Immunodefisiensi
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Immunodefisiensi

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    Immunodefisiensi Immunodefisiensi Presentation Transcript

    • Immunodefisiensi (HIV sebagai Role Model) Ricky Herlianto Jopi Chandra Sindhutomo Jason Julianus Alfredo Bambang (2012-060-152) (2012-060-153) (2012-060-172) (2012-060-193)
    • Definisi • Penyakit immunodefisiensi didefinisikan sebagai kegagalan, kerusakan atau kemunduran fungsi dari satu atau lebih komponen dalam sistem imun yang pada akhirnya dapat menyebabkan penyakit atau kelainan yang serius
    • Jenis Immunodefisiensi     Secara umum terdapat 2 jenis immunodefisiensi immunodefisiensi primer (congenital) Immunodefisiensi sekunder (didapat / acquired) Immunodefisiensi baik primer maupun sekunder dapat meningkatkan kerentanan terhadap infeksi, terkena kanker dan juga dapat mencetuskan penyakit autoimun.
    • Immunodefisiensi Primer   Penyakit immunodefisiensi primer disebabkan karena adanya kelainan genetik Ada berbagai jenis kelainan immunodefisiensi primer, contohnya  kelainan pada sistem imun innate  defisiensi antibody  defisiensi sel T
    • Terapi    Transplantasi antibody, sumsum tulang atau stem cell enzyme replacement. Saat ini juga berkembang gene therapy dengan menggunakan virus yang telah dimodifikasi.(1)(5)
    • Immunodefisiensi Sekunder
    • HIV/AIDS
    • Pendahuluan   HIV termasuk dalam keluarga lentivirus, dan merupakan suatu retrovirus.(2) Salah satu karakteristik unik dari lentivirus adalah kemampuannya untuk menyebabkan efek sitopatik dalam jangka pendek, dan infeksi yang latent dalam jangka panjang
    • Pendahuluan   Terdapat dua tipe virus HIV, yaitu HIV-1 dan HIV-2. HIV-1 paling banyak menyebabkan AIDS. HIV-2 menyebabkan AIDS yang progresinya lebih lambat.(1)
    • Pendahuluan   Menurut penelitian, HIV-1 kemungkinan berasal dari virus yang menyerang simpanse (Pantroglodytes), yang banyak terdapat di Afrika Pusat. Di sisi lain, HIV-2, dengan gen 40-60% homolog dengan HIV-1, datang dari sooty mangabey (Cercocebus atys), yang banyak terdapat di Africa Barat dari Senegal sampai Pantai Gading
    • Filogenetik HIV
    • A phylogenetic tree based on the complete genomes of primate immunodeficiency viruses. The scale (0.10) indicates a 10% difference at the nucleotide level.
    • Epidemiologi HIV
    • Struktur HIV
    • Genom HIV
    • Mekanisme Masuknya HIV dan Siklus Kehidupan HIV
    • Tahapan Infeksi HIV
    • Infeksi HIV   Infeksi HIV dibagi menjadi tiga fase, yaitu infeksi awal atau akut  Pada infeksi akut, infeksi terjadi di jaringan mukosa, yang merupakan reservoir untuk sel T dan tempat dimana sebagian besar sel T memori berdiam. Dalam 2 minggu, jumlah sel T CD4 berkurang drastis.(1)(5)   transisi dari infeksi akut ke infeksi kronis infeksi lanjutan atau kronis
    • Fase Transisi    Fase transisi dimulai dengan sel dendritik yang memfagosit virus dan membawanya ke nodus limfatikus. Di nodus limfatikus, sel dendritik mentransfer virus HIV kepada sel T CD4. Fase transisi diakhiri dengan bekerjanya sistem imun humoral dan selular, yang menyebabkan jumlah virus di plasma berkurang dalam waktu 12 minggu menjadi jauh lebih rendah (berakhirnya viremia). Selama fase transisi, ada kemungkinan terjadi peningkatan jumlah sel T CD4 karena diferensiasi dari progenitor.(1)
    • Fase Infeksi Kronis dan Clinical Latency   Pada fase infeksi kronis, penderita asimptomatik atau hanya mendapat gejala ringan. Hal ini karena jumlah virus HIV di plasma menurun secara drastis Fase clinical latency dapat berlangsung selama bertahun-tahun. Dengan berjalannya waktu, penderita juga akan menjadi lebih mudah terinfeksi penyakit karena berkurangnya sel T CD4 secara bertahap
    • Pathogenesis HIV
    • Untuk lebih jelasnya, gambarnya dapat dilihat di file pdf asli poster nature reviews immunology *dilampirkan pada slide paling akhir (slide versi PDF)
    • Awal  Infeksi HIV dimulai dari penerobosan virus melewati sawar mukosa (mucosal barrier)  melewati celah antar sel  melalui mikroabrasi atau sobekan pada epitel  mekanisme transcytosis  Sel dendritik juga memegang peranan penting dalam penerobosan virus melewati sawar mukosa
