Student Guidance 2012

STUDENT GUIDANCE

IMMUNE RESPONSE SEMESTER II Academic Year 2011/2012

MEDICAL FACULTY BRAWIJAYA UNIVERSITY 2012

BLOCK 3: IMMUNE RESPONSE MODULE Semester 2, Academic Year 2011/2012 1. Overview Immune response module will be held in second semester within 5 days. It consist of principal of innate immunity and adaptive immunity, and overview of abnormality of immune responses and the diseases. This block will use expert lecture, tutorial, discussion and seminar as a learning method. For evaluations we use: scoring of discussion activities, scoring of modul tasks and multiple choice question in the Block Examination. 2. Learning Objectives Upon completion of this module, the student will be able to : a. explain about principal of Innate Immunity and adaptive immunity b. explain about antigen recognition, processing and presentation c. explain about maturation, activation and regulation of T and B lymphocytes d. explain about effector mechanism of humoral and cellular Immunity e. explain about immune respons in some kinds of diseases: hypersensitivity, autoimmunity, immune deficiency, and cancer immunology. f. explain about immunity to cancer, transplantation immunology and vaccination. 3.Modules PART ONE: BASIC CONCEPTS IN IMMUNOLOGY Submodul 1. Overview in immunology a. Function of Immune response b. Principals of innate immunity and adaptive immunity c. Cells and organ of system immun Submodul 2. Innate Immunity and Complement a. Recognition of microbes by the innate immune system b. Components of innate immunity: epithelial barriers, phagocytes, NK cells c. Role of innate immunity in stimulating adaptive immune responses d. The Complement system Submodul 3. Antigen Recognition and Presentation in adaptive immunity a. Antigen capture, processing and presentation b. MHC types and function c. T cell receptor and immunoglobulin Submodul 4. Maturation and activation of Lymphocytes & a. Maturation and activation of T Lymphocytes b. Maturation and activation of B Lymphocytes Submodul 5. Effector Mechanism of cell mediated immunity a. Types of Cell-Mediated Immunity b. The effector functions of CD4+ and CD8+ T lymphocytes c. How do effector T cells eradicate infections and resistance of pathogenic microbes. Submodul 6. Effector Mechanism of humoral immunity

PART TWO: IMMUNE SYSTEM AND DISEASES Submodul 7. Allergy/Hypersensitivity a. Immediate hypersensitivity b. Antibody mediated hypersensitivity c. Immune complex mediated hypersensitivity d. T cell mediated hypersensitivity Submodul 8.Immune deficiency a. General features of Immunodeficiency b. Congenital Immunodeficiency c. Acquired immunodeficiency and immune response against HIV Submodul 9. Tolerance & Autoimmmunity a. Types of Immune Tolerance b. Susceptible genes in autoimmunity c. Pathogenesis of Autoimmunity d. Autoimmune diseases Submodul 10.Immunity to cancer , vaccination & immune transplantation a. Immunity to cancers b. Vaccinations c. Immune transplantation 4. References: 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006 3. Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th ed. New York, Garland and Science; 2008

5. Lecturers/tutors of Immune Response Department Lecturer/Tutor

Code

1. DR.Dr. Endang Sri Wahyuni, MS

ESW

2. Dr. Sudjari DTM&H, Msi, SpParK 3. DR.Dr.LoekiEnggarfitri, MKes, SpParK 4. Agustina Tri Endarti, Ssi, PhD

SDR LK

5. Prof.DR.Dr. Edi Widjajanto, MS, SpPK 6. DR.Dr. KusworiniHandono, M.Kes 7. Dr. Maimun Zulhaidah, SpPK 8. Dr. Hani Susianti, SpPK

EW

9. Prof.DR.Dr.Sanarto Santoso, DTM&H, SpMK 10. Prof. DR.Dr. Soemarno, SpMK 11. Dr. Roekistiningsih, SpMK 12.DR.Dra. Sri Winarsih, Apt 13.Dr. Aulia, SpM

SN

Dept of Paediatric

14. DR. Dr. Wisnu Barlianto, SpA(K) 15. Dr. Irene Ratridewi, SpA 16. Dr. Diana Anggarani, SpA, MKes

WN IR DA

Dept of ENT-Head & Neck

17.Dr. Endang Retnoningsih, SpTHTKL (K) 18.Dr. Iriana Maharani, SpTHT-KL

ER

Dept of Pulmonology

19. Dr. Yani Jane Sugiri, SpP 20.Dr. Iin Nurchozin, SpP

YJS IN

Dept of Internal Medicine

21.Prof.DR.Dr.Handono Kalim, SpPDKR 22.Dr. B.P. Putra Suryana, SpPD-KR 23.Dr.Cesarius SinggihWahono, SpPD 24.Dr.Niniek Burhan, SpPD-KPTI 25.Dr.Didi Candradikusuma, SpPD

HK

26.Dr. TaufiqHidayat, SpKK (K) 27. Dr. ArifWidiatmoko, SpKK 28.Dr. HerwindaBrahmanti, SpKK

TH AW HD

Dept of Physiology Dept of Parasitology

Dept of Clinical Pathology

Dept of Microbiology

Dept of Dermatoveneorolo gy

AT

KR MZ HN

SM RK SW AU

IM

PS CSW NB DC

Time Schedule Time

Wednesday 14-3-12

Thursday 15-3-12

Monday 19-3-12

Tuesday 20-3-12

Self Learning

Wednesday 21-3-11

07.00-08.00

Self Learning

Self Learning

Self Learning

Self Learning

08.00-10.00

LECTURE SubModul 1: Overview of Immune response

LECTURE SubModul 4: Maturation and activation of T & B Lymphocytes

LECTURE SubModul 6: Effector mechanism of humoral immunity & Cytokines

LECTURE SubModul 8: Immune deficiency

Lecturers: A : EW B : KR KBI: HK

Lecturers: A : ESW B : SDR KBI: SN

Lecturers: A : SN B : SM KBI: EW

Lecturers: A : WN B : PS KBI: CSW

Small group discussion SubModul 1& 2

Small group discussionSubM odul 3&4

Small group discussion SubModul 5&6

Small group discussionSubM odul 7&8

20 groups 20 tutors

20 groups 20 tutors

20 groups 20 tutors

20 groups 20tutors

10.00-12.00

Thursday 22-3-2012 Self Learning

12.00-13.00

Lunch Break

Lunch break

Lunch break

Lunch break

Lunch break & Friday praying

13.00-15.00

LECTURE SubModul 2: Innate Immunity & Complement

LECTURE SubModul 3: Antigen Recognition

LECTURE SubModul 5: Effector mechanism of cell mediated immunity

LECTURE SubModul 7: Allergy/Hypersen sitivity

LECTURE SubModul 9: Tolerance &Autoimmmunity

LECTURE SubModul 10: Immune response to tumors & Vaccination & Immune Transplantation

Lecturers: A : KR B : ESW KBI: SN

Lecturers A : KR B : SDR KBI: SM

Lecturers: A : ESW B : SDR KBI: SM

Lecturers: A : WN B : CSW KBI: HK

Lecturers: A: PS B: HK KBI: CSW

Lecturers: A: EW B: PS KBI: WN

15.00-16.00

Small group discussionSubM odul 7&8 20 groups 20tutors

Class A : R. Amphy FKUB, Class B : R. Biomedic, Class BI: R.4.05

SCHEDULE OF SMALL GROUP DISCUSSIONS Day/date

Group

Wednesday 14 March 2012 10.00 – 12.00 WIB

A1 A2 A3 A4 A5 A6 A7 B1 B2 B3 B4 B5 B6 B7 B8 BI 1 BI 2 BI 3 BI 4 BI 5 A1 A2 A3 A4 A5 A6 A7 B1 B2 B3 B4 B5 B6 B7 B8 BI 1 BI 2 BI 3 BI 4 BI 5 A1 A2 A3 A4 A5 A6 A7 B1 B2 B3 B4 B5 B6 B7 B8 BI 1

