfoid untuk mencari CTL yang sesuai dengan TCR yang sesuai dengan penentu antigenik yang ada di permukaan (APC) mereka. CTL masih dalam keadaan tidak aktif. CTL kini mengenali penentu antigenik spesifik yang ada pada APC dengan bantuan TCRnya dan mengikatnya. Pengiktirafan tersebut juga dibantu oleh protein CD8 yang mengikat protein MHC Kelas I APC. Pengikatan CTL dengan APC adalah langkah pertama dalam pengaktifan CTL.

APC dengan penentu antigenik pada protein MHC Kelas II dapat mengenali dan berinteraksi dengan TH-sel yang membawa TCR kognitif. Interaksi antara APC dan TH sel membawa kepada pengikatan mereka antara TCR dan penentu antigenik di satu pihak, dan protein CD4 dari TH-cell dan MHC protein APC di sisi lain. Ini membawa kepada rangsangan kedua-dua TH-cell dan APC dan mereka menghasilkan satu siri sitokin. Sitokin, interleukin-1, yang dihasilkan oleh APC mengaktifkan TH& # 8211 sel dan T yang diaktifkanH-cell menghasilkan interleukin-2 yang mendorong CTL berkembang biak dan menjadi sel pembunuh.

CTL yang diaktifkan kini mampu menyerang sel tubuh yang dijangkiti. Sel-sel yang dijangkiti seperti itu dikenali oleh CTL dengan bantuan TCR yang mengikat penentu antigenik yang dinyatakan pada permukaan sel-sel tubuh yang tertanam dalam protein MHC Kelas I. Protein CD8 CTL mengikat protein MHC Kelas I sel-sel badan yang dijangkiti. Pengaktifan TH-cells dan CTL ditunjukkan secara gambarajah Rajah 10.43.

(v) Peranan Sel T sitotoksik:

Sel T sitotoksik memainkan peranan penting dalam imuniti sel yang dimediasi sel. Setelah diaktifkan, CTL menjadi sel pembunuh yang mampu memusnahkan sel-sel tubuh yang dijangkiti, dan juga sel-sel malignan. CTL pembunuh ini keluar dari tisu limfoid dan masuk ke dalam darah dan limfa. Semasa beredar, mereka menemui sel sasaran dan memusnahkannya dengan apa yang disebut & # 8216lethal hit & # 8217.

CTL yang diaktifkan mempunyai butiran besar dalam sitoplasma mereka. Ini mengandungi enzim proteolitik, yang disebut granzim, dan juga protein beracun yang disebut perforin. Sel sasaran yang kebanyakannya sel tubuh dijangkiti oleh patogen intraselular seperti virus, beberapa bakteria dan kadang-kadang beberapa kulat, memaparkan penentu antigenik patogen di permukaannya yang dikompleks dengan protein MHC Kelas I.

Apabila CTL pembunuh beredar menemui sel badan yang dijangkiti, ia mengenali penentu antigenik dan mengikatnya dengan protein TCR dan CD8 dengan cara yang serupa dengan interaksinya dengan APC. Setelah bersentuhan dengan sel yang dijangkiti, butiran CTL berpindah ke titik kontak dan mereka melepaskan molekul perforin yang berpolimerisasi untuk membentuk lubang pada membran sel sasaran.

Melalui liang-liang ini, granzim masuk ke dalam sitoplasma sel sasaran menyebabkan kemusnahan kandungannya. Sel sasaran akhirnya mengalami lisis. Ini dipanggil & # 8216lethal hit & # 8217. CTL sekali lagi dapat mensintesis butiran sitoplasma dan dapat menyerang sel sasaran yang lain.

Kesan sitotoksik CTL ditunjukkan secara gambarajah dalam Rajah 10.44:

Selain sel tubuh yang dijangkiti, CTL yang diaktifkan juga dapat menyebabkan serangan mematikan pada sel barah. Sel-sel ini, seperti sel-sel badan yang dijangkiti, mengekspresikan antigen tumor tertentu yang dikompleks dengan MHC Kelas I di permukaannya dan dengan demikian menjadi sasaran aktiviti CTL.

CTL yang beredar memerhatikan penampilan sel-sel tumor seperti itu dan menghilangkannya dengan cepat menyebabkan lisis. Ini dikenal sebagai pengawasan kekebalan tubuh dan merupakan fenomena yang sangat penting dalam menjaga tubuh bebas dari sel-sel barah yang timbul oleh transformasi sel-sel tubuh yang normal.

Aspek penting lain dari tindak balas sel T adalah penghasilan klon sel T memori (seperti yang ditunjukkan dalam Rajah 10.43). Seperti memori sel-B, sel-sel ini tetap tersebar ke seluruh badan dan mencari antigen yang mendorong tindak balas sel-T awal. Sel-sel memori segera menerkam antigen dan memusnahkannya. Semasa pertemuan kedua ini, memori sel-T berkembang dengan cepat untuk mendorong tindak balas sel T sekunder yang lebih kuat.

Sebagai tambahan kepada pembunuhan langsung sel tubuh dan sel tumor yang dijangkiti, sel T sitotoksik juga menghasilkan sitokin yang berbeza yang terlibat dalam pertahanan terhadap penceroboh asing. Antaranya adalah protein, yang disebut faktor pengaktifan makrofag, yang menarik makrofag ke tempat jangkitan dan mengaktifkannya. Protein lain yang dihasilkan oleh sel-T adalah penghambat migrasi yang menghalang makrofag keluar dari tempat jangkitan, sehingga makrofag tetap terbatas pada tempat jangkitan.

Fungsi utama CTL adalah pada patogen intraselular yang tidak diserang oleh antibodi yang dihasilkan dalam imuniti humoral. Melalui serangan mematikan yang mengakibatkan lisis, patogen intraselular seperti itu terdedah kepada tindakan antibodi dan mereka dihilangkan melalui fagositosis dan peneutralan. Oleh itu, imuniti sel-sel dan imuniti humoral bekerjasama untuk melindungi tubuh.


Tindak Balas Kekebalan Humoral

Seperti disebutkan, antigen adalah molekul yang merangsang tindak balas dalam sistem kekebalan tubuh. Tidak setiap molekul bersifat antigen. Sel B mengambil bahagian dalam tindak balas kimia terhadap antigen yang ada di dalam badan dengan menghasilkan antibodi spesifik yang beredar ke seluruh tubuh dan mengikat dengan antigen setiap kali dijumpai. Ini dikenali sebagai tindak balas imun humoral. Seperti yang dibincangkan, semasa pematangan sel B, satu set sel B yang sangat spesifik dihasilkan yang mempunyai banyak molekul reseptor antigen dalam membrannya ([Gambar 2]).

