Immune Response to Infection

Question 1

How does the immune system respond better to infection the second time?

Answer 1

Specificity and memory are two essential features of adaptive immune responses: Hence, adaptive arm of immune response provides better protection upon second and subsequent exposures to a pathogen while innate arm tends to react the same to all pathogens and all exposures.

Question 2

What are the two phases of an immune response?

Answer 2

Antigen recognition and antigen eradication: In the first stage, there’s clonal selection and clonal expansion followed by differentiation into effector and memory cells. In the second stage, lymphocytes coordinate an immune response, which eliminates the source of the antigen.

Question 3

What are the 4 pathogen niches? Provide examples

Answer 3

1. Extracellular (Staphylococcus, Streptococcus, Candida, Microbiota, Worms):
2. Intracellular vacuolar (salmonella, chlamydia, plasmodium):
3. Surface adherent (enteropathogenic and enterohaemorrhagic E.coli): stick intimately to the surface of epithelial cells and cause disease
4. Intracellular cytosolic (Listeria, Mycobacterium)

Question 4

How does immune response to injury begin?

Answer 4

Triggered by tissue damage occurring either through injury or action of infectious agents on tissues. Once this happens, battery of germline-encoded molecular receptors which detect ligands and activities from microbes produced. The host cell then communicates with neighbouring cells through diff lipid and protein mediators such as interleukins and chemokines which allow intercellular communication from once cell to another, spreading + amplifying immune response. Leads to priming of adaptive immune response by antigen-presenting cell.

Question 5

How does immune response to injury end?

Answer 5

Typically through clearance of infection once no living/spreading pathogens in the body. Cytokine production then stopped as continuous production leads to tissue damage. Tissue damage is also repaired where macrophage + phagocytic cells clear apoptotic cells. Immune memory generated.

Question 6

What are the properties and components of the innate immune system?

Answer 6

It is fast acting, first line of defence and involves germline encoded receptors. Physical barriers such as skin, epithelial tissue and mucous are first line. Humoral components such as complement, lectins (collectins and ficolins), pentraxins and antimicrobial peptides involved. Cellular components include macrophages, NK cells, neutrophils and dendritic cells.

Question 7

What are the properties and components of the adaptive immune system?

Answer 7

Slower but longer lasting, variable receptors that mature over time through DNA recombination. Humoral components include antibodies (immunoglobulins of different types) and complement. Cellular components include T-cells and B-cells.

Question 8

What are the main differences in innate and adaptive immunity?

Answer 8

Timing of the response, Cell types, Receptors and ligands, Cytokines and chemokines, molecular effector machineries.

Question 9

Compare the features of innate and adaptive immunity

Answer 9

Specificity: Innate recognises structures shared by classes of molecules such as PAMPs and around 1000 molecular patterns are recognised. Adaptive recognises specific structural details of microbe known as the antigen and each microbe recognised individually. Can recognise over 10^7 different antigens.

Receptors: Innate immune cells have pattern recognition receptors which are encoded in the germline and have limited diversity. Adaptive immune cells have receptors encoded by genes produced by somatic recombination of gene segments resulting in greater diversity.

Number+Type and Distribution of receptors: Innate have under 100 different types of invariant receptors which are non-clonal (identical receptors on all cells of same lineage). Adaptive has only two types of receptors but millions of types of each (Ig and TCR) which are clonal (clones of lymphocytes with distinct specificities express different receptors).

Question 10

What is the general principle of communication in immune system?

Answer 10

Microbial molecules present in system detected by naive host cells through ligands and activities. Naive host cell undergoes gene expression changes to become activated and produce antimicrobial molecules and communication signals. These signals are transducted to activate other host cells.

Question 11

What is the initial innate human response and role of pahgocytes?