Monday 19 March 2012 10.00 – 12.00 WIB

Tuesday 20 March 2012 10.00 – 12.00 WIB

Room (GPPFKUB) R. 2.01 R. 2.02 R. 2.03 R. 2.04 R. 2.05 R. 2.06 R. 2.07 R. 3.01 R. 3.02 R. 3.03 R. 3.04 R. 3.05 R. 3.06 R. 3.07 R. 3.08 R. 3.09 R. 3.10 R. 3.11 R. 3.12 R. 3.13 R. 2.01 R. 2.02 R. 2.03 R. 2.04 R. 2.05 R. 2.06 R. 2.07 R. 3.01 R. 3.02 R. 3.03 R. 3.04 R. 3.05 R. 3.06 R. 3.07 R. 3.08 R. 3.09 R. 3.10 R. 3.11 R. 3.12 R. 3.13 R. 2.01 R. 2.02 R. 2.03 R. 2.04 R. 2.05 R. 2.06 R. 2.07 R. 3.01 R. 3.02 R. 3.03 R. 3.04 R. 3.05 R. 3.06 R. 3.07 R. 3.08 R. 3.09

Tutor MZ DA SW IM WN IN RK HD YJS CSW NB DC TH AW LK ESW AT PS SDR AU IR DA ER IN MZ DC LK HN ESW SDR WN AU AT HD YJS CSW RK PS TH AW HD YJS AU DA SDR NB IR DA IM IN MZ DC HN TH AW RK

Wednesday 21 March 2012 10.00 – 12.00 WIB

Thursday 22 March 2012 15.00 – 16.00 WIB

BI 2 BI 3 BI 4 BI 5 A1 A2 A3 A4 A5 A6 A7 B1 B2 B3 B4 B5 B6 B7 B8 BI 1 BI 2 BI 3 BI 4 BI 5 A1 A2 A3 A4 A5 A6 A7 B1 B2 B3 B4 B5 B6 B7 B8 BI 1 BI 2 BI 3 BI 4 BI 5

R. 3.10 R. 3.11 R. 3.12 R. 3.13 R. 2.01 R. 2.02 R. 2.03 R. 2.04 R. 2.05 R. 2.06 R. 2.07 R. 3.01 R. 3.02 R. 3.03 R. 3.04 R. 3.05 R. 3.06 R. 3.07 R. 3.08 R. 3.09 R. 3.10 R. 3.11 R. 3.12 R. 3.13 R. 2.01 R. 2.02 R. 2.03 R. 2.04 R. 2.05 R. 2.06 R. 2.07 R. 3.01 R. 3.02 R. 3.03 R. 3.04 R. 3.05 R. 3.06 R. 3.07 R. 3.08 R. 3.09 R. 3.10 R. 3.11 R. 3.12 R. 3.13

WN AT SW PS RK WN PS AU CSW AW IN IM SW AT SDR HN TH DA YJS NB MZ ESW DC HD PS RK WN AT ER HD DC NB IN AU TH AW IR ESW SW CSW SDR HN MZ YJS

PANDUAN UNTUK TUTORIAL Tutorial (small group discussions) akan diadakan selama 5 hari perkuliahan Respon Imun, mulai dari pukul 10.00 sampai 12.00 WIB, kecuali pada hari Kamis, 23 Maret 2012, tutorial dilakukan pada jam 15.00 – 16.00 WIB. Semua mahasiswa semester II akan dibagi menjadi 20 kelompok, dan tiap kelompok akan dibimbing oleh satu orang tutor. (Jadwal dan ruangan seperti tertera di atas).

Tugas Mahasiswa: - Membaca modul (student guidance) dan referensi sebelum jadwal tutorial - Mengerjakan modul tasks secara tertulis (tulisan tangan sendiri) sebelum tutorial dan ditulis di buku log masing-masing. - Berperan aktif selama diskusi berlangsung dan sesuai dengan topik yang dibicarakan. - Meminta tandatangan tutor untuk jawaban modul task masing-masing setiap sebelum mulai diskusi kepada tutor. - Setiap 1 kelompok diskusi, harus mengumpulkan 1 laporan diskusi, paling lambat 1 hari setelah diskusi topik. Dikumpulkan ke Pak Didik, di lantai 3 GPP FKUB. Tugas tutor: - Membaca teacher guidance - Absensi mahasiswa - Melakukan evaluasi untuk setiap mahasiswa dalam kelompok diskusi tersebut selama tutorial berjalan. - Mengingatkan waktu sesuai jadwal. - Memberikan arahan bila diskusi menyimpang. - Mengevaluasi dan menandatangani buku log mahasiswa. Panduan tutorial: - Mahasiswa dan tutor harus siap di ruangan masing-masing sesuai jadwal - Perkenalan diri tutor (bila dirasakan masih diperlukan) - Pemilihan ketua dan sekretaris untuk tiap topic yang dibahas - Diskusi dipimpin oleh ketua kelompok - Pencatatan hasil diskusi dan membuat oringkasan hasil diskusi oleh sekretaris

SubModul 1 INTRODUCTION TO THE IMMUNE SYSTEM Deskripsi Area Kompetensi

Area Kompetensi 3 dari Standart Kompetensi Dokter Indonesia Komponen Kompetensi Mengingat dan mengerti tipe respon imun, fase-fase respon imun, sel dan jaringan yang terlibat dalam sistem imun Kemampuan akhir yang 1. Mampu menyebutkan tipe respon imun diharapkan 2. Mampu menjelaskan perbedaan respon imun alami dan respon imun adaptif 3. Mampu menjelaskan fase respon imun adaptif humoral dan seluler 4. Mampu menyebutkan sel-sel dan jaringan yang terlibat dalam sistem imun Metoda pembelajaran 1. Belajar mandiri/tugas modul 2. Kuliah pakar 3. Diskusi kelompok Waktu Kuliah pakar 50 menit dan diskusi kelompok 50 menit Tutor 1. Prof, DR, Dr, Handono Kalim, SpPD-KR 2. Prof, DR. Dr. Edy Widjayanto, MS, SpPK(K) 3. DR.Dr. Kusworini Handono, Mkes, SpPK Evaluasi Penilaian aktivitas diskusi, penilaian tugas modul, Ujian tertulis (tes MCQ) Referensi Abbas AK dan Lichtman AH. Basic Immunology, 2 nd ed. Philadelphia, Saunders ; 2004

Overview Fungsi fisiologi sistem imun adalah melindungi individu terhadap infeksi. Imunitas alami merupakan pertahahan awal, diperantarai oleh sel dan molekul yang selalu ada dan siap mengeliminasi mikroba-mikroba infeksius yang masuk kedalam tubuh. Respon imun adaptif merupakan bentuk imunitas yang distimulasi oleh mikroba, mempunyai spesifitas terhadap substansi asing dan memberikan respon yang lebih efektif terhadap setiap paparan mikroba. Limfosit merupakan sel yang berperan dalam imunitas adaptif dan satu-satunya sel yang mempunyai reseptor yang didistribusikan secara clonal untuk mengenal antigen. Imunitas adaptif terdiri dari a) imunitas humoral, dimana antibodi yang disekresikan akan menetralkan dan membersihkan ekstraseluler mikroba dan toksin, dan b) imunitas yang diperantarai sel, dimana sel limfosit T akan mengeliminasi mikroba intraseluler. Respon imunitas adaptif terdiri dari serangkaian fase : pengenalan antigen, oleh limfosit, aktivasi limfosit untuk berproliferasi dan berdeferensiasi menjadi