Gambar 2: Reseptor sel B tertanam di membran sel B dan mengikat pelbagai antigen melalui kawasan pemboleh ubahnya.

Setiap sel B hanya mempunyai satu jenis reseptor antigen, yang menjadikan setiap sel B berbeza. Setelah sel-sel B matang di sumsum tulang, mereka berpindah ke kelenjar getah bening atau organ limfa lain. Apabila sel B menemui antigen yang mengikat reseptornya, molekul antigen dibawa ke dalam sel oleh endositosis dan muncul semula di permukaan sel yang terikat pada molekul MHC kelas II. Apabila proses ini selesai, sel B akan peka. Dalam kebanyakan kes, sel B yang peka mesti menemui sel T jenis tertentu, yang disebut sel T penolong, sebelum diaktifkan. Sel T penolong mesti diaktifkan melalui perjumpaan dengan antigen (dibincangkan di bawah).

Sel T helper mengikat ke kompleks antigen-MHC kelas II dan terdorong untuk melepaskan sitokin yang mendorong sel B untuk membelah dengan cepat, yang menjadikan ribuan sel yang serupa (klonal). Sel-sel anak ini menjadi sel plasma atau sel memori B. Sel-sel memori B tetap tidak aktif pada saat ini, sampai yang lain kemudian bertemu dengan antigen, yang disebabkan oleh jangkitan semula oleh bakteria atau virus yang sama, mengakibatkan mereka membelah menjadi populasi baru sel plasma. Sel-sel plasma, sebaliknya, menghasilkan dan mengeluarkan sejumlah besar, hingga 100 juta molekul per jam, molekul antibodi. Antibodi, juga dikenal sebagai imunoglobulin (Ig), adalah protein yang dihasilkan oleh sel plasma setelah dirangsang oleh antigen. Antibodi adalah agen imuniti humoral. Antibodi berlaku dalam darah, dalam rembesan gastrik dan lendir, dan pada susu ibu. Antibodi dalam cairan tubuh ini dapat mengikat patogen dan menandakannya untuk dimusnahkan oleh fagosit sebelum boleh menjangkiti sel.

Antibodi ini beredar di aliran darah dan sistem limfa dan mengikat dengan antigen setiap kali dijumpai. Pengikatannya dapat melawan jangkitan dengan beberapa cara. Antibodi boleh mengikat virus atau bakteria dan mengganggu interaksi kimia yang diperlukan untuk menjangkiti atau mengikat sel lain. Antibodi dapat mewujudkan jambatan antara zarah-zarah yang berlainan yang mengandungi laman antigen yang menyatukan mereka semua dan mencegahnya berfungsi dengan baik. Kompleks antigen-antibodi merangsang sistem pelengkap yang dijelaskan sebelumnya, memusnahkan sel yang membawa antigen. Sel-sel fagosit, seperti yang sudah dijelaskan, tertarik oleh kompleks antigen-antibodi, dan fagositosis ditingkatkan ketika kompleks ada. Akhirnya, antibodi merangsang keradangan, dan kehadirannya di lendir dan pada kulit mencegah serangan patogen.

Antibodi melapisi patogen ekstraselular dan meneutralkannya dengan menyekat laman utama pada patogen yang meningkatkan infektiviti mereka (seperti reseptor yang & # 8220dock & # 8221 patogen pada sel inang) ([Rajah 3]). Peneutralan antibodi dapat mencegah patogen masuk dan menjangkiti sel inang. Patogen yang dilapisi antibodi dinetralkan kemudian dapat disaring oleh limpa dan dihilangkan dalam air kencing atau tinja.

Antibodi juga menandakan patogen untuk dimusnahkan oleh sel fagositik, seperti makrofag atau neutrofil, dalam proses yang disebut opsonisasi. Dalam proses yang disebut fiksasi pelengkap, beberapa antibodi menyediakan tempat untuk mengikat protein pelengkap. Gabungan antibodi dan pelengkap mendorong pembersihan cepat patogen.

Penghasilan antibodi oleh sel plasma sebagai tindak balas terhadap antigen disebut imuniti aktif dan menggambarkan tindak balas aktif tuan rumah terhadap sistem imun terhadap jangkitan atau vaksinasi. Terdapat juga tindak balas imun pasif di mana antibodi berasal dari sumber luar, bukannya sel plasma individu, dan diperkenalkan ke inang. Contohnya, antibodi yang beredar di badan wanita hamil bergerak melintasi plasenta ke janin yang sedang berkembang. Anak mendapat manfaat daripada kehadiran antibodi ini sehingga beberapa bulan selepas kelahiran. Sebagai tambahan, tindak balas imun pasif adalah mungkin dengan menyuntikkan antibodi kepada seseorang dalam bentuk antivenom kepada toksin gigitan ular atau antibodi dalam serum darah untuk membantu melawan jangkitan hepatitis. Ini memberi perlindungan segera kerana badan tidak memerlukan masa yang diperlukan untuk meningkatkan tindak balasnya sendiri.

Gambar 3: Antibodi dapat menghambat jangkitan dengan (a) mencegah antigen mengikat sasarannya, (b) menandai patogen untuk dimusnahkan oleh makrofag atau neutrofil, atau (c) mengaktifkan lata pelengkap.


