immunology pt 2 electric boogaloo

what do we study in immunology

how does out body fight and defeat pathogens

examples of pathogenic viruses

influenza

measles

Hepatitis B and C

HIV (Human immunodeficiency virus)

examples of pathogenic bacteria

staphylococcus aureus

neisseria gonorrhoeae

bordatella pertussis

examples of pathogenic protozoa

giardia

leishmania

plasmodium

examples of pathogenic fungi

candida albicans

cryptococcus neoformans

aspergillus

examples of pathogenic worms

schistosomes

helminths

immunology

the study of mechanisms of defence

immune response

the responses that we make against pathogens

immunity

the state of protection from infectious disease

how is immunity to pathogens achieved- what is involved?

innate and adaptive immunity working together to first eliminate pathogen and remember pathogen

they need each other to work, they cannot work separately

innate immunity is the immediate response

adaptive immunity is activated approx 4 days later

innate immunity

immediate response

antigen non specific

no memory

components: barriers eg skin, cells eg phagocytes, non cellular eg cytokines (small proteins secreted)

adaptive (acquired) immunity

approx 96 hours after entry of pathogen

antigen specific

has memory response

components: cells eg B and T cells, humoral→ antibodies ( produced by B cells that bind pathogen to eliminate it from body and cytokines also produced by B and T cells

cells of innate immune response vs adaptive

monocytes B and T lymphocytes

eosinophil

neutrophil

macrophage

dentritic cell

natural killer (NK) cell

Primary lymphoid organs

bone marrow(red?) and thymus

Secondary lymphoid tissue and organs

lymph nodes, bone marrow(yellow?), spleen, mesenteric lymph nodes

Lymph nodes

highly specialised structures supplied by lymphatic vessels, wherein antigen collected from tissues is trapped and leads to T and B cell activation

Spleen

specialises in trapping blood borne pathogens leads to B and T cell activation

MALT

surface area 400m^2, major sites entry most pathogens ( mucous membranes, digestive, respiratory and urogenital tracts), less organised structures, leads to B and T cell activation

2 types of adaptive immunity

- Antibody based (humoral) immunity

- T cell based (cell mediated) immunity

- Both are closely linked and based on lymphocyte

Antigen

- Any molecule that can be recognised by the adaptive immune response

- Usual antigens are proteins, glycoproteins and polysaccharides of pathogens, antigens include protien coats of viruses, bacterial surface proteins, pollens, nickel and other allergens, vaccines….

Key functions of innate immune cells

- Phagocytosis

- Antiviral responses (interferons)

- Antigen presentation leads to the activation of T cells

- Defence against parasitic infections

Mechanical/ chemical barriers to prevent pathogen entry

- Tears/ saliva

- Stomach acid

- Mucus linings

- Skin and mucosal epithelial

Phagocytosis

- Neutrophil-- released into blood and die within hours

- Macrophage-- found in tissues

- Dendritic cell

- Bacterium binds to cell surface receptors on the phagocyte, inducing engulfment of the bacterium into a vesicle called a phagosome.

- This then fuses with lysosomes, now called a phagolysosome, which contains toxic small molecules and hydrolytic enzymes that kill and degrade the bacterium

Macrophage

- Tissue resident immune cell ( derived form blood monocytes)

- Cytoplasmic granules

- Primary function-- patrol tissues to kill bacteria and clear dead cells

- Attracted by chemokines

- Recognise bacteria

- Eat bacteria to clear ( phagocytosis)

- Eat dead/ dying cells

- Attract other leukocytes

innate and adaptive immunity have cellular and non cellular components

- Innate activated first following pathogen entry

- Innate-- non cellular components includes cytokines

- Adaptive the response learns and improves with time

- Part of innate activation response leads to activation of cells from adaptive immunity-- which can heighten the activities from innate cells

- Humoral (fluid component) normally reserved for the antibody response generated by B cells

What happens if innate immune cells fail to eliminate pathogen?

relies of adaptive system, T cells activated first the B cells which can boost activity of innate immune cells

B lymphocytes produce?

antibodies to fight pathogen

T cells differentiate into?

effector T cells to fight pathogen (helper or killer)

How frequent does a lymphocyte recognise antigen of pathogen?