sel efektor dan memori, eliminasi mikroba, penurunan respon imun dan terbentuknya sel memori dengan umur panjang Terdapat beberapa populasi limfosit yang berbeda fungsinya yang dapat diidentifikasi melalui ekspresi membrane molekulnya. Limfosit B merupakan sel yang memproduksi antibodi. Limfosit B mengekspresikan antibodi pada membran yang dapat mengenal antigen dan efektor sel B mensekresikan antibodi yang dapat menetralisasi dan mengeliminasi antigen. Limfosit T mengenal fragmen peptide antigen protein yang disajikan pada sel lain. Limfosit T helper akan mengaktifasi sel fagosit untuk merusak mikroba yang ditelannya dan mengaktifasi limfosit B untuk memproduksi antibodi. Limfosit T sitolitik membunuh sel yang terinfeksi mikroba didalam sitoplasma. Sel penyaji antigen (APC) akan menangkap setiap antigen mikroba yang masuk melalui epithelia, membawa antigen tersebut kedalam organ limfoid dan menyajikannya untuk dikenali oleh limfosit. Limfosit dan APC berkumpul di organ limfoid perifer, dimana respon imun diawali dan berkembang. Limfosit naïve bersirkulasi melalui organ limfoid perifer untuk mencari antigen asing. Limfosit T efektor akan bermigrasi ke tempat infeksi dimana mereka berfungsi mengeliminasi infeksi. Limfosit B efektor tetap berada di organ limfoid dan dalam sumsum tulang dimana mereka akan mensekresi antibodi yang akan masuk ke dalam sirkulasi dan akan mencari serta mengeliminasi mikroba. Modul tasks: 1. Describe the principal components of innate immunity 2. List the major characteristics of innate and adaptive immunity! 3. Describe the differences between humoral and cellular immunity! 4. Describe the fundamental properties of adaptive immune response! 5. Describe subpopulations of lymphocytes and their functions!

Direction : The module-tasks should be written, done by the student individually prior the small group discussion. To work with the module, the student may refer to the reference as mentioned above.

SubModule 2 INNATE (NON SPECIFIC) IMMUNITY & THE COMPLEMENT 2.1 INNATE (NON SPECIFIC) IMMUNITY Competency Area Competency component Objectives

Learning methodes Equipments Time Lecturer

Evaluation Refferences

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of Innate Immunity Upon completion of this submodul, student will be able to: 1. Differentiate between innate and adaptive immunity 2. Explain the role of the skin, mucous membranes and normal microbiota in innate immunity (first line of defense) 3. Describe the second line of defense Lecture, tutorial and discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1.5 hrs 1. Prof.Dr.dr. Sanarto Santoso, DTM&H, SpMK 2. DR.Dr. Endang Sri Wahyuni, MS 3. DR.Dr. Kusworini Handono, M.Kes, SpPK Activity in discussions, tasks modules, MCQ test 1. Abbas AK, Lichtman AH, Pillai S, 2007. Cellular and Molecular Immunology, 6th ed. Saunders, Elsevier. Philadelphia. 2. Tortora GJ, Funke BR, Case CL, 2007. Innate Immunity : Nonspecific Defenses of the Host, in Microbiology an Introduction, 9th ed. Pearson Benjamin Cummings, SanFransisco.

2.1 Overview: Innate (non specific) Immunity Our ability to ward off disease caused by microbes or their products and to protect against environmental agents such as pollen, drugs, foods, chemicals, and animal hair is called immunity, or resistance. Vulnerability or lack of immunity is referred to as susceptibility. In general there are two types of immunity : innate and adaptive. Innate (nonspesific) immunity refers to defenses that are present at birth. They are always present and available to provide rapid responses to protect us against disease. Innate immunity does not involve specific recognition of a microbe and acts

against all microbes in the same way. Further, innate immunity does not have a memory component – that is, it cannot recall previous contact with a foreign molecule. Among the components of innate immunity are the first line of defense (skin and mucous membranes) and the second line of defense (NK cells and phagocytes, inflammation, fever and antimicrobial substances) Adaptive (specific) immunity refers to defenses that involve specific recognition of microbe once it has breached the innate immunity defenses. Unlike innate immunity, adaptive immunity is slower to respond, but it does have a memory component. Adaptive immunity involve lymphocytes called T cells and B cells. It has recently been learned that the responses of the innate system are activated by protein receptors in the plasma membranes of defensive cells; these activators are called toll-like receptors (TLRs). Innate immune responses represent immunity’s early-warning system and are designed to prevent microbes from gaining access into the body and to help eliminate those that do gain access.

Module Tasks 01. Define the following terms : a. innate immunity b. adaptive immunity 02. Identify physical and chemical factors that prevent microbes from entering the body through : a. skin b. digestive tract 03. Describe the role of normal microbiota in innate immunity 04. Describe the process of phagocytosis, and include the stages of adherence and ingestion 05. Define inflammation, and list its characteristic 06. Why is inflammation beneficial to the body? 07. How is fever related to innate immunity?

2.1 THE COMPLEMENT Competency Area Competency component Objectives

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of Complements Upon completion of this submodul, student will be able to:

1. Describe the way of complement activation. 2. Describe about the function of complement. 3. Explain the relation between innate immune response and adaptive immune response through complement system. 4. To know the protection mechanism of host cells towards destroy effect of complement activation. Learning methodes Equipments Time Lecturer

Evaluation Refferences

Self learning, Expert Lecture, discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1.5 hrs 1. Prof.Dr.dr. Sanarto Santoso, DTM&H, SpMK 2. DR.Dr. Endang Sri Wahyuni, MS 3. DR.Dr. Kusworini Handono, M.Kes, SpPK Activity in discussions, tasks modules, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006 3. Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th ed. New York, Garland and Science; 2008

2.2OVERVIEW: THE COMPLEMENT Complement was discovered many years ago as a heat – labile component of normal plasma that augments the opsonization of bacteria by antibodies and allow some antibodies to kill bacteria. This activity was said to “complement” the antibacterial activity of antibody, hence the name is complement. Complement is the other major effector mechanisms of humoral immunity and also an important effector mechanism of innate immunity. Complement is a system of serum and cell surface proteins that interact with one another and with other molecules of the immune system to generate important effectors of innate and adaptive immune responses. The complement system is made up of a large number of distinct plasma protein; one is activated directly by antigen-bound antibody to trigger a cascade of

reactions, each of which results in the activation of another complement component. Some activated complement proteins bind covalently to bacteria, opsonizing them for engulfment by phagocytes bearing complement receptors. The classical, mannose binding lectin pathway and alternative pathway consist of proteolytic enzymes that generate inflammatory mediators and opsonins. Those pathways lead to the formation of a common terminal cell lytic complex that is inserted in cell membranes. The activated complement component may have the potential to destroy any cells to which they bind. Host cells are protected from such inadvertent damage by a series of complement – regulatory proteins. MODULE TASKS

1. List the differences between complement activation by classical pathways and alternative pathway. 2. Describe the function of complement according to microbial infection. 3. Why the host can be safe from complement activation effect?

