10.

SISTEM IMUN

TIANA MILANDA

SISTEM IMUN
Kekebalan/imunitas : resistensi suatu organisme terhadap infeksi mikroba patogen tertentu Sistem imun : mekanisme pertahanan diri suatu organisme (sel inang) terhadap infeksi Dasar imunitas : kemampuan sistem imun untuk mengenali substansi asing/antigen (sel hewan, virus, bakteri, toksin, toksoid, vaksin, dll) dari sel/ substansi sel inang

ANTIGEN
Antigen : suatu bahan asing yang dapat menimbulkan respon imun. Semakin asing komposisi atau struktur kimia suatu antigen, semakin menginduksi respon imun.

Antigen umumnya bahan dengan BM tinggi. Ada 2 senyawa alami antigenik : 1. Protein lebih efektif 2. Polisakarida, terutama polisakarida kompleks berukuran besar, contoh : kapsul bakteri

ANTIGEN
Antigen dapat berupa : 1. Bahan yang larut dalam air: toksin bakteri, toksoid atau protein serum 2. Partikulat : sel hewan, virus, atau bakteri lebih efektif
Determinan antigen/epitop : Antigenbinding situs reaktif pada sites Antibody A permukaan atau bagian dalam antigen yang Antigen berikatan dengan antibodi menentukan kespesifikan Antibody B Antibody C respon imun
Epitopes (antigenic determinants)

ANTIGEN
Jumlah epitop per antigen : sekitar 2-3, ada yg sampai 200 Bentuk epitop antigen biasanya spesifik untuk spesies tertentu Antigen heterogenetik/heterofil : kelompok antigen yang terdapat pada spesies-spesies yang berbeda Contoh : antigen Forssman pada sel darah merah marmot, kuda, sapi, kucing, ayam dan beberapa bakteri menginduksi antibodi yang sama/mirip

HAPTEN
Hapten : bahan-bahan yang tidak bersifat antigenik, tetapi bila bergabung dengan molekul antigen seperti protein, dapat berfungsi sebagai epitop antigen Contoh : oligosakarida, lemak dan asam nukleat

AJUVAN
Ajuvan : bahan yang ditambahkan pada antigen untuk merangsang pembentukan antibodi, Contoh : - Alum dan garam-garam alumunium lainnya - Natrium alginat - Endotoksin bakteri - Suspensi air-minyak dengan/tanpa mikroba patogen yang telah dilemahkan/dimatikan, contoh : ajuvan Freund yang berisi minyak mineral, zat pengemulsi dan suspensi M. tuberculosis

SUMBER ANTIGEN
Antigen alami : Antigen jaringan manusia : antigen pada sel darah dan jaringan Antigen bakteri dan virus Antigen hewan dan tumbuhan Antigen buatan : Vaksin Toksoid

ANTIGEN PADA SEL DARAH

Antigen pada sel darah manusia : antigen A, B, Rh, MN, Ss, P, dll. Antigen A dan B digunakan untuk penggolongan darah berdasarkan reaksi isoantibodi

ANTIGEN PADA SEL DARAH

Transfusion with incompatible blood :leads to destruction of the transfused cells can be fatal Another red blood cell antigen, the Rh factor Creates difficulties when an Rh-negative mother carries successive Rh-positive fetuses erytroblastosis fetalis

ANTIGEN PADA JARINGAN

The immune systems ability to distinguish self from nonself tissue transplantation Transplanted tissues are usually destroyed by the recipients immune system MHC (major histocompatibility complex) molecules are responsible for stimulating the rejection of tissue grafts and organ transplants The chances of successful transplantation are increased : If the donor and recipient MHC tissue types are well matched If the recipient is given immunosuppressive drugs

ANTIGEN PADA BAKTERI

Antigen bakteri terdiri dari komponen struktural sel, eksotoksin dan enzim Komponen struktural sel : 1.1. Kapsul : kapsul pada pneumokokus, antigen kapsular 2. K atau Vi pada Salmonella typhi 3.2. Flagel : antigen H pada Salmonella typhi 4.3. Endotoksin : kompleks polisakarida-fosflipid-protein, 5. seperti antigen O pada Salmonella typhi. 6. Struktur antigen digunakan sebagai dasar klasifikasi suatu bakteri