10^5-10^6

How can the relevant T cell encounter the antigen that it recognises?

the T cells recirculate

Where do B and T lymphocytes mature?

Bone marrow and Thymus

How can we generate an effective immune response with these lymphocyte numbers?

T cell clonally expands to produce enough T cells to eliminate the pathogen--- B cells similarly clonally expanded

Specific Adaptive Immunity(Antibody based [humoral] immunity)

- Each B cell expresses a specific B cell receptor on the surface membrane

- This receptor can be secreted as antibody or immunoglobin

- Any particular B cell clone will only express antibody of one specificity

- The overall B cell population within an individual will be very diverse

- Antigen only binds to specific B cell

- This cline proliferates (expands)-- expanded clones differentiate into Memory B cells and antibody secreting Plasma cells hence lag time

- Result-- large amount of antibody secreted specific for selecting antigen

Antibody is most effective against?

extracellular microbes, bacteria/ viruses in blood, circulating toxins

Antibody is less effective against?

intracellular viruses and bacteria

What do T cells express on their surface?

a specific T Cell Receptor (TCR) on surface membrane-- unlike B cells, the TCR is not secreted

2 major types of T cell

- Cytotoxic T cells (CTL) expresses the CD8 molecule on surface-- once activated can kill virally infected cells and CTLs also target cancer cells

- T helper (Th) cells express the CD4 molecule on the surface-- once activated can help other cells eg B cells, CTL and macrophage

- They are co-receptors (required for T cell activation)

-


What does the T helper cell do?

- Helps B cell

- Produce antibodies against extracellular bacteria

- Helps CTL

- CTLs kill virally infected cells

- Activates macrophage (Mo)

- Killing activity is increased in Mo eg against intracellular pathogens eg Mycobacteria

Linking innate and adaptive immune responses

- Professional antigen presenting cells (APCs)-- dendritic cell, macrophage (innate immunity) and B cell (adaptive immunity)

- Role of APCs-- enables the T cell to 'see pathogen' leading to its activation

- Key APC for Naïve T cell activation is the dendritic cell

- The macrophage and B cell act as APCs to effector T cells

What are dendritic cells key for?

key APCs for Naïve CD4+ and naïve CD8+ T cell activation

Naïve T cells encounter antigens in peripheral lymphoid organs

- Pathogens and their proudcts must be transported to lymphoid tissue

- Pathogens that gain entry at a skin wound for example are transported in lymph and trapped in lymph nodes nearest to the sit of infection

- Pathogens infecting mucosal sites are transported across the mucosa into lymphoid tissue such as the tonsils and Peyer's patches

- Antigens introduced directly into the bloodstream are picked up by APCs in the spleen

Dendritic cells are positioned at sites of pathogen entry

- Microbes enter the body most often through the skin and the gastrointestinal and respiratory tracts

- These tissues are lined by epithelia that contain dendritic cells and all are drained by lymphatic vessels

- Dendritic cells can uptake pathogen by several mechanisms

- Phagocytosis, pinocytosis, receptor mediated endocytosis and process antigen for presentation to naïve CD4+ and naïve CD8+ T cells

Capture and presentation of antigens by dendritic cells (why are DC's (dendritic cells) so important as APCs?)

- Sites of microbe entry-- skin, GI tract, lungs (organs with epithelial layers, populated by DC)

- Sites of lymphocyte activation-- peripheral lymphoid organs (lymph nodes, spleen), mucosal and cutaneous lymphoid tissues

- DC's migrate antigens and present them to naïve T cells in lymph nodes

Pathways of T lymphocyte recirculation

.

