hubs191 immunology

what is immunology?

study of an organism’s defence system in health and disease

• immune system composed of

  • organs (spleen)

  • cells (T-cells)

  • molecules (antibodies)

  • organised system that interact together to defend the body against disease

what are the main components of the immune system (lymphatic)?

• tonsils

• thymus

• spleen

• bone marrow

• lymph nodes

includes primary and secondary lymphoid organs:

• primary = where while blood cells made (bone marrow & thymus)

• secondary = where these white blood cells turn into immune cells (spleen & lymph nodes)

what is special about the bone marrow in the lymphatic system?

primary lymphoid organ

• source of stem cells that develop into cells of the ‘innate’ and ‘adaptive’ immune responses

what is special about the thymus in the lymphatic system?

primary lymphoid organ

• ‘school’ for white blood cells → T-cells

• developing T-cells learn not to react to self

• only 10% ‘graduate’ all others either cannot recognise pathogens or attack themselves, thus thymus has lots of dead/dying cells as well

what is special about the spleen in the lymphatic system?

secondary lymphoid organ

• site of initiation for immune responses again blood-borne pathogens

• no lymphatic drainage

what is special about the lymph nodes in the lymphatic system?

secondary lymphoid organ

• located along lymphatic vessels → yes lymphatic drainage

• lymph fluid from blood and tissue is filtered

• site of initiation of immune responses

what are the 3 general ‘layers’ of protection in the immune system

1. chemical and physical barriers

2. innate ‘arm’

3. adaptive ‘arm’

what is involved in the first layer of the immune system: physical and chemical barriers?

skin:

• made of top epidermis and inner dermis

• epidermis contains lots of layers with the top layer being dead cells → cannot infect

• dermis = thick layer of connective tissue and phagotic immune cells → hard to pierce through

  • phagotic cells will digest pathogens

  • also contains sweat glands = hypertonic

  • sebaceous gland = acidic (produce sebum)

  • lysozome = breaks down bacteria cell wall

mucosal layer:

• 1-2 layers

• made of epithelium = tightly packed cells w/ mucus-producing goblet cells (alive)

• line parts of the body exposed to air or lead to outside

• traps and moves pathogens to be killed/removed

  • stomach - low ph

  • gull bladder - bile

  • mucus

  • defensins

  • lysozymes (only in tears/urine)

what is the mucociliary escolator?

inner

1. mucous gland (produce mucus)

2. basement membrane

3. columnar cell (have cilia attached)

4. goblet cell (secrete mucus)

5. cilia (beat & move mucus)

6. mucus (traps dust/pathogens)

(cilia move mucus up to the pharynx)

what is innate immunity/defences?

brute force immune cells

• (includes skin/mucosal barrier)

• already in place

• rapid response - hours

• fixed

• limited specificites

• has no specific memory

• also includes internal defences:

  • phagocytes

  • natural killer cells

  • inflammation

  • fever

what is adaptive immunity/defence?

highly specialised response to pathogens

• improves during the response

• slow - days/weeks

• variable

• highly specific

• has memory

• includes:

  • humoral immunity: b-cells

  • cellular immunity: t-cells

what is the relationship between innate and adaptive reponses/immunity?

they are both intertwined and must work together - ‘two arms’

what is blood composed of?

plasma:

• proteins

• other solutes

• water

cells:

• platelets

• white blood cells

• red blood cells

what is important about bone marrow stem cells?

they are a source of blood cells as these hematopoietic stem cells can become any type of blood cell (hematopoiesis)

• eg myeloid

  • red blood cells (erythrocytes)

  • granulocytes, monocytes, dendritic cells, platelets (innate immune cells)

• lymphoid

  • T and B lymphocytes (adaptive immune cells)

what are granulocytes and how do they appear in blood vs tissue?

type of white blood cell that has granules filled with chemicals in the cytoplasm in which they can release

• blood:

