1	CLSC320 Principles of Immunology Fundamental Concepts in Immunology Program for Clinical Laboratory Science Unit - 01 Normal Immune Responses
2	Unit – 01 Guidelines Reading assignment: Pages 2 - 37 of textbook Learning objectives: Those listed on page 3 of textbook Key terms: Those listed on pages 3 - 5 of textbook
3	Overview of Immune System - 1 Composition: 1.lymphoid tissue ˜primary lymphoid tissue ˜secondary lymphoid tissue &Bone marrow &Thymus gland &lymph nodes &spleen &peripheral lymphoid tissue 2.cells of various types ˜lymphocytes &B-cells &T-cells &natural killer-cells (NK-cells)
4	Overview of Immune System - 2 Composition: continued 3.cells of various types - continued ˜Accessory cells &monocytes/macrophages &polymorphonuclear leukocytes - neutrophils &eosinophils &basophils granulocytes 4.soluble molecules ˜cytokines ˜immunoglobulins ˜complement components
5	Responses to Foreign Material Three responses to foreign material (antigen) - see table 1-1 on page 7 1.Natural (nonspecific or innate) immune response 2.Specific (acquired) immune response 3.Tolerance ˜the body=s first defense mechanisms ˜those defense mechanisms one is born with: &anatomic barriers (skin, mucous membranes) &physiological barriers (temp, pH, mediators) &phagocytic barriers (neutrophils, macrophages) &inflammatory barriers (serum proteins) ˜the immune systems response to contact with antigen ˜Humoral immunity (B-cells = immunoglobulins) ˜Cell-mediated immunity (T-cells) immunity
6	Five Functions of Immune System Five functions of the immune system 1.Surveillance: 2.Defense: 3.Regulation: 4.Immunity: 5.Tolerance: ˜recognition of non-self or foreign antigen ˜initiation of immune response (natural or acquired) to eliminate or inactivate antigen ˜control of immune response by regulatory mechanisms to maintain homeostasis ˜acquired protection following exposure to antigen ˜induction of a state of unresponsiveness towards antigens
7	Immune System Overview – Fig. ANTIGEN IMMUNE SYSTEM NATURAL IMMUNE RESPONSE SPECIFIC IMMUNE RESPONSE cooperation RESOLUTION End of response NO RESOLUTION antigen present HUMORAL IMMUNE RESPONSE CELL-MEDIATED IMMUNE RESPONSE interdependent Resolution = antigen removed No Resolution = disease state
8	Natural (Non-Specific) Immunity - 1 Characteristics of system 1.First line of defense against invading antigens 2.Present in all humans as a product of creation and micro- evolutionary processes 3.They are not acquired because of exposure to an antigen 4.Lacks the ability to recognize an antigenic structure 5.Does not have a memory and is not enhanced by subsequent exposure to antigens 6.Action may be enhanced by specific (acquired) immune responses
9	Natural (Non-Specific) Immunity - 2 Four components of the system 1.Two anatomic (physical) barriers: ˜skin - 5 factors ˜mucous membranes - 3 factors &mechanical barrier &continous renewal of epithelial cells &sebaceous glands secrete sebum which contains lactic acid and fatty acids &pH (3 - 5) of skin surface &normal bacterial flora can metabolize sebum &traps foreign microorganisms &normal bacterial flora compete for attachment sites and nutrients &cilia propel microorganisms from body
10	Natural (Non-Specific Immunity - 3 Four components of the system - continued 2.Three physiological barriers: ˜Temperature ˜Low pH ˜Chemical mediators &body temperature (37^oC) inhibits growth of some pathogens &fever response inhibits growth of some pathogens &acidic pH of stomach (1.5 - 3.5) &lysozymes (tears and saliva) cleave bacterial cell walls &interferon - antiviral &complement - lyses cells & enhances phagocytosis
11	Natural (Non-Specific) Immunity - 4 Four components of the system - continued 3.Phagocytic/endocytic barriers: ˜Endocytic action &various cells internalize (endocytose) and break down antigens ˜Phagocytic action - see Figure 1-4 on page 11 &internalization and digestion of antigen &cells that are phagocytic include: Lmonocytes - blood Lmacrophages - tissue Lneutrophils ˜Natural killer cells &can destroy tumor cells using cytokines without antibody interaction
12	Natural (Non-Specific) Immunity - 5 Four components of the system - continued 4.Inflammatory barriers: ˜leakage of serum proteins (acute phase proteins) due to tissue damage &C-reactive protein -binds to bacteria and activates complement &histamine -increased permeability & vasodilation &kinins Lbradykinin - induces pain &coagulation enzymes -clot forms and walls off area of infection
13	OSF - 1 Natural (Non-Specific) Immunity On pages 12 - 14 AOne Step Further@ presents a more in- depth discussion of the inflammatory process. This presentation is contained on a separate slide presentation called A One Step Further #1" The student may call up the slide program OSF - 1 later or click on the arrow below to view slides now.