ANTIGEN ALAMI LAINNYA

Antigen pada struktur terluar virus yang terdiri dari protein, lipoprotein atau glikoprotein Antigen hewan dan tumbuhan dapat berbahaya bagi kesehatan. Contoh : antigen regweed (sejenis rumputrumputan) yang menyebabkan hay fever

ANTIGEN BUATAN
Vaksin : - suspensi mikroba hidup yang dilemahkan (contoh : vaksin poliomielitis Sabin) atau - mikroba mati (contoh : vaksin demam tifoid, vaksin poliomielitis Salk) atau - produk-produknya (contoh : toksin bakteri) - bagian dari selnya (contoh : fragmen struktur terluar virus hepatitis B vaksin hepatitis B) yang dapat menimbulkan kekebalan sel inang terhadap infeksi mikroba tersebut Toksoid : toksin yang telah dirusak, tanpa mengubah antigenisitasnya menghasilkan antibodi antitoksin

TIPE SISTEM IMUN

Imunitas non spesifik/alamiah (innate immunity) Is present before any exposure to pathogens and is effective from the time of birth Involves nonspecific responses to pathogens Imunitas spesifik/dapatan (acquired/adaptive immunity) Develops only after exposure to inducing agents such as microbes, toxins, or other foreign substances Involves a very specific response to pathogens

Innate and acquired immunity

INNATE IMMUNITY Rapid responses to a broad range of microbes

ACQUIRED IMMUNITY Slower responses to specific microbes

External defenses Skin Mucous membranes Invading microbes (pathogens) Secretions

Internal defenses Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Cell-mediated response (cytotoxic lymphocytes) Humoral response (antibodies)

Innate immunity
Innate immunity provides broad defenses against infection : external and internal defenses External defenses
Intact skin and mucous membranes Form physical barriers that bar the entry of microorganisms and viruses Certain cells of the mucous membranes produce mucus A viscous fluid that traps microbes and other particles

Innate immunity
In the trachea, ciliated epithelial cells Sweep mucus and any entrapped microbes upward, preventing the microbes from entering the lungs Secretions from the skin Give the skin a pH between 3 and 5, which is acidic enough to prevent colonization of many microbes Also include proteins such as lysozyme, an enzyme that digests the cell walls of many bacteria

External Defenses

Internal Defenses
Internal defenses : 1. Phagocytic cells 2. Antimicrobial proteins 3. Inflammantory respons 4. Natural killer cells

Homeopoietic system

Leukosit
Granulosit : Neutrofil : pertahanan tubuh terhadap infeksi bakteri serta proses peradangan kecil melalui fagositosis. Aktivitas dan matinya neutrofil dalam jumlah besar menyebabkan nanah. Eosinofil : pertahanan tubuh terhadap infeksi parasit. Basofil dan mast cell bertanggung jawab terhadap reaksi alergi dengan mengeluarkan histamin yang menyebabkan peradangan. Monosit membagi fungsi fagositosis dengan neutrofil. Monosit dikenal sebagai makrofag, setelah meninggalkan aliran darah serta masuk ke dalam jaringan. Sel natural killer: sel yang dapat membunuh sel tubuh yang telah terinfeksi virus atau telah berubah sel kanker.

Leukosit
Agranulosit : Sel B: membuat antibodi yang akan berikatan dengan antigen utuh, lalu menghancurkannya. Sel B menghasilkan sel memori Sel T: terdiri dari dari sel T helper dan sel T sitotoksik. Kedua sel T mengkoordinasi sistem imun dan menghancurkan antigen/bakteri yang telah menginfeksi sel.

The lymphatic system

Macrophages, can be found migrating through the body and in various organs of the lymphatic system
1 Interstitial fluid bathing the tissues, along with the white blood cells in it, continually enters lymphatic capillaries. Interstitial fluid Lymphatic capillary 2 Fluid inside the lymphatic capillaries, called lymph, flows through lymphatic vessels throughout the body.

Adenoid Tonsil 4 Lymphatic vessels return lymph to the blood via two large ducts that drain into veins near the shoulders.