  • neutrophils: 75% of all leukocytes (WBC & type of granulocyte) and are highly phagocytic ‘eat and kill’ (numbers in blood increase during infection)

  • blood granulocytes can circulate in the blood and can move into tissue during inflammation

• tissue:

  • mast cells: line mucosal surfaces (not in blood)

  • release granules that attract white blood cells to areas of tissue damage

what are the 2/3 types of phagocytic cells?

monocytes → macrophages:

• in blood = monocyte = inactive (patrol)

• once enters tissues = macrophage = active (high phagocytosis) ~ spleen/liver

  • macrophages can become resident or move through tissues

  • 3 key functions:

    1. phagocytosis

    2. release of chemical messengers

    3. shows pathogenic info to T cells (links innate and adaptive arms)

dendritic cells:

• found in blood and all tissues exposed to the environment

• found in low numbers but are very effective

• phagocytic

• most important cell type to help trigger adaptive immune responses

how do cells of the immune system move around the body?

• cells are carried in the blood and in the lymph

• cells can leave blood and enter tissues (specifically at site of infection)

• lymph tissue collects into lymphatic vessels → these drain lymph into lymph nodes

how do innate cells recognise pathogens?

through pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors

for viruses:

• single/double stranded RNA

for bacteria:

• cell wall

  • lipopolysaccharide

  • endotoxins

  • lipoteichoic acid

• flagella

  • flagellin

• nuclic acid

  • unmethylated CpG DNA

toll like receptors - pattern recognition receptors

• function in phagocytic immune cells (macrophages/dendritic) to detect microbial components and trigger immune responses

• can be on cell surface and recognise bacterial/yeast cell wall components

• or inside cell in phagolysosome vesicle where they detect bacterial/viral nucleic acids

what happens during fever/pyrexia?

• abnormally high temperature (37+)

• resetting of body thermostat by hypothalamus

• activated phagocytes/immune system produce pyrogens (‘fire generating’ cells) specifically pryogen interleukin-1 (after ingesting bacteria)

• this is useful to the body because higher temp:

  • slows down microbial replication

  • enhances immune cell function

• system reversed when

  • decreased phagocytosis (less microbes to be ingested)

  • decreased pryogen interleukin-1

  • decreased temperature

a common virus-associated pathogen associated molecule pattern (PAMP) is:

1. unmethylated CpG DNA

2. ds RNA

3. ss DNA

4. lipopolysaccaride/endotoxin

double stranded RNA

• unmethylated CpG DNA = bacteria

• ss DNA - not actually recognisable

• lipopolysaccaride/endotoxin = bacteria

what are the 4 steps to the inflammatory response?

1. chemical signals from tissue-resident cells act to attract more cells to the site of injury or infection

2. Neutrophils enter blood from bone marrow (highly phagotic granulacytes) and cling to cell walls

3. chemical signals from resident cells dilate blood vessels and make capillaries ‘leakier’

4. neutrophils squeeze through the leaky capillary wall and follow the chemical trail to the injury site

what are the 5 stages of phagocytosis?

1. phagocyte adheres to pathogens or debris

2. phagocyte forms pseudopods (hug) that eventually engulfs the particles forming a phagosome

3. lysosome fuses with the phagocytic vesicle, forming a phagolysosome

4. toxic compounds and lysosomal enzymes destroy pathogens

5. sometimes exocytosis of the vesicle removed indigestible and residual material

(many myeloid cells are phagocytic)

how are phagocytosed microbes killed?

in the phagolysosome there is

• a low pH environment

• reactive oxygen (hydrogen peroxide) and reactive nitrogen intermediates (nitric oxide)

• enzymes

  • proteases

  • lipases

  • nucleases

what is the complement cascade?

