L22 - Hypersensitivity type 3 and 4

Question 1

what is an immune complex

Answer 1

formed by binding of antibody to soluble antigen

Question 2

difference in what happens to large or small immune complexes

Answer 2

large:
rapidly cleared by macrophages easily

small:
when there is excess soluble antigen present –> if not cleared it can be depoisited in tissues

= T3 hypersensitivity reactions

Question 3

describe the clearance of immune complexes in healthy individuals

Answer 3

1. Antibody binds to soluble antigen forming IC
2. C1 complex binds to Fc receptors on the bound antibodies actiovating classical copmplement cascade
3. C3 converase produced and C3b molecules ‘depoisited’ on surface of immune complex
4. Complement receptors (CR1) on blood cells bind to C3b and C5b molecules
5. transported to liver and spleen where phagocytes with Fc receptors bind to iIC via antibdoes Fc region

–> IC degraded and blood cells/ethryocytes are released/stripped of bound IC

Question 4

dfifference between T2 and T3 hypersensitivity reactions

Answer 4

both use same isotype of antibodies - IgG - with Fc receptors

T2 –> antibody on cell/EC<

T3 –> antbody on soluble antigen = Immune complex

Question 5

which antibody are T3 HS reactions primarily mediated by

Answer 5

IgG

Question 6

how could you get damage from an envirnmental antigen from inhalation - T3

Answer 6

1. Local immune complexes form in alveoli of lungs
2. accumalation of fluid,protein and cells in the avelolar wall –> slows down gas exchange
3. inflammation and fibrosus cause permanent damage

Question 7

describe how Immune Complexes Interact with Fc Receptors on Basophils and Platelets

Answer 7

Antigen-antibody clusters bind to Fc receptors (FcγR) on basophils and platelets

= active basophils produce histamine

= platelet activation induces release of pro-inflammatory mediators like serotonin and platelet factor 4.

Mediators initiate local inflammation and contribute to vascular changes.

Question 8

define inflammation

Answer 8

body’s protective response to infection, injury, or harmful stimuli

• Vascular changes – increased blood flow and permeability
• Immune cell recruitment – especially neutrophils, macrophages, and lymphocytes.
• Chemical mediators – cytokines, chemokines, prostaglandins, histamine, and complement proteins.

Question 9

how do Immune complexes interact with complement to trigger inflammation

Answer 9

Activate the classical complement pathway -resulting in cleavage of:

C3 → C3a + C3b
C5 → C5a + c5b

= ‘a’s are anaphylotoxins bind to C3aR, C5aR receptors on mast and basiphils = degranulation –> histamine release
= ‘b’s are bound by CR receptors

Question 10

explain how immune complexes affect macrophaes to trigger inflammation

Answer 10

ICs are phagocytosed –> intracellular signalling –> macrophages produce IL-1 and TNF-a

= inflmmatory cytokines

Question 11

name the inflammatory cytokines produced by activated macrophages due to ingestion of immune complexes

Answer 11

Il-1 and TNF-a

Question 12

how do IL-1 and TNF-a cause fever

Answer 12

Act on the hypothalamus to raise the body temperature set point.

= Promote production of prostaglandin E2 (PGE2) → fever –> helps inhibit pathogen replication.

Question 13

what do ‘Histamine, serotonin, C3a, C5a, IL-1, and TNF-α’ all contribute to in inflammatory response

Answer 13

vascular permeability

= endothelialcells retract exposingf basement membrane –> ICs can get lodged here

= can trigger locxal complement acytivation causing tissue damage

Question 14

describe the steps involved in formation of microthrombi from Immune complexes

Answer 14

1. platelets express CD32 receptor which binds to IgG of ICs
2. platelets also bind to exposed collagen of basement membrane via GPVI