Lymph nodes

Blood capillary Tissue cells Lymphatic vessel

Spleen
Peyers patches (small intestine) Appendix

Lymphatic vessels

Lymph node

Masses of lymphocytes and macrophages

3 Within lymph nodes, microbes and foreign particles present in the circulating lymph encounter macrophages, dendritic cells, and lymphocytes, which carry out various defensive actions.

1. Phagocytic Cells
Phagocytes attach to their prey via surface receptors
1 Pseudopodia surround microbes. 2 Microbes are engulfed into cell. MACROPHAGE

Microbes

And engulf them, forming a vacuole that fuses with a lysosome

3 Vacuole containing microbes forms. Vacuole Lysosome containing enzymes 4 Vacuole and lysosome fuse. 5 Toxic compounds and lysosomal enzymes destroy microbes. 6 Microbial debris is released by exocytosis.

2. Antimicrobial Proteins
Numerous proteins function in innate defense By attacking microbes directly of by impeding their reproduction About 30 proteins make up the complement system Which can cause lysis of invading cells and help trigger inflammation Interferons Provide innate defense against viruses and help activate macrophages

3. Inflammatory Response
In local inflammation, histamine and other chemicals released from injured cells promote changes in blood vessels that allow more fluid, more phagocytes, and antimicrobial proteins to enter the tissues
Pathogen
Pin Blood clot

Macrophage Chemical signals Phagocytic cells Capillary

Blood clotting elements

Phagocytosis

Red blood cell

1 Chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable. 2 Fluid, antimicrobial proteins, and clotting elements move from the blood to the site. Clotting begins. 3 Chemokines released by various kinds of cells attract more phagocytic cells from the blood to the injury site. 4 Neutrophils and macrophages phagocytose pathogens and cell debris at the site, and the tissue heals.

4. Natural Killer Cells

Natural killer (NK) cells Patrol the body and attack virus-infected body cells and cancer cells Trigger apoptosis in the cells they attack

Acquired immunity
In acquired immunity, lymphocytes provide specific defenses against infection Lymphocytes Arise from stem cells in the bone marrow The vertebrate body is populated by two main types of lymphocytes B lymphocytes/B cells T lymphocytes/T cells

Lymphocyte Development
Newly formed lymphocytes are all alike But they later develop into B cells or T cells, depending on where they continue their maturation As B and T cells are maturing in the bone and thymus
Bone marrow Lymphoid stem cell Thymus

B cell

T cell

Blood, lymph, and lymphoid tissues (lymph nodes, spleen, and others)

Acquired immunity
Acquired immunity includes two branches The humoral immune response involves the activation and clonal selection of B cells, resulting in the production of secreted antibodies The cell-mediated immune response involves the activation and clonal selection of T cells

Clonal selection : binding of antigen to a mature lymphocyte induces the lymphocytes proliferation and differentiation

The humoral immune response

Generates a clone of short-lived activated effector cells and a clone of long-lived memory cells
B cells that differ in antigen specificity Antigen molecules Antigen molecules bind to the antigen receptors of only one of the three B cells shown.

Antigen receptor The selected B cell proliferates, forming a clone of identical cells bearing receptors for the selecting antigen.

Some proliferating cells develop into long-lived memory cells that can respond rapidly upon subsequent exposure to the same antigen.

Antibody molecules Clone of memory cells Clone of plasma cells

Some proliferating cells develop into short-lived plasma cells that secrete antibodies specific for the antigen.

In the secondary immune response

Memory cells facilitate a faster, more efficient response
1 Day 1: First exposure to antigen A 2 Primary response to antigen A produces antibodies to A 3 Day 28: Second exposure to antigen A; first exposure to antigen B 4 Secondary response to antigen A produces antibodies to A; primary response to antigen B produces antibodies to B

104 Antibody concentration (arbitrary units) 103

102

Antibodies to A

Antibodies to B

101

100 0 7 14 21 28 35 42 49 56

Time (days)

B Cell Receptors for Antigens

B cell receptors Bind to specific, intact antigens Are often called membrane antibodies or membrane immunoglobulin (Ig) Antibodi : substansi khusus yang dibentuk sel B sebagai respon terhadap antigen

ANTIBODI
Antigenbinding site Light chain Antigenbinding site Disulfide bridge

Variable regions

C C

Constant regions Transmembrane region

Heavy chains B cell Cytoplasm of B cell

Plasma membrane

(a) A B cell receptor consists of two identical heavy chains and two identical light chains linked by several disulfide bridges.

