ABBAS 1 Flashcards
Features of the innate immunity
- 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
Features of adaptive immunity
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
Innate immunity’s first line of defence
Epithelial barriers
Specialised cells
Natural antibiotics
Fxn: block microbe entry
Innate immunity’s second line of defence
Phagocytes
Natural Killer cells (NK cells)
Complement system
Natural Killer cells
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
Complement system
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
Adaptive immunity
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
Humoral Immunity
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)
Cell mediated immunity
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
Induced immunity
- Active immunity
- Passive immunity
Induced active immunity
Induce immunity by infection or vaccination
Induced passive immunity
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
Properties of adaptive
- Specificity and diversity
- Memory
- Clonal expansion
- Self-limited immune response
- Self tolerance
- Specificity and diversity
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
- Memory of adaptive immunity system
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
- Clonal Expansion
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
- Self-limited immune response
Immune response declines as infection is eliminated
System returns to normal state
- Self-tolerance
Does not react against host’s own potentially antigenic substances: self-antigens
Lymphocytes Features
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
Maturation of lymphocytes
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
B cells functions
o Express membrane forms of Abs – serve as receptors that recognise Ags
o Initiate process of activation of cells
T cells functions
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
NK cells functions
o Kill infected host cells
o Do not express clonally distributed Ag receptors (unlike B and T cells)
o Rapidly attack infected cells
Naive Lymphocytes functions
o Kill infected host cells
o Do not express clonally distributed Ag receptors (unlike B and T cells)
o Rapidly attack infected cells
Effector cells functions
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
Memory cells functions
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
Antigen Presenting Cells (APCs)
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
Antigen presentation to T lymphocytes by APC
Professional APCs (specialised cells tt display Ags to T cells and provide additional activating signals)
o Dendritic cells (DC)
- Capture protein Ag of microbes
- Transport Ag to regional lymph nodes
- Display parts of Ag for recognition by T lymphocytes
o Macrophages
- Phagocytose microbes that invade epithelium
- 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
Antigen presentation to B lymphocytes by APC
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
Effector cells - Leukocytes
Innate immunity
- Granulocytes
- Macrophages
Leukocytes directly recognise microbes, eliminate
Macrophages
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)
Lymphoid organs
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)
Functions of Secondary Lymphoid organs
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
Lymph Nodes
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
Spleen
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
Cutaneous and mucosal lymphoid systems
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
B cell organisations in Lymph Nodes
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
Anatomical organisation of
B lymphocytes in Spleen
Within Follicles
Anatomical organisation of T lymphocytes in Lymph Nodes
Concentrated outside, and adjacent to follicles, in the paracortex
Paracortex contains DCs – present Ag to T cell
Anatomical organisation of T lymphocytes in Spleen
Concentrated in periarteriolar lymphoid sheaths surrounding small arterioles
Naive T cells organisation
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
Upon activation of lymphocytes by microbial antigens
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
Lymphocytes recirculation and migration into tissues
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
Naive T cells recirculation
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
B lymphocytes circulation
o Enter lymph nodes thru HEVs
o Upon Ag contact differentiated progeny
Remain in lymph nodes
Migrate to bone marrow
How does epithelial serve as first line of defence in innate immunity?
- Physical and functional barriers to infection
- Impede entry of microbes
- Interfere with growth of microbes thru production of natural antimicrobial agents
Phagocytes
- Neutrophils and macrophages
- Ingest microbes into vesicles
- Destroy them by producing microbicidal substances in vesicles
Cytokines
- Soluble proteins secreted by macrophages, DCs and NK cells
- Stimulate inflammation and lymphocyte response
Development of response
- Capture and display of microbial Ags
- Cell-mediated immunity: activation of T cells and elimination of cell-associated microbes
- Humoral immunity: activation of B cells and elimination of extracellular microbes
Adaptive step 1. Capture and display of microbial antigens
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
Major Histocompatibility protein (MHC)
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)
- 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
Adaptive step 2. Cell-mediated immunity
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)
Adaptive step 3. Humoral Immunity
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
Heavy chain class switching
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
Affinity Maturation
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
Decline of immune response and immunological memory
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
