ABBAS 1

Question 1

Features of the innate immunity

Answer 1

• Provides early defence against infections by mediating RAPID initial responses against infections
• Always present in healthy individuals
• Blocks entry of microbes and rapidly eliminate those that do enter host tissue
• Only recognise and react against microbes, do not react against non-infectious foreign substances
• Enhance adaptive immune responses against infectious agents

Question 2

Features of adaptive immunity

Answer 2

o Develops more slowly
o Mediates the later, more effective, defence against infections
o Stimulated by microbes that invade tissues
o Provide defence against infectious agents that can resist innate immunity
o Adaptive response only triggered if microbes or their antigens pass thru epithelial barriers and are delivered to lymphoid organs to be recognised by lymphocytes
o Cooperates with innate immunity: Ab binds to microbes (Antigen/Ag) – coated microbes avidly bind to and activate phagocytes (component of innate immunity) – ingest and destroy microbes

Question 3

Innate immunity’s first line of defence

Answer 3

 Epithelial barriers
 Specialised cells
 Natural antibiotics
 Fxn: block microbe entry

Question 4

Innate immunity’s second line of defence

Answer 4

 Phagocytes
 Natural Killer cells (NK cells)
 Complement system

Question 5

Natural Killer cells

Answer 5

o Bone marrow derived lymphocytes of innate immune responses
o Kill microbe-infected cells
o Activate phagocytes by secreting Interferon-γ (IFN-γ)
o Do not express clonally distributed antigen receptors (Immunoglobulin for B cell; T cell receptor for T cell)
o Activation is regulated by a combination of cell surface stimulatory and inhibitory receptors – inhibitory receptors recognise self-MHC

Question 6

Complement system

Answer 6

o System of serum and cell surface proteins
o Complement proteins generate effectors of both innate and adaptive immune responses
o 3 pathways of complement activation (differ in initiation method)
1. Classical pathway: activated by antigen-antibody complexes
2. Alternative pathway: microbial surfaces
3. Mannose-binding lectin pathway: plasma lectins tt bind to microbes
o Each pathway involves a cascade of proteolytic enzymes
 Generate inflammatory mediators and opsonins for phagocytosis by macrophages and neutrophils
 Lead to formation of a lytic complex that inserts in cell membranes

Question 7

Adaptive immunity

Answer 7

2 types :
o Humoral immunity: Ab from B cells recognise antigens produced by extracellular microbes
o Cell-mediated immunity: T cells recognise antigens produced by intracellular microbes

Question 8

Humoral Immunity

Answer 8

o Mediated by antibodies produced by B lymphocytes
o Ab secreted into circulation and mucosal fluids
o Ab neutralise and eliminate microbes and microbial toxins
 Outside of host cells
 In blood
 In lumens of mucosal organs eg. GIT, respiratory tract
o Fxn of Ab
 Stop microbes at mucosal surfaces and in blood from colonising host cells and connective tissues
 Prevent infections from getting established by blocking their ability to infect host cells
o Ab cannot gain access to microbes within infected cells -> cell-mediated immunity (T lymphocytes)
o Ab produced by B cells can recognise diff types of molecules (protein, carb, lipid)

Question 9

Cell mediated immunity

Answer 9

o For intracellular microbes
o T lymphocytes
 Activate phagocytes to destroy microbes ingested by phagocytes into intracellular vesicles
 Kill infected host cells (harbouring infectious microbes in cytoplasm)
 Most T cells can only recognise protein Ag

Question 10

Induced immunity

Answer 10

• Active immunity

- Passive immunity

Question 11

Induced active immunity

Answer 11

Induce immunity by infection or vaccination

Question 12

Induced passive immunity

Answer 12

o Confer immunity onto naive individual (not previously exposed to microbe’s antigens) by transferring Ab or lymphocytes from an actively immunised person
o Useful for rapidly conferring immunity even before individual is able to mount an active response
o Does not induce long-lived resistance to infection
o Eg. Newborns are protected against infections thru acquiring Ab from mothers via placenta and milk since own immune system immature to respond to pathogen