    • Infeksi Makrofag    Selain sel T CD4, terdapat juga sel-sel lain yang juga diinfeksi oleh virus HIV seperti makrofag, sel dendritik, dan sel folikular dendritik Makrofag memiliki kadar CD4 yang rendah, tetapi memiliki banyak proteoglikan heparan sulfat yang disebut syndecan pada permukaannya Syndecan juga dapat memediasi absorpsi virus HIV dengan menempel ke gp120
    • Infeksi sel Dendritic   Sel dendritik memiliki kadar CD4, CXCR4, dan CCR5 yang lebih rendah dari sel T CD4, sehingga tidak terlalu rentan terhadap virus HIV sel dendritik memiliki DC-SIGN pada permukaannya yang berfungsi untuk mengagregasikan virus pada permukaan, sehingga saat berkontak dengan sel T CD4, virus HIV dapat dengan mudah berpindah
    • • Sel dendritik bertanggungjawab untuk menginisiasi respon imun adaptif terhadap virus di nodus limfatikus. Lebih jauh lagi, sel dendritik dapat mengaktifasi sel NK dengan sekresi IL-12, IL-15 dan IL-18. • Sel dendritik memiliki SAMHD1 dan APOBEC3G yang dapat menginhibisi replikasi virus HIV, tetapi interaksi dari capsid HIV dengan cyclophilin (CYPA) di sel dendritik dapat menginduksi terbentuknya interferon tipe 1 yang bersifat antiviral melalui cryptic cytoplasmic sensor
    • Sel T   + CD4 sebagai reservoir virus infeksi dapat menyebabkan sel T CD4 menjadi berhenti berproliferasi dan tidak aktif. Dalam kondisi seperti itu, sel T CD4 disebut sebagai latent reservoir, dan memiliki masa hidup yang sangat panjang, dengan waktu paruh 44 bulan, bahkan setelah 7 tahun penderita menjalani supresi replikasi virus.(8)
    • Transmisi Virus HIV    Transmisi HIV dapat melalui berbagai cara. Cara yang paling umum adalah melalui kontak seksual, baik pada lawan jenis ataupun sesama jenis. HIV pada anak-anak paling banyak ditransfer dari ibunya, baik saat didalam rahim, saat melahirkan, ataupun saat menyusui anaknya. Metode lain yang juga sering terjadi adalah pemakaian jarum suntik secara bersama-sama. (1)
    • Terapi
    • • • • • • • • • • REFERENSI Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular immunology. 7th 1. Edition. United States of America: Elsevier; 2012. 2. Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Localzo J. Harrison’s Principles of Internal Medicine. 18th edition. New York: McGrawHill; 2012. 3. Arason G, Jorgensen G, Ludviksson B. Primary Immunodeficiency and Autoimmunity: Lessons From Human Diseases. Scand J Immunol. 2010;71:317–28. 4. Ballow M. Primary immunodeficiency disorders: Antibody deficiency. J Allergy Clin Immunol. 2002 Apr;109(4):581–91. 5. Rich RR, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM. Clinical Immunology Principles and Practice. 3rd edition. China: Elsevier; 2008. 6. Bhardwaj N, Hladik F, Moir S. The immune response to HIV. 2012 [cited 2013 Sep 2]; Available from: http://web2.mendelu.cz/af_239_nanotech/data/up/mats/nri1201_hiv_references. pdf 7. Levy JA. HIV pathogenesis: 25 years of progress and persistent challenges: AIDS. 2009 Jan;23(2):147–60. 8. Stebbing J, Gazzard B, Douek DC. Where Does HIV Live? N Engl J Med. 2004;350(18):1872–80. 9. http://www.nature.com/nri/posters/hiv
    • Thank You For Your Attention
    • Supplement to Nature Publishing Group The immune response to HIV Nina Bhardwaj, Florian Hladik and Susan Moir Since HIV was discovered as the causative agent of AIDS almost 30 years ago, HIV infection has become a devastating pandemic, with millions of individuals becoming infected and dying from HIV-related disease every year. A global research effort over the past three decades has discovered more about HIV than perhaps any other pathogen. Immunologists continue to be intrigued by the capacity of HIV to effectively knock out an essential component of the IMMUNOLOGY Breaching the mucosal barrier Donor virus population Stratified squamous epithelium Vagina or ectocervix Inserted HIV genome Endocervix HIV virion Infected intraepithelial CD4+ T cell Impermeable tight junctions between cells CD1a+ Langerhans cell Langerin Advanced disease HIV