Mekanisme Imunologis di Mukosa Pernapasan Sebagai Respons Terhadap Polutan Udara

Mekanisme Imunologis di Mukosa Pernapasan Sebagai Respons Terhadap Polutan Udara

Audi Yudhasmara, Widodo judarwanto

Setiap hari manusia menghirup lebih dari 10.000 L udara yang mengandung berbagai polutan udara yang dapat menimbulkan konsekuensi negatif bagi kesehatan paru-paru. Mukosa pernapasan yang dibentuk oleh epitel saluran napas adalah titik kontak pertama untuk polusi udara di paru-paru, yang berfungsi sebagai penghalang mekanis dan imunologis. Dalam keadaan normal, sel-sel epitel saluran napas yang dihubungkan oleh persimpangan ketat mengeluarkan lendir, cairan pelapis permukaan jalan nafas, peptida pertahanan inang, dan antioksidan dan mengekspresikan reseptor pengenalan pola kekebalan tubuh bawaan untuk menanggapi zat asing yang masuk dan patogen.

 

Dalam kondisi paparan polusi udara, pertahanan epitel saluran napas terganggu oleh penurunan fungsi penghalang, gangguan pertahanan inang terhadap patogen, dan respon inflamasi yang berlebihan. Inti dari perubahan mekanis dan imunologis yang disebabkan oleh polusi udara adalah aktivasi jalur sensitif-redoks dan peran antioksidan dalam menormalkan efek negatif ini. Varian genetik pada gen yang penting dalam fungsi sel epitel dan fenotipe berkontribusi terhadap keragaman respons terhadap polusi udara dalam populasi pada tingkat individu dan kelompok dan menyarankan perlunya pendekatan yang dipersonalisasi untuk melemahkan respons imun mukosa pernapasan terhadap polusi udara.

Respons imun pernapasan terdiri dari beberapa tingkat respons seluler yang terlibat secara berurutan untuk mengendalikan infeksi. Keterlibatan bertahap fungsi efektor dengan biaya kebugaran inang yang meningkat secara progresif membatasi kerusakan jaringan. Selain itu, ada mekanisme spesifik untuk mempromosikan toleransi penyakit sebagai respons terhadap infeksi pernapasan. Faktor lingkungan, obesitas, dan proses penuaan dapat mengubah efisiensi dan pengaturan respons berjenjang ini, sehingga meningkatkan patologi dan mortalitas. Dalam Ulasan ini, kami menjelaskan jenis sel yang mengoordinasikan pembersihan patogen dan perbaikan jaringan melalui sekresi sitokin, dan membahas bagaimana lingkungan dan komorbiditas mempengaruhi respons ini.An external file that holds a picture, illustration, etc. Object name is nihms865888f1.jpg

Keterangan gambar: Keterlibatan bertahap dari respons berjenjang setelah infeksi pernapasan. Patogen dan senyawa berbahaya tertentu terdeteksi oleh sel-sel sensor yang terletak di dalam saluran pernapasan. Sel-sel sensor segera memulai respon imun bawaan yang mungkin cukup untuk membersihkan infeksi lokal. Sebagai contoh, sel-sel sensor dapat mengeluarkan faktor-faktor seperti interferon (IFNs) yang mengarah ke pembersihan patogen (izin pathogen langsung, panah atas). Dalam beberapa kasus, sitokin orde pertama secara langsung merekrut sel efektor yang membersihkan patogen; misalnya, CXCL8 memediasi perekrutan neutrofil untuk membersihkan bakteri (perekrutan dan / atau aktivasi efektor langsung, panah kedua dari atas). Selain itu, respons dua tingkat dapat digunakan, di mana sel-sel sensor mengeluarkan sitokin orde pertama yang bekerja pada populasi sel limfoid residen jaringan, yang mengintegrasikan sinyal-sinyal ini dan melepaskan sitokin orde dua yang sesuai. Sitokin-sitokin ini pada gilirannya merekrut dan mengaktifkan sel-sel efektor dan fungsi-fungsi efektor khusus untuk tipe patogen, yang berfungsi untuk mempromosikan pembersihan patogen dan perbaikan jaringan.

Saluran pernapasan melakukan fungsi penting pertukaran gas yang diperlukan untuk kehidupan. Sistem kekebalan yang beroperasi dalam saluran pernapasan harus kompatibel dengan fungsi vital ini dalam menjaga saluran udara terbuka setiap saat. Namun, udara yang dihirup tidak selalu berbahaya karena mengandung mikroba dan partikel lingkungan, beberapa di antaranya dapat menyebabkan penyakit pernapasan jika mencapai ceruk yang sesuai. Inhalansia ini perlu dihilangkan dengan cepat oleh sistem kekebalan tubuh karena kegagalan untuk melakukannya dapat menyebabkan respons peradangan yang mengakibatkan pembengkakan yang menutup saluran udara atau infeksi yang dapat menyebabkan pneumonia berat.