14	Specific (Acquired) Immunity - 1 Definitions: 1.Specific:the recognition of a particular epitope on an antigenic molecule by the CD4+ and CD8+ T lymphocytes via their surface antigen receptors. 2.Acquired:the immunity obtained through interaction of the antigen with the immune system after having successfully evaded the natural immune responses. Types of specific immune responses: see table 1-3 on page 14 1.Humoral immune response:the production of antibodies by plasma cells 2.Cell-mediated immune response:the interaction between cells via cytokines
15	Specific (Acquired) Immunity - 2 Antigen Specific immune responses Humoral immune response Cell-mediated immune response Antibodies produced Antibodies bind to antigen Antigen destroyed Activate phagocytosis Activate T_cytotoxic cells Antigen containing cells destroyed
16	Specific (Acquired) Immunity - 3 1.Mechanism: - see figure 1-7 on page 16 Humoral Immune Response Extracellular antigens (mainly bacteria) and certain intracellular antigens (those that migrate between cells i.e. malaria) are detected by the immune system and antigen presenting cells (APC=s) phagocytize them. The processed antigen is then expressed on the APC=s surface bound to class II MHC (Major Histocompatibility Complex) molecules. The class II MHC (Major Histocompatibility Complex) bound antigen is then detected by T_Helper lymphocytes (CD4+) by the T cell receptor (TCR) which is also associated with the CD3 receptor. - see figure 1-9 on page 18
17	Specific (Acquired) Immunity - 4 1.Mechanism: - continued Humoral Immune Response T_Helper cells that have recognized MHC - II bound antigen will: 1.activate macrophages to: Lphagocytize and destroy antigen Lsecrete cytokines - see table 1-2 page 10 Lstimulate B cells to transform into antibody producing plasma cells Lenhance phagocytosis Lpromote inflammatory response 2.activate B cells to: Lphagocytize and destroy antigen Ltransform into plasma cells and memory cells
18	Specific (Acquired) Immunity - 5 1.Mechanism: - continued Humoral Immune Response Secreted antibodies will: Lform antibody-antigen complexes Lneutralize bacterial toxins Lopsonization of antigen to promote phagocytosis Lactivate complement
19	Specific (Acquired) Immunity - 6 1.Mechanism: Cell-Mediated Immune Response T_Cytotoxic lymphocytes recognize infected cells by: Linfected cell expresses antigen on surface Lantigen is associated with MHC I type molecule LT_Cytotoxic lymphocytes use TCR=s + CD3 to recognize surface antigen Activated T_Cytotoxic lymphocytes destroy infected cells 2.Types of responses: see figure 1-14 on page 21 Primary specific immune response Secondary specific immune response = the 1st exposure to antigen = subsequent exposure to antigen
20	Specific (Acquired) Immunity - 7 3.Major immunologic events during specific immune responses Cell-Mediated Immune Response Cognitive phase (recognition phase in humoral) LCD4+ binds with MHC II bound antigen LCD8+ binds with MHC I bound antigen Activation phase (proliferation & differentiation in humoral) LCD4+ produces cytokines that: Nstimulates macrophage phagocytosis Nstimulates B cells to differentiate into plasma cells & memory cells Nstimulates CD8+ to form cytotoxic function LCD8+ produces cytokines that: Nstimulates CD8+ to form cytotoxic function
21	Specific (Acquired) Immunity - 8 3.Major immunologic events during specific immune responses -cont=d Cell-Mediated Immune Response Effector phase (resolution phase in humoral) L in humoral immune response effector cell is: Nplasma cells - release antibodies NCD4+ cells - release cytokines Lin cell-mediated immune response effector cell is: NCD8+ cell Lmiscellaneous effector cells: Nmacrophages Ndendritic cells Nneutrophils NOTE: table 1-5 on page 23 for key cell features.