penetration and infection A few hours Increased number of immature transitional B cells CCR5 HIV uptake by DC-SIGN blocks DC maturation APOBEC3G Conventional DC Lack of effective antiviral immunity CD8+ T cell response 1 week NK cell Type I IFNs NK cell activation Draining lymphatic vessels Early infection CD8 T cell + HIV-specific B cell and antibody response TCR MHC class I Follicular B cell Clonal expansion of HIV-specific CD8+ T cells IL-10 HIV-bearing DC TReg cell Activated mature B cell Increased B cell apoptosis and GC destruction Inadequate CD4+ T cell help Exhausted memory B cell Increased in association with HIV viraemia Follicular DC Decreased number of resting memory B cells and splenic marginal zone B cells Inadequate CD4+ T cell help T cell zone Medulla Follicular hyperplasia Short-lived plasmablast B cell follicle Decreased class-switch recombination (Nef-mediated) Paucity of HIVspecific IgA at mucosal sites Increased turnover and polyclonal activation of B cells TFH cell MHC class II Naive mature B cell Immune activation (pro-inflammatory cytokines) Subcapsular sinus macrophage CD4+ T cell CTLA4 Infected memory T cell HIV virions and HIV-bearing cells CD8 T cell Inhibition of viral replication Decreased response to antigens Amplification in draining lymph nodes + IL-12, IL-15, IL-18 pDC CD4+ HIV-bearing stromal DC TRIM5 CYPA Chronic infection Local amplification of initial founder virus(es) in a single focus of CD4+ T cells Internalized virion DC dysfunction SAMHD1 Type I IFNs IL-7 T cell-attracting chemokines DC-SIGN CD4 IL-10 CD4+ T cell lymphopenia Transcytosis of HIV virions Infected CD4+ T cell Subepithelial DC Stroma CYPA and TRIM5 recognize HIV capsid The B cell response to HIV Tear in the mucosal epithelium Monocyte SAMHD1 and APOBEC3G restrict HIV replication Columnar epithelium CD1a The DC response to HIV HIV uptake by langerin leads to virus degradation Scientists Helping Scientists™ | WWW.STEMCELL.COM HIV-infected donor cell Lack of tight junctions between cells Mucus layer adaptive immune system — CD4+ T helper cells. This Poster summarizes how HIV establishes infection at mucosal surfaces, the ensuing immune response to the virus involving DCs, B cells and T cells, and how HIV subverts this response to establish a chronic infection. Based on a clearer understanding of HIV infection and the response to it, the field has now entered an era of renewed optimism for the development of a successful vaccine. Decreased natural immunity to secondary pathogens Hypergammaglobulinaemia Poor antibody response CD4 IDO Viral RNA pDC Systemic infection 2–4 weeks TRAIL TLR7 IFN-induced T cell apoptosis Few high-affinity broadly neutralizing antibodies Efferent lymphatic TReg cell differentiation promoted by IDO HIV reservoirs in gutassociated and other lymphoid tissues Weeks Months gp120 gp41 Years gp41 gp120 Several years gp120 CD4binding site The T cell response to HIV T cell-attracting chemokines Galectin 9 TRAIL-induced T cell apoptosis TReg cell • Non-neutralizing • Lack of viral control Suppression + TIM3 of CD8 T cell response • Neutralizing, but limited breadth • Virus acquires escape mutations • Neutralizing with wider breadth • ~20% of infected individuals • Affinity matured, broadly neutralizing • ~1% of infected individuals HIV-specific CD8+ T cell Cytokines and other soluble factors Chemokine-mediated recruitment of new CD4+ T cells for HIV to infect TCR MHC class I Viral replication Several months T cell-escape mutations in HIV • First Env and Nef • Later Gag and Pol Viral spread Broadly neutralizing HIV-specific antibodies • ↓ MHC class I binding • ↓ TCR recognition • ↓ Epitope processing Several years Cell Isolation Solutions for HIV Research From STEMCELL Technologies STEMCELL Technologies offers a complete portfolio of fast and easy cell isolation solutions for HIV research, allowing viable, functional cells to be isolated from virtually any sample source for use in cell-based models and assays. STEMCELL Technologies’ products are used by leading HIV research groups worldwide, including the National