Struktur imunoglobulin terdiri dari unit monomer yang terdiri dari 2 rantai polipeptida ringan (sekitar 25.000 dalton) dan 2 rantai polipeptida berat (sekitar 50.000 dalton)yang dihubungkan dengan ikatan sulfida

Immunoglobulin gene rearrangement

V4V39 DNA of undifferentiated B cell V1 V2 V3 V40 J1 J2 J3 J4 J5 Intron C

1 Deletion of DNA between a V segment

and J segment and joining of the segments DNA of differentiated B cell V1 V2 V3 J5 Intron

2 Transcription of resulting permanently rearranged, functional gene pre-mRNA V3 J5 Intron 3 C RNA processing (removal of intron; addition of cap and poly (A) tail) Poly (A) 4 Translation Light-chain polypeptide V C B cell B cell receptor

mRNA Cap

V3 J5

Variable Constant region region

JENIS ANTIBODI
Berdasarkan urutan asam amino dalam rantai beratnya, antibodi terbagi menjadi : 1. Imunoglobulin G (IgG) tipe (gamma) 2. Imunoglobulin M (IgM) tipe (mui) 3. Imunoglobulin A (IgA) tipe (alfa) 4. Imunoglobulin D (IgD) tipe (delta)
IgM (pentamer) First Ig class produced after initial exposure to antigen; then its concentration in the blood declines Promotes neutralization and agglutination of antigens; very effective in complement activation (see Figure 43.19) Most abundant Ig class in blood; also present in tissue fluids Only Ig class that crosses placenta, thus conferring passive immunity on fetus Promotes opsonization, neutralization, and agglutination of antigens; less effective in complement activation than IgM (see Figure 43.19) IgA (dimer) Secretory component J chain Present in secretions such as tears, saliva, mucus, and breast milk Provides localized defense of mucous membranes by agglutination and neutralization of antigens (see Figure 43.19) Presence in breast milk confers passive immunity on nursing infant IgE (monomer) Triggers release from mast cells and basophils of histamine and other chemicals that cause allergic reactions (see Figure 43.20) J chain

IgG (monomer)

IgD (monomer)

Present primarily on surface of naive B cells that have not been exposed to antigens Acts as antigen receptor in antigen-stimulated proliferation and differentiation of B cells (clonal selection)

Transmembrane region

IgG
- 70-80 % dari Ig total
- IgG terbagi menjadi 4 sub kelas IgG1 (59%), IgG2 (30%), IgG3 (8%) dan IgG4 (3%), semuanya berbentuk monomer. - IgG diwariskan ibu ke janin melalui plasenta dan kolostrum . - Fungsi IgG : pertahanan diri utama pada bbrp minggu pertama setelah kelahiran, pertahanan diri setelah IgM

IgM
- 6 % dari Ig total

- Makroglobulin berukuran 5 kali lebih besar dari IgG, karena terdiri dari 5 unit monomer dengan suatu peptida tambahan (rantai J berfungsi menstabilkan struktur IgM. - Adanya 5 monomer membuat ikatan IgMantigen lebih dari 1 situs, sehingga efektif thd bakteri/virus. - Situs IgM : sebagian besar pada aliran darah - Fungsi IgM: merupakan antigen pertama yang muncul setelah stimulasi antigen.