Mengawal imuniti oleh glukokortikoid dalam kesihatan dan penyakit

Haiwan menerima rangsangan persekitaran dari isyarat saraf untuk menghasilkan hormon yang mengawal tindak balas imun. Glukokortikoid (GC) adalah sekumpulan hormon steroid yang dihasilkan dalam korteks adrenal dan pengantara terkenal untuk sistem saraf dan imun. Rembesan GC disebabkan oleh irama dan tekanan sirkadian, dan tahap GC plasma tinggi pada fasa aktif haiwan dan dalam keadaan tekanan. Secara klinikal, GC digunakan untuk alergi, autoimun, dan keradangan kronik, kerana mempunyai kesan anti-radang yang kuat dan mendorong apoptosis limfosit. Reseptor glukokortikoid (GR) bertindak sebagai faktor transkripsi dan menekan ekspresi sitokin keradangan, kemokin, dan prostaglandin dengan mengikat motifnya, elemen tindak balas glukokortikoid, atau faktor transkripsi lain. Pada tikus, GR menekan keradangan antigen-stimulated yang dimediasi oleh makrofag, sel dendritik, dan sel epitelium, dan mengganggu tindak balas imun sitotoksik dengan merendahkan pengeluaran interferon-γ dan menghalang pengembangan sel T pembantu jenis-1, sel CD8 + T, dan semula jadi sel pembunuh. Kesan penghambatan imun ini mencegah kematian akibat keradangan yang berlebihan, tetapi pada masa yang sama meningkatkan kerentanan terhadap jangkitan dan barah. GC juga dapat mengaktifkan sistem imun. Kitaran sirkadian sekresi GC mengawal ayunan diurnal pengedaran dan tindak balas sel T, sehingga menyokong pemeliharaan sel T dan perlindungan imun yang berkesan terhadap jangkitan. Lebih-lebih lagi, beberapa laporan menunjukkan bahawa GR berpotensi untuk meningkatkan aktiviti sel B2 yang menghasilkan Th2, Th17, dan imunoglobulin. Tekanan mempunyai dua kesan yang berbeza terhadap tindak balas imun: penekanan imun yang menyebabkan kematian akibat jangkitan dan barah, dan pengaktifan imun yang berlebihan untuk menyebabkan keradangan kronik dan penyakit autoimun. Secara konsisten, GC yang disebabkan oleh tekanan sangat menekan kekebalan yang dimediasi sel dan menyebabkan jangkitan virus dan perkembangan tumor. Mereka juga dapat meningkatkan perkembangan sel T penolong patogen dan menyebabkan kerosakan tisu melalui radang saraf dan usus. Kajian lepas telah melaporkan kesan positif dan negatif GC pada sistem imun. Sifat GC yang bertentangan ini dapat mengatur keseimbangan imun antara tindak balas terhadap antigen dan keradangan yang berlebihan dalam keadaan stabil dan keadaan tekanan.

Kata kunci: CXCR4 Imuniti yang dimediasi sel Irama sirkadian Glucocorticoid Glucocorticoid reseptor IL-7R Stress Th17 cell Th2 cell.


Bab 43 - Sistem Imun

  • Mikroba yang menyerang mesti menembusi penghalang luaran yang terbentuk oleh kulit dan selaput lendir, yang menutup permukaan dan melapisi bukaan badan haiwan.
  • Sekiranya berjaya, patogen menemui barisan kedua pertahanan bukan spesifik, mekanisme selular dan kimia bawaan yang bertahan terhadap sel asing yang menyerang.

Kulit dan membran mukus memberikan penghalang jangkitan pertama.

  • Kulit yang utuh adalah penghalang yang biasanya tidak dapat ditembus oleh bakteria atau virus, walaupun lecet seminit mungkin memungkinkannya keluar.
  • Begitu juga, selaput lendir yang melapisi saluran pencernaan, pernafasan, dan genitouriner melarang kemasukan mikroba yang berpotensi berbahaya.
    • Sel-sel membran mukus ini menghasilkan lendir, cecair likat yang memerangkap mikroba dan zarah-zarah lain.
    • Di trakea, sel epitel bersilia menyapu lendir dengan mikroba yang terperangkap, mencegahnya memasuki paru-paru.
    • Pada manusia, misalnya, rembesan dari sebum dan kelenjar peluh memberi kulit pH antara 3 hingga 5, yang cukup berasid untuk mencegah penjajahan oleh banyak mikroba.
    • Penjajahan mikroba juga dihambat oleh tindakan mencuci air liur, air mata, dan rembesan lendir yang terus-menerus memandikan epitel yang terdedah.
      • Semua rembesan ini mengandungi protein antimikroba.
      • Salah satunya, enzim lisozim, mencerna dinding sel banyak bakteria, memusnahkannya.
      • Asid merosakkan banyak mikroba sebelum mereka memasuki saluran usus.
      • Satu pengecualian, virus hepatitis A, dapat bertahan keasidan gastrik dan mendapat akses ke tubuh melalui saluran pencernaan.

      Sel fagosit dan protein antimikroba berfungsi pada awal jangkitan.

      • Mikroba yang menembusi barisan pertahanan pertama menghadapi barisan pertahanan kedua, yang bergantung terutamanya pada fagositosis, pengambilan organisma yang menyerang oleh jenis sel putih tertentu.
      • Fungsi fagosit berkaitan erat dengan tindak balas keradangan yang berkesan dan juga dengan protein antimikroba tertentu.
      • Fagosit melekat pada mangsanya melalui reseptor permukaan yang terdapat pada mikrob tetapi bukan sel badan normal.
      • Setelah melekat pada mikroba, fagosit menelannya, membentuk vakuola yang menyatu dengan lisosom.
        • Mikroba dimusnahkan di dalam lisosom dengan dua cara.
          • Lisosom mengandungi oksida nitrat dan oksigen bentuk toksik lain, yang bertindak sebagai agen antimikrobial yang kuat.
          • Lisosim dan enzim lain merosakkan komponen mitokondria.
          • Kapsul luar beberapa sel bakteria menyembunyikan polisakarida permukaannya dan mencegah fagosit melekat padanya.
          • Bakteria lain ditelan oleh fagosit tetapi menentang pencernaan, tumbuh dan berkembang biak di dalam sel.
          • Sel yang rosak oleh mikroba menyerang melepaskan isyarat kimia yang menarik neutrofil dari darah.
          • Neutrofil memasuki tisu yang dijangkiti, melanda dan memusnahkan mikroba di sana.
          • Neutrofil cenderung merosakkan diri kerana mereka memusnahkan penjajah asing, dan jangka hayat rata-rata mereka hanya beberapa hari.
          • Setelah beberapa jam dalam darah, mereka berhijrah ke tisu dan berkembang menjadi makrofag, yang merupakan fagosit yang panjang dan besar.
          • Beberapa makrofag berhijrah ke seluruh badan, sementara yang lain tinggal secara kekal di tisu tertentu, termasuk paru-paru, hati, ginjal, tisu penghubung, otak, dan terutama di kelenjar getah bening dan limpa.
          • Mikroba yang memasuki darah terperangkap dalam limpa, sementara mikroba dalam cairan interstitial mengalir ke limfa dan terperangkap di kelenjar getah bening.
          • Di kedua-dua lokasi tersebut, mikroba segera menemui makrofag penduduk.
          • Eosinofil meletakkan diri mereka pada dinding luaran parasit dan mengeluarkan enzim pemusnah dari butiran sitoplasma.
          • In addition to lysozyme, other antimicrobial agents include about 30 serum proteins, known collectively as the complement system.
            • Substances on the surface of many microbes can trigger a cascade of steps that activate the complement system, leading to lysis of microbes.
            • These proteins are secreted by virus-infected body cells and induce uninfected neighboring cells to produce substances that inhibit viral reproduction.
            • Interferon limits cell-to-cell spread of viruses, helping to control viral infection.
            • Because they are nonspecific, interferons produced in response to one virus may confer short-term resistance to unrelated viruses.
            • One type of interferon activates phagocytes.
            • Interferons can be produced by recombinant DNA technology and are being tested for the treatment of viral infections and cancer.
            • When injured, mast cells release their histamine.
            • Histamine triggers both dilation and increased permeability of nearby capillaries.
            • Leukocytes and damaged tissue cells also discharge prostaglandins and other substances that promote blood flow to the site of injury.
            • Increased local blood supply leads to the characteristic swelling, redness, and heat of inflammation.
            • Blood-engorged leak fluid into neighboring tissue, causing swelling.
            • First, they aid in delivering clotting elements to the injured area.
              • Clotting marks the beginning of the repair process and helps block the spread of microbes elsewhere.
              • Phagocyte migration usually begins within an hour after injury.
              • Injured cells secrete chemicals that stimulate the release of additional neutrophils from the bone marrow.
              • In a severe infection, the number of white blood cells may increase significantly within hours of the initial inflammation.
              • Another systemic response to infection is fever, which may occur when substances released by activated macrophages set the body’s thermostat at a higher temperature.
                • Moderate fever may facilitate phagocytosis and hasten tissue repair.
                • Characterized by high fever and low blood pressure, septic shock is the most common cause of death in U.S. critical care units.
                • Clearly, while local inflammation is an essential step toward healing, widespread inflammation can be devastating.
                • They also attack abnormal body cells that could become cancerous.
                • NK cells attach to a target cell and release chemicals that bring about apoptosis, or programmed cell death.