Question 13

Properties of adaptive

Answer 13

1. Specificity and diversity
2. Memory
3. Clonal expansion
4. Self-limited immune response
5. Self tolerance

Question 14

1. Specificity and diversity

Answer 14

 Specific for many diff antigens
 Lymphocyte repertoire (total collection of lymphocyte specificities) is very diverse
 Lymphocytes express clonally distributed receptors for Ags
o Many different clones
o Each clone expresses an Ag receptor diff from the receptors of the other clones
 Clonal selection
o Clones of lymphocytes specific for diff Ags arise before encounter with Ags
o Each Ag elicits an immune response by selecting and activating lymphocytes of a specific clone
 At natural state, very few cells are specific for any 1 Ag
 To mount effective defence
o The few cells proliferate to generate a large number of cells
o Marked expansion of the pool of lymphocytes specific for any Ag subsequent to exposure to that Ag
o Positive feedback loops that amplify immune responses
o Selection mechanisms that preserve the most useful lymphocytes

Question 15

2. Memory of adaptive immunity system

Answer 15

 Larger and more effective responses to repeated exposures to the same Ag
 Primary immune response = response to the 1st exposure to Ag
o Mediated by naive lymphocytes (seeing Ag for the 1st time)
 Secondary immune response = subsequent encounters with the same Ag
o More rapid, larger, better able to eliminate Ag
o Memory lymphocytes (long-lived cells induced during primary immune response) activated
 Immunologic memory optimises ability of immune system to combat persistent and recurrent infections since each encounter generates more memory cells and activates previously generated memory cells
 Vaccines confer long-lasting protection against infections due to memory

Question 16

3. Clonal Expansion

Answer 16

 When lymphocytes are activated by Ag
o Undergo proliferation
o Generate many clonal progeny cells, all with same Ag specificity
 Ensures adaptive immunity keeps pace with rapidly proliferating microbes

Question 17

4. Self-limited immune response

Answer 17

 Immune response declines as infection is eliminated

 System returns to normal state

Question 18

5. Self-tolerance

Answer 18

 Does not react against host’s own potentially antigenic substances: self-antigens

Question 19

Lymphocytes Features

Answer 19

 Express receptors for Ags
 Mediate immune response
 Innate: NK cells
 Adaptive: B and T cells
 Morphologically similar but heterogeneous in lineage, fxn and phenotype
 Distinguishable by surface proteins (monoclonal antibodies) – Cluster of Differentiation (CD)
 CD is recognised by a cluster or group of Abs

Question 20

Maturation of lymphocytes

Answer 20

 Arise from stem cells in bone marrow
 Site of maturation (Generative lymphoid organs)
o B cell: bone marrow
o T cell: thymus
 Mature lymphocytes leave generative lymphoid organs, enter circulation and peripheral lymphoid organs
 10¹² lymphocytes in circulation and lymphoid tissues
 Ag-specific lymphocytes proliferate and differentiate into effector and memory cells upon contact of microbial Ags

Question 21

B cells functions

Answer 21

o Express membrane forms of Abs – serve as receptors that recognise Ags
o Initiate process of activation of cells

Question 22

T cells functions

Answer 22

o Ag receptors only recognise peptide fragments of protein Ags bound to specialised peptide display molecules – Major Histocompatibility Complex (MHC) molecules – on APCs
o Helper T cells (CD4+ T cells)
 Help B cells produce Abs
 Help phagocytes destroy ingested microbes
 Prevent or limit immune response (regulatory T lymphocytes)
o Cytotoxic/cytolytic T lymphocytes(CTLs) (CD8+ T cells)
 Lyse cells harbouring intracellular microbes

Question 23

NK cells functions

Answer 23

o Kill infected host cells
o Do not express clonally distributed Ag receptors (unlike B and T cells)
o Rapidly attack infected cells

Question 24

Naive Lymphocytes functions

Answer 24

o Kill infected host cells
o Do not express clonally distributed Ag receptors (unlike B and T cells)
o Rapidly attack infected cells

Question 25

Effector cells functions

Answer 25

o Differentiated progeny of naive cells o Can produce molecules to eliminate Ags o B effector: plasma cells (Ab-secreting cells) o T effectors  CD4+ (Helper T cells): produce cytokines – activate B cells and macrophages  CD8+ (CTLs): kill infected host cells o Short-lived o Die as Ag is eliminated o Some may migrate to special anatomic sites and live for long, esp plasma cells

Question 26

Memory cells functions

Answer 26

o Survive for long time even in absence of Ag o Frequency of cells increase with age due to exposure to environmental microbes o Functionally inactive – do not perform effector fxns unless stimulated by Ag

Question 27

Antigen Presenting Cells (APCs)

