BASIC PRINCIPLES OF IMMUNE SYSTEM

1. BASIC PRINCIPLES OF IMMUNE SYSTEM Purnomo Soeharso Department of Medical Biology FMUI

2. Immunity : Defence capacity of the body to combat diseases  counter infection.The cells and molecules responsible for immunity constitute the immune system.Their collective and coordinative response to introduction of foreign substance represent the immune response.Specific definition : Immunity is a reaction to foreign substances including microbes, as well as macromolecules (proteins, polysacharides). The reactions include cellular and molecular types (events).

3. Benefit of immunology for health/medicine1. The immune system is potentially manipulated in order the system to be under controlled condition to combat diseases.The manipulation of immune system may be applied by :- manipulation of antigen potentially enter the body  vaccination.- manipulation of antigen recognition/interaction with cells or molecules of immune system immunotherapy

4. History of vaccination :Discovered by Edward Jenner, based on the observationthat milkmaids who had recovered from smallpox, never suffer from smallpox infection again in the future.Jenner’s experiment :- take materials (exudates) from cowpox pustule and injected to the arm of 8 year-old boy.- After several weeks the boy was intentionally inoculated with smallpox  the disease did not develop  the boy become immune to smallpox infection.Jenner’s method was considered later as vaccination.It led to the widespread acceptance of this method for inducing immunity to infectious diseases.

5. 2. Immune reactions in vivo or in vitro are usefulfor diagnosis and therapy of infectious diseases, toxin poisoning or venom exposure.Examples :The level of antibody to virus or bacteria in serum is considered to be adequate indicator for disease progression.Anti-toxin or anti-venom antibodies are useful to treat one who are suffering from toxin or venom exposure. Anti-venom antibodies should be given (injected) toone who suffered snake bite immedietly.

6. Components of immune system :1. Innate / natural immunity - defense mechanisms present prior to exposure to infectious microbes or foreign molecules. - exist since fetal development period and persist permanently throughout life. - create nonspecific response  nonspecific immunity - represent the first line of defense mechanisms against foreign invasion into the body.

7. 2. Acquired / adaptive immunity - defense mechanisms acquired in a certain period of life. - create specific response  specific immunity. - develop due to induction / stimulation of foreign substance that successfully invade the body. - foreign substances capable of inducing immune response are called antigen.

8. The major elements of the innate and adaptive immunity

9. When pathogens (infectious agents) invade the body, they are firstly facing elements of natural (innate) immunity.They eventually meet the adaptive immune system provided they successfully break the natural immunity  the adaptive immune system react specifically to eliminate & destroy pathogens.Adaptive immune system create immune memory  give similar & better reaction in the secondary future infection.

10. Elements constitute defense mechanisms in innate immunity :1. External (epithelial) surface of the body. - epidermal skin is an effective barrier to prevent microbial invasion. - mucous epithelia of nasopharynx, gut, respiratory tract, genitourinary tract are equipped with physical (cilia) and chemical (enzymes) barriers to prevent / inhibit microbial entry. 2. Phagocytes cells which engulf microorganisms/particles capable of crossing surface epithelia  reticuloendothelial system produced by stem cells in bone marrow : tissue macrophages & blood monocytes.

11. 3. NK cells  leucocytes which are able to recognize membrane surface changes on virus infected cells  NK cells bind and kill the infected cells.4. Soluble factors - interferon  proteins that are produced by virus infected cells & lymphocytes  activate NK cells & induce resistance to neighboring infected cells. - complements  serum proteins activated complement is coating bacteria & bring the bacteria ready for phagocytosis  opsonisation. Leads to lysis of bacterial membrane  lytic pathway.

12. InflammationBody reaction to injury, caused by microorganisms/ particle invasion or scratched. Inflammatory reaction leads elements of immune system to be mobilized toward the site of infection.Inflammatory reactions include :1. vasodilatation  increase in the diameter of blood vessels  increase blood supply to site of infection.2. increase capillary permeability due to endothelial retraction  lead macromolecules (serum proteins) drip out the capillary & infiltrate the site of infection.3. Influx of phagocytic cells  neutrophyls, monocytes & lymphocytes penetrate away from capillary & migrate to the site of infection.