22	Specific (Acquired) Immunity - 9 3.Characteristics of Specific Immune responses Cell-Mediated Immune Response Specific antigen recognition L Antigen recognition by T lymphocytes Nonly the CD4+ and CD8+ cells can specifically recognize antigens. Nrecognition is via TCR + CD3 complex and the CD4 and CD8 Nonly small peptide fragments (degraded proteins) are recognized Nfree peptides or those membrane proteins associated with self MHC molecules are not recognized
23	Specific (Acquired) Immunity - 10 3.Characteristics of Specific Immune responses Cell-Mediated Immune Response Specific antigen recognition - continued L Antigen recognition by B lymphocytes Nlack the ability to recognize specific antigens Ncan not discriminate between self and foreign antigens Ncan not trigger an immune response because they lack TCR/CD3 receptors Ncan bind to specific antigens NB cell receptors (BCR=s) are immunoglobulins NB cell recognition is not MHC dependent NB cells are activated by T_Helper cells
24	Specific (Acquired) Immunity - 11 3.Characteristics of Specific Immune responses Cell-Mediated Immune Response Lymphocyte Diversity LAlmost a limitless number of antigens can be recognized Leach lymphocyte can only recognize one antigen epitope L clonal selection =the process where a specific epitope causes the proliferation of a clone of lymphocytes that have the specificity for that epitope
25	Specific (Acquired) Immunity - 12 3.Characteristics of Specific Immune responses Cell-Mediated Immune Response Immunologic Memory La function of B and T lymphocytes Linstead of becoming Aeffector cells@ some antigen stimulated cells become Amemory cells@ L subsequent exposure to the same antigen results in: Nmore rapid response Nhigher response Ndifferentiation of Amemory cells@ into Aeffector cells@. secondary immune response
26	Specific (Acquired) Immunity - 13 3.Characteristics of Specific Immune responses Cell-Mediated Immune Response Regulation of Immune responses Lclonal selection L Clonal deletion Npositive selection of cells that can recognize antigens in the context of the self MHC molecule Nnegative selection of cells that have specificity for self-antigens L three mechanisms involved in regulation are: Nself-regulation Ngenetic control Nother regulators
27	Specific (Acquired) Immunity - 14 3.Characteristics of Specific Immune responses Cell-Mediated Immune Response Regulation of Immune responses L self-regulation Nas antigen level : intensity of response : Ncytokines and antibodies secretion : as antigen levels : Neffector cells are short-lived L genetic control NMHC-linked immune response genes insures immune response is only to foreign antigens L other regulators Nstimulating antigen Nlymphocytes and accessory cells Nidiotypic interaction Nneuroendocrine modulation
28	Conferring Specific Immunity 1.Ways of inducing immunity Passive immunity Active immunity Limmunity that is acheived by the introduction of preformed cells or antibodies from previously immunized organism. Limmunity that is acheived by the introduction of a stimulating antigen and the corresponding immune response. Note:each type of immunity may be achieved by either natural means or artificial means.
29	Conferring Passive Immunity 1.Ways of inducing immunity Passive immunity L Natural Passive Immunity L Artificial Passive Immunity Nantibodies from mother via placental or milk Npreformed antibodies injected (immunoglobulin shots) adiphtheria & tetanus astreptococci & rubella apoliovirus & mumps atetanus & botulism toxin ahepatitis & rabies arabies & HIV
30	Conferring Active Immunity 1.Ways of inducing immunity - continued Active immunity L Natural Active Immunity L Artificial Active Immunity Na result of a natural infection (get sick) Nvaccination with: acold virus aflu virus akilled (inactivated) vaccines alive (attenuated) vaccines atoxins or venoms
31	OSF - 2 Specific (Acquired) Immunity On page 28 AOne Step Further@ presents a more in-depth discussion of the vaccine for hepatitis B This presentation is contained on a separate slide presentation called A One Step Further #2" The student may call up the slide program OSF-2 later or click on the arrow below to view slides now.
32	OSF - 3 Specific (Acquired) Immunity On page 30 AOne Step Further@ presents a more in-depth discussion of the vaccine design. This presentation is contained on a separate slide presentation called A One Step Further #3" The student may call up the slide program OSF-3 later or click on the arrow below to view slides now.
33	Immunologic Tolerance - 1 1.Tolerance to Self-antigens L acquired characteristic of immune system L self-reacting lymphocytes are: Ndestroyed Nblocked from maturing Nblocked from reacting L T-lymphocytes Nmature in thymus gland Nthose that fail to recognize self-antigens are destroyed Nthose that recognize antigens bound to MHC molecules are allowed to mature.