SubModul 3 ANTIGEN CAPTURE AND PRESENTATION TO LYMPHOCYTE Description Competency Area Competency component

Objectives

Learning Methods

Equipments Time Lecturer

Evaluation References

Area of competence 3 of Indonesian Medical Doctor Competencies Standard Understand the concept of antigen recognition by T and B lymphocytes, antigen processing by the APC, structure and function of MHC and APC in antigen presenting cells. 1. Able to explain the antigen recognized by T and B lymphocytes 2. Able to explain the antigens are processed and presented by APC 3. Able to mention the type of MHC molecule and explain the function of MHC molecule 1. Self learning/modul task 2. Lecture 3. Small group discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture: 2 hours, discussiion: 2hours. 1. DR. Dr. Kusworini Handono, Mkes, SpPK 2. dr. Sudjari, DTM&H., MSi.,Sp.ParK 3. Prof. DR.Dr. Soemarno, SpMK Activity in discussions, modul tasks, MCQ test 1. Abbas AK dan Lichtman AH. Basic Immunology, 2 nd ed. Philadelphia, Saunders ; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006

1. Overview Adaptive immune response is began when antigen receptor on the cell surface of lymphocytes recognize antigens. T and B lymphocytes have a different way of introduction to the types of antigens. Antigen receptor on B lymphocytes were called immunoglobulin receptor, it can recognize various macromolecules (proteins, polysaccharides, lipids and nucleic acids) or small molecules are soluble or attached to the cell surface. On the other hand, T lymphocytes can only recognize peptide fragment or protein antigen if that fragment is presented by special molecules that exist on the surface of host cells. Induction of immune responses to antigens of microbial protein is dependent on special mechanisms that capture and present in those antigens, then they are specifically recognized by T lymphocytes. Microbes and parasites antigen that enter to the body

through epithelial cells will be captured by professional Antigen Presenting Cells (APC), especially by dendritic cells in epithelial tissue, then that antigen is transported to lymph node or it will be captured by APC in lymph node or spleen. Protein from microbial antigens are processed by APC and presented to naïve T cells circulating through lymphoid organs. Proteins is captured by the APC from extracellular environment will be degraded by using proteolytic enzymes which exist in the vesicles of APC. The peptides will be bound with MHC class II molecules. Next, this peptide is bound with MHC class II molecule`s cleft. This peptide will be recognized by CD4+ T cells. We know that CD4+ T cells are specific for peptides derived from extracellular proteins. The protein is produced by microbes or parasites in the cytoplasm of infected cells would be degraded by enzyme protease and followed by bound in cleft of new MHC class I molecules. MHC class I molecules that carry on these peptides will be recognized by CD8+. Those cytolytic CD8+ T lymphocytes are specific for peptide binding to MHC class I which derive from cytosolic protein. The role of MHC molecules for present antigens that T cells will only recognize protein antigens which bind with cell surface molecules, and specific types of T cells (helper or cytolytic) that will responses to types of microbes or parasites. Those microorganisms will be attacked by T cells Microbes or parasites will activate APC to express a membrane protein (co stimulator) and secrete cytokines that provide signals and together with antigen joint to stimulate T cells. B lymphocytes recognize antigen protein and non protein in original form. Still unknown whether there is a specific mechanism of antigen presentation is required to induce B cells response.

Module Task . 1. If antigens enter to the body through the skin, antigen will be concentrated. Which organs are concentrated? What kind of cell is involved in the process of antigen capture? 2. What is the difference between the antigens presented by MHC molecules of class I and class II 3. What isthe difference between antigen recognition by T cells, and antigen recognition by B cells?

SubModule 4 LYMPHOCYTE MATURATION & ACTIVATION 4.1 Lymphocyte Maturation Competency Area Competency component Objectives

Learning methodes Equipments Time Lecturer

Evaluation Refferences

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of T lymphocyte and B lymphocyte maturation Upon completion of this submodul, student will be able to: 1. To know the sequence event begining from the forming of somatic receptor genes recombination to receptor gene expression 2. Understand about the steps of B lymphosite maturation 3. Understand about the steps of T lymphocyte maturation 4. To know how is the selection process of lymphocyte maturation Self learning, Expert Lecture, discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1.5 hrs 1. DR.Dr. Endang Sri Wahyuni, MS 2. Dr. Sudjari DTM&H, SpParK 3. Prof.DR.Dr.Sanarto Santoso, DTM&H, SpMK Activity in discussions, modul tasks, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006 3. Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th ed. New York, Garland and Science; 2008

4.1 Overview : Lymphocyte maturation A: The maturation of lymphocytes from bone marrow stem cells consist of three types of processes: proliferation of immatute cells, expression of antigen receptor genes, and

selection of lymphocytes that express useful antigen receptor. These event are common to B and T lymphocytes, eventhough B lymphocyte mature in the bone marrow and T lymphocytes mature in a specialized organ called the thymus. Each of the three processes that occur during lymphocyte maturation plays a special role in the generation of the lymphocyte repertoire. B: Immature lymphocytes undergo tremendous proliferation at several stage during their maturation. The proliferation of developing lymphocyte maximizes the number of cells that are available to express useful antigen receptors and to mature into functionally competent lymphocyte. Proliferation of the erliest lymphocyte precursor is stimulated mainly by growth factor, a certain Interleukin, which is produced by stromal cells in the bone marrow and the thymus. The Interleukin stimulates proliferation of B and T lymphocyte progenitors before they express antigen receptors, thus generating a large pool of cells in which diverse antigen receptors may be produced. After antigen receptors take over the function of delivering the signals for proliferation, ensuring thet only the clones with intact receptors are selected to expand. C: Selection process of lymphocyte maturation: Lymphocyte are positively selected to recocnize peptide antigens displayed by self MHC molecules. Immature lymphocyte that strongly recognize self antigens are negatively selected and prevented from completing their maturation, thus eliminating cells with the potential of reacting in harmfull ways against self tissue.

Module tasks: 1. Explain about where the maturation take place 2. Explain about the steps of B lymphocyte maturation 3. Explain about the steps of T lymphocyte maturation 4. How is

the selection process of lymphocyte maturation: and describe the

definition of positive selection and negative selection.

4.2 Lymphocyte Activation Competency Area Competency component Objectives

Learning methodes Equipments Time Lecturer

Evaluation Refferences

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of T and B lymphocyte activation, and immune respons regulation Upon completion of this submodul, student will be able to: 1. Describe about T lymphocyte activation 2. Describe the sequence of T lymphocyte activation 3. Describe about B lymphocyte activation 4. Describe the sequence of B lymphocyte activation 5. Explain the mechanism of immune system regulation Self learning, Expert Lecture, discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1.5 hrs 1. DR.Dr. Endang Sri Wahyuni, MS 2. Dr. Sudjari DTM&H, SpParK 3. Prof.DR.Dr.Sanarto Santoso, DTM&H, SpMK Activity in discussions, modul tasks, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006 3. Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th ed. New York, Garland and Science; 2008

6.2. Overview: Lymphocyte Activation Cell-mediated immunity, the arm of the adaptive immune system that combats intracellular microbes, which may be microbes that are ingested by phagocytes and live within these cells or microbes thet infect non phatogenicytic cells. The responses of T lymphocytes consist of sequential phases: recocnition of cellassocisted microbes by naive T cells, expansion of the antigen-specific clones by proliferation, and differentiation of some of the progeny into effector cells and memory cells. APCs exposed to microbes or to cytokines produced as part of the innate immune reactions to microbes express costimulators that are recognized by receptors on T cells and deliver necessary “second signals” for T cell activation.

In response to antigen recognition and costimulation, T cells secrete cytokines, some of which induce proliferation of the antigen-stimulated T cells and others mediate the effector functions of T cells. Humoral immunity is mediated by antibodies, which neutralize and help to eliminate extracellular microbes and their toxins. Humoral immune respons are initiated by the recoqnition of antigen by spesific immunoglobulin, (Ig) receptors of naive B cells. The binding of antigen-Ig reseptors of specific B cells, and biochemical signals are delivered to the inside of the B cells by Igassociated signaling proteins with the second signal for B cell activation induce B cell clonal expansion The components of immune system regulation are antibody to the specific antigen, idiotype epitope (idiotope) antibody, and regulator T cells. Module task : 1.

Draw the scheme about the sequence of T lymphocyte activation!

2.

What is the role of costimulator in T cells activation?

3.

Mention the molecules that are involved in CD4+T cell activation (molecules that expressed by APC and T cell).

4.