IgA
- 10% dari Ig total - Struktur dasar : 2 rantai berat dan 2 rantai ringan dalam bentuk polimer (sebagian besar dimer, sebagian kecil trimer) melalui ikatan disulfida. - Situs IgA : serum, sekresi tubuh eksternal (air mata, air liur, air mani, air seni dan kolostrum, dan sekresi di selaput lendir paru-paru dan usus - Fungsi IgA : perlindungan utama pada bayi yang baru lahir, melindungi mukosa dan permukaan luar tubuh

IgD
Function not fully understood

Found on B-cell surface during different stages of maturation Possible involvement in cell differentiation

IgE
Most IgE bound to IgE receptor on mast cells Antigen binding to IgE releases inflammatory substances
Histamine Pathogenesis of hay fever, allergic asthma

The allergic response

IgE Allergen 1 3 2 Histamine

Granule Mast cell 1 IgE antibodies produced in response to initial exposure to an allergen bind to receptors or mast cells. 2 On subsequent exposure to the same allergen, IgE molecules attached to a mast cell recognize and bind the allergen. 3 Degranulation of the cell, triggered by cross-linking of adjacent IgE molecules, releases histamine and other chemicals, leading to allergy symptoms.

NAMA FUNGSIONAL ANTIBODI

Pemberian nama antibodi menggambarkan reaksi in vitro/in vivo antibodi dengan antigen, yaitu : 1. Antitoksin : menetralkan toksin 2. Opsonin : membuat mikroba lebih peka terhadap fagositosis 3. Aglutinin : menggumpalkan antigen 4. Presipitin : pengendapan/flokulasi antigen 5. Antibodi pengikat komplemen : penambatan /fiksasi komplemen (protein antimikrobal) 6. Lisin : lisis/penguraian antigen Jika multifungsi, antibodi dapat diberi beberapa nama

Antibody-mediated mechanisms of antigen disposal

Binding of antibodies to antigens inactivates antigens by Viral neutralization (blocks binding to host) and opsonization (increases phagocytosis) Virus Agglutination of antigen-bearing particles, such as microbes Bacteria Precipitation of soluble antigens Activation of complement system and pore formation Complement proteins

MAC

Pore
Bacterium Soluble antigens

Foreign cell

Enhances Phagocytosis

Leads to Cell lysis

Macrophage

Acquired immunity
Acquired immunity includes two branches The humoral immune response involves the activation and clonal selection of B cells, resulting in the production of secreted antibodies The cell-mediated immune response involves the activation and clonal selection of T cells

Clonal selection : binding of antigen to a mature lymphocyte induces the lymphocytes proliferation and differentiation

T Cell Receptors for Antigens

Each T cell receptor Consists of two different polypeptide chains T cells bind to small fragments of antigens V That are bound to normal C cell-surface proteins called MHC (major histocompatibility complex) molecules
AntigenBinding site Variable regions Constant regions Transmembrane region

Plasma membrane

chain chain Disulfide bridge Cytoplasm of T cell

T cell

(b) A T cell receptor consists of one chain and one chain linked by a disulfide bridge.

MHC molecules
Infected cells produce MHC molecules Which bind to antigen fragments and then are transported to the cell surface in a process called antigen presentation A nearby T cell Can then detect the antigen fragment displayed on the cells surface Depending on their source Peptide antigens are handled by different classes of MHC molecules

Class I MHC molecules

Found on almost all nucleated cells of the body
Display peptide antigens to cytotoxic T cells
Infected cell Antigen fragment 1 A fragment of foreign protein (antigen) inside the cell associates with an MHC molecule and is transported to the cell surface.

1 Class I MHC molecule T cell receptor 2

2 The combination of MHC molecule and antigen is recognized by a T cell, alerting it to the infection.

(a) Cytotoxic T cell

The activated cytotoxic T cell

Secretes proteins that destroy the infected target cell
2 The activated T cell releases perforin 1 A specific cytotoxic T cell binds to a molecules, which form pores in the class I MHCantigen complex on a target cell membrane, and proteolytic target cell via its TCR with the aid of enzymes (granzymes), which enter the CD8. This interaction, along with target cell by endocytosis. cytokines from helper T cells, leads to the activation of the cytotoxic cell. 3 The granzymes initiate apoptosis within the target cells, leading to fragmentation of the nucleus, release of small apoptotic bodies, and eventual cell death. The released cytotoxic T cell can attack other target cells.