14. Signs of inflammation : rubor  redness tumor  eudema (swelling) kalor  heat dolor  painful  functio laesa (loss of function) of infected tissue

15. Specific/acquired immunityAcquired as a result of induction & exposure to foreign substances (antigen).Fundamental characteristics of specific immunity :- create immune memory  provide more effective response in further secondary infection  basic principle of vaccination.- create focus response to certain/fixed antigen that invades body & eliminate/destroy it  increase protective capacity of innate immunity.

16. Specific Immunity involves 2 types of immunity :1. Humoral immunity : is mediated by molecules (serum proteins) which recognize and eliminate free antigens(do not attach the cell or are not cell component)  called antibody  bind and react specifically to antigen.2. Cellular immunity (cell mediated immunity) : is mediated by cells  T lymphocytes  recognize and bind antigen on the cell surface or nonself antigen  produce immune mediator or lyse/destroy such cell expressing antigen.Antibodies and specific T lymphocytes are potentially transferred to naive individuals  passive immunisation.

17. Humoral and cellular response to antigen stimulation indicate fundamental characteristics :1. SpecificityThe immune response is specific to a particular antigen.The antibody or lymphocyte are able to recognize part of protein complex or any other macromolecules. Part of molecules recognized by specific antibody or lymphocyte is called determinant or epitope.2. DiversityThe total number of antigenic specificities of the lymphocytes in an individual  lymphocyte repertoire estimated the capacity to discriminate 109 determinants.

18. When a lymphocyte is stimulated by antigen  the lymphocyte is going to proliferate yielding a specific clone  “clonal selection theory”.3. MemoryThe effectiveness of immune response to a particular antigen is increasing in secondary exposure to this antigen and so on  called “immunological memory” & mediated by “memory cells”.4. Self limitationNormal immune response is declining & disappearingafter a period of destimulation (stimulation is sunpended)

20. 5. Discrimination of self from nonselfAble to discriminate foreign antigen from self components. Lymphocytes react to foreign antigen stimulation otherwise give no response to self molecules or self components  immune tolerance.Failure of immune tolerance to self components  autoimmune diseases  create pathological consequences for the sufferer.

21. Organs involved in immune systemOrgans of immune system are classified into two groups based on their function in immune system :- primary (central) lymphoid organs.- secondary (peripheral) lymphoid organs. Immature lymphocytes are undergoing maturation to become mature lymphocytes in primary lymphoid organs  becoming immunocompetent cells. The primary lymphoid organs in mammals are :- bone marrow  B lymphocyte maturation- thymus  T lymphocyte maturation

22. Secondary lymphoid organs  collect antigens from tissues or circulation & provide sites for immuno- competent cells to interact effectively with antigens.Lymph nodes  collect antigens from intracellular fluid of various tissues.Lien (spleen)  filtered antigen from blood/circulation  create response to systemic infection.Mucous associated lymphoid tissue (MALT) in gut, respiratory tract, genitourinary tract  (Peyer’s patch, tonsils, adenoids) trapped antigens which enter via mucous membrane.

26. Cells involved in specific immune systemThe entire cells of specific immune system derive from pluripotent “stem cells” in bone marrow & develop through hematopoeisis process.They differentiate into 2 lineages :1. myeloid lineage  produce phagocytes and other blood cells.2. lymphoid lineage  produce lymphocytes.Phagocytes are differentiated into two groups :- monocytes  able to pass away from vascular system & transform to tissue phagocytes  macrophages.- Polymorphonuclear cells  neutrophyls, basophyls, eosinophyls.

29. Lymphocytes are produced in bone marrow, circulate in blood and lymphoid system & occupy lymphoid organs.Lymphocyte recognize & interact with antigen through itsreceptor on the cell surface.2 types of lymphocytes  discriminated based on their membrane protein marker :B lymphocytes  CD 11 marker on their surface.T lymphocytes  CD 3 marker on their surface.

30. B lymphocytesProduced and develop in bone marrow. Equipped with Ab molecules as antigen receptor; the ab receptor is fixed in cell membrane through its Ch terminal. When naive B cell get in contact with specific antigen  it will proliferate & differentiate to be B memory cells capable of secreting specific antibody  plasma cells.

31. T lymphocytesDevelop from stem cells in bone marrow. They migrate to the thymus & differentiate to become mature T lymphocytes.Mature T cells express “antigen binding protein” on their surface, represent as T cell receptor (TCR)  compose of 2 protein subunits  or , connected to each otherby disulphide bonds.TCR recognize antigen on the cell surface in association with (presented by) MHC (HLA) molecules.When naive T cell contact to antigen  T cell proliferate &differentiate to become memory and effector T cells.

