Immunology 1

Question 1

Primary lymphoid organs

Answer 1

· Where lymphocytes (B, T and NK cells) are produced

· E.g. à thymus, bone marrow, foetal liver

· B cells produced in bone marrow – bone marrow is primary site of haematopoiesis

· Immature T cells formed in bone marrow and migrate to thymus to mature

Question 2

Primary lymphoid organ - T Cell Selection in Thymus

Answer 2

o Stepwise differentiation

o Positive selection à can the TCR signal?

o Negative selection à does cell react against our own body? – important as this protects against autoimmune disease

o Final selection and exit

· Thymic involution è thymus shrinks/atrophies as we age, functional tissue gets replaced w/fat

o total thymic output of new T cells decreases BUT no. T cells in repertoire stays the same

Question 3

Secondary lymphoid organs - Spleen

Answer 3

o Filter antigens that are found in the blood

o White pulp = lymphoid tissue

o Distinct T and B cell zones

o Afferent and efferent lymphatic vessels

o Arterial and venous connections

Question 4

Secondary lymphoid organs - Lymph nodes

Answer 4

o Act as filters and slow down flow of lymph

o Contain lymphocytes which can trap + phagocytose any foreign antigen

o Lymph enters via afferent lymphatic vessels and leaves via efferent

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 5

Secondary lymphoid organs - Mucosa associated lymphoid tissue (MALT)

Answer 5

o Defends epithelium

o Specialised tissues called Peyer’s patches in gut (large collection of lymphocytes – mainly B cells)

o Cutaneous immune system e.g. Langerhans cells (type of DC)

Question 6

Secondary Lymphoid organs

Answer 6

· Where lymphocytes can interact with antigens and other lymphocytes

· E.g. à spleen, lymph nodes, appendix, mucosal associated lymphoid tissue – all interconnected via lymphatic system and blood

· Bring cells in close proximity to antigen

Question 7

Dendritic cells

Answer 7

· Dendritic cells present antigens

· Migrate to lymph nodes via afferent lymph vessels

· Present antigens to T cells

· T cells enter lymph nodes through high endothelial venules and move around within T cell area à transiently interact w/large no. of dendritic cells à leave node via efferent lymphatic vessels

Characteristics :
APC
Bridge between innate and adaptive immune systems

Effective against : For activation of adaptive immunity

Activating factors : Phagocytosis
Recogition of PAMPs

Effector mechanism : Costimulatory molecules

Upregulate MHC

Cytokine secretion

Migrate to lymph node for T cell maturation/ B cell

Question 8

Lymphotcytes

Answer 8

Summarise how T-lymphocytes and B-lymphocytes recognise antigen and are subsequently activated.

· Repertoire à range of genetically distinct BCRs or TCRs

· Antigen à molecules that induce an adaptive immune response, mostly protein, large signalling molecules normally not found in the body which act as ‘red flags’ activating the immune system

· Epitope à small areas of molecular structures of foreign antigen

Question 9

B Lymphocytes

Answer 9

· Humoral immunity

· B cell receptor: membrane bound antibodies (membrane bound antibody will be the same as that produced by activated plasma cell)

· Activated to become plasma cells which produce antibodies à neutralisation, opsonization, agglutination

o NEUTRALISATION è antibody prevents bacterial adherence

o OPSONIZATION è antibody promotes phagocytosis

o COMPLEMENT ACTIVATION è antibody activates complement, which enhances opsonization and lyses some bacteria

Question 10

Antibodies

Answer 10

o 4 protein chains à 2 heavy + 2 light

o Made of Fab and Fc regions

o Linked by intermolecular disulphide bonds

o Each heavy chain has variable and constant region

§ CONSTANT REGION – identical in all antibodies of same isotype/class, but differs in antibodies of diff. isotypes

§ VARIABLE REGION – differs depending on B cell that produce it, but is same for all antibodies produced by single B cell or B cell clone

o 5 types à IgG (most common), IgA (dimer), IgM (pentamer), IgE, IgD

§ Antibody isotypes/classes differ in biological properties, functional locations and ability to deal w/different antigens

o First BCR is an IgM

Question 11

IgG

Answer 11

· Most prevalent antibody molecule in serum

· Survives intact om serum for longest time

· Able to cross placenta to allow maternal protection of newborn

· Important in cell-mediated cytotoxicity, fighting viruses and toxins

Question 12

IgA

Answer 12

· Main Ig in secretions (saliva, breast milk, tears) and mucosal epithelia (respiratory, genital and intestinal tracts)