Answer 27

```  Located in common portals of entry of microbes o Skin o GIT o Respiratory tract  Action o Capture Ag o Transport Ag to peripheral lymphoid tissues o Display Ag to lymphocytes ```

Question 28

Antigen presentation to T lymphocytes by APC

Answer 28

Professional APCs (specialised cells tt display Ags to T cells and provide additional activating signals) o Dendritic cells (DC) 1. Capture protein Ag of microbes 2. Transport Ag to regional lymph nodes 3. Display parts of Ag for recognition by T lymphocytes o Macrophages 1. Phagocytose microbes that invade epithelium 2. Present protein Ag to T cells  Respond to microbes by producing surface and secreted proteins req tog with Ag to activate naive T lymphocytes to proliferate and diff into effector cells

Question 29

Antigen presentation to B lymphocytes by APC

Answer 29

o B cells may directly recognise Ags of microbes (released or on microbial surface) o Macrophages lining lymphatic channels capture Ags, display to B cells o Follicular dendritic cells (FDC) - Reside in germinal centres of lymphoid follicles in peripheral lymphoid organs - Display Ags that stimulate diff of B cells in follicles - Do not present Ag to T cells

Question 30

Effector cells - Leukocytes

Answer 30

Innate immunity 1. Granulocytes 2. Macrophages Leukocytes directly recognise microbes, eliminate

Question 31

Macrophages

Answer 31

 Tissue-based phagocytic cell derived from blood monocytes  Innate and adaptive immune responses  Activated by 1. Microbial products eg. Endotoxin (aka lipopolysaccharide (LPS); component of bacterial cell wall; stimulates cytokine secretion, induce microbicidial activities of macrophages, stimulate exp of adhesion molecules for leukocytes on endothelium; contains lipid and carb components; recognised by Toll-Like Receptors (TRLs)/Pattern Recognition Receptors expressed by effector cells) 2. Molecules eg. CD40 ligand (CD40L) 3. T cell cytokines eg. Interferon-γ (IFN-γ)  Different forms – microglia (CNS), Kupffer cells (liver), alveolar macrophages (lung), osteoclasts (bone)

Question 32

Lymphoid organs

Answer 32

Primary - Sites of T and B lymphocyte maturation Eg. Bone marrow , Thymus , Foetal liver Secondary - Where adaptive immune responses to microbes are initiated Eg. Lymph nodes , Spleen , Mucosal and cutaneous immune system (Mucosal Associated Lymphoid Tissues - MALT)

Question 33

Functions of Secondary Lymphoid organs

Answer 33

o Optimise interaction of Ags, APCs and lymphocytes to promote devp of adaptive immune responses o Anatomic organisation enables APCs to concentrate Ags in these organs o Enable lymphocytes to locate and respond to Ags o Bring helper T cells tog with B cells (both specific for the same Ag) together for productive interaction

Question 34

Lymph Nodes

Answer 34

o Lymph is drained from tissues and epithelia to the nodes via lymphatics o Lymph enters via afferent lymphatic vessels and leaves via efferent o Act as filters and slow down flow of lymph o Dendritic cells pick up Ags of microbes from epithelia, transport to lymph nodes o Microbial Ags that enter thru epithelia or colonise tissues become concentrated in draining lymph nodes o Lymph-borne Ags o As lymph passes thru lymph nodes, APCs in nodes sample Ags of microbes in lymph o Lymphocytes in lymph can trap + phagocytose any foreign antigen o B and T cells enter and leave via systemic circulation o Diff. regions for B and T cells o Medullary sinus à macrophages, direct to T cell or B cell area depending on response needed

Question 35

Spleen

Answer 35

o Filter Blood-borne Ags o Blood entering spleen flows thru sinusoids (network of channels) o White pulp = lymphoid tissue o Distinct T and B cell zones o Ags are trapped and concentrated by DC and macrophages in spleen o Contains abundant phagocytes – ingest and destroy microbes in blood o Afferent and efferent lymphatic vessels o Arterial and venous connections

Question 36

Cutaneous and mucosal lymphoid systems

Answer 36

o Cutaneous lymphoid system: under skin epithelia, e.g. Langerhans cells (type of DC) o Mucosal lymphoid system: under epithelia of GIT and respiratory tracts o Mucosal lymphoid tissues  Pharyngeal tissues  Peyer’s patches (Intestine - large collection of lymphocytes – mainly B cells) o Sites of immune responses to Ags that breach epithelia

Question 37

B cell organisations in Lymph Nodes

Answer 37

 Concentrated in follicles located around the periphery/cortex of each node  Follicles contain FDCs (in close proximity to B cells)– activate B cells by secreting chemokines all the time, attracting B cells from blood into follicles; chemokines are chemoattractant cytokines – stimulate WBC movement, regulate WBC migration from blood to tissues; naive B cells express receptor for chemokines  Germinal centre: central region of follicle if B cells have recently responded to Ag

