1s: Introduction (Immune response/physiology) Flashcards by Kim Alipio

3 constitutive barriers to infection

Skin Barrier

Mucosal surface barrier

commensal barrier

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Skin barrier

Tightly packed keratinised cells

physiological factors (low pH, low O2 tension)

Sebaceous glands (hydrophobic oils repel water/microorganisms, lysozyme destroyed cell walls, ammonia/defensins have anti-bacterial properties)

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Mucosal surface barrier

Secreted mucous (physical barrier, secretory IgA prevent entry/attachment into epithelia, lysozyme, lactoferrin starves bacteria of iron)

Cilia (trap and remove pathogens)

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Commensal bacteria barrier

100 tn bacteria (compete for resources, produce FAs and bactericides to inhibit growth)

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What are examples of cells of the innate immune system? give some of their features

Polymorphonuclear cells – neutrophils, eosinophils, basophils; Monocytes and macrophages; Natural killer cells; Dendritic cells

express receptors for cytokines/chemokines to detect inflammation
express PRRs to detect pathogens
capable of phagocytosis/oxidative and non-oxidative killing
secrete cytokines and chemokine to regulate inflammation

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Give some soluble components of the innate immune system

Complement

Acute phase proteins

Cytokines and chemokines

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polymorphonuclear cells (neutrophils, eosinophils, basophils/mast cells): role and function

Produced in bone marrow
Migrate rapidly to site of injury
Express receptors for cytokines/chemokines (to detect inflammation)
Express pattern recognition receptors – to detect pathogens
Express Fc receptors for Ig (to detect immune complexes)
Capable of phagocytosis / oxidative & non-oxidative killing – particularly neutrophils
Release enzymes, histamine, lipid mediators of inflammation from granules
Secrete cytokines and chemokines to regulate inflammation

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Mononuclear cells (monocytes, macrophages, lymphocytes)

– monocytes produced in bone marrow and circulate in blood to migrate to tissues to differentiate into macrophages
- Present within tissue
- Express receptors for cytokines and chemokines (to detect inflammation)
- Express pattern recognition receptors –to detect pathogens
- Express Fc receptors for Ig (to detect immune complexes)
- Capable of phagocytosis / oxidative and non-oxidative killing
- Secrete cytokines and chemokines to regulate inflammation
- Capable of presenting processed antigen to T cells

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examples of macrophages

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How does phagocyte recruitment work (which cells can do this?)

Macrophages, Granulocytes (Neutrophils) & Dendritic cells

Cellular damage and bacterial products trigger the local production of inflammatory cytokines and chemokines

Cytokines activate vascular endothelium enhancing its permeability

Chemokines attract phagocytes

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Recognition of the microorganisms

PRRs = TLRs and mannose receptors

recognise PAMPS (DNA/RNA)

Fc receptors also recognise Fc of Ig to allow recognition of immune complexes

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Endocytosis as facilitated by opsonisation

Opsonins = bridge between pathogen and phagocyte receptors e.g.

antibodies binding to Fc receptors.
complement components binding to complement receptors (CR1)
acute phase proteins e.g. CRP

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Formation of the phagolysosome

Pathogen taken up into phagosome which fuses with lysosome. → protected compartment in which killing of the organism occurs

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microbial killing mechanisms: oxidative killing

NADPH oxidase complex converts oxygen to ROS e.g. superoxide and hydrogen peroxide

Myeloperoxidase catalyses production of hydrochlorous acid from hydrogen peroxide and chloride

Hydrochlorous acid is a highly effective oxidant and anti-microbial

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Non-oxidative killing

Release of lysozyme and lactoferrin into phagolysosome

enzymes present in distinct specific granules which can provide broad coverage against many bacteria and fungi

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Death of a Phagocyte: The Role of Neutrophils

The phagocytosis depletes neutrophil’s glycogen reserves and is followed by neutrophil death
As the cell dies, residual enzymes release and liquify local tissues
Accumulation of dead/dying neutrophils in tissues → pus formation
Extensive pus formation causes abscess formation

