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PERAN PSIKONEUROALERGOLOGI PADA DERMATOLOGI Dr. Dr. Cita

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PERAN PSIKONEUROALERGOLOGI PADA DERMATOLOGI Dr. Dr. Cita PERAN PSIKONEUROALERGOLOGI PADA DERMATOLOGI Dr. dr. Cita Rosita Sigit Prakoeswa, Sp.KK(K), FINSDV, FAADV Bagian Kulit dan Kelamin FK UNAIR/RSUD Dr Soetomo Surabaya Abstrak Psikoneuroimunologi adalah sebuah interdisiplin ilmu dengan fokus komunikasi biokimia antara otak, perilaku dan sistem imun. Psikoneuroalergologi merupakan turunan Psikoneuroimunologi yang lebih memfokuskan pada keterkaitan alergi imunologi dengan faktor psikososial. Peningkatan manifestasi alergi diduga berhubungan dengan faktor-faktor lingkungan seperti stres. Berbagai penelitian telah dilakukan dan terbukti adanya disfungsi hipotalamus- hipofisis-adrenal (HPA) dalam respon terhadap stres dapat memfasilitasi penyimpangan sistem imun dan dengan demikian, dapat meningkatkan risiko sensitisasi dan eksaserbasi alergi terutama dalam kondisi stres. Secara klinis dan fisiologis telah dapat dijelaskan mengenai stres psikologis yang merupakan kontributor penting pada perjalanan penyakit alergi melalui efeknya secara langsung maupun tidak langsung terhadap respon imun, ekspresi neuropeptide kulit, dan fungsi sawar kulit. Kata kunci: psikoneuroimunologi, psikoneuroalergologi, hipotalamus-hipofisis-adrenal Abstract Psychoneuroimmunology is an inter disiplinary field that specifically examines the biochemical cross talk between brain, behavior and the immune system. Psychoneuroallergology at the cross road between allergy immunology concept and psycosocial factors. The increase of allergic manifestation may be associated with environmental factors such as stress. A growing number of studies have suggested an altered Psychoneuroimmunology in Dermatology 1 hypothalamus-pituitary- adrenal (HPA) axis function to stress in allergy. It is speculated that a dysfunctional HPA axis in response to stress may facilitate and/or consolidate immunological aberrations and thus, may increase the risk for allergic sensitization and exacerbation especially under stressful conditions. It has been established via clinical and physiological means that psychological stress is a significant contributor to allergy course through its direct and indirect effects on immune response, cutaneous neuropeptide expression, and skin barrier function. Key words: psychoneuroimmunology, psychoneuroallergology, hypothalamus-pituitary-adrenal Pendahuluan Psikoneuroimunologi adalah sebuah interdisiplin ilmu dengan focus komunikasi biokimia antara otak, perilaku dan sistem imun.1 Psikoneuroalergologi merupakan turunan Psikoneuroimunologi yang lebih memfokuskan pada keterkaitan alergi imunologi dengan faktor psikososial. 2 Istilah 'Alergi' mengacu pada peningkatan kepekaan terhadap lingkungan seperti tungau debu, serbuk sari, bulu jamur atau makanan pada keluarga. Reaksi hipersensitivitas ditandai dengan produksi berlebihan imunoglobulin E (IgE). Gangguan alergi terutama mencakup dermatitis atopik (DA), asma alergi (AA), rhinitis alergi (RA) dan alergi gastrointestinal.3 Presentasi Alergen oleh sel dendritik mengawali respon late phase dengan mengaktifkan sel T-helper (Th) mensekresi interleukin (IL) -4, IL-5 dan IL-13 dalam jumlah tinggi, yang mencerminkan dominasi Th2 yang memiiki peran penting dalam kronisitas perjalanan peradangan alergi. IL-4 dan IL-13 menstimulasi sintesis IgE dan menginduksi switching sel B dari isotypes Ig lain menjadi IgE. Selanjutnya terjadi peningkatan ekspresi Vascular Cells Adhesion Molecule 1 Psychoneuroimmunology in Dermatology 2 (VCAM-1) dan terjadi perekrutan serta invasi eosinofil ke lokasi peradangan. IL-5 menginduksi eosinofil untuk mensekresikan Eosinophyl Cationic Protein (ECO) yang berkontribusi terhadap kerusakan sel. Peran penting disfungsi imunitas dalam patomekanisme penyakit alergi, termasuk DA telah dibuktikan pada berbagai studi, namun demikian banyak hal yang belum dapat dijelaskan.3,4 Salah satu hipotesis yang potensial untuk menjelaskan peningkatan prevalensi alergi terutama DA adalah peran berbagai faktor, antara lain gaya hidup, nutrisi, polusi maupun stress psikososial pada immunopatologi penyakit tersebut.3,4 Pada makalah ini dibahas peran psikoneuroalergologi pada patogenesis alergi, termasuk dampak potensial dari hiporesponsif maupun hiper responsif aksis HPA pada onset dan perjalanan kronis alergi pada bidang dermatologi, dalam hal ini Dermatitis Atopik menjadi salah satu contoh manifestasi alergi pada dermatoogi. Selain itu, juga dibahas berbagai faktor yang berkontribusi pada disfungsi aksis HPA pada alergi, serta terapi stres dengan target sistem neuroimun sebagai upaya penatalaksanaan alergi yang komprehensif. Disfungsi Aksis HPA – faktor penting pada alergi. Karakter atopik pada masa awal kehidupan berhubungan dengan hiper responsif (respon yang