32. Subpopulation of T cells :Helper T cells (TH) & Cytotoxic T cells (TC)  discriminated based on their protein marker on the cell surface  CD4 marker for TH CD8 marker for TCAfter contact with antigen TH cells develop into effectorcapable of cytokine (lymphokine) secretion  activateB cells, TC cells, phagocytic cells etc. TC develop into effector which mediate cytotoxic reactions  killing/ lysis cells expressing antigen :- virus infected cells- cells infected by intracellular microbes- tumor cells- allograft cells

34. Major Histocompatibility Complex (MHC)Membrane proteins, expressed by gene cluster & inherited in tight linkage modes.MHC products play important roles in antigen (Ag) recognition by immunocompetent cells & discrimination between self and nonself  define tissue compatibilityamong individuals of the same species  called transplantation antigens.MHC is also critical for the creation of humoral and cell mediated immunity  TH & TC recognize Ag in association with MHC molecules  establish antigen repertoire which give response to TH & TC  implicatein the susceptibility to disease & autoimmunity.

35. HLA code for 3 kind of molecules : HLA class I, class II & class III. HLA class I is coded by regio A, B and CHLA class II is coded by regio DP, DQ and DReach regio constitute alleles which are multiple  create huge variation of individuals, despite of brothers or sisters.HLA class I molecules present Ag recognized by TC  carriedby almost all nuclear cells.HLA class II molecules present Ag recognized by TH carried by antigen presenting cells (APC)  macrophages, dendritic cells, B lymphocytes, etc.

41. Humoral immunityMediated by antibodies, proteins that are presence in serum & body liquid of mammals  belong to protein serum fraction,  globulin  immunoglobulin (Ig).Produced and secreted by B lymphocytes that has been stimulated by specific antigen  becoming committed cells (sensitized B lymphocytes) and develop to plasma cells.Function as effector that mediate binding to free antigen(no attachment or not part of cell components), neutralize and eliminate such antigen away from the body.

43. Ig moleculesProtein of 150.000. mw, compose of 4 subunits :2 heavy (H) chains, each make pairing with light (L) chain. Each subunit is connected to its complement bydisulphide bond. The molecule is divided into two domains :V (variable) domain  aminoterminal part, varies among molecules & define the specificity of Ig to Ag. The aminoterminal end undergo modification to become “antigen binding site”C (constant) domain  constant & identical in similar Ig type.

45. Immunoglobulin molecule variations1. Isotype variation  defined by determinant present in Ch and Cl which discriminate Ig of the same species.2. Allotype variation  defined by the variation of amino acids in either H or L chain, coded by different alleles  expressed by individuals of the same species.3. Idiotype variation  defined by variation of Vh and Vl constructing Ag binding site  define the specificity of Ig to Ag.

48. 5 Ig classes available in all species, defined by Ig H chain.IgG – the predominant Ig in normal serum, constitute 70 – 75% of total Ig. Distribute intra and extra vascular; represent dominant antibodies accumulate during secondary immune response, especially function as anti-toxin.IgM – include 10% of total Ig. Present as pentamer molecules, distribute intravascular. Represent the predominant Ab in early response to microbial infection.

49. IgA – include 15 – 20% of total Ig. Present in dimeric conformation, equipped with “secretory component”, recognized as sIgA. Predominant in mucous secret i.e. saliva, tracheobronchial secret genitourinary mucous, etc.IgD – less than 1% of total Ig, fixed in cell membrane of B lymphocytes. Function as antigen receptor & necessary for B cell stimulation to become plasma cells.IgE – available in small proportion, attach to basophyl and mast cell membrane. Involved in developing immunity to parasites (helminthes) and hypersensitivity disease i.e. asthma.

50. Phases of immune response :1. Cognitive phase – antigen recognition through antigen binding to specific receptor on lymphocyte surface. B lymphocyte – bind Ag to surface Ig. T lymphocyte – bind Ag fragment – MHC (HLA) to TCR.2. Activation phase - lymphocyte proliferation – clonal expansion of specific lymphocyte to certain antigen. - lymphocyte differentiation B lymphocyte  secreting cells (plasma cells)  Ab bind to free Ag (soluble Ag).