Answer 11

Neutrophils are the first to respond (short lived for around 6 hours) followed by macrophages and naive host cells become activated upon interaction with the microbe. Phagocytes control infection and limit/repair tissue damage. Uncontrolled phagocytic activity can lead to: granulomas, excessive inflammation and inappropriate adaptive immunity and tissue damage.

Question 12

How do phagocytes respond in a pathogen specific way?

Answer 12

Recognise key markers on pathogen which distinguish it such as LPS in bacteria which is a major pattern recognition molecule. Fungi have beta-glucan and dectin receptors recognise them.

Question 13

Compare phagocyte response when infected with a bacteria, fungi and virus

Answer 13

Bacteria: If bacterial mRNA released upon phagocytosis of cell, phagocyte releases inflammatory cytokines, expresses antimicrobial genes, metabolic genes and immunomodulatory genes.

Fungi: If fungi recognised, proinflammatory cytokines produced, antimicrobial genes expressed as well as metabolic genes and immunomodulatory genes.

Viruses: When viruses recognised, interferons produced as well as proinflammatory cytokines, antimicrobial genes expressed as well as metabolic genes and immunomodulatory genes.

Question 14

What occurs during macrophage activation?

Answer 14

Macrophage when infected with an intracellular pathogen first recognises the pathogen and upon recognition, releases a set of cytokines, exemplified by IL-12. This is recognised by T-cells which produce a type 2 interferon or IFN-gamma which in turn acts on the macrophage resulting in production of new genes that are directly toxic to the growth of pathogen hence the macrophage becomes activated and kills the phagocytosed microbe. Hence there is cross-talk between lymphocytes and macrophages even in the innate immune response.

Question 15

What qualities do activated macrophages show?

Answer 15

When activated, macrophages express new genes induced by microbes and cytokines. They display enhanced phagocytosis and migration, cytokine/chemokine production, expression of cell surface molecules, antimicrobial activity, antigen presentation and T cell activation.

Question 16

What is the function of different interferon types?

Answer 16

The detection of viruses and gram-negative bacteria results in the production of interferons. Type 1, most notably IFN-alpha-beta, mainly involves signalling on target cells leading to expression of number of genes, esp anti-viral ones. Type 2 is produced mainly during infection with intracellular pathogens such as viruses and gram-negative bacteria.

Question 17

What is the function of interferons?

Answer 17

Interferons are special cytokines that have direct antiviral activities. Antiviral genes code for nucleases, inhibition of virus entry and exit, inhibition of viral uncoating and replicators as well as inhibitor of protein translation.

Question 18

Where are interferons produced?

Answer 18

Every single primary infected cell can produce type 1 interferons which can act on neighbouring cells so tissue becomes better able to resist viral infection. The type 3 interferon is similar to type 1 in gene expression but expression pattern is more limited – these are only produced at epithelial surfaces while type 1 can be produced deeper within tissue as well. Type 2 only produced by lymphocytes. Every cell can respond to type 1 and 2 interferons.

Question 19

How are virus infected cells killed and removed by NK cells?

Answer 19

NK cells recognise a virus-infected cell due to down-regulation of MHC on the surface and therefore, NK is licenced to target this host cell to kill through delivery of granzymes causing apoptosis. Virus needs a cellular host which it no longer has – removal of niche is a protective factor. Many intracellular bacteria such as salmonella also use host cell to replicate so death of host cell is effective control.

Question 20

What are commonalities between CTLs and NK cells?

Answer 20

Virus-infected cells are killed by action of CTLs and NK cells as cell death removes viral replicative niches. CTLs and NK cells directly kill infected cells and are hence contact dependent. However host cells infected with intracellular bacterial pathogens can undergo other forms of contact-independent cell death.

Question 21

What are 2 examples of anti-microbial enzymes?

Answer 21

1. Phagocyte oxidase produces large amounts of a reactive oxygen species
2. Inducible nitric oxide synthase produces nitric oxide (another radical) toxic to intracellular pathogen
   These are only made in the sites of infection and these genes not present in a naive cell.