· Dimeric in secretions – consists of 2x IgA molecules, J chain and molecule of secretory component which protects molecule from proteolytic attack + facilitates its transfer across epithelial cells into secretions

Question 13

IgM

Answer 13

· Predominant antibody in early immune response

· Pentameric structure – 5 Ig units held together by J chain and disulphide bonds

· 10 potential antigen binding sites so very efficient at agglutination of bacteria and activation of complement pathway

Question 14

IgE

Answer 14

· Involved in protection against parasitic infections

· Binding of antigen to IgE coupled w/an Fc receptor on mast cells and basophils è triggers an allergic reaction by activation of mast cells and release of mediators like histamine

Question 15

IgD

Answer 15

· Mainly found on surface of B cells as receptor molecules (BCR)

· Involved in B cell activation

Question 16

Antibodies variations

Answer 16

Diff B cells produce antibodies w/ diff. antigen-binding regions – diversity achieved by immunoglobulin gene rearrangement

· Somatic recombination à process of gene segment rearrangement that occurs to create a repertoire of antigen receptors

o As B cell develops, unused genes in each array are cut out so that only one gene of each multigene family/region gets passed down

· VDJ and VJ recombinases are responsible for looping and cleavage of immunoglobulin genes – also randomly add or remove nucleotides to create a viable joint between both DNA fragments

o Heavy chain undergoes VDJ rearrangement first

o Then light chain undergoes VJ rearrangement

· VDJ recombinase cuts extra genes we don’t want, splices together 2 wanted genes (variable + joining genes variety creates diversity)

· SCID (severe combined immunodeficiency) – due to mutations in genes coding for V(D)J recombinase - characterised by variation of VDJ enzymes

· Diversity generated by:

o 1. Germline diversity

o 2. Combinational diversity

o 3. Junctional diversity

o 4. Heavy + light chain diversity

o 5. Somatic hypermutation – antigen induces point mutations in variable regions

· Negatively select self-reactive B cells

· B receptor is a membrane bound antibody paired w/accessory immunoglobulin heterodimer to enhance signal transduction

Question 17

Activation of B cells

Answer 17

o B cell activated by antigen binding to IgM BCR

o Short-lived plasma cell produced to trigger apoptosis OR germinal centre formed à long-lived plasma cell, memory B cell (using affinity selection or class-switching)

o Germinal centre

§ Specialised structure within which B cells undergo rounds of proliferation accompanied by affinity maturation

§ Iterative process of

o T cell independent activation

§ Polysaccharides on surface of bacteria + binding to antigen itself

§ Don’t need T cells

§ Only IgM

§ No memory

§ Repeating carbohydrate subunits on bacteria (bacterial polysaccharides, cell wall components) engage multiple BCRs overcoming the need for a second signal

§ No affinity maturation nor class switching (only low affinity IgMs)

o T cell dependent activation

§ T cell has recognised antigen and binds to B cell

§ Initiates greater immune response

§ All Ig classes

§ Has memory

§ Antigen engulfed and processed by B cell and by dendritic cell which express on their surface à recognised by T helper cells à cytokine release à B cell activation (rapid division and differentiation into plasma or memory cells) + class switching

Question 18

T Lymphocytes - T helper cells (CD4)

Answer 18

release cytokines to induce a response from other immune cells

o Main ones include Th1, Th2, Treg, Th17, Tfh

o Th1 à pro-inflammatory, boost cellular immune response è IFN gamma, TNF, IL-12

o Th2 à pro-allergic, boost multicellular response è IL-4, IL-5, IL-13

o Tfh à pro-antibody è IL-21

o Th17 à pro-inflammatory, control bacterial and fungal infection è IL-17, IL-23, IL-6

o Treg (Th0) à anti-inflammatory, limits immune response è IL-10, TGF beta

Question 19

T lymphocytes - cytotoxic T cell (CD8)

Answer 19

kill infected cells or tumour cells by inducing apoptosis (3 major mechanisms to kill infected or malignant cells)

o 1. Secrete IFN gamma and TNF

§ Have anti-tumour and anti-viral microbial effects

o 2. Production and release of cytotoxic granules

§ Cytotoxic granules (also found in NK cells) contain 2 families of proteins à perforin and granzymes