Explain about the steps of CD8+T cell activation

5.

What is memory T cell?

6.

Explain about the steps of B lymphocyte activation by CD4+Tcell!

SubModule 5 EFFECTOR MECHANISM IN CELLULAR IMMUNE RESPONSE Competency Area Competency component Objectives

Learning methods Equipments Time Lecturer

Evaluation Refferences

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of effector mechanism in cellular immune response Upon completion of this submodul, student will be able to: 1. Describe the types of Cell-Mediated Immunity and the migration of effector T lymphocytes to sites of infection 2. Describe the effector functions of CD4+ and CD8+ T lymphocytes 3. Explain how do effector T cells eradicate infections and resistance of pathogenic microbes. Self learning, Expert Lecture, discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1.5 hrs 1. Prof. DR.Dr. Soemarno, SpMK 2. Dr. Sudjari DTM&H, Msi, SpParK 3. DR.Dr. Endang Sri Wahyuni, MS Activity in discussions, modul tasks, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006 3. Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th ed. New York, Garland and Science; 2008

Overview: Effector Mechanism In Cellular Immune Response Cell mediated immunity is the arm of adaptive immunity that eradicates infections by intracellular microbes. Cell-mediated immune reactions are of two types : CD4+ T cells activate macrophages to kill ingested microbes that are able to survive in the vesicles of phagocytes, and CD8+ CTLs kill cells harboring microbes in their cytoplasm, thus eliminating reservoirs of infections Effector T cells are generated in peripheral lymphoid organs, mainly lymph nodes draining sites of microbes entry, by the activation of naïve T lymphocytes. The effector T cells are able to migrate to any site of infection.

The migration of effector T cells is controlled by adhesion molecules, which are induced on these cells after activation and bind to their ligands, which are induced on endothelial cells by microbes and by cytokines produced during innate immune responses to microbes. The migration of T cells is independent of antigen, but cells that recognize microbial antigens in tissues are retained at these sites. Effector cells of the Th1 subset of CD4+ T cells recognize the antigens of microbes that have been ingested by macrophages. These T cells express CD40 ligand and secrete IFN-γ, which function cooperatively to activate macrophages. Th17 cells are recently recognize subset of CD4 effector T cells. They induce local epithelial and stromal cells to produce chemokines that recruit neutrophil to sites of infection early in the adaptive immune respons and they may enhance leucocyte recruitment and inflammation. The remaining subset of effector T cells are the regulatory T cells (T reg cells), a heterogeneous class of cells that suppress cell activity and help prevent the development of auroimmunity during immune reponses. Activated macrophages produce substances, including reactive oxygen intermediates, nitric oxide, and lysosomal enzymes, that kill ingested microbes. Macrophages also produce cytokines that induce inflammation and other cytokines that promote fibrosis and tissue repair. Effector CD4+ T cells of the Th2 subset stimulate eosinophilic inflammation and inhibit macrophage activation. Eosinophils are important in host defense against helminthic parasites. The balance between activation of Th1 and Th2 cell determines the outcomes of many infections, with Th1 cells promoting and Th2 cells suppressing defense against intracellular microbes. Th2 have more role in humoral immunity, because they can stimulate B cells to produce antibodies. CD8+ T cells differentiate into CTLs that kill infected cells, mainly by inducing DNA fragmentation and apoptosis. CD4+ and CD8+ T cells often function cooperatively to eradicate intracellular infections. Many pathogenic microbes have evolved mechanisms to resist cell mediated immunity. These mechanism include inhibiting phagolysosome fusion escaping from the vesicles of phagocytes, inhibiting the assembly of class 1 MHC-peptide complexes and producing inhibitory cytokines or decoy cytokine receptors

Module Task 1. How the effector T lymphocyte migrates to the sites of infections ? 2. Explain the effector function of CD4+ T lymphocytes 3. Explain the effector function of CD8+ T lymphocytes 4. What are some of the mechanisms by which intracellular microbes resist the effector mechanisms of cell-mediated immunity ? 5. A much more recently subset of CD4 effector T cells are the Th17 and T reg describe briefly the function of these subset .

Submodul 6: EFFECTOR MECHANISM IN HUMORAL IMMUNE RESPONSE & CYTOKINES Competency Area Competency component Objectives

Learning methods Equipments Time Lecturer

Evaluation Refferences

Area of competence 1 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of effector mechanism in humoral immune response and cytokines Upon completion of this submodul, student will be able to: 1. Describe the type of receptors in cells which contribute in effector of humoral immunity 2. Describe the function of effector of humoral immunity in combating microbes 3. Define cytokines and describe its nomenclature 4. Describe the general properties of cytokines and its receptor 5. Describe cytokines that mediate and regulate innate immunity 6. Describe cytokines that mediate and regulate adaptive immunity 7. Describe cytokines that stimulate hematopoiesis Self learning, Expert Lecture, discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1.5 hrs 1. Prof.Dr.dr. Sanarto Santoso, DTM&H, SpMK 2. Prof.DR.Dr. Edi Widjajanto, MS, SpPK 3. Prof. DR.Dr. Soemarno, SpMK Activity in discussions, modul tasks, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006 3. Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th ed. New York, Garland and Science; 2008

6.1 OVERVIEW: EFFECTOR MECHANISM IN HUMORAL IMMUNE

RESPONSE Humoral immunity is conducted by antibodies, which have physiologic function in defense against extracellular microbes and microbial toxin. This type of immunity contrast with cell-mediated immunity, the other effector arm of adaptive immune system which is mediated by T lymphocytes and function to eradicate microbes that infect and live within hoost cells. The types of microorganism that are combated by humoral immunity are extracellular bacteria, fungi and even obligate intracellular microbes such as viruses which are the targets of antibodies before enter host cells or when they are released from infected cells. The main function of antibodies to neutralize and eliminate pathogen and microbial toxin. Antibodies are produced by B lymphocytes as plasma cells in the primary and secondary lymphoid organs, but the antibodies perform their effector function at site distant from their production sites.The antibodies that mediate protective immunity may be derived from short-live or long-live antibody-producing plasma cells following the activation of naïve or memory B cells. Many of the effector function of antibodies are mediated by the heavy chain constant regions of Ig molecules, and different of Ig heavy chain isotypes serve distinct effector fuction. Even though, all these function are triggered by binding of antigen to the variable region of antibodies. Leukocytes Fc receptors promote the phagocytosis of opsonized particles and deliver signals that stimulate the microbicidal activities of leukocytes. Binding of opsonized particles to phagocytes receptor, particularly FcyR I, will activate phagocytes. MODULE TASKS 1. What the difference between innate and adaptive of humoral immunity effector 2. Explain the mechanisms of adaptive humoral immunity effector toward Staphylococcus aureus when they enter body through injury. 6.2 Overview: CYTOKINES Cytokines are proteins secreted by the cells of innate and adaptive immunity that mediate many functions of these cells. Cytokines are produced in response to microbes and other antigens, and different cytokines stimulate diverse responses of cells involved in immunity and inflammation. Cytokines mediate their actions by binding with high affinity to receptors, which belong to a limited number of structural families. The cytokines that mediate innate immunity are produced mainly by activated macrophage and include TNF and IL-1 that mediate acute inflammatory reactions to microbes; IL-12 and IL-18 stimulate production of the macrophage-activating cytokine IFN-γ. The cytokines that mediate and regulate adaptive immune responses are produced mainly by antigen-stimulated T lymphocytes, and they include IL-2 a T cell growth factor; IL-4 stimulates IgE production and the development of TH2 cells from naïve helper T cells; IL-

5 activates eosinophyl. In the activation phase of adaptive immune responses, cytokines stimulate the growth and differentiation of lymphocytes, and in the effector phases of innate and adaptive immunity, they activate different effector cells to eliminate microbes and other antigens. Cytokines also stimulate the development of hematopoietic cells. In clinical medicine, cytokines are important as therapeutic agents and as targets for specific antagonists in numerous immune and inflammatory diseases.