berlebihan) aksis HPA terhadap stress.5,6 Mekanisme terjadinya disfungsi aksis HPA pada bayi yang mengarah pada terjadinya alergi masih belum dapat dijelaskan, namun beberapa studi menunjukkan bahwa faktor genetik dan pembentukan saat fetus (fetal programming) berperan penting pada hal tersebut.7,8 Pada kondisi stress, peningkatan kortisol endogen pada anak dengan predisposisi yang mengarah ke respon imun Th-2, akan Psychoneuroimmunology in Dermatology 3 lebih meningkatkan resiko sensitisasi alergi dan onset terjadinya penyakit alergi. Kortisol yang menginduksi stimulasi IL-4 selanjutnya akan menginduksi produksi IgE dari sel B.9 Selama perjalanan penyakit, hiper responsif pada aksis HPA kemudian akan berubah menjadi hipo responsif. Berbagai faktor yang berpengaruh terhadap perubahan fungsi aksis HPA tersebut belum diketahui dengan pasti, namun diduga disregulasi tersebut dapat disebabkan oleh proses inflamasi kronis dengan sekresi. Gambar 1. Faktor stres dapat mempengaruhi regulasi imun pada perjalanan penyakit alergi melalui kondisi hiperresponsif maupun hiporesponsif aksis HPA. 4 sitokin proinflamasi yang terus-menerus atau stres kronik karena kondisi alergi dan juga adanya problem sosial. Pada kondisi alergi kronis pada anak, kegagalan peningkatan respon kortisol yang memadai pada kondisi stres, dimana hal ini seharusnya dibutuhkan dalam pengendalian respon inflamasi antara lain mengontrol sekresi sitokin proinflamasi, adhesi leukosit dan aktivasi eosinofil, justru meningkatkan resiko Psychoneuroimmunology in Dermatology 4 eksaserbasi dan kronisitas penyakit alergi (dengan faktor pencetus stres).4,5 Dengan demikian, alergi pada masa anak tampaknya dapat diinisiasi dan berlanjut karena adanya disfungsi aksis HPA. Selain hal tersebut, pada gambar 1 dapat dijelaskan bahwa hiper-reaktif maupun hipo reaktif aksis HPA dapat mengakibatkan terjadinya disregulasi imun yang dapat mengawali maupun mendorong terjadinya penyakit atopik, menunjukkan peran penting regulasi imun.4 Peran Stres dan Imunitas pada Patomekanisme dan Penatalaksanaan alergi Sistem saraf pusat (SSP) berespon terhadap stres psikologis, seperti dijelaskan pada gambar 2.1 Aksis HPA merespon stres psikologis melalui mekanisme sentral dengan meningkatkan hormon stres yaitu corticotropin-releasing hormone (CRH) dan adrenocorticotropic hormone (ACTH).10 Selanjutnya tejadi peningkatan Pituitary prolactine (PRL) yang dapat menggagalkan inhibisi terhadap proliferasi limfosit yang diinduksi oleh stres.11 CRH dan ACTH menstimulasi norepinephrine (NE) dan pelepasan kortisol dari korteks adrenal dan secara langsung menstimulasi berbagai sel imun di darah dan perifer melalui reseptor-reseptornya. Regulasi ini diperankan oleh kortisol melalui mekanisme negative feedback (tanda panah terputus) karena adanya pelepasan CRH dan ACTH oleh hipotalamus dan hipofisis (pituitary). Selanjutnya terjadi peningkatan pelepasan serotonin pada batang otak (5HT), maupun Substansi P (SP), gastrin-releasing peptide (GRP), dan calcitonin gene related peptide (CGRP) pada ganglia dorsalis.12,13,14 Pada kulit, sel imun melepaskan sitokin, kemokin, dan neuropeptida yang memodulasi inflamasi di kulit, nyeri, dan gatal, dan mentransmisi stimulus sensoris Psychoneuroimmunology in Dermatology 5 melalui ganglia dorsalis dan traktus spinalis pada area spesifik di SSP. Sel mast kutaneus berhubungan erat dengan SP, CGRP, pituitary adenylate cyclase activating protein (PACAP), dan opioid-releasing neurons, dan responsif tethadap berbagai neuromediator tersebut. Sel mas kutaneus mensistesis dan mensekresi berbagai mediator inflamasi akibat respon dari berbagai stimulus fisik maupun biokimia. Dengan demikian terjadilah produksi lokal neuro-hormon dan neuropeptida, dengan keluarnya SP dari serabut saraf pada kulit akibat respon terhadap stres.1 Gambar 2. Peran stres psikologis pada patomekanisme alergi. 1 Stres psikologis yang terus berlanjut dapat merusak fungsi permeabilitas sawar, dan menginduksi peningkatan glukokortikoid endogen, dimana hal ini dapat merubah homeostasis dan integritas permeabilitas, begitu juga yang terjadi pada pertahanan antimikrobial. Efek negatif ini sebagian besar terjadi akibat inhibisi sintesis lipid edidermal Psychoneuroimmunology in Dermatology 6 yang dimediasi glukokortikoid. Formulasi topikal lipid dapat menormalkan fungsi ini meskipun stres fisiologis terus berlangsung, sehingga terapi ini sungguh menjanjikan efektifitasnya pada pasien alergi dengan stres psikologis yang tinggi dan adanya disfungsi sawar. Namun demikian sampai saat ini belum ada publikasi tentang studi randomisasi dengan kontrol yang membandingkan respon klinis pasien alergi khususnya Dermatitis Atopik dengan stres vs tanpa stres dengan pemberian terapi topikal yang bertujuan memperbaiki integritas sawar. Pengetahuan mengenai perbedaan tersebut seharusnya dibutuhkan bagi klinisi, dalam
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