MHC molecules (Major Histocompatibility Complex molecules)

- Name derives from finding that this gene loci is involved in tissue compatibility in transplants

- Transplanted organ recognised as 'non self' by the immune system

- What does it recognise?-- MHC molecules

- MHC genotype matching between donor and recipient is needed for allografts

MHC molecules

- MHC class I and II act as antigen presenting structures-- function is to bind peptide and present to T cells

- MHC II molecules are expressed on professional APCs

- MHC I molecules are expressed on all nucleated cells

What do naïve T cells need?

another cell to present antigen to it so it can 'see the antigen', this cell is the dendritic cell which use MHC molecules to present antigen to naïve T cells

Naïve CD4+ or CD8+ t cell activation

- Dendritic cell presents antigen peptide bound to MHC molecules to naïve T cells

- In this case the naïve T cell recognises the MHC/ peptide complex through its TCR

- This provides 'signal 1' for naïve T cell activation

- Naïve CD4+ T cell activation-- dendritic cells present peptide from processed pathogen on MHC II molecules to CD4+ T cells

- Naïve CD8+ T cell activation-- dendritic cells present peptide (eg viral peptide) on MHC class I molecules to CD8+ T cells

What can phagocytes act as?

antigen presenting cells (APCs) eg dendritic cell and macrophage, dendritic cell (DC) is the key APC for naïve T cell activation

Ag processing and presentation (1-4)

1. Catabolism of protein antigen to peptides inside host cell-- some peptides bind to an MHC molecule

2. MHC II molecule binds to a peptide derived from the pathogen

3. Loaded MHC II/ peptide complex travels to the cell surface to display antigen to T cells

4. The T cell receptor (TCR) of this given CD4+ T cell recognises its ligand, this MHC/ peptide complex. CD4 makes contact with an invariant region of the MHC II molecule

AG processing and presentation (4a)

4a. If this is a naïve T cell then APC is a dendritic cell. Other interactions ('signal 2') are required for Naïve T cell activation. Activation of naïve T cells is required to initiate the T cell mediated immune response

MHC class II molecules expressed by APCs present antigen (ie peptide) to T cells which express CD4 (helper T cells)

professional antigen presenting cells (APCs) express MHC II molecules B cell and macrophage present antigen to effector CD4+ T helper cells

Outcome of antigen presentation by B cells

differentiation into plasma cells and memory B cells

What do CD4+ helper T cells do

- Neutrophil, macrophage-- Killing activity is increased in Macrophage

- Killer T cell-- Cytotoxic T lymphocyte (CTLs kill virally infected cells

- B cells-- Produce antibodies against extracellular bacteria

What does CD8+ T cell do

• Effector cell ( cytotoxic T lymphocyte) and following recognition of MHC I/ viral peptide complex it can kill this virally infected tissue

  • Cytokines, secreted chemical messengers to instruct differetn function

  • Perforings pierce holes in target cell and granzymes initiate programmed cell death (apoptosis)

  • CTLs also key cellular players in killing tumour cells-- in this case tumour antigen is displayed on MHC class I molecules by cancer cells

Key functions of innate immune cells

1. Phagocytosis

2. Antigen presentation leads to activation of T cells

3. Antiviral responses (interferons)

4. Defence against parasitic infections

Interferons

- Cytokines (proteins) produced by host cells in response to viral and microbial infections

- Induces an antiviral state in cells

- Natural killer (NK) cells and plasmacytoid dendritic cells are important cellular sources of interferons

SARS-CoV-2

- Severe acute respiratory syndrome coronavirus 2 is a new β coronavirus responsible for the viral pandemic known as COVID-19

- SARS-CoV-2 can lead to an excessive inflammatory innate immune response and impaired adaptive immune response, leading to tissue damage at the systemic level.