Module Tasks 1. Define cytokines and describe its nomenclature 2. Describe briefly the general properties of cytokines

Sub Module 7 HYPERSENSITIVITY Competency area Competency component Objectives

Learning methods Equipment Time Lecture

Evaluation References

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of Hypersensitivity 1. Understand the mechanism effector of immediate hypersensitivity 2. Understand the mechanism effector of antibody mediated hypersensitivity 3. Understand the mechanism effector of immune complex mediated hypersensitivity 4. Understand the mechanism effector of T cell mediated hypersensitivity Self learning, Expert lecture, Discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hours, discussion : 1,5 hours 1. DR. Dr. Wisnu Barlianto, SpA(K) 2. dr. C. Singgih Wahono, SpPD 3. Prof. DR. Dr. Handono Kalim, SpPD-KR Activity in discussions, modul task, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology Function and Disorders of the Immune system, 3th , Philadelphia, Saunders Elsevier, 2009. Page : 205 – 222 2. Decker JM. Immunology Tutorials. August 2003, http://microvet.arozona.edu/Courses/MIC419/Tut orials/Allergy.html 3. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology . 6th Int ed. Philadelphia Saunders Elsevier 2007 : 419-462

Overview


Immune responses that cause tissue injury are called hypersensitivity reactions, and the diseases caused by these reactions are called hypersensitivity diseases or immune-mediated inflammatory diseases




Hypersensitivity reactions may arise from uncontrolled or abnormal responses to foreign antigens or autoimmune responses against self antigens




Hypersensitivity reactions are classified according to the mechanism of tissue injury




Immediate hypersensitivity (type I, commonly called allergy) is caused by the production of IgE antibody against environmental antigens or drugs *allergens), sensitization of mast cells by the IgE, and degranulation of these mast cells on subsequent encounter with the allergen




The clinical and pathologic manifestation of immediate hypersensitivity are due to the actions of mediators secreted by the mast cells. These include amines, which dilate vessels and contract smooth muscles; arachidonic acid metabolities, which also contract muscles; and cytokines, which induce inflammation, the hallmark of the late phase reaction. Treatment of allergies is designed to inhibit the production of and antagonize the actions of mediators and to counteract their effects on end organs




Antibodies against cell and tissue antigens may cause tissue injury and disease (type II hypersensitivity). IgM and IgG antibodies promote the phagocytosis of cells to which they bind, induce inflammation by complement – and Fc receptormediated leukocyte recruitment, and may interfere with the functions of cells by binding to essential molecules and receptors




Antibodies may bind to circulating antigens to form immune complexes, which deposit in vessels and cause tissue injury (type III hypersensitivity). Injury is due mainly to leukocyte recruitment and inflammation




T-cell – mediated diseases (type IV hypersensitivity) caused by TH1-mediated delayed-type

hypersensitivity

reactions

or

reactions, or by killing of host cells by CD8+ CTLs.

TH17-mediated

inflammatory

Module task 1. Explain the mechanism of immunopathologic, tissue injury and diseases cause by various type hypersensitivity reaction ! 2. Explain the sequence of events in a typical immediate hypersensitivity reaction !

Sub Modul 7 HIPERSENSITIVITAS Area kompetensi

Area kompetensi 3 dari standart Kompetensi Kedokteran Indonesia Komponen Kompetensi Mengingat dan mengerti konsep dan prinsip-prinsip hipersensitivitas Kemampuan akhir 1. Mengerti mekanisme kejadian hipersensitivitas tipe cepat yang diharapkan 2. Mengerti mekanisme kejadian hipersensitivitas yang diperantarai oleh antibodi 3. Mengerti mekanisme kejadian hipersensitivitas yang diperantarai oleh kompleks imun 4. Mengerti mekanisme kejadian hipersensitivitas yang diperantarai oleh sel T Metode belajar Belajar sendiri/tugas modul, kuliah pakar, diskusi kelompok Sarana Ruang kelas, komputer, LCD, layar, lembar balik, papan putih, spidol Waktu Kuliah pakar 2 jam, diskusi kelompok 1,5 jam Tutor 1. DR. Dr. Wisnu Barlianto, SpA(K) 2. 3.

Evaluasi

dr. C. Singgih Wahono, SpPD Prof. DR. Dr. Handono Kalim, SpPD-KR

Aktivitas dalam diskusi kelompok, keaktifan dalam diskusi kelompok, mengerjakan tugas modul dan tes pilihan ganda (MCQ test) 1. Abbas AK, Lichtman AH. Basic Immunology Function and Disorders of the Immune system, 3th ed , Philadelphia, Saunders Elsevier, 2009. Pages : 205 – 222 2. Decker JM. Immunology Tutorials. August 2003, http://microvet.arozona.edu/Courses/MIC419/Tutorials/ Allergy.html 3. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology . 6th Int ed. Philadelphia Saunders Elsevier 2007 : 419-462

Daftar pustaka

Ringkasan


Respon

imun

yang

menyebabkan

kerusakan

jaringan

disebut

reaksi

hipersensitivitas, dan penyakit yang disebabkan oleh reaksi tadi disebut penyakit hipersensitivitas atau penyakit keradangan akibat proses imun


Reaksi hipersensitivitas mungkin berasal dari respon yang tidak terkontrol atau abnormal terhadap antigen asing atau respon autoimun terhadap antigen self




Reaksi hipersensitifitas diklasifikasikan berdasarkan mekanisme kerusakan jaringan




Hipersensitivitas tipe cepat (tipe I, umumnya disebut alergi) disebabkan oleh produksi antibody IgE melawan antigen lingkungan atau obat (allergen), sensitisasi sel mast oleh IgE, dan degranulasi sel mast pada paparan ulang alergen




Mekanisme klinik dan patologi hipersensitivitas tipe cepat disebabkan oleh kerja mediator yang diproduksi / di sekresi oleh sel mast. Disini termasuk vaso aktif amin yang menyebabkan delatasi pembuluh darah dan kontraksi otot polos; metabolit asam arakidonat yang juga menyebabkan kontraksi otot; serta sitokin yang merangsang keradangan, merupakan tanda dari reaksi fase lambat. Pengobatan alergi dirancang untuk menghambat produksi dan melawan kerja mediator dan meniadakan efeknya pada organ sasaran.




Antibodi melawan sel dan anti jaringan mungkin menyebabkan kerusakan jaringan dan penyakit (hipersensitivitas tipe II). Antibodi IgM dan IgG memungkinkan fagositosis dari sel yang diikatnya, merangsang keradangan akibat serbukan lekosit yang diperantarai oleh komplemen dan reseptor Fc, dan mungkin berpengaruh pada fungsi dari sel yang terikat pada molekul utama dan reseptor




Antibodi mengikat antigen dalam sirkulasi dan membentuk kompleks imun yang mengumpul di pembuluh darah dan menyebabkan kerusakan jaringan (hipersensitivitas tipe III), kerusakan ini terutama disebabkan oleh serbukan lekosit dan proses keradangan




Penyakit yang diperantarai sel T (hipersensitivitas tipe IV) disebabkan oleh reaksi hipersensitivitas tipe lambat yang diperantarai TH1 atau reaksi keradangan yang diperantarai TH17 atau kematian sel host oleh CD8+ CTLs (limfosit sitotoksik)

TUGAS MODUL: 1. Jelaskan mekanisme imuno - patologi dan mekanisme kerusakan jaringan serta penyakit yang disebabkan oleh berbagai macam reaksi hipersensitivitas 2. Jelaskan tahapan yang khas terjadi pada reaksi hipersensitivitas tipe cepat ?

