Immunology 1 - The immune response to infection

Question 1

What are the constitutive barriers to infection?

Answer 1

Skin

Mucosal surfaces

Commensal bacteria (compete for scarce resources and produce fatty acids + bactericidins to inhibit pathogen growth)

Question 2

What are the features of skin that provide a barrier to infection?

Answer 2

Tightly packed keratinised cells

Low pH and low O2 tension

Sebaceous glands which produce:

• Hydrophobic oils that repel microorganisms and water
• Lysozyme which destroys the structural integrity of the cell wall
• Ammonia and defensins which have antibacterial properties

Question 3

What features of the mucosal surfaces provide a barrier to infection?

Answer 3

Cilia that trap and remove pathogens

Secreted mucous which acts as a physical barrier and produces:

• Secretory IgA (prevent attachment/entry into epithelia)
• Lysozyme
• Lactoferrins which starve microorganisms of iron

Question 4

What are the cells of the innate immune system?

What are the soluble components of the innate immune system?

Answer 4

Cells

Polymorphonuclear cells:

• Neutrophils, eosinophils, basophils

Monocytes and macrophages

NK cells

Dendritic cells

Soluble components

Complement, acute phase proteins, cytokines, chemokines

Question 5

What is the main difference in function between neutrophils and macrophages?

Answer 5

Macrophages can present antigen on their surface following phagocytosis, but neutrophils cannot

Question 6

What are macrophages called in the:

Liver

Kidney

Bone

Spleen

Lung

Neural tissue

Connective tissue

Skin

Joints

Answer 6

Liver = Kuppfer cell

Kidney = Mesangial cell

Bone = Osteoclast

Spleen = Sinusoidal lining cell

Lung = Alveolar macrophage

Neural tissue = Microglia

Connective tissue = Histiocyte

Skin = Langerhans cell

Joints = Macrophage-like synoviocyte

Question 7

Give two examples of pattern recognition receptor

Answer 7

Toll like receptor

Mannose receptor

Question 8

How is pus formed?

Answer 8

Following phagocytosis, neutrophils die

When they die, they release residual enzymes which causes the liquefication of closely adjacent material

This forms pus

Question 9

What is opsonisation?

Answer 9

Modification of a pathogen to attract it to a NK or phagocytic cell

May be mediated by antibodies, complement components or acute phase proteins

Enables phagocytosis

Question 10

What is the difference between oxidative and non-oxidative killing?

Answer 10

Oxidative: uses NADPH oxidase and myeloperoxidase to form hydrochlorous acid - this acts as an oxidant and anti-microbial

Non-oxidative: release of lysosymes and lactoferrin into the phagolysosome

Question 11

What role do NK cells play in regulating immunity?

Answer 11

Express inhibitory receptors for self-HLA molecules

If the cell’s self-HLA molecule is down regulated (e.g. because it is infected), it becomes a target cell -> lysis

Question 12

Describe the changes that occurs in dendritic cells following phagocytosis

Answer 12

Dendritic cells mature after phagocytosis -> represents the innate-adaptive transition

1. Upregulate expression of HLA-1
2. Express costimulatory molecules
3. Migrate via lymphatics to lymph nodes (mediated by CCR7)
4. Process non-self antigen and present it to T cells in lymph nodes to prime the adaptive immune response
5. Express cytokines to regulate the immune response

Question 13

What are the primary lymphoid organs and their function?

Answer 13

Bone marrow: B + T cell production, B cell maturation

Thymus: T cell maturation

Question 14

What is a secondary lymphoid organ?

Answer 14

Anatomical sites of interaction between naive lymphocytes and antigens e.g. spleen, lymph nodes and MALT (mucosa associated lymphoid tissue)

Question 15

Describe the process of T cell maturation

Answer 15

Haematopoietic stem cells begin to mature in the bone marrow

Undergo TcR rearrangement in which alpha and beta chain segments are rearranged in a semi-random manner

Migrate to thymus as pre-T cells where they undergo selection for CD4 and CD8

Low affinity for HLA - not selected

Medium affinity - positive selection of ~10% of original cells

• Affinity for HLA class 1 = CD8+ differentiation
• Affinity for HLA class 2 = CD4+ differentiation

High affinity - negative selection to avoid autoreactivity (central tolerance)

Question 16

Recall 2 functions of CD4+ T lymphocytes

Answer 16

Recognise peptides presented on HLA class II molecules

Immunoregulatory functions via cell-cell interactions and cytokine expression -> provides help for development of:

1. Full B cell response
2. Some CD8+ T cell responses

Question 17

Which cells express HLA Class I and which cells express HLA Class 2?

Answer 17

Every cell has MHC I (HLA-A, HLA-B, HLA-C)

Antigen presenting cells have MHC II (HLA-DP, HLA-DQ, HLA-DR)

Question 18

Which cytokines induce development of CD4 T cells into Th1 cells?

Answer 18

IL2 and IFN gamma

Question 19

What is the function of Th1 cells?

Answer 19

‘Help’ CD8 T cell and macropage responses

Question 20

Which cytokines induce development of CD4 T cells into Th17 cells?

Answer 20

IL6 and TGF beta

Question 21

What is the function of Th17 cells?

Answer 21

‘Help’ neutrophil recruitment

Question 22

Which cytokine induces development of CD4 T cells into Treg cells?

Answer 22

TGF beta

Question 23

Which cytokine induces development of CD4 T cells into follicular T helper cells?

Answer 23

IL6

Question 24

Which type of T cell produces CD25 and FOXP3?

