Immune system (wk 10)

antigen vs antibody

Antigen - any molecule that generates a response by the adaptive immune system

• Either self or non-self

• Normally, the body learns to not attack "self" antigens

• If it does respond to self antigens = autoimmune disease

 

Antibody - a molecule produced by the immune system to neutralise antigens

why must immune system know the difference between self and non-self antigens

allows it to recognise, respond to and eliminate harmful entities without harming the organism it should be protecting

First line of defence: Barriers

Prevents the harmful entity from entering the body in the first place

Two types: physical and chemical

Physical

• Epithelial cells of skin, gut, respiratory tract

• Secretions including sweat, wax and tears

• Mucus in the nose, trachea, gut

• Urine

Chemical

• Proteolytic enzymes

• Low stomach pH

• Normal Gut flora

Primary lymphoid organs in immune system

• what are they

• examples

Sites of development of immune cells

• All immune cells start as bone-marrow derived stem cells

• Bone marrow and thymus

 

Bone marrow

• Haematopoiesis occurs -> i.e. where blood cells are made

• Place of growth and storage of immune cells

  • Maternity ward: where immune cells are "born"

  • Retirement: where plasma cells survive/stay -> they ;produce antibodies

Secondary lymphoid organs in immune system

• what are they

• examples

Sites of activation

• Where immune cells reside or migrate between

• Spleen and lymph nodes

• Mucosal and cutaneous associated lymphoid tissues

Peripheral sites in immune system

• what are they

• examples

Other sites immune cells briefly visit

• Skin, liver, gut, CNS, lungs, etc

list the cells of the immune system

• Innate

  • Phagocytes: Neutrophils, monocytes, dendritic cells, eosinophils, basophils, mast cells

• Adaptive

  • Lymphocytes: B and T cells

what is the innate immune system

general immune response to all pathogens/non-self antigens: Cells and molecules recognise physical/chemical essential structures shared by classes of microbes -> through evolution

E.g. different chemicals in bacterial cell walls not in humans

• Present since birth

• Other names

  • Natural / native immunity

  • First line of defence

• Consists of epithelial barriers; molecules and cells in tissues and circulation

function of innate immune system

qualities of innate immune system

• Speed

  • Is fast responding

  • The earliest to respond

• Short duration

• Responds to foreign body in the same way each time encountered

• Interacts with other cells of innate and adaptive immune system

• Does not react to "self" antigens/cells -> not responsible for autoimmune disease

what are Receptors

How innate immune cells differentiate between

• Self and non-self

• Healthy and damaged

types of receptors

What it recognises

Where it is located

Detected by… in immune system

molecules of innate immune system

Complement proteins

Anti-microbial peptides / proteins

Cytokines

Note: antibodies are part of adaptive immune system

function of Complement proteins

• Circulate in blood or on cells

• Dormant

• Triggers a cascade when encountering a microbe

• Three outcomes:

  • Kills target

  • Causes inflammation

  • Opsonize (coat) microbes to enhance phagocytosis

innate

function of Anti-microbial peptides / proteins

• Peptides / proteins with antimicrobial activity made by epithelial / immune cells

  • Against bacteria, fungi and viruses

  • Nature's antibiotics

• Target microbes

innate

function of Cytokines

• Soluble proteins that cause inflammation

• Responsible for communication

  • immune-immune cells

  • immune-other cells

• Many different types

innate and adaptive

what is Phagocytosis

Ingesting and destroying microbes

• By dendritic cells, neutrophils and macrophages

steps of phagocytosis

1. Microbe binds to receptor

2. Phagocyte extends cell membrane around it to form

3. Membrane closes up and pinches off to make a phagosome

4. Phagosome fuses with lysosome to form phagolysosome

5. Microbe killed by enzymes and toxic substances contained by lysosome

   1. Nitric oxide (NO) and Reactive oxygen species (ROS)

how does innate immune system directly kill harmful enemies

harmful pathogens

Complement protein killing

• insert into cell membrane of microbes

• Forms holes in cell membrane to "pop" cells

Eosinophil killing of parasites

• By eosinophils -> specialised cells for parasites

  • Most parasites are to big to be phagocytosed

• Release cytoplasmic granules that damage and kill the parasite

Neutrophil Extracellular Traps (NETs)