Sub Modul 8: IMMUNODEFICIENCY Competency Area Competency component Objectives

Learning methods Equipments Time Lecturer

Evaluation Refferences

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of Immunodeficiency Upon completion of this submodul, student will be able to: 1. Describe the general features of Immunodeficiency 2. Describe about congenital immunodeficiency 3. Explain the mechanism of acquired immunodeficiency and immune response against HIV Self learning, Expert Lecture, discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1 hrs 1. DR. Dr. Wisnu Barlianto, SpA(K) 2. dr. C. Singgih Wahono, SpPD 3. Dr. B.P. Putra Suryana, SpPD-KR Activity in discussions, modul tasks, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 6th Int ed. Philadelphia ; Saunders Elsevier 2007 : 419 – 462

OVERVIEW: IMMUNO DEFICIENCY A. INTRODUCTION Integrity of the immune system is essential for defense against infectious organism and their toxic product. Therefore, it is very important for the survival of all individuals. Defect in one or more components of the immune system is generally called immunodeficiency. This group of diseases is classified into two groups i.e. congenital immunodeficiencies and acquired immunodeficiencies. B. GENERAL FEATURES Many types of immunodeficiencies have been identified, and the clinical significances can be summarized as follows :

•

• • •

Increased susceptibility to infection is the principle consequence of immunodeficiency. Deficient humoral immunity usually results in increased susceptibility to infection by pyogenic bacteria. Defect in cell-mediated immunity lead to infection by viruses and other intracellular microbes. Increased susceptibility to certain types of cancer. Many of these cancers appears to be caused by oncogenic viruses Clinically and pathologically heterogeneous because different diseases involve different components of the immune system. Increased incidence of autoimmunity

C. CONGENITAL (PRIMARY) IMMUNODEFICIENCIES Congenital immunodeficiencies are genetic defects that result in an increased susceptibility to infection, frequently manifested in infancy and childhood. The primary abnormality may be in components of the innate immune system, at different stage of lymphocyte maturation, or in the responses of mature lymphocyte to antigenic, consist of: Defects in innate immunity Severe combined immunodeficiencies Antibody deficiencies Defects in T lymphocyte activation and function Multisystem disorder with immunodeficiencies Therapeutic approaches for congenital immunodeficiencies are passive immunization and bone marrow transplantation. D. ACQUIRED (SECONDARY) IMMUNODEFICIENCIES Acquired immunodeficiencies are often developed because of abnormalities that are not genetic but acquired during life. The causes of acquired immunodeficiencies are : Complication from malnutrition, neoplasm, or infection Iatrogenic immunosuppression (immunosuppressive drugs etc) Human Immunodeficiency Virus (HIV) infection E. HIV AND AIDS Acquired immunodeficiency syndrome (AIDS) is a disease caused by infection with HIV and is characterized by profound immunosuppression, opportunistic infection, malignant tumors, wasting and CNS degeneration. HIV infects a variety of cells of the immune system, including CD4+ helper T cells, macrophages, and dendritic cells. HIV structure and genes HIV particles consist of two identical strands of RNA packed within a core viral proteins and surrounded by a phospholipid bilayer envelope derived from the host cell membrane. The envelope glycoprotein gp120 and gp41 are required for infection of cells. Pathogenesis of HIV infection and AIDS

HIV disease begins with acute infection, and advances to chronic progressive infection of peripheral lymphoid tissues. Dissemination of the virus, viremia, and the development of host immune responses happened during the transition from acute phase to a chronic phase of infection. Lymph nodes and the spleen are sites of continuous HIV replication and cell destruction. Mechanism of immunodeficiency caused by HIV Death of CD4+ is caused by the production of virus in infected cells (direct cytophatic effect) is a major cause of the decline the numbers of these cells, and lead to immunodeficiency state. Immune responses to HIV The early response to HIV infection is similar in many ways to the immune response to other virus, but the responses fail to eradicate all viruses (provide limited protection).

MODUL TASKS

1. How is the mechanism cellular and humoral immune response in protecting individuals from infection? 2. How is the pathogenesis of HIV infect and its replication in T lymphocyte?

3. Why individual immune responses to HIV infection provide very limited protection?

Sub Modul 9: IMMUNOLOGIC TOLERANCE AND AUTOIMMUNITY Competency Area Competency component Objectives

Learning methods Equipments Time Lecturer

Evaluation Suggested Refferences

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of Immunologic tolerance and autoimmunity Upon completion of this submodul, student will be able to: e. Explain about Immunologic tolerance: Central and Peripheral Tolerance, T and B cells Tolerance f. Explain how self tolerance might be broken g. Mention about the role of susceptible genes in autoimmunity h. Describe the role of infections in autoimmunity Lecture, tutorial and discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1.5 hrs 1. Prof.DR.Dr.Handono Kalim,SpPD-KR 2. Dr. B.P. Putra Suryana, SpPD-KR 3. Dr. C. Singgih Wahono, SpPD Activity in discussions, modul tasks, MCQ test 1. Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 2. Male D, Brostoff J, Roth DB, Roitt I. Immunology, 7th ed. Philadelphia, Elsevier Ltd; 2006 3. Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th ed. New York, Garland and Science; 2008

OVERVIEW: IMMUNOLOGIC TOLERANCE & AUTOIMMUNITY Immunologic tolerance is specific unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen, it means that our immune system is inable to make an immune response to that antigen. Normally, all individuals are tolerant of (unresponsive to) their own (self) antigens. These mechanisms are responsible for one of the cardinal features of the immune system, namely, its ability to discriminate between self and nonself (usually microbial) antigens. If these mechanisms fail, the immune

system may attack the individual's own cells and tissues. Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases. Central tolerance (negative selection) is induced by the death of immature lymphocytes that encounter self antigens in the generative lymphoid organs (bone marrow and thymus). Peripheral tolerance results from the recognition of self antigens by mature lymphocytes in peripheral tissues. Central tolerance (negative selection) of T cells is the result of high-affinity recognition of self antigens in the thymus, which tend to be widely disseminated self antigens. Central tolerance may eliminate the potentially most dangerous T cells, which express high affinity receptors for disseminated self antigens. This process of central tolerance affects self-reactive CD4+ T cells and CD8+ T cells, which recognize self peptides (antigens) displayed by class II MHC and class I MHC molecules, respectively. Peripheral tolerance of T cells is induced when mature T cells recognize self antigens in peripheral tissues, leading to functional inactivation (anergy) or death, or when the self-reactive lymphocytes are suppressed by regulatory T cells (immune supression). Anergy (functional inactivation) results from the recognition of antigens without costimulators (second signals) or when T cells use inhibitory receptors to recognize costimulators. Deletion (death by apoptosis) occurs when T cells repeatedly encounter self antigens. In В lymphocytes, central tolerance is induced when immature В lymphocytes interact strongly with self antigens in the bone marrow, the В cells are either killed (negative selection) or they change their receptor specificity (receptor editing). While peripheral tolerance is induced when mature В lymphocytes that encounter high concentrations of self antigens in peripheral lymphoid tissues and do not receive T cell help (because helper T cells are absent or tolerant), become anergic and cannot again respond to that self antigen Autoimmune diseases result from a failure of self-tolerance. This is cause by an adaptive immune response against “self” antigen. Multiple factors contribute to autoimmunity, including immunologic abnormalities, susceptibility genes (especially HLA genes), and environmental triggers such as infections.