                Invertebrates also have highly effective innate defenses.

                • Insect hemolymph contains circulating cells called hemocytes.
                  • Some hemocytes can phagocytose microbes, while others can form a cellular capsule around large parasites.
                  • Other hemocytes secrete antimicrobial peptides that bind to and destroy pathogens.
                  • Sponge cells can distinguish self from nonself cells.
                  • Phagocytic cells of earthworms show immunological memory, responding more quickly to a particular foreign tissue the second time it is encountered.

                  Concept 43.2 In acquired immunity, lymphocytes provide specific defenses against infection

                  • While microorganisms are under assault by phagocytic cells, the inflammatory response, and antimicrobial proteins, they inevitably encounter lymphocytes, the key cells of acquired immunity, the body’s second major kind of defense.
                  • As macrophages and dendritic cells phagocytose microbes, they secrete certain cytokines that help activate lymphocytes and other cells of the immune system.
                    • Thus the innate and acquired defenses interact and cooperate with each other.
                    • Most antigens are large molecules such as proteins or polysaccharides.
                    • Most are cell-associated molecules that protrude from the surface of pathogens or transplanted cells.
                    • A lymphocyte actually recognizes and binds to a small portion of an antigen called an epitope.

                    Lymphocytes provide the specificity and diversity of the immune system.

                    • The vertebrate body is populated by two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells).
                      • Both types of lymphocytes circulate throughout the blood and lymph and are concentrated in the spleen, lymph nodes, and other lymphatic tissue.
                      • A single B or T cell bears about 100,000 identical antigen receptors.
                      • A region in the tail portion of the molecule, the transmembrane region, anchors the receptor in the cell’s plasma membrane.
                      • A short region at the end of the tail extends into the cytoplasm.
                      • B cell receptors are often called membrane antibodies or membrane immunoglobulins.
                      • Depending on their source, peptide antigens are handled by a different class of MHC molecule and recognized by a particular subgroup of T cells.
                        • Class I MHC molecules, found on almost all nucleated cells of the body, bind peptides derived from foreign antigens that have been synthesized within the cell.
                          • ? Any body cell that becomes infected or cancerous can display such peptide antigens by virtue of its class I MHC molecules.
                          • ? Class I MHC molecules displaying bound peptide antigens are recognized by a subgroup of T cells called cytotoxic T cells.
                          • In these cells, class II MHC molecules bind peptides derived from foreign materials that have been internalized and fragmented by phagocytosis.
                          • As a result of the large number of different alleles in the human population, most of us are heterozygous for every one of our MHC genes.
                          • Moreover, it is unlikely that any two people, except identical twins, will have exactly the same set of MHC molecules.
                          • The MHC provides a biochemical fingerprint virtually unique to each individual that marks body cells as “self.”

                          Lymphocyte development gives rise to an immune system that distinguishes self from nonself.

                          • Lymphocytes, like all blood cells, originate from pluripotent stem cells in the bone marrow or liver of a developing fetus.
                          • Early lymphocytes are all alike, but they later develop into T cells or B cells, depending on where they continue their maturation.
                          • Lymphocytes that migrate from the bone marrow to the thymus develop into T cells.
                          • Lymphocytes that remain in the bone marrow and continue their maturation there become B cells.
                          • There are three key events in the life of a lymphocyte.
                            • The first two events take place as a lymphocyte matures, before it has contact with any antigen.
                            • The third event occurs when a mature lymphocyte encounters and binds a specific antigen, leading to its activation, proliferation, and differentiation—a process called clonal selection.
                            • The variability of these regions is enormous.
                            • Each person has as many as a million different B cells and 10 million different T cells, each with a specific antigen-binding ability.
                            • These genes consist of numerous coding gene segments that undergo random, permanent rearrangement, forming functional genes that can be expressed as receptor chains.
                            • Genes for the light chain of the B cell receptor and for the alpha and beta chains of the T cell receptor undergo similar rearrangements, but we will consider only the gene coding for the light chain of the B cell receptor.
                            • The immunoglobulin light-chain gene contains a series of 40 variable (V) gene segments separated by a long stretch of DNA from 5 joining (J) gene segments.
                            • Beyond the J gene segments is an intron, followed by a single exon that codes for the constant region of the light chain.
                            • In this state, the light-chain gene is not functional.
                            • However, early in B cell development, a set of enzymes called recombinase link one V gene segment to one J gene segment, forming a single exon that is part V and part J.
                              • Recombinase acts randomly and can link any one of 40 V gene segments to any one of 5 J gene segments.
                              • For the light-chain gene, there are 200 possible gene products (20 V × 5 J).
                              • Once V-J rearrangement has occurred, the gene is transcribed and translated into a light chain with a variable and constant region. The light chains combine randomly with the heavy chains that are similarly produced.
                              • Failure to do this can lead to autoimmune diseases such as multiple sclerosis.