§ Perforin à forms pore in membrane of target cell, similar to MAC of complement

§ Pore allows granzymes also contained in granules to enter infected or malignant cell

§ Granzymes à serine proteases which cleave proteins inside cells, shutting down production of viral proteins + ultimately resulting in apoptosis of target cell

§ 1. Granule exocytosis

§ 2. Perforin injected on target cell surface

§ 3. Pore opened

§ 4. Granzymes into cell activating caspase enzyme à apoptosis

o 3. FAS – FAS Ligand interactions

§ Activated CD8+ T cells express Fas ligand which binds to Fas receptor on surface of target cell

§ Binding causes Fas molecules on surface of target cells to form a trimer which pulls together signalling molecules

§ Signalling molecules result in activation

§ Because CD8+ T cells can express both molecules, Fas/FasL interactions are a mechanism by which CD8+ T cells can kill each other à used to eliminate immune effector cells during contraction phase at end of immune response

Question 20

Major Histocompatibility Complex (MHC) and T cell receptors (TCR)

Answer 20

· MHC haplotype à combination of MHC alleles found together on a single chromosome

· TCR like Fab (variable) part of antibody à beta homologous to heavy chain, alpha to light etc.

o All TCRs associated w/CD3 complex – important in signal transduction

o Recognise antigens which have been taken in, processed and presented on surface of APCs (B cells, dendritic cells, macrophages)

o Antigen presented on MHC

o TCRs also have co-receptors e.g. CD4, CD8 which stabilise MHC-TCR binding

· MHC is polygenic and polymorphic

o Several class I and class II loci

o Diff. genes for one thing à diff. genes combine to form diff. classes

o MHC is highly polymorphic à lots of alleles – ensures wide variety of MHC to recognise diff. pathogens

o Ensures wide variety of MHC to recognise diff. pathogens

Question 21

CD4 works with MHC II

Answer 21

o 2 transmembrane proteins

o Present in professional APCs only

o Accommodates longer polypeptides

o Presents extracellular antigens

§ 1. Extracellular antigen phagocytosed into an endosome

§ 2. Endosome fuses w/lysosome and antigen is digested

§ 3. In meantime MHC II synthesised in ER, invariant chain blocks peptide binding groove

§ 4. Vesicle containing MHC II buds from ER and fuses with lysosome

§ 5. IC degraded allowing MHC II-antigen complex to form

§ 6. Complex transported to and expressed on cell surface

Question 22

CD8 works with MHC I

Answer 22

o Present in all nucleated cells

o 1 transmembrane component

o Accommodates shorter polypeptides

o Presents intracellular antigens

§ 1. Proteins from intracellular pathogen digested by a proteasome

§ 2. Antigen peptides are transported via TAP (transporter associated w/antigen presentation) into ER

§ 3. In the meantime, MHC class I synthesised in ER

§ 4. Within the ER, MHC I – antigen complex forms

§ 5. Complex transported to and expressed on cell surface

Question 23

Bacteria

Answer 23

· Prokaryotes

· No internal membranes

· Haploid à single copy of chromosomes in cytoplasm

· Different organelles e.g. 70s ribosome

· Poorly defined cytoskeleton

· Cell wall contains peptidoglycan à can have diff. shapes e.g. coccus, rod etc.

· Divide by binary fission

· Can use flagellum to move

· Examples:

o Shigella – faecal-oral transmission

o Neisseria meningitidis – rapid progression, septic shock, severe inflammatory response

o Clostridium difficile + MRSA – hospital acquired

o TB

o Leprosy – transmitted by nasal discharge

o E. Coli

· NEISSERIA MENINGITIDIS:

o Gram -ve diplococci

o Nose and throat commensal

o Causes meningitis

o Symptoms à headaches, photophobia, sepsis, 10% fatality, can infect immunosuppressed

· MYCOBACTERIUM TB:

o Intra-cellular rod

o Causes TB

o Respiratory disease but can be systemic

o Abscesses

o Very hard to treat, can be lifelong

Question 24

Viruses

Answer 24

· Obligate parasites

· Contain RNA or DNA (single or double stranded)

· Use host cell machinery to replicate à ribosomes etc.