Question 38

Anatomical organisation of | B lymphocytes in Spleen

Answer 38

Within Follicles

Question 39

Anatomical organisation of T lymphocytes in Lymph Nodes

Answer 39

 Concentrated outside, and adjacent to follicles, in the paracortex  Paracortex contains DCs – present Ag to T cell

Question 40

Anatomical organisation of T lymphocytes in Spleen

Answer 40

 Concentrated in periarteriolar lymphoid sheaths surrounding small arterioles

Question 41

Naive T cells organisation

Answer 41

o Naive T cells express receptor CCR7 – recognise chemokines produced in regions of lymph nodes and spleen that contain T cells – recruit T cells from blood

Question 42

Upon activation of lymphocytes by microbial antigens

Answer 42

o Lymphocytes alter exp of chemokine receptors o B and T cells migrate toward each other, meet at edge of follicles o Helper T cells interact with and help B cells differentiate into Ab-producing cells o Activated lymphocytes exit node via efferent lymphatic vessels, exit spleen via veins – go into circulation and distant sites of infection

Question 43

Lymphocytes recirculation and migration into tissues

Answer 43

 Naive lymphocytes constantly recirculate bt blood and peripheral lymphoid organs  Activated by Ags to become effector cells  Effector cells o T cells: migrate to sites of infection o B cells - remain in lymphoid organs - Do not migrate to sites of infection - Secrete Abs which enter blood and find microbes and toxins in circulation

Question 44

Naive T cells recirculation

Answer 44

 Mature in thymus and leave to migrate to lymph nodes  Enter lymph nodes thru high endothelial venules (HEVs), specialised postcapillary venules  Express surface receptor L-selectin (protein involved in cell-cell adhesion) – binds to carb ligands expressed only on endothelial cells of HEVs  Bind loosely to HEVs due to interaction of L-selectin with its ligand  Chemokines produced in T cell zones of lymph nodes cause naive T cells to bind strongly to HEVs – migrate thru HEVs into region where Ags are displayed by DCs  Scan surfaces of DCs searching for Ags in lymph node  Recognise antigen, T cell transiently arrested on antigen-presenting DC, forms stable conjugate with APCs – activated T cell  Most T cells in body circulate thru some lymph nodes at least once a day  Likelihood of correct T cell finding its Ag increased in peripheral lymphoid organs since Ags are concentrated there – T cells circulate same areas  Upon activation of T cells, 1. Cells reduce exp of adhesion molecules and chemokine receptors tt keep naive cells in lymph nodes 2. Increase expression of receptors for phospholid (sphingosine-1-phosphate) of which conc is higher in blood – cells are attracted out of nodes into circulation 3. Differentiated effector T cells thus leave nodes and enter circulation

Question 45

B lymphocytes circulation

Answer 45

o Enter lymph nodes thru HEVs o Upon Ag contact differentiated progeny  Remain in lymph nodes  Migrate to bone marrow

Question 46

How does epithelial serve as first line of defence in innate immunity?

Answer 46

1. Physical and functional barriers to infection 2. Impede entry of microbes 3. Interfere with growth of microbes thru production of natural antimicrobial agents

Question 47

Phagocytes

Answer 47

1. Neutrophils and macrophages 2. Ingest microbes into vesicles 3. Destroy them by producing microbicidal substances in vesicles

Question 48

Cytokines

Answer 48

1. Soluble proteins secreted by macrophages, DCs and NK cells 2. Stimulate inflammation and lymphocyte response

Question 49

Development of response

Answer 49

1. Capture and display of microbial Ags 2. Cell-mediated immunity: activation of T cells and elimination of cell-associated microbes 3. Humoral immunity: activation of B cells and elimination of extracellular microbes

Question 50

Adaptive step 1. Capture and display of microbial antigens

Answer 50

 Microbes and protein Ags captured by DCs resident in epithelia  Cell-bound Ags transported to draining lymph nodes  Protein Ags processed in DCs – generate peptides – displayed on APC surface bound to Major Histocompatibility Complexes (MHCs)  Naive T cells recognise peptide-MHC complexes  B cells recognise polysaccharide, protein and non-protein Ags  T cells only recognise protein Ags  Innate immune response o DCs presenting Ags to naive T cells express costimulators and secrete cytokines – stimulate proliferation and differentiation of T lymphocytes o Activate complement system – generate cleavage products of complement proteins tt enhance proliferation and diff of B lymphocytes  Antigen (signal 1) and molecules produced from innate immune response (signal 2) cooperate to activate Ag-specific lymphocytes-> Adaptive immune response  Signal 2 is only triggered by microbes, thus ensuring tt adaptive immune response is induced by microbes, not harmless substances  Ag and costimulator receptors engaged -> signals generated in lymphocytes -> transcription of genes that encode o Cytokines o Cytokine receptors o Effector molecules o Proteins tt control cell cycling