Answer 24

T reg cells

Question 25

By what mechanism do CD8 cells effect their cytotoxicity?

Answer 25

Injection of perforin, which enables granzyme entry OR Fas ligand expression

Question 26

Which cytokines are secreted by CD8 T cells?

Answer 26

IFN gamma and TNF alpha

Question 27

Process of B cell development

Answer 27

Arise from haematopoietic stem cells

Created through semi-random gene rearrangement to produce a diverse receptor repertoire

Cells only survive if there is no recognition of self in the bone marrow (central tolerance)

Question 28

What is the first class of immunoglobulin to be made when a B cell encounters an antigen?

Answer 28

IgM

Question 29

What is a germinal centre reaction?

Answer 29

Process where B cells differentiate into IgG, IgA and IgE secreting plasma cells - requires appropriate signals from CD4+ T cells in the secondary lymphoid tissue

Without CD4 cell function, the B cell response will be restricted to IgM

Question 30

How do CD4 cells activate B cells?

Answer 30

Express CD40 ligand, which interacts with CD40 on immature B cell surface, causing the B cell to differentiate

Question 31

Recall the 2 processes that B cells undergo during a germinal centre reaction

Answer 31

1. Class/Isotype switching
2. Somatic hypermutation (to become very high affinity)

Question 32

Which part of an immunoglobulin determines its class?

Answer 32

Heavy chain

Question 33

Which portion of an immunoglobulin mediates pathogen identification?

Answer 33

Fab portion

Question 34

Which portion of an immunoglobulin mediates activation of complement/ NK cells?

Answer 34

Fc portion

Question 35

Where is complement produced?

Answer 35

>20 types of protein produced in the liver

Question 36

What is the classical pathway?

Answer 36

Antibody + C1 -> C2, C4 -> C3 -> final common pathway C5-C9

Antibody-antigen immune complexes bind to C1, leads to a change in the antibody shape and this exposes the C1 binding site -> activates the cascade

CLASSICAL PATHWAY DEPENDS ON ACTIVATION OF ACQUIRED IMMUNE RESPONSE so it’s a late response

Question 37

What is the mannose binding lectin pathway?

Answer 37

MBL -> C2, C4 -> C3 - final common pathway C5-C9

Mannose binding lectin binds to oligosaccharides/microbial cell
surface carbohydrates on certain virions/infected cells.

This then directly stimulates C4 & C2 but not C1.

NOT DEPENDENT ON THE ACQUIRED IMMUNE RESPONSE.

Question 38

What is the alternative pathway?

Answer 38

PAMP -> C3 -> final common pathway C5-C9

Spontaneous breakdown of C3 in serum due to it binding to components in the bacterial cell wall (e.g. lipopolysaccharide of gram –ve, teichoic acid of gram +ve).

This forms alternative C3 convertase

Involves factors B, I & P.

NOT DEPENDENT ON THE ACQUIRED IMMUNE RESPONSE

Question 39

What are the functions of fully activated complement?

Answer 39

Formation of membrane attack complex via C5-C9 -> punches holes in membranes

Cleaved components of the complement cascade generate other effects:

• Increases vascular permeability and cell trafficking
• Opsonisation of immune complexes so they remain soluble
• Promote basophil and mast cell degranulation
• Opsonisation of pathogens: esp. capsulated bacteria
• Activate phagocytes

Question 40

What are cytokines and chemokines?

Answer 40

Cytokines = small protein messengers which exert autocrine or paracrine effects and have an immunomodulatory action e.g. IL-2, IL-10, TNF-alpha

Chemokines = chemoattractant cytokines which directly recruit and home leukocytes in an inflammatory response e.g. CCL19, CCL21, IL-8

Question 41

What is the role of the CCL19 and CCL21 chemokines?

Answer 41

They are ligands for CCR7 and important for directing dendritic cells to lymph nodes

Question 42

Summarise the immune defence against a pathogen

Answer 42

Pathogen has to get through the constitutive barriers (skin, musoca, commensal bacteria)

Pathogens that get through may become intracellular (viruses, some bacteria) or extracellular (bacteria like staph and strep)

Innate Immune Response

Neutrophils are mobilised very quickly to go to the infection site, and they have pathogen recognition receptors which allows them to phagocytose pathogens -> and then the neutrophils die to form pus

Tissue-resident macrophages are already there but they still have receptors allowing them to go to the precise point of infection and they phagocytose -> but they don’t die and instead stick around to interact with T cells

NK cells can deal with intracellular pathogens providing the infected cell’s expression of self-HLA has changed -> NK cells kill the infected cells

Innate-Adaptive Transition

Dendritic cells with PRRs also phagocytose but then processes the pathogen, matures and upregulates HLA expression so it can present the antigen on its cell surface -> then it migrates to the lymph nodes

Dendritic cells present the peptides to CD4 cells in the lymph nodes -> CD4 cells provide help so that the dendritic cells can prime the CD8 cells

Adaptive Immune Response

CD8 cells go off and kill infected cells (CD8 cells express TCRs that recognise peptides presented by HLA Class 1 -> these peptides tend to come from intracellular pathogens)

B cells can bind to the pathogen’s antigen with their BCR and produce IgM early

Where the dendritic cells have primed CD4 cells, the CD4 cells can help the B cells -> isotype switching + somatic hypermutation and proliferation (germinal centre reaction) -> mature into plasma cells secreting IgG, IgA, IgE

Immunoglobulins will bind to the extracellular pathogen -> immune complexes will activate complement, bind to NK cells and bind to macrophages