- There is an excessive release of cytokines and chemokines, referred to as a 'cytokine storm' seen in patients with severe lung disease with the development of acute respiratory distress syndrome (ARDS) during SARS-CoV-2 infection

- Severe COVID-19 patients show an impaired type I interferon response characterised by undetectable IFN-b and low IFN-a production/activity together with heightened production of pro-inflammatory cytokines - Age and sex influence disease severity

B cells

- Each b cell expresses a specific B cell receptor on the surface membrane

- This receptor can be secreted as antibody or immunoglobin

- Any particular B cell clone will only express antibody of one specificity

- But the overall B cell population (within an individual) will be very diverse

- B cell acts as an antigen presenting Cell (APC) to T cell

Structure of an antibody molecule

- Immunoglobin (Ig) molecule has 2 identical light chains and 2 identical heavy chains

- The Ig molecule has a variable region and a constant region

- Variable region is the site where antigen binding site is located

- Constant region is region which determines the effector function if the Ig molecule

What separates the five classes of immunoglobin?

differences in the heavy chain constant

5 main classes of immunoglobin

- IgM

- IgD

- IgG

- IgE

- IgA

What are the subclasses of IgG and IgA in humans?

- IgG has 4 subclasses (IgG1, IgG2, IgG3, IgG4)

- IgA has 2 subclasses (IgA1 and IgA2)

What are the five classes heavy chains denoted by?

- Lower case Greek letters-- μ (mu), δ (delta), γ (gamma), ε (epsilon), and α (alpha)

- Different classes determine effector functions

What are the light chains denoted by?

- (κ) kappa and (λ) lambda

- No functional differences have been found between antibodies carrying kappa or lambda light chains

- Each antibody has kappa or lambda, not both

Immunoglobin mediated effector functions

1. Neutralisation--eg neutralises toxins by binding to them before they bind to cells and do harm to host cells, binds to viral particles and prevents virus from entering cell)

2. Opsonisation-- process of coating microbes with antibodies so that they are more easily phagocytosed, this is because phagocytes (eg macrophage) express recptors (FcRs) for antibodies so can bind antibody microbe complex

3. Antibody dependent cell mediated cytotoxicity-- antibody binds to antigen (eg viral antigen) receptors for Fc region of antibodies are located on Natural Killer (NK) cells, binds and leads to release of toxic granule contents, cell destruction

Immunoglobin mediated effector function-- 1. neutralisation

1a,b,c,e. Antibodies can bind to toxins and viral particles, protect cells

What receptor does NK cells have?

FcRs which bind to Fc region of different classes of an antibody eg IgG, IgE etc

Immunoglobin mediated effector function-- 3. antibody dependent cell mediated cytotoxicity (ADCC)

a. Ab recognises antigen on infected cell eg virally infected cell

b. NK cell has receptor for Fc region of IgG

c. NK cell releases toxic granule contents-- leads to death of target cell

Antibody dependent cell mediated cytotoxictiy (ADCC)

- Important in defense against extracellular parasites like helminths worms

- Cells involved include NK cells, eosinophils, neutrophil, macrophage

- Antibodies bind to antigens on the parasite, cells have receptors for Fc portion of Ig molecule present on eosinophils, NK cells, macrophages, neutrophils

- Release of lytic enzymes eg neutrophil (lytic enzymes) macrophage (lytic enzymes), tumor necrosis factor (TNF), NK cell (lytic enzymes, perforin, granzymes)

Immunoglobin mediated effector function-- 2. opsonisation

antibodies can coat microbes (ie antibodies bind to antigens through the Fab region. Macrophages have receptors which recognise the Fc region of antibodies (FcRs)-- uptake of microbe by macrophage. Antibody acts as an opsonin

Immunoglobin mediated effector function-- 3. antibody dependent cell mediated cytotoxicity (ADCC)

a. Ab recognises antigen on infected cell eg virally infected cell

b. NK cell has receptor for Fc region of IgG

c. NK cell releases toxic granule contents-- leads to death of target cell

Antibody dependent cell mediated cytotoxictiy (ADCC)

- Important in defense against extracellular parasites like helminths worms

- Cells involved include NK cells, eosinophils, neutrophil, macrophage

- Antibodies bind to antigens on the parasite, cells have receptors for Fc portion of Ig molecule present on eosinophils, NK cells, macrophages, neutrophils

- Release of lytic enzymes eg neutrophil (lytic enzymes) macrophage (lytic enzymes), tumor necrosis factor (TNF), NK cell (lytic enzymes, perforin, granzymes)