                              Antigens interact with specific lymphocytes, inducing immune responses and immunological memory.

                              • Although it encounters a large repertoire of B cells and T cells, a microorganism interacts only with lymphocytes bearing receptors specific for its various antigenic molecules.
                              • A lymphocyte is “selected” when it encounters a microbe with epitopes matching its receptors.
                                • Selection activates the lymphocyte, stimulating it to divide and differentiate, and eventually to produce two clones of cells.
                                • One clone consists of a large number of effector cells, short-lived cells that combat the same antigen.
                                • The other clone consists of memory cells, long-lived cells bearing receptors for the same antigen.
                                • Each antigen, by binding selectively to specific receptors, activates a tiny fraction of cells from the body’s diverse pool of lymphocytes.
                                • This relatively small number of selected cells gives rise to clones of thousands of cells, all specific for and dedicated to eliminating that antigen.
                                • About 10 to 17 days are required from the initial exposure for the maximum effector cell response.
                                • During this period, selected B cells and T cells generate antibody-producing effector B cells called plasma cells, and effector T cells, respectively.
                                • While this response is developing, a stricken individual may become ill, but symptoms of the illness diminish and disappear as antibodies and effector T cells clear the antigen from the body.
                                • This response is faster (only 2 to 7 days), of greater magnitude, and more prolonged.
                                • In addition, the antibodies produced in the secondary response tend to have greater affinity for the antigen than those secreted in the primary response.
                                • The immune system’s capacity to generate secondary immune responses is called immunological memory, based not only on effector cells, but also on clones of long-lived T and B memory cells.
                                  • These memory cells proliferate and differentiate rapidly when they later contact the same antigen.

                                  Concept 43.3 Humoral and cell-mediated immunity defend against different types of threats

                                  • The immune system can mount two types of responses to antigens: a humoral response and a cell-mediated response.
                                    • Humoral immunity involves B cell activation and clonal selection and results in the production of antibodies that circulate in the blood plasma and lymph.
                                      • Circulating antibodies defend mainly against free bacteria, toxins, and viruses in the body fluids.

                                      Helper T lymphocytes function in both humoral and cell-mediated immunity.

                                      • When a helper T cell recognizes a class II MHC molecule-antigen complex on an antigen-presenting cell, the helper T cell proliferates and differentiates into a clone of activated helper T cells and memory helper T cells.
                                      • A surface protein called CD4 binds the side of the class II MHC molecule.
                                      • This interaction helps keep the helper T cell and the antigen-presenting cell joined while activation of the helper T cell proceeds.
                                      • Activated helper T cells secrete several different cytokines that stimulate other lymphocytes, thereby promoting cell-mediated and humoral responses.
                                      • Dendritic cells are important in triggering a primary immune response.
                                        • They capture antigens, migrate to the lymphoid tissues, and present antigens, via class II MHC molecules, to helper T cells.

                                        In the cell-mediated response, cytotoxic T cells counter intracellular pathogens.

                                        • Antigen-activated cytotoxic T lymphocytes kill cancer cells and cells infected by viruses and other intracellular pathogens.
                                        • Fragments of nonself proteins synthesized in such target cells associate with class I MHC molecules and are displayed on the cell surface, where they can be recognized by cytotoxic T cells.
                                          • This interaction is greatly enhanced by the T surface protein CD8 that helps keep the cells together while the cytotoxic T cell is activated.
                                          • The death of the infected cell not only deprives the pathogen of a place to reproduce, but also exposes it to circulating antibodies, which mark it for disposal.
                                          • Once activated, cytotoxic T cells kill other cells infected with the same pathogen.
                                          • Because tumor cells carry distinctive molecules not found on normal cells, they are identified as foreign by the immune system.
                                          • Class I MHC molecules on a tumor cell present fragments of tumor antigens to cytotoxic T cells.
                                          • Interestingly, certain cancers and viruses actively reduce the amount of class I MHC protein on affected cells so that they escape detection by cytotoxic T cells.
                                          • The body has a backup defense in the form of natural killer cells, part of the nonspecific defenses, which lyse virus-infected and cancer cells.

                                          In the humoral response, B cells make antibodies against extracellular pathogens.

                                          • Antigens that elicit a humoral immune response are typically proteins and polysaccharides present on the surface of bacteria or transplanted tissue.
                                          • The activation of B cells is aided by cytokines secreted by helper T cells activated by the same antigen.
                                            • These B cells proliferate and differentiate into a clone of antibody-secreting plasma cells and a clone of memory B cells.
                                            • These include the polysaccharides of many bacterial capsules and the proteins of the bacterial flagella.
                                            • These antigens bind simultaneously to a number of membrane antibodies on the B cell surface.
                                            • This stimulates the B cell to generate antibody-secreting plasma cells without the help of cytokines.
                                            • While this response is an important defense against many bacteria, it generates a weaker response than T-dependent antigens and generates no memory cells.
                                            • Each plasma cell is estimated to secrete about 2,000 antibody molecules per second over the cell’s 4- to 5-day life span.
                                            • A secreted antibody has the same general Y-shaped structure as a B cell receptor, but lacks a transmembrane region that would anchor it to a plasma membrane.
                                            • In addition, for some humans, the proteins of foreign substances such as pollen or bee venom act as antigens that induce an allergic, or hypersensitive, humoral response.
                                            • Two classes exist primarily as polymers of the basic antibody molecule: IgM as a pentamer and IgA as a dimmer.
                                            • The other three classes—IgG, IgE, and IgD—exist exclusively as monomers,
                                            • Some antibody tools are polyclonal, the products of many different clones of B cells, each specific for a different epitope.
                                            • Others are monoclonal, prepared from a single clone of B cells grown in culture.
                                              • These cells produce monoclonal antibodies, specific for the same epitope on an antigen.
                                              • These have been used to tag specific molecules.
                                              • For example, toxin-linked antibodies search and destroy tumor cells.
                                              • In viral neutralization, antibodies bind to proteins on the surface of a virus, blocking the virus’s ability to infect a host cell.
                                              • In opsonization, the bound antibodies enhance macrophage attachment to and phagocytosis of the microbes. Neither the B cell receptor for an antigen nor the secreted antibody actually binds to an entire antigen molecule.
                                              • Agglutination is possible because each antibody molecule has at least two antigen-binding sites.
                                              • IgM can link together five or more viruses or bacteria.
                                              • These large complexes are readily phagocytosed by macrophages.
                                              • The first complement component links two bound antibodies and is activated, initiating the cascade.
                                                • Ultimately, complement proteins generate a membrane attack complex (MAC), which forms a pore in the bacterial membrane, resulting in cell lysis.