• By neutrophils

• Release internal contents on bacteria/fungi -> traps and kills the pathogen

harmful cells (cancer)

Natural Killer cells

• Attach to cell via receptors

• Inject cytotoxic granules into cell to kill it

what is Inflammation

tissue reaction that brings defence cells/proteins to site of infection/damage

1. injured tissue + mast cells releases

   1. Histamines

      1. increase permeability of blood vessels in area

      2. Brings more blood flow to area

      3. More fluid in area = more antibodies, antimicrobial proteins, complement proteins

   2. Chemokines

      1. Special type of cytokine

      2. Make cell migration possible

      3. Cells follow from least concentration of chemokines to highest concentration

      4. allows them to arrive at sight of injury

2. immune system responsds

   1. phagocytes attracted to area

      1. Neutrophils/macrophages migrating to site of scratch injury

   2. complement proteins move to area

Innate vs Adaptive Immunity

cells in innate vs adaptive immune response

cells in adaptive immunity

• Only lymphocyte

• Two types:

  • B cells

    • Develop in bone marrow

    • Plasma B cells, memory B cells

  • T cells

    • Develop in thymus

      • Stem cells made in bone marrow and move to thymus

    • Cytotoxic T cells, helper cells, suppressor cells, memory T cells

Antigen receptors purpose

Allow lymphocytes to recognise its targets

• are membrane bound

• Each single lymphocyte only has one type of antigen receptor

• few lymphocytes with the same antigen receptor

antigen receptor types

types

• B cell receptor = BCR

  • Two antigen binding sites

  • Can bind to free antigens in blood

• T cell receptor = TCR

  • One antigen binding site

  • Cannot bind to free antigens -> must be presented an antigen by a dendritic cell

parts of antigen receptor

• variable regions - antigen binding sites

• constant regions

pros and cons of antigen receptors in human immune system

• Pros: Large variety of antigen receptors

• Cons: low frequency

  • Barely any other lymphocytes with the same antigen receptor in the body

  • Must undergo clonal expansion

    • Means each lymphocyte must clone itself to respond to specific pathogen

  • Why the adaptive immune system responds slower

why is adaptive immune system slower (to respond) than innate

• antigen receptors are made by randomly reorganising gene segments during development -> somatic recombination

• i.e. have the receptor before you are exposed to the antigen

• So that when you are exposed, the dendritic cell can find a T cell with a matching antigen and produce an appropriate immune response

• Why adaptive immune response is slower

+takes time for dendritic cell to travel from infection site to lymph node and find a helper T cell to present processed antigen to

purpose of B cells

 produce antibodies

• Neutralises extracellular antigens/microbes and microbial toxins

  • Extracellular microbe - survive outside a host cell

  • Intracellular microbe - survive inside a host cell

• B cell recognises an antigen -> B cell proliferates -> B cell differentiates into plasma and memory B cells

types of b lymphocytes

• Plasma B cells = produce the antibody

• Memory B cells = remembers antibody for specific antigen

another name for antibodies

immunoglobulin

Function of antibodies

what are Isotype

Isotype - "flavour" of antibody

• Five different types

• Different isotypes have different effector functions

• To switch between isotypes, B cells need help from T cells

  • Since IgM is produced first

  • B cell gets signal from T cell to then produce IgG/E/A -> allows B cell to change DNA (whole cell switches)

  • Called "class switching"

list all isotypes

five:

IgM

IgD

IgG

IgE

IgA

IgM isotype function

• BCR of Naïve B cells

• Produced first

  • Do not need T cells to make this isotype

  • T cells needed to make other isotypes

• Function:

  • Neutralise pathogens

  • Activate complement proteins

star shape → the only pentamer

IgD isotype function

• BCR of Naïve B cells

• Function not understood

Y shape

IgG isotype function

• Most abundant in blood

• For antibacterial and antiviral defence

• Function:

  • Neutralise antigens

  • Opsonise

  • Activate complement

• Crosses placenta into baby during pregnancy

  • So when baby is born it already has maternal antibody in blood

  • Natural passive immunity

Y shape

IgE isotype function

• For defence against worms and parasites

• Function:

○ Activate mast cells, basophils, eosinophils

• Involved in allergy

Y shape

IGA isotype function

• Most abundant in mucosal sites

  • Pushed from gut into lumen

  • To neutralise pathogens before they can even get to gut

  • First line of defence

• Function

  • Neutralise pathogen

  • Controls commensal microbes in lumen of gut and lungs

looks like an X shape

Function of T cells

• Antibody/innate immune system are good at dealing with extracellular pathogens

  • Antibodies / phagocytes cannot get inside cells

• Need T cells to fight intracellular pathogens / transformed cells

• T cells can also help B cell and macrophage function

Role of dendritic cells

Dendritic cells link the innate and adaptive immune systems

• Captures antigen via phagocytosis

• Dendritic cell process the antigen -> chops it up into little pieces

• Migrates to nearest lymph node

• Presents antigen to naïve T cell and activates it

 

So T cells are MHC (or HLA) restricted -> must have an antigen presented to them by a dendritic cell before activating

 

Types of T cells

what is Immunological memory

B and T cells have memory cells

• Remember the antigen and the antibodies used/way to kill it after primary exposure

• Upon secondary exposure, B/T cells can multiply faster = neutralise pathogen/antigen faster

how does vaccination work

• The production of memory B/T cells allow vaccinations to be effective

• By inoculating a patient = giving them the primary exposure to the virus

  • Introducing the antigen to their immune system

  • Allows their body to find the antibodies / chemicals or proteins to kill it

• Upon secondary exposure to pathogen (i.e. when patient contracts it naturally) = they have a less severe reaction to pathogen

Successful vs unsuccessful immune responses

Successful:

• It only responds to harmful or "non-self" antigens

  • E.g. virus protein coat, cancer cells, asbestos

• Does not "overproduce" a response -> i.e. response is controlled

Unsuccessful:

• not activated at the right times

  • Responds to "self" or non-harmful antigens

  • E.g. dust, pollen, own healthy cells

  • Autoimmune disease

• cannot neutralise infection/antigen effectively

  • Cannot get rid of infection or cancer

  • Due to genetic mutations

  • Cancer / immunodeficiency

define Autoimmunity

→ how does this link to autoimmune disease

Immune system fails to ‘tolerate’ self cells

• occurs when tolerance mechanisms fail

• Autoimmunity = Predisposing genetic factors + ‘Environmental’ triggers

Autoimmune disease are caused by a lose of immune tolerance to specific self antigens

• A highly specific immune attack against one cell type or molecule in the body

  • E.g. type 1 diabetes -> only pancreatic cells attacked

• Due to large variety of antigen receptors = likely to have self-reactive cells that attack its own healthy body cells

• Body has immune tolerance mechanisms

  • Either delete or suppress potentially self-reactive cells

how does immune system prevent autoimmunity

Immune tolerance mechanisms

Central tolerance

• While cells are being developed

• Delete highly self-reactive clones during development in thymus/bond marrow

• Cells with some autoreactivity aren't deleted

Peripheral tolerance

• After cells are developed

• Supress activation of autoreactive cells

• Due to "regulatory" T cells

Treatment for autoimmune diseases

Traditionally managed with broad-acting immunosuppression

• By supressing whole immune system = we supressauto-reactive B and T cells

Can now use therapeutic monoclonal antibodies

• Target specific cells / molecules causing autoimmunity

• Target underlying mechanisms causing autoimmunity

immunotherapy for cancer

We now know that the body is constantly looks for cancerous cells and killing them

 

Promising new cancer therapies target the immune system

• Therapeutic antibodies

  • Remove the ‘immunological brakes’

  • Apply the ‘immunological accelerator’ -> allow the immune system to more effectively fight antigen

  • Mostly aimed at activating cytotoxic T cells

• Engineered T cells

  • Chimeric Antigen Receptor (CAR) T cells