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Oxidative killing

Pathogen recognition

Opsonisation

Non-oxidative killing

A. is mediated by TLRs which recognise PAMPS

B. may be mediated by antibodies, complement components or APP and facilitates phagocytosis

C. describes killing mediates by ROS generated by action of the NADPH oxidase complex

D. may be mediated by bactericidal enzymes such as lysozyme

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Innate immune system summary

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Natural Killer Cells (NK cells): Role and Function

Present within blood and may migrate to inflamed tissue
Express inhibitory receptors for self-HLA molecules - prevent inappropriate activation by normal self
Express a range of activatory receptors, including natural cytotoxicity receptors, that recognise heparan sulphate proteoglycans
Cytotoxic - kill ‘altered self’ as in malignant or virus infected cells which lack inhibitory signals

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Natural Killer Cells (NK cells): Role and Function

Present within blood and may migrate to inflamed tissue
Express inhibitory receptors for self-HLA molecules - prevent inappropriate activation by normal self
Express a range of activatory receptors, including natural cytotoxicity receptors, that recognise heparan sulphate proteoglycans
Cytotoxic - kill ‘altered self’ as in malignant or virus infected cells which lack inhibitory signals

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Dendritic Cells (role and function)

INNATE-ADAPTIVE transition

Reside in peripheral tissues

Express Fc receptors for Ig - to detect immune complexes

Following phagocytosis dendritic cells mature:

Upregulate expression of HLA molecules
Express costimulatory molecules
Migrate via lymphatics to lymph nodes – mediated by CCR7

Present processed antigen to T cells in lymph nodesa → prime the adaptive immune response

Express cytokines to regulate the immune response

Neutrophils

NK cells

Dendritic Cells

Macrophages

A. derived from monocytes and resident in peripheral tissue

B. Polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms

C. Lymphocytes that express inhibitory receptors capable of recognising HLA Class I molecules and have cytotoxic capacity

D. Immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells

What are the components of the Adaptive Immune System?

Humoral immunity → B lymphocytes and antibody

Cellular immunity → T lymphocytes (CD4 and CD8 T cells)

Soluble components → cytokines and chemokine

Primary and secondary lymphoid organs definition and examples

Primary = organs involved in lymphocyte development

bone marrow (T and B from HPSCs) → site of B cell maturation
thymus → site of T cell maturation, most active in foetal and neonatal period, involutes after puberty (+VE and -VE selection)

Secondary = anatomical sites of interaction between naive lymphocytes and microorganisms

spleen
lymph nodes
MALT

All T cells express ____ and either

Positive and negative selection of T cells

T cell receptor recognises HLA/peptide complex

Characteristics of the adaptive immune system

* **Wide repertoire of antigen receptors** * Receptor repertoire is **_not_** entirely genetically encoded * Genes for segments of receptors are rearranged and nucleic acids deleted/added at the sites of rearrangement almost randomly (potential to create 10¹¹ to 10¹² receptors * Autoreactive cells are likely to be generated (mechanisms delete/tolerate these) **Exquisite specificity** – *detects small differences in molecular structure* **Clonal expansion** – *cells with appropriate specificity will proliferate during infection* **Immunological memory** – *memory cells*

MHC I vs MHC II

CD4+ helper cells

CD8+ T cells (specialised cytotoxic cells)

Recognise peptides derived from intracellular proteins in association with HLA class I (HLA-) A, HLA-B, HLA-C) - Mnemonic: **1 letter for Class I** Kill cells directly → **Perforin** (pore forming) and **granzymes** & Expression of **Fas ligand** Secrete **cytokines e.g. IFNg, TNFa** → important in defence against viral infections & tumours

CD4+ T cell subsets

## Footnote A. express receptors that recognise peptides usually derived from intracellular proteins and expressed on HLA Class I molecules B. Subset of lymphocytes that express Foxp3 and CD25 C. subset of cells that express CD4 and secrete IFN gamma and IL-2 D. Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells

T cell memory

Response to successive exposures to antigen is qualitatively and quantitatively different from that of first exposure Pool of ‘memory’ T cells ready to respond to antigen → **More easily activated than naïve cells**

B cell maturation and activation Stem cells in bone marrow become lymphoid progenitors → pro B cells →pre B cells Peripherally → IgM expressing B cells * with antigen engagement they develop into plasma cells that secrete IgM * OR they can undergo germinal centre reaction and develop into plasma cells expressing IgG, IgA and IgE