                                                Immunity can be achieved naturally or artificially.

                                                • Immunity conferred by recovering from an infectious disease such as chicken pox is called active immunity because it depends on the response of the infected person’s own immune system.
                                                  • Active immunity can be acquired naturally or artificially, by immunization, also known as vaccination.
                                                  • Vaccines include inactivated bacterial toxins, killed microbes, parts of microbes, viable but weakened microbes, and even genes encoding microbial proteins.
                                                  • These agents can act as antigens, stimulating an immune response and, more important, producing immunological memory.
                                                  • Routine immunization of infants and children has dramatically reduced the incidence of infectious diseases such as measles and whooping cough, and has led to the eradication of smallpox, a viral disease.
                                                  • Unfortunately, not all infectious agents are easily managed by vaccination.
                                                    • For example, the emergence of new strains of pathogens with slightly altered surface antigens complicates development of vaccines against some microbes, such as the parasite that causes malaria.
                                                    • This occurs naturally when IgG antibodies of a pregnant woman cross the placenta to her fetus.
                                                    • In addition, IgA antibodies are passed from mother to nursing infant in breast milk.
                                                    • Passive immunity persists as long as these antibodies last, a few weeks to a few months.
                                                      • This protects the infant from infections until the baby’s own immune system has matured.
                                                      • This confers short-term, but immediate, protection against that disease.
                                                      • For example, a person bitten by a rabid animal may be injected with antibodies against rabies virus because rabies may progress rapidly, and the response to an active immunization could take too long to save the life of the victim.
                                                        • Most people infected with rabies virus are given both passive immunizations (the immediate defense) and active immunizations (a longer-term defense).

                                                        Concept 43.4 The immune system’s ability to distinguish self from nonself limits tissue transplantation

                                                        • In addition to attacking pathogens, the immune system will also attack cells from other individuals.
                                                          • For example, a skin graft from one person to a nonidentical individual will look healthy for a day or two, but it will then be destroyed by immune responses.
                                                          • Interestingly, a pregnant woman does not reject the fetus as a foreign body. Apparently, the structure of the placenta is the key to this acceptance.
                                                          • In the ABO blood groups, an individual with type A blood has A antigens on the surface of red blood cells.
                                                            • This is not recognized as an antigen by the “owner,” but it can be identified as foreign if placed in the body of another individual.
                                                            • These antibodies arise in response to bacteria (normal flora) that have epitopes very similar to blood group antigens.
                                                            • Thus, an individual with type A blood does not make antibodies to A-like bacterial epitopes—these are considered self—but that person does make antibodies to B-like bacterial epitopes.
                                                            • If a person with type A blood receives a transfusion of type B blood, the preexisting anti-B antibodies will induce an immediate and devastating transfusion reaction.
                                                            • Each response is like a primary response, and it generates IgM anti-blood-group antibodies, not IgG.
                                                            • This is fortunate, because IgM antibodies do not cross the placenta, where they may harm a developing fetus with a blood type different from its mother’s.
                                                            • This situation arises when a mother that is Rh-negative (lacks the Rh factor) has a fetus that is Rh-positive, having inherited the factor from the father.
                                                            • If small amounts of fetal blood cross the placenta late in pregnancy or during delivery, the mother mounts a humoral response against the Rh factor.
                                                            • The danger occurs in subsequent Rh-positive pregnancies, when the mother’s Rh-specific memory B cells produce IgG antibodies that can cross the placenta and destroy the red blood cells of the fetus.
                                                            • She is, in effect, passively immunized (artificially) to eliminate the Rh antigen before her own immune system responds and generates immunological memory against the Rh factor, endangering her future Rh-positive babies.
                                                            • Because MHC creates a unique protein fingerprint for each individual, foreign MHC molecules are antigenic, inducing immune responses against the donated tissue or organ.
                                                            • To minimize rejection, attempts are made to match MHC of tissue donor and recipient as closely as possible.
                                                              • In the absence of identical twins, siblings usually provide the closest tissue-type match.
                                                              • However, this strategy leaves the recipient more susceptible to infection and cancer during the course of treatment.
                                                              • More selective drugs, which suppress helper T cell activation without crippling nonspecific defense or T-independent humoral responses, have greatly improved the success of organ transplants.
                                                              • Bone marrow transplants are used to treat leukemia and other cancers as well as various hematological diseases.
                                                              • Prior to the transplant, the recipient is typically treated with irradiation to eliminate the recipient’s immune system, eliminating all abnormal cells and leaving little chance of graft rejection.
                                                              • However, the donated marrow, containing lymphocytes, may react against the recipient, producing graft versus host reaction, unless well matched.

                                                              Concept 43.5 Exaggerated, self-directed, or diminished immune responses can cause disease

                                                              • Malfunctions of the immune system can produce effects ranging from the minor inconvenience of some allergies to the serious and often fatal consequences of certain autoimmune and immunodeficiency diseases.
                                                              • Allergies are hypersensitive (exaggerated) responses to certain environmental antigens, called allergens.
                                                                • One hypothesis to explain the origin of allergies is that they are evolutionary remnants of the immune system’s response to parasitic worms.
                                                                • The humoral mechanism that combats worms is similar to the allergic response that causes such disorders as hay fever and allergic asthma.
                                                                • Hay fever, for example, occurs when plasma cells secrete IgE specific for pollen allergens.
                                                                • Some IgE antibodies attach by their tails to mast cells present in connective tissue, without binding to the pollen.
                                                                • Later, when pollen grains enter the body, they attach to the antigen-binding sites of mast cell-associated IgE, cross-linking adjacent antibody molecules.
                                                                • These inflammatory events lead to typical allergy symptoms: sneezing, runny nose, tearing eyes, and smooth muscle contractions that can result in breathing difficulty.
                                                                • Antihistamines diminish allergy symptoms by blocking receptors for histamine.
                                                                • Anaphylactic shock results when widespread mast cell degranulation triggers abrupt dilation of peripheral blood vessels, causing a precipitous drop in blood pressure.
                                                                  • Death may occur within minutes.
                                                                  • In systemic lupus erythematosus (lupus), the immune system generates antibodies against various self-molecules, including histones and DNA released by the normal breakdown of body cells.
                                                                    • Lupus is characterized by skin rashes, fever, arthritis, and kidney dysfunction.
                                                                    • In MS, T cells reactive against myelin infiltrate the central nervous system and destroy the myelin sheath that surrounds some neurons.
                                                                    • People with MS experience a number of serious neurological abnormalities.
                                                                    • It was thought that people with autoimmune diseases had self-reactive lymphocytes that escaped elimination during their development.
                                                                    • We now know that healthy people also have lymphocytes with the capacity to react against self, but these cells are inhibited from inducing an autoimmune reaction by several regulatory mechanisms.
                                                                    • Autoimmune disease likely arises from some failure in immune regulation, perhaps linked with particular MHC alleles.
                                                                    • For individuals with this disease, long-term survival requires a bone marrow transplant that will continue to supply functional lymphocytes.
                                                                    • Several gene therapy approaches are in clinical trials to attempt to reverse SCID.
                                                                    • Recent successes include a child with SCID who received gene therapy in 2002 when she was 2 years old. In 2004, her T cells and B cells were still functioning normally.
                                                                    • For example, certain cancers suppress the immune system. An example is Hodgkin’s disease, which damages the lymphatic system.
                                                                    • For example, hormones secreted by the adrenal glands during stress affect the number of white blood cells and may suppress the immune system in other ways.
                                                                    • Similarly, some neurotransmitters secreted when we are relaxed and happy may enhance immunity.
                                                                    • Physiological evidence also points to an immune system–nervous system link based on the presence of neurotransmitter receptors on the surfaces of lymphocytes and a network of nerve fibers that penetrates deep into the thymus.