· Divide by budding out of host cell or cytolysis

· Transmission à blood (HIV, hepatitis), airborne (influenza), vectors, faecal-oral

· Examples:

o HIV

o Smallpox

o Polio

o HPV

· HIV

o ssRNA virus

o reverse transcriptase (turns RNA into DNA to insert into host genomes)

o infects T cells

o leads to AIDs

o very low CD4 T cell count à increased risk of infection

Question 25

Fungi

Answer 25

· Single celled eukaryotes

· Yeast, filaments (hyphae) or combination

· Yeast replicate by budding/dividing

· Filaments spread by extending

· Opportunistic à cause cutaneous, mucosal and/or systemic disease/mycoses e.g. if immunosuppressed

· CANDIDA ALBICANS

o Combination yeast + filaments (depending on environment)

o Natural yeast in our bodies – commensal of mouth and skin but opportunistic

o Can cause candiasis (thrush) – cutaneous, mucosal spread, inflamed

Question 26

Protozoa

Answer 26

· Unicellular eukaryotic organisms

· Lifecycle involving 2 or more hosts

· Transmission by vectors

· Replicated in host by binary fission or formation of trophozoites inside cell (asexual reproduction)

· Infection acquired by ingestion or through a vector e.g. insect or invertebrate vector

· PLASMODIUM FALCIPARUM

o Mosquito vector

o Infects liver + blood cells to develop and reproduce

o In humans replicates asexually

o Can cause malaria

o Symptoms à fever, headache, anaemia, malaise, hepatosplenomegaly (large liver + spleen), jaundice

· LEISHMANIA SPP.

o Replicates in blood, immune cells + other tissues

o Replicates by binary fission

o Sandfly vector

o 3 forms: cutaneous, mucocutaneous, visceral

o Can cause leishmaniasis – skin, mucous membrane, lesions, hepatosplenomegaly etc.

Question 27

Helminths

Answer 27

· Multicellular eukaryotes

· Parasitic worms

· Life cycles including human hosts

· Reproduce sexually w/adult forms shedding eggs

· Diff types à roundworms, flatworms (flukes), tapeworm

· SCHISTOSOMA SPP.

o Flatworm

o Life cycle involves water snail, then enters humans

o Causes schistosomiasis

o Symptoms depend on where egg deposits e.g. in GI, GI symptoms

Question 28

Immune response to infection

Answer 28

· Steps of the immune response to infection

o Microbial detection à bacteria, fungi, protozoa, viruses etc.

o Innate immune response à epithelia, phagocytes (neutrophils, macrophages, DCs), NK cells, innate lymphoid cells

o Adaptive immune response à lymphoid tissues, T and B lymphocytes, antibodies, cytotoxic T cells

o Memory response à memory T and B cells, quick and specific response, life-long immunity

RECOGNITION -> REACTION -> ACTIVATION + RESPONSE -> RESOLUTION

· INNATE RESPONSE – provides rapid pre-programmed responses as a first line defence

· ADAPTIVE RESPONSE – takes longer, but more specific + can produce immunological memory

· RESOLUTION – after successful resolution of an infection, must have regulatory control to bring system back to its normal resting state

Question 29

Pathogen niches during infection influences type of response

Answer 29

o EXTRACELLULAR à pathogen multiplies outside of cells and typically dies if internalized by phagocytes – e.g. staphylococcus, streptococcus, Candida, microbiota, worms

§ Are accessible to antibodies and complement

o INTRACELLULAR à pathogen only replicates inside of cells – e.g. salmonella, chlamydia, legionella, Coxiella, plasmodium, helminths

§ Not accessible to antibodies and complement so immune cells need to recognise and tackle infected host cell to get to pathogen

o SURFACE ADHERENT à enteropathogenic + enterohaemorrhagic E. Coli

o INTRACELLULAR but CYTOSOLIC à viruses, listeria, burkholderia, mycobacterium

Question 30

Innate Immunity

Answer 30

Physical barriers à skin, mucous, epithelial cells

Humoral à complement, lectin (collectins, ficolins),

pentraxins, antimicrobial peptides

Cellular -> neutrophils, macrophages, dendritic cells, natural killer cells

0 - 12 HOURS - DAYS

Cytokines
· ILs à activate cells via genes, transcription factors etc.