Institute of Allergy and Infectious Disease and the Ragon Institute. • EasySep™ (www.EasySep.com) is a fast, easy and column-free immunomagnetic cell separation system for isolating highly purified immune cells in as little as 25 minutes. Cells are immediately ready for downstream functional assays. Name of antibody 2G12 Perforin and granzymes Perforin pore Apoptosis LAG3 TIM3 CTLA4 HIV-infected CD4+ T cell CD4+ T cell depletion and immunodeficiency PD1 Decreased T helper cell function CD8+ T cell response insufficient to clear infection • Chronic infection • Repeated T cell activation Upregulation of inhibitory receptors on CD8+ T cells • RoboSep™ (www.RoboSep.com) fully automates the immunomagnetic cell isolation process, reducing hands-on time, minimizing human exposure to potentially hazardous samples and eliminating crosscontamination, making it the method of choice for HIV research labs. • RosetteSep™ (www.RosetteSep.com) is a unique immunodensitybased cell isolation system for one-step enrichment of untouched human cells directly from whole blood during density gradient centrifugation. • SepMate™ (www.SepMate.com) allows hassle-free PBMC isolation in just 15 minutes. The SepMate™-50 tube contains a unique insert that prevents mixing between the blood and density medium, allowing all density gradient centrifugation steps to be carried out quickly and consistently. To learn more about our specialized cell isolation products for HIV research, or to request a sample or demonstration, visit www.stemcell.com/HIV. T cell exhaustion (loss of effector function and proliferative capacity) Source or approach B cell immortalization Phage-display library Target on HIV Properties Carbohydrates on gp120 CD4-binding site of gp120 Unique heavy-chain domain swap IgG1 b12 Long heavy-chain CDR3; heavy-chaindominant binding 2F5 and B cell Membrane-proximal Autoreactive; bind host 4E10 immortalization external region of gp41 lipids PG9 and Large screen; gp120 conformational Dependent on PG16 cultured clone epitope in variable quaternary structure; loops (V1–V2) long heavy-chain CDR3 VRC01 and Large screen; CD4-binding site of Highly mutated; mimic NIH45-46 single-cell sort gp120 CD4 binding to gp120 PGT121 Large screen; gp120 V3 Diverse, with and cultured clone carbohydratesimilarities to 2G12 PGT125 dependent epitope 10E8 Large screen; Membrane-proximal Binds cell-surface cultured clone external region of gp41 epitopes Abbreviations Affiliations APOBEC3G, apolipoprotein B mRNA editing, catalytic polypeptide-like 3G; CCR5, CC-chemokine receptor 5; CDR3, complementarity-determining region 3; CTLA4, cytotoxic T lymphocyte antigen 4; CYPA, cyclophilin A; DC, dendritic cell; DC-SIGN, DC-specific ICAM3-grabbing nonintegrin; GC, germinal centre; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IL, interleukin; LAG3, lymphocyte activation gene 3; NK, natural killer; PD1, programmed cell death protein 1; PDC, plasmacytoid DC; SAMHD1, SAM domain- and HD domain-containing protein 1; TCR, T cell receptor; TFH cell, T follicular helper cell; TIM3, T cell immunoglobulin domain- and mucin domain-containing protein 3; TLR7, Toll-like receptor 7; TRAIL, TNF-related apoptosis-inducing ligand; TReg cell, regulatory T cell; TRIM5, tripartite motif-containing protein 5. Nina Bhardwaj is at the NYU Langone Medical Center, Smilow Research Building, New York 10016, USA. e-mail: Nina.Bhardwaj@nyumc.org Acknowledgements N.B. thanks D. Frleta for his review and contributions to the poster. © 2012 Macmillan Publishers Limited. All rights reserved Florian Hladik is at the Department of OBGYN, University of Washington, Seattle, Washington 98195, USA. e-mail: fhladik@fhcrc.org Susan Moir is at the Laboratory of Immunoregulation, NIAID/NIH, Bethesda, Maryland 20892, USA. e-mail: smoir@niaid.nih.gov The authors declare no competing financial interests. Edited by Kirsty Minton; copyedited by Isabel Woodman; designed by Simon Bradbrook. © 2012 Nature Publishing Group. All rights reserved. http://www.nature.com/nri/posters/hiv Supplementary text and further reading available online.