                                                                    AIDS is an immunodeficiency disease caused by a virus.

                                                                    • In 1981, increased rates of two rare diseases, Kaposi’s sarcoma, a cancer of the skin and blood vessels, and pneumonia caused by the protozoan Pneumocystis carinii, were the first signals to the medical community of a new threat to humans, later known as acquired immunodeficiency syndrome, or AIDS.
                                                                      • Both conditions were previously known to occur mainly in severely immunosuppressed individuals.
                                                                      • People with AIDS are susceptible to opportunistic diseases.
                                                                      • Because AIDS arises from the loss of helper T cells, both humoral and cell-mediated immune responses are impaired.
                                                                      • The main receptor for HIV on helper T cells is the cell’s CD4 molecule.
                                                                      • In addition to CD4, HIV requires a second cell-surface protein, a coreceptor.
                                                                      • However, these drugs are very expensive and not available to all infected people, especially in developing countries.
                                                                      • In addition, the mutational changes that occur with each round of virus reproduction can generate drug-resistant strains of HIV.
                                                                      • Transmission of HIV requires the transfer of body fluids containing infected cells, such as semen or blood, from person to person.
                                                                      • In December 2003, the Joint UN Program on AIDS estimated that 40 million people worldwide are living with HIV/AIDS. The best approach for slowing the spread of HIV is to educate people about the practices that lead to transmission, such as using dirty needles or having unprotected intercourse.

                                                                      Lecture Outline for Campbell/Reece Biology, 7th Edition, © Pearson Education, Inc. 43-9


                                                                      Cell-Mediated Immunity

                                                                      Many states in the United States require that professors and teachers (among others) be checked periodically for tuberculosis. This chronic disease, caused by Mycobacterium tuberculosis, evokes an immune response that, unfortunately, does not cure the patient, but does provide an inexpensive test for the disease called the tuberculin test (or Mantoux test).

                                                                      A tiny amount of protein, extracted from the bacteria, is injected into the skin. If the subject is currently infected, or has ever been infected, with the bacteria, a positive test results. In 24 hours or so, a hard, red nodule develops at the site of the injection. This nodule is densely packed with lymphocytes and macrophages.

                                                                      (In Europe, most people produce a positive tuberculin reaction, not because they have had the infection, but because earlier they had been vaccinated against tuberculosis with a preparation of a related (but harmless) bacterium called BCG.)

                                                                      The response to tuberculin is called "delayed" because of the time it takes to occur (in contrast to the "immediate" responses characteristic of many antibody-mediated sensitivities like an allergic response to a bee sting).

                                                                      DTH is a cell-mediated response (in fact, anti-tuberculin antibodies are rarely found in tuberculin-positive people). The T cells responsible for DTH are members of the CD4 + subset.

                                                                      Contact Sensitivity

                                                                      Many people develop rashes on their skin following contact with certain chemicals. Nickel, certain dyes, and the active ingredient of the poison ivy plant are common examples.

                                                                      The response takes some 24 hours to occur, and like DTH, is triggered by CD4 + T cells.

                                                                      The actual antigen is probably created by the binding of the chemical to proteins in the skin. After the antigen is engulfed by dendritic cells in the skin, they migrate to nearby lymph nodes where they present fragments of the antigen to CD4 + T cells .

                                                                      The activated T cells migrate from the lymph nodes to the skin (link to a description of how they do this) to elicit the inflammatory response.

                                                                      Killing intracellular parasites

                                                                      Some human pathogens avoid exposure to antibodies by taking up residence within cells. These include all viruses (discussed in the next section), and some bacteria such as

                                                                      • the bacterium that causes Legionnaires's disease
                                                                      • Listeria monocytogenes, that humans sometimes acquire from contaminated food, and

                                                                      These microorganisms are engulfed by phagocytic cells, like macrophages, but evade the normal intracellular mechanisms that should destroy them.

                                                                      However, the macrophages can present fragments of antigens derived from these parasites. These are displayed in the class II histocompatibility molecules of the macrophages. CD4 + T cells responding to these epitopes release lymphokines that stimulate the macrophages sufficiently that they can now begin to destroy the organisms.

                                                                      Anti-Viral Immunity

                                                                      Any cell in the body is a potential target for one kind of virus or another. However, all cells express class I histocompatibility molecules at their surface. These can display antigenic fragments of viral components. CD8 + T cells that can bind to these epitopes can then destroy the cell (often before it can release a fresh crop of viruses to spread the infection).

                                                                      Graft Rejection

                                                                      Grafts of a kidney, heart, lung, liver, etc. from one human to another always (unless donated by an identical twin) are seen by the recipient's immune system as antigenic and elicit an immune response. If unchecked, this response will eventually lead to destruction of the graft. Both CD4 + and CD8 + T cells participate in graft rejection. They are responding to differences between donor and host of their class II and class I histocompatibility molecules (respectively).

                                                                      Nude mice are homozygous for a gene that is essential for the development of a thymus. Lacking a thymus they cannot produce T cells and hence are unable to reject grafts. Link to a view of nude mice carrying various skin grafts without rejecting them.