9 major proteins/complexes act in sequence to clear pathogens from blood and tissues

• 3 complement (C3) pathways

  • classical - complement binds to pathogen through antibody

  • alternative - complement binds directly to pathogen

  • lectin - complement binds to pathogen through a carbohydrate

• 1 of these pathways leads to all three effects (amplification) - C3 → C3a + C3b

  • label (opsonisation) - coating microbe with antibody or C3b fragment ~ C3b stays attached to pathogens

  • recruit - inflammatory mediators like C3a and C5(a) attract phagocytes to the site by inducing mast cells degranulation.

  • destroy - microbes coated with C3b are phagocytosed. the membrane attack complex (MAC) causes lysis through punching holes into the cell membrane → cell dies

what are the 3 main ways immune cells communicate with each other? (just names)

1. soluble molecules (cytokines or chemokines) binding to receptors on a cell membrane

2. cell surface-bound receptors binding to a cell surface-bound ligand

3. antigen (pathogen parts) being presented to cell surface bound receptors

how does ‘soluble molecules (cytokines or chemokines) binding to receptors on a cell membrane’ work for immune cell communication?

1. toll like receptors:

   • water soluble PAMPs (recognisable pattern part of pathogen) bind to TOL (pattern rec receptor) on surface which sends signal to nucleus

   • changes gene expression

2. cytokin receptor:

   • has extracellular/transmembrane/intercullular signalling (cytoplasmic tail) components

   • cytokine bonds to receptor, sending signal to nucleus which in/decreases gene expression

   • each cytokine has a specific receptor

3. chemokine receptor:

   • has extracellular/transmembrane/intercullular signalling (cytoplasmic tail) components

   • chemokine binds and sends signal to cell

     1. always causes cell movement (toward higher chemokine concentration)

     2. and sometimes changes gene expression as well/function of the cell

how does ‘surface bound receptors binding to surface bound ligands’ work for immune cell communication?

between T and B cells - alters function of one or both of the cells depending on if signalling parts are inside the cytoplasm or not

• handshake - 1 has ligand, 1 has receptor

• particular ligand to receptor

• in/decreases regulation of gene transcription

how does ‘antigen being presented to a cell surface bound receptor’ work for immune cell communication?

between dendritic cell (or antigen presenting cell) and T-cell (B-cell can bind/recognise antigens directly)

• dendritic cell shows antigen to T cell

• activated t cell and function changes

  • gene transcription can change

  • increases regulation of their function

    • eg make more cyto/chemokines

    • make proteins to make then better killer cells

• each T cell can only recognise 1 type of pathogen

antigen is presented through the MHC complex of the antigen presenting cell - there are 2 types

what is an antigen?

anything that has potential to be recognised by the immune system (B and T cells)

• foreign antigen: anything from ‘outside’ (transplants, pathogens, some chemicals)

• self-antigen: autoimmune issues

how do activated dendritic cells communicate with T cells?

activated dendritic (innate) cells:

• make cytokines that bind to receptors on T cell membranes

  • cytokines key to send signals

• have cell surface-bound receptors that bind to T cell surface-bound ligand (or vice versa)

• present antigen to cell surface-bound receptors on T cells

this activates T cells = work better and/or grow/divide

example of innate and adaptive immune responses interacting

what are the 2 types of MHC complexes on antigen presenting cells?

1. MHC-1: presents endogenous (intracellular) antigens eg viruses

   • present on all nucleated cells

2. MHC-2: presents exogenous (extracellular) antigens

   • present only on antigen presenting cells

   • grab from outside and pulls it into the cell - dendrites best at this

what are cytokines and chemokines?

cytokines:

• molecules such as interleukins and interferons that control growth and activity of immune cells

chemokines:

• molecules that stimulate cell migration

both produced by innate and adaptive immune system cells and cells that influence the immune system eg epithelial cells

how do helper T cells activate B cells?

activated helper T-cells activated b cells by:

• making cytokines that bind to receptors on B cell membranes

• have cell surface-bound receptors that bind to a B cell surface bound ligand (or vice versa)

this communication leads to the activation of the B cell, and helps the B cell to make antibodies (essential for strong immune response against pathogens)

how does the complement cascade and B cells link innate and adaptive responses?