Central tolerance of B cells

No recognition of self-antigens → survive Recognition of self-antigens in bone marrowa → negative selection to avoid autoreactivity

Immunoglobulin Ig structure

Soluble proteins made up of **two heavy and two light chains** Heavy chain determines the antibody class * IgM, IgG, IgA, IgE, IgD, * subclasses of IgG and IgA also occur. Antigen is recognised by antigen binding regions **(Fab)** of both heavy & light chains Effector function is determined by the constant region of the heavy chain **(Fc)**

Antibody functions

* Identify pathogens/toxins (Fab-mediated) – *esp. bacteria of all kinds* * Interact with other components of immune response (Fc-mediated) * Complement * Phagocytes * NK cells

B cell memory - features of the secondary immune response

Response to successive exposures to antigen is qualitatively and quantitatively different from that of first exposure * the **lag time** between antigen exposure and the production of antibody is decreased (to _2-3 days)_ * the **titre** of antibodies produced is greatly increased * the response is dominated by **IgG antibodies of high affinity** * the response may be **independent of help from CD4+T lymphocytes**

B cell summary

A. area within secondary lymphoid tissue where B cells proliferate and undergo affinity maturation and isotope switching B. include both the bone marrow and thymus; sites of B and T cell development C. carries lymphocytes from lymph nodes back to the blood circulation D. site of selection of T cells with inappropriately high or low affinity for HLA molecules and of maturation of T cells into CD4+ or CD8+ cells

A. germinal centre B. primary lymphoid organs C. thoracic duct D. thymus

A. exist within the bone marrow and develop from the HPSCs B. cell dependent on the presence of CD4 T cell help for generation C. are generated rapidly following antigen reconginition and are not dependent on CD4 T cell help D. divalent antibody present within mucous which helps provide a constitutive barrier to infection

A. pre-B cells B. IgG secreting plasma cells C. IgM secreting plasma cells D. IgA

What are complement

**\>20 types of protein** = produced in **liver** and present as **inactive molecules** in circulation when triggered, enzymatically activate each other in a biological cascade

What are the 3 pathways of complement activation?

Classical pathway (Antibody + C1 → C2,4 → C3) Mannose Binding Lectin (MBL → C2,4 → C3) Alternative pathway (PAMP (LPS, teichoic acid) → C3)

Classical pathway (Antibody + C1 → C2,4 → C3)

* Changed antibody site exposes C1 binding site * C1 binding to antibody activates cascade * **Antibody-antigen immune complexes**

Mannose Binding Lectin (MBL → C2,4 → C3)

* Changed antibody site exposes C1 binding site * C1 binding to antibody activates cascade * **Antibody-antigen immune complexes**

Alternative pathway (PAMP (LPS, trichroic acid) → C3)

* C3 binding to bacterial cell wall components * E.G. LPS (gram -ve) or teichoic acid (gram +ve) Involves **factors B, I, P** **Not dependant on acquired immune response**

C3 activation → complement cascade: what happens?

* Increase vascular permeability and cell movement * Opsonisation of immune complexes so soluble * Opsonisation of pathogens to promote phagocytosis * Active phagocytes * Promote mast cell and basophil degranulation **Form MAC (via C5-C9) to punch holes in membranes**

A. binding of immune complexes to this protein triggers the classical pathway of complement activation B. cleavage of this protein may be triggered via the classical, MBL or alternative pathway C. binds to microbial suface carbohydrates to activate the complement cascade in an immune complex independent manner D. part of the final common pathway resulting in the generation fo the MAC

A. C1 B. C3 C. MBL D. C9

What are cytokines?

* Small protein messengers * Immunomodulatory function * Autocrine or paracrine dependent action * Examples include IL-2, IL-6, IL-10, IL-12, TNF-alpha, TGF-beta

Chemokine (chemoattractant cytokines)

* Direct recruitment / homing of leukocytes in an inflammatory response * **_CCL19 and CCL21_ are ligands for _CCR7_ and important in directing dendritic cells to lymph nodes** * Other examples of chemokines include IL-8, RANTES, MIP-1 alpha and beta