Cytotoxic T cell Perforin

Released cytotoxic T cell Cancer cell

Granzymes 1 TCR Class I MHC molecule CD8 2 Pore 3

Apoptotic target cell

Target cell

Peptide antigen

Cytotoxic T cell

Class II MHC molecules

Located mainly on dendritic cells, macrophages, and B cells Display antigens Microbe fragment of to helper T cells 1 A foreign protein
(antigen) inside the cell associates with an MHC molecule and is transported to the cell surface. 2 The combination of MHC molecule and antigen is recognized by a helper T cell, alerting it to the infection. 2 1 Class II MHC molecule T cell receptor

Antigenpresenting cell Antigen fragment

(b)

Helper T cell

The role of helper T cells in acquired immunity

1 After a dendritic cell engulfs and degrades a bacterium, it displays bacterial antigen fragments (peptides) complexed with a class II MHC molecule on the cell surface. A specific helper T cell binds to the displayed complex via its TCR with the aid of CD4. This interaction promotes secretion of cytokines by the dendritic cell. Cytotoxic T cell Dendritic cell Bacterium Peptide antigen Class II MHC molecule TCR 2 1 CD4 Dendritic cell Cytokines 2 Proliferation of the T cell, stimulated by cytokines from both the dendritic cell and the T cell itself, gives rise to a clone of activated helper T cells (not shown), all with receptors for the same MHCantigen complex. 3 Helper T cell Cell-mediated immunity (attack on infected cells) Humoral immunity (secretion of antibodies by plasma cells)

B cell
3 The cells in this clone secrete other cytokines that help activate B cells and cytotoxic T cells.

B Cells: A Response to Extracellular Pathogens

1 After a macrophage engulfs and degrades 2

A B cell that has taken up and degraded the 3 The activated B cell proliferates same bacterium displays class II MHCpeptide a bacterium, it displays a peptide antigen and differentiates into memory antigen complexes. An activated helper T cell complexed with a class II MHC molecule. B cells and antibody-secreting bearing receptors specific for the displayed A helper T cell that recognizes the displayed plasma cells. The secreted complex is activated with the aid of cytokines antigen binds to the B cell. This interaction, antibodies are specific for the with the aid of cytokines from the T cell, secreted from the macrophage, forming a same bacterial antigen that clone of activated helper T cells (not shown). activates the B cell. initiated the response.

Bacterium Macrophage Peptide antigen Class II MHC molecule

1

B cell
2 3

TCR

CD4 Cytokines

Secreted antibody Clone of plasma cells molecules Endoplasmic reticulum of plasma cell

Helper T cell

Activated helper T cell

Clone of memory B cells

The roles of the major participants in the acquired immune response

Humoral immune response Cell-mediated immune response First exposure to antigen

Intact antigens

Antigens engulfed and displayed by dendritic cells

Antigens displayed by infected cells

Activate

Activate

Activate

B cell

Helper T cell

Secreted cytokines activate

Cytotoxic T cell

Gives rise to

Gives rise to

Gives rise to

Plasma cells

Memory B cells

Active and memory helper T cells

Memory cytotoxic T cells

Active cytotoxic T cells

Secrete antibodies that defend against pathogens and toxins in extracellular fluid

Defend against infected cells, cancer cells, and transplanted tissues

Autoimmune Diseases
In individuals with autoimmune diseases The immune system loses tolerance for self and turns against certain molecules of the body Rheumatoid arthritis Is an autoimmune disease that leads to damage and painful inflammation of the cartilage and bone of joints Other examples of autoimmune diseases include - Systemic lupus erythematosus - Multiple sclerosis - Insulin-dependent diabetes

Immunodeficiency Diseases
An inborn or primary immunodeficiency Results from hereditary or congenital defects that prevent proper functioning of innate, humoral, and/or cell-mediated defenses In severe combined immunodeficiency (SCID) Both the humoral and cell-mediated branches of acquired immunity fail to function An acquired or secondary immunodeficiency Results from exposure to various chemical and biological agents Range from temporary states to chronic diseases That physical and emotional stress can harm immunity

Acquired Immunodeficiency Syndrome (AIDS)

People with AIDS Are highly susceptible to opportunistic infections and cancers that take advantage of an immune system in collapse Because AIDS arises from the loss of helper T cells Both humoral and cell-mediated immune responses are impaired The loss of helper T cells Results from infection by the 1m human immunodeficiency virus (HIV)