Multiple genes predispose to autoimmune diseases, the most important of these being MHC (HLA) genes. Particular MHC alleles may contribute to the development of autoimmunity because they are inefficient at displaying self antigens, leading to defective negative selection of T cells, or because peptide antigens presented by these MHC alleles may fail to stimulate regulatory T cells. There are some other genes that have role in autoimmunity such as: complement, Fas and FasL, AIRE. Infections predispose to autoimmunity, by induce a local innate immune response, and this may lead to increased expression of costimulators and cytokines by tissue APCs. As a result, these activated tissue APCs may be able to stimulate selfreactive T cells that encounter self antigens in the tissue (break T cell anergy). The second mechanism is by cross-reactions between microbial and self antigens (molecular mimicry). Infections may also injure tissues and release antigens that are normally sequestered from the immune system.

Modul Tasks 1. What is immunologic tolerance? What is the function of immunologic tolerance for our body? 2. How is central tolerance induced in T lymphocytes? 3. How is peripheral tolerance induced in T lymphocytes? 4. How may MHC genes play a role in the development of autoimmune diseases? 5. How can autoimmunity be developed? Mention some risk factors for autoimmunity? 6. Mention some diseases that include in organ specific autoimmune diseases

Sub Modul 10: IMMUNE TRANSPLANTATION TUMOR IMMUNOLOGY VACCINATION Competency Area Competency component Objectives

Learning methods Equipments Time Lecturer

Evaluation Refferences

Area of competence 3 of Indonesian Medical Doctor Competencies Standard To apply the concept and principles of Immunodeficiency Upon completion of this submodul, student will be able to: 1. Describe the definition of graft, recipient, donor 2. Explain about graft rejection 3. Understand and explain about immune surveillance 4. Explain about innate immunity and adaptive immunity against cancer 5. Describe about types of human vaccine 6. Describe about primary and secondary antibody response Self learning, Expert Lecture, discussion Classroom, computer, LCD, screen, flipchart/whiteboard, spidols Lecture : 2 hrs, discussion: 1 hrs 1. Prof.DR.Dr. Edi Widjajanto, MS, SpPK 2. Dr. Wisnu Barlianto, SpA 3. Dr. B.P. Putra Suryana, SpPD-KR

Activity in discussions, modul tasks, MCQ test Abbas AK, Lichtman AH. Basic Immunology, 2nd ed. Philadelphia, Saunders; 2004 Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 6th Int ed. Philadelphia ; Saunders Elsevier 2007 : 419 – 462

12.1 Overview: TRANSPLANTATION IMMUNOLOGY

Transplantation is the process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a (usually) different individual. The individual who provides the graft is called the donor, and the individual who receives

the graft is called either the recipient or the host. If the graft is placed into its normal anatomic location, the procedure is called orthotopic transplantation; if the graft is placed in a different site, the procedure is called heterotopic transplantation. Transfusion refers to the transfer of circulating blood cells or plasma from one individual to another. In clinical practice, transplantation is used to overcome a functional or anatomic deficit in the recipient. This approach to treatment of human diseases has increased steadily during the past 40 years, and transplantation of kidneys, hearts, lungs, livers, pancreata, and bone marrow is widely used today. More than 30,000 kidney, heart, lung, liver, and pancreas transplantations are currently performed in the United States each year. In addition, transplantation of many other organs or cells is now being attempted. A major factor limiting the success of transplantation is the immune response of the recipient to the donor tissue. This problem was first appreciated when attempts to replace damaged skin on burn patients with skin from unrelated donors proved to be uniformly unsuccessful. During a matter of 1 to 2 weeks, the transplanted skin would undergo necrosis and fall off. The failure of the grafts led Peter Medawar and many other investigators to study skin transplantation in animal models. These experiments established that the failure of skin grafting was caused by an inflammatory reaction called rejection. Several lines of experimental evidence indicated that rejection is caused by an adaptive immune response Graft transplanted between two genetically identical or syngeneic individuals is called a syngeneic graft. A graft transplanted between two genetically different individuals of the same species is called an allogeneic graft (or allograft). A graft transplanted between individuals of different species is called a xenogeneic graft (or xenograft). The molecules that are recognized as foreign on allografts are called alloantigens, and those on xenografts are called xenoantigens. The lymphocytes and antibodies that react with alloantigens or xenoantigens are described as being alloreactive or xenoreactive, respectively. Alloantigens elicit both cell-mediated and humoral immune responses. Recognition of transplanted cells as self or foreign is determined by polymorphic genes that are inherited from both parents and are expressed codominantly. Major

histocompatibility complex (MHC) molecules are responsible for almost all strong (rapid) rejection reactions. Allogeneic MHC molecules are presented for recognition by the T cells of a graft recipient in two fundamentally different ways. The first way, called direct presentation, and the second way, called indirect presentation. For historical reasons, graft rejection is classified on the basis of histopathologic features or the time course of rejection after transplantation rather than on the basis of immune effector mechanisms. Based on the experience of renal transplantation, the histopathologic patterns are called hyperacute, acute, and chronic. The strategies used in clinical practice and in experimental models to avoid or delay rejection are general immunosuppression and minimizing the strength of the specific allogeneic reaction. An important goal in transplantation is to induce donorspecific tolerance, which would allow grafts to survive without nonspecific immunosuppression.

Module task 1. Explain two ways that T cells recognize allogeneic MHC! 2. Explain the type of graft rejection!

12.2 Overview: Tumor Immunology

Some tumor elicit specific immune responses that suppresses or modify their growth. A partially functioning immune system can lead to the outgrowth of tumors, suggesting that the immune system does play an important role in suppressing development. Tumors evade or suppress the immune system in a number of ways, and regulatory T cells have received much attention in this area. Monoclonal antibodies have been successfully developed for tumor immunotherapy in several cases, including anti-CD20 for B-cell lymphoma, and anti-VEGF antibodies in colorectal cancer. Attempts are also being made to develop vaccines incorporating peptides designed to generate effective cytotoxic and helper T-cell responses. The efficiency of dendritic cells in presenting

tumor antigens has been improved by pulsing the individual’s dendritic cells in vitro with modified tumor cells or tumor antigens and then replacing them in the body. This approach has been extended in animal experiments to the transfection of tumor cells with genes encoding co-stimulatory molecules or cytokines that attract and activate dendritic cells. The possibility of the near eradication of cervical cancer has been brought a step closer by the development of an effective vaccine against specific strains of the cancer-causing human papilloma virus. Module Task 1. How do tumors evade the immune response?

12.3 Overview: Vaccination The greatest triumphs of modern immunology have come from vaccination, which has eradicated or virtually eliminated several human diseases. It is the single most successful manipulation of the immune system so far, because it takes advantage of the immune system’s natural specificity and inducibility. Nevertheless, there are many important infectious diseases for which there is still no effective vaccine. The most effective vaccines are based on attenuated live microorganism, but these carry some risk and are potentially lethal to immunosuppressed or immunodeficient individuals. Better techniques for developing live-attenuated vaccines, or vaccines that incorporate both immunogenic components and protective antigens of pathogens, are therefore being sought. Most current viral vaccine are based on live attenuated virus, but many bacterial vaccines are based on components of the microorganism, including components of the toxins that it produces. Protective responses to carbohydrate antigens can be enhanced by conjugation to a protein. Vaccines based on peptide epitopes are still at an experimental stage and have the problem that the peptide is likely to be specific for particular variants of the MHC molecules to which they must bind, as well as being only very weakly immunogenic. A vaccine’s immunogenicity often depends on adjuvants that can help, directly or indirectly, to activate antigen-presenting cells that are necessary for the initiation of immune responses. Adjuvant activate these cells by engaging the innate immune system and providing ligands for Toll-like and other receptors on antigen-presenting cells. The development of oral vaccines is particularly

important for stimulating immunity to the many pathogens that enter through the mucosa. Cytokines have been used experimentally as adjuvants to boost the immunogenicity of vaccines or to bias the immune response along a specific path.

Module tasks 1. Explain the differences between primary and secondary antibody responses! 2. Explain the Immunization schedule for children < 1 year in Indonesia! 3. What is an adjuvant and how does it work?