· Chemokines à bring cells to infected area, chemotaxis

· Interferons à anti-viral cytokines

Phagocytes
· Neutrophils and macrophages

· Detect PAMPs or DAMPs

· Activated by inflammatory cytokines + chemokines

Natural Killer Cells
· Kill virus infected cells

Complement
· Protein cascade, activated by pathogens entering the body

· Opsonise, lyse and neutralise pathogens

Question 31

Adaptive Immunity

Answer 31

Humoral à antibodies (immunoglobulins – various types), complement

Cellular à cytotoxic T cells, T helper cells, T regulatory cells, B lymphocytes and plasma cells 5 – 7 DAYS

Dendritic cells
· Link innate to adaptive immunity

· Located throughout body

· Samples area (until find pathogen)

· Become activated by presenting pathogen via MHC I or II

· Move to lymph nodes (where adaptive immune response is initiated) to activate B and T cells

T Cells
· CD4+ T cells – helper cells – activate B cells w/cytokines

· CD8+ T cells – cytotoxic cells – kill virus infected cells

B cells
· Differentiate into plasma cells – produce pathogen specific antibodies

· Antibodies cover, neutralise and kill pathogens

Question 32

Immune system response

Answer 32

Optimal response à need coordination between innate and adaptive arms + way to scale response and recruit the right components

o Soluble messengers e.g. interleukins and interferons important in this

o Depending on antigenic stimulus, diff. mediators produced each w/ capability to recruit particular cell type

Communication within immune system

Microbial ligands (Detection) -> Naive host cells (Gene expression changes) -> Cytokines + Chemokines (Signal trasnduction) -> ‘Activated’ host-cells

First responders detect infection and try to control microbial growth

Secreted effectors such as chemokines and cytokines trigger inflammation and activate cells

Phagocytes (DCs and macrophages), as well as B cells, present antigens and activate T cells

T cells activate B cells and together contribute to humoral and cellular immunity to infection

Genetic and environmental factors can predispose individuals to infections

Question 33

Pathogen specific Phagocyte responses

Answer 33

o Specificity starts w/pathogen-specific responses made by macrophages – leads to activation of those phagocytes turning on specific gene expression programmes + inducing secretion of various interleukins and soluble mediators

o BACTERIA

§ Live bacteria phagocytosed -> bacterial mRNA released -> immune response -> inflammatory cytokines, antimicrobial genes, metabolic genes, immunomodulatory genes

§ Dead bacteria phagocytosed -> no bacterial mRNA -> no immune response -> resolution of inflammation

o FUNGI

§ Proinflammatory cytokines -> antimicrobial genes, metabolic genes, immunomodulatory genes

o VIRUSES

§ Interferon production -> proinflammatory cytokines -> antiviral genes -> immunomodulatory genes

Question 34

Inteferons

Answer 34

o Special cytokines

o Direct antiviral activities

o Induce expression of host defence programmes against a range of pathogens, but some also have specific anti-viral activities

o Antiviral genes include à nuclease, viral entry and exit inhibitors, viral uncoating and replication inhibitors, protein translation inhibitors

o Immunomodulatory roles à enhanced T cell responses, anti-inflammatory actions, tissue repair

Question 35

Humoral Innate Immunity and Cell Activation

Answer 35

o Soluble effector mechanisms

§ Complement mediated bacterial destruction

§ Lectin-binding to neutralise cell attachment or entry

§ Iron chelation (siderophores) to prevent replication

§ Antibiotic-like peptides

o Cellular effector mechanisms

§ Reactive oxygen and nitrogen radicals à which damage pathogen membranes and DNA

§ Acidification and digestion within phagosomes

Question 36

Antigen Presenting Cells (APC) and Cell Activation

Answer 36

o Activated macrophages and DCs present antigens in combination w/MHC-I or MHC-II to T cells

o Cytokines produced by APCs produce a suitable milieu for T cell activation e.g. IL-12 promotes T cell replication

o T cells provide cytokines that activate phagocytes e.g. IFN-gamma upregulates MHC-II expression for antigen presentation

o Responses are specific to general class of pathogens

Question 37

Broad Classification of T Cell functions

Answer 37

o Phagocyte activation à enhances killing of pathogens, inflammation

o Direct killing of infected cells à removal of replicative niches

o B cell activation à antibody production + affinity maturation

o Innate lymphoid cells/gamma-delta T cells (distinctive TCR on surface) à type of early responders (MHC independent actions)