Untuk melakukan penahanan patogen, respons imun dalam saluran pernapasan mengikuti program keteraturan, bertahap dari berbagai tingkat pertahanan1. Sel-sel sensor lokal pertama kali mendeteksi mikroorganisme penyerang. Peristiwa deteksi ini dapat memicu respons pertahanan sel-intrinsik yang mengandung patogen, menyebabkan sekresi kemoatraktan untuk merekrut sel-sel responden cepat seperti neutrofil, dan mengingatkan sel-sel limfoid residen paru-paru melalui sekresi sitokin urutan pertama (Gambar 1). Limfosit residen jaringan yang merespons sitokin orde pertama meliputi sel limfoid bawaan (ILC), limfosit mirip bawaan, sel pembunuh alami (NK) dan sel T (TRM) memori residen jaringan. Limfosit ini, pada gilirannya, mengubah sinyal sitokin orde pertama menjadi sitokin orde dua yang merekrut dan meningkatkan aktivasi sel efektor yang dapat menghilangkan patogen atau mengeluarkan partikel asing. Pada setiap tahap proses, mekanisme efektor juga diaktifkan yang berpotensi dapat mengendalikan infeksi dan dengan demikian mencegah aktivasi respon imun berikutnya, membatasi kerusakan inflamasi. Dengan demikian, program pertahanan kekebalan bertahap ini memastikan bahwa respons minimum yang diperlukan terhadap mikroba terlibat. Sementara sensor spesifik dan mekanisme efektor berbeda-beda, respons inti berjenjang ini berlaku untuk respons imun tipe 1 dan respons imun tipe 2 karena mewakili pola regulasi imun yang muncul yang umum untuk berbagai patogen.

Berbagai pengaruh internal dan eksternal mengubah aktivasi atau regulasi tingkatan ini, seringkali dengan konsekuensi patologis. Secara khusus, faktor lingkungan eksternal, termasuk suhu dan polutan, dapat mengubah kemanjuran respon antimikroba, seperti halnya faktor internal seperti penyakit paru-paru, penuaan dan obesitas. Memang, orang-orang di ujung ekstrem dari spektrum usia serta orang gemuk lebih rentan terhadap infeksi pernapasan2,3, dan memahami bagaimana kondisi ini mengubah fungsi imunologis sangat penting untuk desain terapi yang meningkatkan hasil klinis pada populasi berisiko ini. .

Sensor yang berbeda dan mekanisme efektor dari respon seluler yang bertanggung jawab atas pertahanan host antimikroba dalam saluran udara dan paru yang melakukan segera setelah infeksi mikroba. Kami telah membagi diskusi kami tentang respon imun tipe 1 dan tipe 2 untuk mengeksplorasi fitur-fitur yang sama dari paradigma respon imun ini. Sementara respons imun pernapasan sering berujung pada priming respons imun adaptif, kami tunduk pada ulasan lain pada topik ini4,5 dan sebaliknya kami fokus pada respon bawaan awal yang terjadi dalam beberapa menit hingga beberapa jam dari tantangan pernapasan. Respons ini dimediasi oleh berbagai jenis sel dan sitokin, bagaimana faktor internal dan eksternal mengganggu sifat respons ini, dan bagaimana timbulnya patologi.

Mekanisme pertahanan khusus tersedia untuk melindungi sistem pernapasan terhadap infeksi sambil meminimalkan kerusakan jaringan. Patogen yang berhasil menembus lapisan lendir dan memasuki AEC memicu pertahanan intrinsik sel dan pelepasan sitokin orde pertama yang menginformasikan limfosit resident jaringan. Selain itu, makrofag residen, sel DC dan mast berfungsi sebagai sensor utama patogen yang masuk yang menembus penghalang epitel. Berbagai limfosit bawaan dan memori yang menetap di jaringan menafsirkan kombinasi sitokin orde pertama untuk menghasilkan sitokin orde kedua yang pada gilirannya bertindak pada sel efektor untuk menghilangkan patogen dan zat berbahaya. Sementara respons ini dioptimalkan untuk pertahanan kekebalan di paru-paru, berbagai faktor eksternal dan internal, termasuk suhu sekitar, polutan, penuaan, dan obesitas dapat mengubah efisiensi yang digunakan tingkat pertahanan. Selain itu, sifat sistem imun pernapasan yang sangat teratur mungkin kondusif untuk metastasis dan pertumbuhan tumor (Kotak 3).

Respons imun dini di paru-paru masih dipenuhi dengan banyak pertanyaan yang tidak terjawab. Misalnya, apa jalur molekuler yang menegakkan toleransi penyakit? Bisakah kita meningkatkan pengetahuan seperti itu untuk terapi pengobatan penyakit radang akut dan kronis? Bidang lain yang menarik adalah untuk menentukan konsekuensi fungsional dari pemicu sel iNKT atau sel TRM dengan sitokin versus antigen spesifik. Selain besarnya respon, apakah ada hasil imunologis yang berbeda secara mendasar dari stimulasi limfosit ini dengan sitokin orde pertama dibandingkan antigen? Bidang penelitian lebih lanjut mungkin menyelidiki apakah paparan sebelumnya terhadap patogen yang diberikan atau alergen menentukan tanggapan di masa depan terhadap antigen yang tidak terkait. Misalnya, apakah pajanan terhadap virus X membentuk komposisi sel limfoid residen jaringan yang berbeda, dan jika demikian, apakah tantangan selanjutnya oleh alergen atau bakteri menginduksi hasil yang berbeda? Bisakah ini menjelaskan kerentanan individu terhadap koinfeksi atau asma?

Faktor penuaan dan obesitas meningkatkan kerentanan manusia terhadap berbagai infeksi saluran napas, baik dengan merusak mekanisme resistensi inang dan / atau dengan merusak toleransi penyakit. Upaya mengurangi peradangan patologis pada populasi ini dapat memberikan cara alternatif untuk membatasi morbiditas dan mortalitas dari penyakit menular. Dengan demikian, memahami bagaimana keterlibatan respons imun berjenjang berintegrasi dengan mekanisme toleransi penyakit, dan bagaimana penuaan dan obesitas mengubah struktur berjenjang yang mendasarinya, akan menawarkan wawasan lebih lanjut untuk pengobatan penyakit pernapasan yang lebih baik.

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