Question 22

What are soluble effector mechanisms of pathogen destruction?

Answer 22

1. Complement mediated bacterial destruction
2. Lectin-binding to neutralise cell attachment or entry
3. Iron chelation (siderophores) to prevent replication
4. Antibiotic-like peptides

Question 23

What are cellular effector mechanisms of pathogen destruction?

Answer 23

1. Reactive oxygen and nitrogen radicals

2. Acidification and digestion within phagosomes

Question 24

Why are dendritic cells better APCs than macrophages?

Answer 24

Dendritic cells better at presenting antigens compared to macrophages as they can produce a lot of type 1 interferon during infection – presents antigen to T-cell through MHC molecule and produce cytokines depending on class of infection. Naïve T-cell then responds to the MHC and cytokines produced by the DC which helps itself and the DC (Interferon-gamma needed for naïve T-cell to differentiate to TH1 cell while IL-17 produced during fungal infection converts T-cell to a T17 cell.

Question 25

How are T-cells activated?

Answer 25

Activated macrophages and DCs present antigens in combination with MHC-I and MHC-II to T cells. Cytokines produced by APCs produce a suitable milleu for T cell activation e.g. IL-12 promotes T cell replication. T cells then porvide cytokines that activate phagocytes like IFN-gamma which upregulates MHC-II expression for antigen presentation. Responnses specific to class of pathogen.

Question 26

How do T cells then help B cell produce antibodies?

Answer 26

T cell activated by cognate MHC and foreign peptide recognition. B cell becomes licenced for antibody production against antigen presented on BCR. Antibody mediated enhanced antimicrobial response occurs causing opsonisation and complement activation. TH1 cells involved in producing interferon gamma 1 while cytotoxic T-cell involved in directly killing the infected cell, leading to apoptosis of host cells and removal of replicative niches.

Question 27

How do T cells and B cells enhance antimicrobial immunity?

Answer 27

1. Phagocyte activation - enhanced killing of pathogens and inflammation
2. Direct killing of infected cells - removal of replicative niches
3. B cell activation - antibody production and affinity maturation
4. Innate lymphoid cells - MHC independent action and early responders
5. Cytokines - inflammattion, phagocytosis and killing of microbes.

Question 28

What are the defining cytokines, principal target cells, major immune reactions, host defence and role in disease of Th1, Th2 and Th17?

Answer 28

Th1 - produces IFN-gamma, targets macrophages, major reaction is macrophage activation, defends against intracellular pathogen and responsibly for autoimmunity and chronic inflammation.

Th2 - produces IL-4, IL-5 and IL-13. Activates eosinophils. Major immune reaction is eosinophil and mast cell activation, alternative macrophage activation. Defends against helminths and causes allergy.

Th17 - Produces IL-17 and IL-22, targets neutrophils, main function is neutrophil activation and recruitment, tagrtes extracellular bacteria and fungi. Causes autoimmunity and inflammation if left uncontrolled.

Question 29

What dysfunction causes complement defect, leukocyte adhesion defect and chronic granulomatous disease?

Answer 29

Dysfunction in various complement genes, genes involved in migration and adhesion, loss of reactive oxygen species production respectively.

Question 30

What does Chediak-Higashi syndrome result in?

Answer 30

Compromised lysozymes

Question 31

What causes defect in cytokine genes and their receptors?

Answer 31

Loss of cell to cell communication

Question 32

What does SCID result in?

Answer 32

Severe reduction and function of T and B cells

Question 33

What does X-linked agammaglobulinaemia result in?

Answer 33

Decreased serum IgG of all types

Question 34

What does HIV result in?

Answer 34

Reduced CD4 helper T cells

Question 35

What does irradiation and chemotherapy result in?

Answer 35

Loss of bone marrow precursors

Question 36

What does immunosuppresion result in?

Answer 36

Depletion or impairment of lymphocytes