34	Immunologic Tolerance - 2 1.Tolerance to Self-antigens - continued L B-lymphocytes Nmature in bone marrow Nlack of T_Helper cell stimulation Nthose that react with self-antigens are eliminated by clonal abortion Ncan be induced to nonreactivity creating a state of anergy (unresponsiveness). 2.Tolerance generated during an immune response L Four mechanisms that induce tolerance Nclonal exhaustion Nanti-idiotype antibodies Nfeedback inhibition NT_Suppressor cells
35	Immunologic Tolerance - 3 2.Tolerance generated during an immune response - continued L Four mechanisms that induce tolerance Nclonal exhaustion Nanti-idiotype antibodies Nfeedback inhibition NT_Suppressor cells alymphocyte depletion due to: Uvigorous immune response Urepeated antigenic stimulation aantibodies formed against idiotypes can block sites of antigen attachment amolecules produced during immune response may block lymphocyte activation acytokine inhibition
36	Artificially Induced Tolerance 3.Artificially induced tolerance L Some examples of proteins that, when introduced into an organism, may inhibit the immune response: Nanti-lymphocyte monoclonal antibodies Nimmunosuppressive therapy with: airradiation achemotherapy (cyclosporin A) Nallogenic cells acells from same species but different individuals Nsoluble protein antigens
37	Normal Immune Responses Press the ESC key to end program
38	One Step Further Inflammation OSF - 1 Pages 12 - 14 7click to return to main program
39	Inflammation - 2 Definition: a non-specific immune response to any type of tissue injury or invasion of an infectious agent Events occuring during inflammation: eSystemic events Žincreased blood supply to area of injury Žincreased capillary permeability Žincreased concentration of acute phase reactants eHematopoietic events Žincreased leukocyte count Žincreased number of immature neutrophils - shift- to-left Žincreased levels of fibrinogen (Factor I) Žincreased Factor XII activation (coagulation) Žincreased Erythrocytic Sedimentation Rate (ESR)
40	Inflammation - 3 Events occuring during inflammation: - continued eCellular events Žleukocytes migrate out of capillaries under influence of chemotactic attraction Žleukocytes accumulate at site of injury due to: adhesion molecules (new surface receptors) that are induced by TNF (tumor necrosis factor) Types of inflammatory reactions: eAntibody-Mediated Inflammation - type I hypersensitivity eImmune-complex-Mediated Inflammation - type III hypersensitivity eT cell-Mediated Inflammation - type IV hypersensitivity
41	Inflammation - 4 Types of inflammatory reactions: - continued eAntibody-Mediated Inflammation - type I hypersensitivity Žobserved as an immediate skin reaction Žcaused by mast cells/basophils releasing mediators such as: histamine vasodilator & smooth muscle constrictor prostaglandins increased vascular permeability & platelet aggregator cytokines products produced by one cell that affects another cell
42	Inflammation - 5 Types of inflammatory reactions: - continued eAntibody-Mediated Inflammation - type I hypersensitivity ŽMechanisms of response: IgE produced in response to initial stimulation of immune system IgE binds to IgE (Fc) receptors on mast cells/basophils (@sensitization@) when allergen (antigen) binds with more than two IgE molecules on mast cell/basophil it causes cell to release granular contents (@degranulation@) granular mediators released ŽMediator induced changes that take place: infiltration by cells erythema, heat, & itching
43	Inflammation - 6 Types of inflammatory reactions: - continued eAntibody-Mediated Inflammation - type I hypersensitivity ŽClinical expressions: immediate hypersensitivity asthma allergies hay fever eImmune-complex-Mediated Inflammation - type III hypersensitivity Žinflammation that occurs when immune- complexes (ag-ab) are formed in the circulatory system and then are deposited in or on tissue ŽMechanisms of response: next slide #
44	Inflammation - 7 Types of inflammatory reactions: - continued eImmune-complex-Mediated Inflammation - type III hypersensitivity ŽMechanisms of response: IgG capable of activating complement or IgM that does activate complement, are formed and react with the inducing antigen to form ag-ab complexes within the circulatory system. These immune-complexes are then deposited on or in various tissues such as: ]glomerular basement membrane (Goodpasture=s syndrome) ]endothelial cells of blood vessels