Question 51

Major Histocompatibility protein (MHC)

Answer 51

o Heterodimeric membrane protein o Serves as a peptide display molecule for recognition by T lymphocytes o 2 classes 1. MHC Class I: present on all nucleated cells (thus absent in RBC), bind peptides from cytosolic proteins, recognised by CD8+ T cells - Present peptides derived from degradation of viral and other cytosolic proteins - Degradation of proteins is mediated by cytosolic and nuclear proteasomes (protein complexes that use proteases to degrade unneeded proteins) 2. MHC Class II: restricted to professional APCs, macrophages, B lymphocytes; bind peptides from endocytosed proteins, recognised by CD4+ T cells Activated T helper cells produce cytokines to activate other cells such as B cells - Bind to peptides that are derived from proteins degraded in endocytic pathway i.e. phagocytosed pathogens that are degraded

Question 52

Adaptive step 2. Cell-mediated immunity

Answer 52

 Naive T cells o Activated by Ag and costimulators in lymphoid organs o Secrete cytokine growth factors and respond to cytokines secreted by APCs  Ag + costimulation + cytokine -> proliferation of T cells and differentiation into effector T cells  Naive CD4+ T cells -> Helper T cells o Produce cytokines o Express cell surface molecules tt bind to receptors on B cells and macrophages -> promote Ab production and macrophage killing of ingested microbes o Recruit and activate neutrophils (polymorphonuclear leukocyte (PMN), most abundant WBC, recruited to inflammatory sites, phagocytoses and digests microbes enzymatically) -> destroy microbes  Naive CD8+ T cells -> CTLs o Directly kill cells harbouring microbes in cytoplasm o Usually viruses that escape from phagocytic vesicles into cytoplasm where they are inaccessible to killing machinery of phagocytes (confined to vesicles)

Question 53

Adaptive step 3. Humoral Immunity

Answer 53

 Activated B cells proliferate and differentiate into plasma cells -> secrete Abs  Many polysaccharide and lipid Ags have multiple identical antigenic determinants/epitopes (specific portion of a macromolecular Ag to which Ab binds; for T cell, epitope is peptide portion tt binds to MHC for TCR recognition)  Epitopes able to engage many Ag receptor molecules on each B cell -> initiate B cell activation  Globular protein Ags unable to bind to many Ag receptors -> full response of B cells to protein Ag requires CD4+ helper T cells  B cells ingest protein Ags -> degrade Ags -> display peptides bound to MHC for recognition by helper T cells  Helper T cells express cytokines and cell surface proteins – work tog to activate B cells  Each B cell secretes Abs tt have the same Ag-binding site as the BCR that first recognised Ag  Polysaccharides and lipids stimulate secretion of IgM  Protein Ags stimulate helper T cells -> induce production of IgG, IgA and IgE  Heavy chain class (isotype) switching  Affinity maturation

Question 54

Heavy chain class switching

Answer 54

o Process by which a B cell changes the isotype of Abs it produces, but with same Ab specificity o Change from IgM to IgG, IgA or IgE without changing Ab specificity o Regulated by helper T cell cytokines and CD40 ligand o Involves recombination of heavy chain VDJ segments with downstream constant region gene segments o Provide plasticity in Ab response, enable Abs to serve many fxns

Question 55

Affinity Maturation

Answer 55

o Process tt leads to increased affinity of Abs for a protein Ag as a humoral response progresses o Results from somatic mutation of Ig genes followed by selective survival of B cells producing highest affinity Abs o Helper T cells help in Ab production with higher affinity for Ag o Increases quality of humoral immune response

Question 56

Decline of immune response and immunological memory

Answer 56

 Most effector lymphocytes induced by pathogen die by apoptosis after microbe is eliminated -> homeostasis  Microbes provide essential stimuli for lymphocyte survival and activation  Effector cells are short-lived  As stimuli eliminated, activated lymphocytes not kept alive  Long-lived memory cells o Can survive for years after infection o Expanded pool of Ag-specific lymphocytes (more than Ag-specific naive cells present before encounter with Ag) o Respond faster and more effectively than naive cells o Goal of vaccination: generate memory cells