Question 38

MHC Class I

Answer 38

o Expressed by all nucleated cells

o Present peptides derived from degradation of viral and other cytosolic proteins

o Degradation of proteins is mediated by cytosolic and nuclear proteasomes (protein complexes that use proteases to degrade unneeded proteins)

o Resulting peptides displayed on class I MHC to CD8 T Cells

Question 39

MHC Class II

Answer 39

o Expressed by APCs like DCs, macrophages and B cells

o Bind to peptides that are derived from proteins degraded in endocytic pathway i.e. phagocytosed pathogens that are degraded

o Peptides presented to CD4 T cells

o Activated T helper cells produce cytokines to activate other cells such as B cells

Question 40

Fever

Answer 40

• Abnormal elevation from body’s temperature set point
• Due to macrophages and leukocytes releasing inflammatory cytokines such as TNF-α and IL-1β, which stimulate the thermoregulatory centre in anterior hypothalamus
• Common response to infection
  o Inhibits multiplication of sensitive microbes
  o Increases host metabolism and stimulates immune responses e.g. phagocytosis
• Consequences of high fever
• Other causes of fever
  o Autoimmune disease
  o Cancer

Question 41

Cytokines and Chemokines

Answer 41

• Are polypeptides/soluble chemical signals, which can be rapidly disseminated throughout the body
• In innate immunity, they are prinicipally secreted by macrophages activated by microbe recognition and distressed tissues
• In adaptive (cell-mediated) immunity they are secreted by Th1 and Th2 lymphocytes
• Can change the function of the same or another cell
• Act in a pleiotropic (different effects in different cells) or synergistic fashion (different cytokines acting on same cells)
• Paracrine and/or autocrine effects
• Important chemokines that
• Excessive signalling – less easily controlled as compared to cell-cell contact
• Chemokines are cytokines which attract cells along a concentration gradient from low to high concentration (process of chemotaxis)
  o They are secreted by: damaged tissues, immune cells
  o And include: bacterial pdts, complements, cytokines, leukotrienes (LTB4 especially)
• Chemotaxis
  o Directed movement of a cell along a gradient of increasing concentration of a chemo-attractant
  o Examples of chemoattractants: C5a, IL-8

Question 42

Monocytes-macrophages

Answer 42

Characteristics:
Bean shaped nucleus
Inactive in blood
Migrate into tissue and becomes active

Effective against : Intracellular bacteria

Activating factors :
Factors by host tissue
IFN-gamma
PAMPs/PRR (TLR)

Effector mechanism :
Secrete cytokines – IL-12, IL-1, TNF

Release of arachidonic acid metabolites (inflammatory)

Phagocytosis

Growth factors that remodel injured tissues

Question 43

Neutrophils

Answer 43

Characteristics : Lobated nucleus
Normally not found in tissue
Most abundant WBC in circulation

Effective against : Bacteria, fungi
Activating factors : Bacterial components, fMLP
Complement components
Cytokines, chemokines (ie Th1 activation)
Arachidonic acid metabolities

Effector mechanism : Phagocytosis, Cytokines

Question 44

Eosinophils

Answer 44

Characteristics : Eosinophilic granulated cytoplasm
Effective against : Parasite/ antibody-coated helminths
Activating factors : IgE crosslinked to parasites?
Effector mechanism : Patho: type I hypersensitivity

Question 45

NK cells

Answer 45

Characteristics : T lymphocytes of innate immunity

Effective against : Antigen-presenting host cells (viral infection, infested w/ bacteria)

Activating factors : IL-12
IFN-1 (by distressed cells)

Effector mechanism : IFN-gamma & cytokine secretion (activate macrophages)

Granule release (cellular cytotoxicity)

ADCC

Question 46

Recruitment of neutrophils to site of inflammation

Answer 46

• Circulating neutrophils and monocytes possess surface carbs that bind weakly to selectins on endothelium surface, which results in rolling of cells
• In the presence of cytokines, histamine, thrombin, selectins are also upregulated on endothelial surfaces – rolling of cells on surface increased
• Usually, integrins present in a low-affinity state on unactivated leukocytes
• But at site of infections, leukocytes can concentrate because endothelial cells respond to cytokines/ other inflammatory products from activated macrophages (IL-1, TNF etc) by producing chemokines
• Chemokines upregulate the expression of leukocyte integrins for their ligands on endothelium
• Firm binding of integrins to ligands arrests the rolling leukocytes on endothelium
• Cytoskeleton of leukocytes rearrange and cells spread out on the endothelial surface
• Thus at site of infection, leukocytes extravasate (diapedesis)
• Chemokines stimulate motility of leukocytes – they extravasate and move along chemotactic gradient to site of infection