45	Inflammation - 8 Types of inflammatory reactions: - continued eImmune-complex-Mediated Inflammation - type III hypersensitivity ŽMechanisms of response: continued When complement is activated, fragments C3a, C4a, and C5a are released and cause: ]chemotactic attraction of neutrophils ]increased vascular permeability ]aggregation of platelets ]infiltration by mononuclear cells ŽClinical expression: Arthus reaction ]localized edema ]inflammation Systemic serum sickness
46	Inflammation - 9 Types of inflammatory reactions: - continued eT cell-Mediated Inflammation - type IV hypersensitivity Žinteraction of antigen with specific T cells plus class II MHC molecules ŽMechanisms of response: immune cells infiltrate site of antigen stimulation where coagulation/kinin system is activated resulting in: ]fibrin formation ]hardened fibrous tissue ŽClinical expression: delayed hypersensitivity reaction
47	Inflammation - 10 Regulation of inflammatory reactions: eAs the level of antigen decreases inflammation subsides eFormed or released mediators assist in the regulation: Ženzymes Žcomplement Žfibrinolytic products Žkinin system products Žvarious amines Acute Phase response: eA rapid response to inflammation due to release of: ŽC-reactive proteins (CRP) Ž"-2 macroglobulins Žfibrinogen (Factor I) Žserum amyloid A protein (SAA)
48	Inflammation - 11 Laboratory Diagnosis of Inflammation: eMeasure the level of the following products: ŽErythrocytic Sedimentation Rate (ESR) ŽC-reactive protein (CRP) ŽInterleukin-6 (IL-6) Žfibrinogen (Factor I) Žserum amyloid A protein (SAA)
49	Inflammation - 12
50	One Step Further Hepatitis B Vaccine OSF - 2 Page 28 7click arrow to return to main program
51	HBV - 2 History: 1982 -first vaccine made available for use purified suspension of inactivated HBV surface antigens antigen obtained from chronic HBsAg carriers Now -vaccine made from recombinant HBV antigen Indications for vaccination against HBV: ePre-exposure ePost-exposure ePerinatal exposure Žhealth care professionals Žthose at increased risk for exposure to HBV Žindividuals who have been exposed to body fluids of patient who has tested positive for HBV Žif mother tests positive for HBsAg at delivery, the newborn is treated same as post-exposure patient
52	HBV - 3 Vaccination/ L protocol: ePre-exposure Ž2 doses given 1 month apart Ž3rd dose given after 6 months ePost-exposure Ždose administered within 24 hrs of exposure Žbooster given 1 month post-exposure ŽHBV immunoglobulin shot given (Ig=s to HBsAg) Žstandard immunoglobulin shot given (Ab=s from immunized individuals)
53	HBV - 4 Laboratory Testing: eImmune status confirmed by: ŽPre-vaccination testing: ŽPost-vaccination testing: HBc positive HBs positve indicates current infection HBc negative HBs positve confirms sero-conversion
54	HBV vaccine - 5 7click arrow to return to main program
55	One Step Further Vaccine Design OSF - 3 Page 30 7click arrow to return to main program
56	Vaccine Design - 2 Types of vaccine formulations (designs): eattenuated esynthetic antigen elive viral vector eSubunits eNaked DNA Attenuated vaccines: eFirst type of vaccines used eStill used for the following: ŽMycobacterium tuberculosis ŽSalmonella typhii ŽBordetella pertussis eshort-lived and limited protection eLive attenuated viral vaccines are more effective than are killed ones: ŽPolio vaccines ŽMeasles vaccines
57	Vaccine Design - 3 Synthetic Antigen Vaccines: eSynthesized peptides that resemble antigenic determinants (epitopes) of a particular infectious agent eThis type of vaccine made possible with developments in: Židentification of bacterial antigenic structure Žrecombinant DNA technology Židentification of specific epitopes eApplications of this type of vaccine include: ŽHepatitis B vaccines ŽHerpes simplex vaccines
58	Vaccine Design - 4 Live Viral vector vaccines: eUses a live recombinant viral vector (carrier) eGene that codes for the desired antigenic detrminants (epitopes) are inserted into a non-pathogenic virus eAltered virus is then used as the vaccine eApplications under investigation include: ŽHIV ŽHBV ŽHerpes simplex vaccines
59	Vaccine Design - 5 Subunit vaccines: eConsists of specific, defined regions of purified antigen from pathogenic organisms eThese subunits are capable of inducing a protective immune response eApplications under investigation include: ŽDiphtheria - tetanus toxin ŽBacterial polysaccharides of: Hemophilus influenzae Pneumococcus ŽHBsAg
60	Vaccine Design - 6 Naked DNA vaccines: einject only the DNA molecule (naked DNA) of pathogenic organism into host muscle tissue eMuscle cells incorporate naked DNA eMuscle cells then will synthesize antigenic structures of introduced DNA code
61	HBV vaccine - 7 7click arrow to return to main program