1. antibody produced by the B cell (adaptive) can bind to a pathogen → initiates complement cascade (innate)

2. and if complement fragments bind to a antigen, this can help activate B cells to produce more antibodies

(a cycle) - innate and adaptive immunity interacting

what is the big picture, 10 step process of the immune response when you step on a nail?

1. stand o nail, break physical barrier (skin)

2. pathogens enter the body

3. chemical mediators (produces by mast cells) leads to vasodilation and entry of phagocytic cells (neutrophils) to the tissue to ‘eat and destroy’

4. complement pathway triggered (but not classical as antibodies not yet produced)

5. dendritic cells in the skin become activated through recognition of pathogen associated molecular patterns (PAMPs)

6. dendritic cells move to local lymph node

7. once in lymph activated dendritic cells activate T cells via MHC

8. antigen + T cells and complement activate B cells

9. B cells produce antibody

10. complement, phagocytosis and antibodies help clear the pathogen

does volume of cells = function of cells in the blood?

no. white blood cells are a minor constituent of blood (buffy coat) but main cells involved in immunity

how does antigen sampling and presentation work (dendritic cells)

• dendritic cells are present in major organs and can phagocytose the antigen

• during this process they break it down into peptides (string on amino acids)

• dendritic cells migrate from organs (eg skin) to draining lymph node

• the present peptides on MHC protein complex to T cells (→ immune response begins)

how does adaptive immunity work using CD4 (helper T cells) and CD8 (killer T cells)?

step 1: pathogen/vaccine introduction

• pathogens/vaccines introduce foreign antigens into the body

• these are picked up by antigen presenting cells (dendritic cells)

• cells process and display the antigen on MHC molecules (MHC2 for CD4+ and MHC1 for CD8+)

• leads to helper or killer T cell activation (2 pathways)

step 2: T cell activation by APC

• helper T cells recognise the antigens on MHC2 and become activated

• or killer T cells recognise antigens on MHC1 - and with help of helper cells start process of becoming activated killer T cells

step 3a: helper T cells help B cells

• B cells recognise native antigens

• helper T cells interact and help B cells become plasma cells which produce antibodies (which neutralise pathogens) - final function

step 3b: helper T cells helps killer T cells

• helps killer cells release cytokines (activates killer cells)

step 4: killer T cells kill virus infected cells

• final function

what is the purpose of antigen uptake?

1. clearance of pathogens through the innate response

2. for presentation to T cells for initiating the adaptive response (and do something about the infection)

how did the adaptive immune response begin/evolve?

• evolved 50 million years ago

• phagocytes evolved to keep remnants of pathogens and display these to other cells of the immune system

• all vertebrates and later discovered jawless fish have adaptive immunity (along with innate like everything else)

how does MHC1 molecules detect and respond to endogenous threats?

1. virus infects the cell

   • virus uses hosts machinery to make viral proteins in the cytoplasm

2. proteasome enzyme breaks down proteins into peptides (blender) & tagged for immune display

3. peptide transport to ER

   • peptides moved into the ER where MHC1 molecules are being assembled

4. MHC1 loading

   • inside ER, peptide is loaded onto a MHC1 molecule and this complex is shipped to the cell surface

5. killer T cells then recognise and initiate response

how does MHC2 molecules detect and respond to exogenous threats?

1. phagocytosis

   • antigen presenting cell engulfs an exogenous antigen and forms vesicle inside cell

2. phagolysosome formation

   • formed and antigen broken down into peptides

3. peptide loading on MHC2

   • MHC2 not degraded in phagolysosome but are waiting to bind onto broken down peptides → complex is formed

4. transport to cell surface

   • complex is transported to plasma membrane of the antigen presenting cell and is displayed on the surface

5. recognition by helper T cells

   • helper T cells scan the MHC2 molecules - if the peptide is foreign the helper gets activated and begins immune response