                                                                      Graft-versus-host disease

                                                                      Grafts of bone marrow are used to provide, or restore, a source of blood cells for the recipient.

                                                                      For example, a number of different cancers are treated so vigorously &mdash by radiation and cytotoxic chemicals &mdash that the patient's bone marrow is destroyed in the process. Grafts of bone marrow can restore the patient. Sometimes the patient's own bone marrow &mdash stored earlier and, if needed, treated to remove any cancer cells &mdash is used.

                                                                      Sometimes the marrow must come from another person. In this case, there is no danger of rejecting the graft because the recipient has no functioning immune system. However, if there are any histocompatibility differences between donor and recipient (and there always are some, unless the patient's own marrow is used or that of an identical twin), then the T cells of the donor will mount an immune response against the tissues of the recipient. Fortunately, graft-versus-host disease can usually be controlled with immunosuppressive drugs.


                                                                      Immune System Responses

                                                                      There are two systems of immunity in mammals, cell-mediated immune response and humoral immune response. Both use lymphocytes produced from stem cells in the bone marrow.

                                                                      – Humoral immune response

                                                                      • Uses B-lymphocytes produced in the bone marrow, where they also mature.
                                                                      • There are many different types of B-lymphocytes.
                                                                      • When an foreign antigen enters the blood it combines with a few B-lymphocytes which then divide rapidly through mitosis forming a clone of plasma cells. These then produce mainly antibodies but also memory cells. The memory cells can live for large periods of time, sometime even for life.

                                                                      – Cell-mediated immune response

                                                                      • Uses T-lymphocytes which are produced in the bone marrow and mature in the thymus gland.
                                                                      • Once matured T-lymphocytes circulate the body in the blood until it meets an antigen it has the receptor site for. It is then stimulated to divide by mitosis many times forming clones.
                                                                      • Three types of T-lymphocyte:
                                                                        • Killer cells – cause lysis of target cells, will destroy virus infected or cancer cells.
                                                                        • Helper cells – activate B-lymphocytes to produce antibodies.
                                                                        • Suppressor cells – turn off immune response, e.g. turning off antibody production.

                                                                        Content: Humoral Vs Cell-Mediated Immunity

                                                                        Comparison Chart

                                                                        Definition of Humoral Immunity

                                                                        Humoral immune response or antibody-mediated response is associated with the B cells, where the role of these cells (B cells) is to identify the antigens or any foreign particle that are present in the circulation in blood or lymph. This immune response is also assisted with helper T cells which along with the B cells get differentiated into plasma B cells that can produce antibodies.

                                                                        As soon as B cells produce antibodies, they will bind to an antigen neutralize them and causes phagocytosis or cell lysis (destruction of the cells). The antigen is the foreign particle, which is usually a carbohydrate or a protein that triggers an immune response, but above that our body has tremendous capability to identify the antigens.

                                                                        Any kind exposure of antigens leads to the development of secondary immunological response which increases the level of the immune response. The immunoglobulins or antibodies mediate the humoral immunity, these are a particular group of proteins produced by the B-lymphocytes.

                                                                        This following points can explain the eventual process:

                                                                        • Antigens triggers to the body.
                                                                        • Antigens bind to the B cells present in the blood circulation.
                                                                        • Helper T cells or Interleukins assist the B cells and initiate B cell proliferation which activates plasma B cells.
                                                                        • Plasma cells carry antibodies which are antigen-specific and has specific binding receptors of the activated B cells.
                                                                        • These antibodies travel throughout the body and bind to the antigens.
                                                                        • The B cells after destroying the antigens, produce memory cells which in turn provide future immunity when the same antigen triggers the body again.

                                                                        Definition of Cell-Mediated Immunity

                                                                        T lymphocytes assist the Cell-mediated immunity or cellular immunity. In this type, cytokines have released that help to activate the T cells which further destroys the infected cell. Likewise the B cells, T cells originate in bone marrow but matures in the thymus and later gets circulate in the bloodstream and lymphoid tissue.

                                                                        The antigen present on the surface of the antigen-presenting cells (APCs) with the abnormal Major Histocompatibility Complex (MHC) protein. Abnormal or aberrant MHC molecules are formed from the antigens which have been destroyed or broken down or from any infected virus (exogenous antigens) or the from tumour cells that are actively producing foreign proteins (endogenous antigens).

                                                                        Now helper T-cells release the cytokines, that will activate the T cells, which will recognize the aberrant MHC-antigen complex and will bind to it and differentiate into cytotoxic T cell. After this cell will undergo lysis (cell destruction).

                                                                        This following points can explain the eventual process:

                                                                        • Antigen-presenting cells (APCs) will display the antigens present on its surface and binds to T cells.
                                                                        • Interleukins (secreted by helper T cells) facilitates the activation of T cells.
                                                                        • Along with the MHC-I and the endogenous antigens, the T cells proliferate and produce the cytotoxic T cells.
                                                                        • The T cells destroy the infected cells exhibiting antigens.
                                                                        • In case of exogenous antigens and MHC-II displayed on the plasma membrane together, the T cells trigger to proliferate helper T cells which release interleukins and cytokines and also arouse the B cells to produce antibodies against them. This process is also supported by the natural killer cells (NK) and macrophages, which destroys the antigens.

                                                                        7 COMMENTS AND CONCLUSION

                                                                        Understanding penicillin hypersensitivity has proven to be extremely complex, involving both humoral and cellular immune components. Whilst testing for penicillin-specific IgE in patients is relatively straightforward evaluating if an individual might experience a T cell–mediated response is complicated and requires more detailed investigation. Although the dominant T-cell subsets in various penicillin-induced DHRs can be defined, the underlying causes of these reactions and the molecular targets are yet to be fully explained. Furthermore, not all of these reactions are persistent, and patients can be de-labelled as allergic to penicillin. 148 Hence, prediction of who may experience a penicillin-induced DHR, and if so, in what form, remains clinically obscure. As the formation of penicillin-haptenated proteins can occur either intracellularly or extracellularly, there is potential to invoke activation of different T-cell subsets that paint distinct clinical pictures. Whilst the breadth of potential haptenation sites in the human proteome may generate a diverse range of neopeptides enabling these reactions across HLA backgrounds. Thus, the question may be—“why don't more people experience these reactions?” Whether dampening of responses by regulatory T cells 40, 149 or biases towards particular TCR sequences 150, 151 shape reaction susceptibility, as suggested in adverse responses to other drugs, is worthy of further investigation. Understanding these factors and defining the precise targets of penicillin-responsive T cells represent the next hurdles to unravelling the mechanisms of these complex reactions.