= actiavtes platelets by combination of both pathways

3. Platelets link to each other through Fibrinogen bridges = microthromibi

= limited space means that build up limits blood flow

Question 15

how does complement reduce formation of insoluble ICs on tissues

Answer 15

complement components increase solubility of immune complexes

= increases their hydrophilicity and reduces their tendency to aggregate
= CR receptors on blood cells also allow removal from circulation to spleen/liver

defiencies in complement can cause problems

Question 16

why is MAC NOT formed in immune complexes

Answer 16

no membrane for C5b to anchor to properly/insert into

= prevents rest of MAC assembly

Question 16

how do immune complexes cause a cycle of complement activation in SLE patients

Answer 16

immune complex form

complement activation

tissue damage

antigen release from cells

–> more ICs form

Question 16

describe the dual role of patuents with systemic lupus erthyematous - SLE

Answer 16

patients have autoantibdoies against DNA,cytoplasmic proteins of their own cells

antibodies bind following apoptosus to form immune complexes

1. complement binding to ICs improves solubility and helps clearance by CR1 and ethryocyteds
2. overloadfed sysrem causes deposition in cappilary beds activating complement in tissues –> more damage

Question 17

what is ATG

Answer 17

Anti-thymocyte globulin

= polyclonal antibody produced in horse or rabbit against human T cells

used as an immunosuppressant to reduce chance of rejection in graft/transplant

Question 18

what is the probelm with using ATg as an immunosuppressant in transplants

Answer 18

derived from non-human source

= can be recognised as forign and immune reponse created = serum sickness

Question 19

what is serum sickness

Answer 19

exposure to forign protein caysing antigen:antibody immune complexes to form ajnd be depoisited thoughout body

= systemic Type 3 hypersensitivity

Question 20

how can we reduce chance of serum sickness when using things like ATG as an immunosuppressant

Answer 20

engineering monoclonal antibodies ro reduce the amount of non-human protein used

= orthoclones have complimnetarity regions frommouse and the REST of protein is human
= less to be recognised as forign

Question 21

whats another word for T4 hypersensitivity

Answer 21

delayed-type

= atleast 12 hours to manifest

Question 22

what type of peiople can T4 HS take place in and can not take place

Answer 22

can –> antibody-defienct humans

can’t –> AIDs patients

= T cells needed

Question 23

what do each of the 3 types of T4 HS reactions include

Answer 23

Th1 cells - classic: macrophage activation by Th1--> chemokines and cytokines produced Th2: eosinophils activation --> inflammatory mediators causing allergic response CD8+: cytotoxic lysis by cells

Question 24

desfcribe the Th1 cell T4 hypersensitity reaction

Answer 24

Th1 activated by APC in lymph = produces IFN-y activates macrophages = inflammation and edema

Question 25

whata re the 3 forms of T4 HS and their clinical appearance

Answer 25

1. Contact --> eczema 2. Tuberculin --> local induration 3. Granuloma --> hardening

Question 25

define a hapten

Answer 25

small molecule that cannot trigger an immune response on its own --> can become immunogenic when attached to a larger carrier protein.

Question 26

describe contact hypersensitivity

Answer 26

1. sensitising agents behave as haptens = binds to 'self-proteins' = new antigen structures 2. langerhands cells/APCs enguld and present to Th1 cells in lymph nodes 3. Keratinocytes also activated by TLRs that recognise pathogen ascociated patterns 3. Activated Th1 cells + keratinocytes secrete IFN-y + TNF-a 4. macrophages activated

Question 27

role of TNF-a and Il-1 on macrophages

Answer 27

upregulate ROS and NO production to enhance killing capacity inside phagolysosomes promote cytokine and chemokine secretion for further activation and recruitmenyt - CXCL8 upregulate MHC-2 for better presenation and activation of T-cells

Question 28

name a hapten

Answer 28

metal ions = nickel in watch strap - liophillic low Mr allows pentration of dermis and epidermis

Question 29

how do metal ions act as haptens to create new antigenic structures

Answer 29

bind to self-peptides in MHC-2 groove = recognised as foreign despite it being a normal/self protein

Question 30

how can CD8+ T cell be actiavted in contact hypersensitivity 4 responses

Answer 30

haptens such as pentadecacetochol from poison ivy can enter cells NOT just enter body like metal ions attach to intracellular self proteins --> presented on MHC-1 to CD8+ cells recognisd as foreign and activate cytotoxic CD8 T cells = direct killing + indirect cytokine killing (IFN-y for macrophages)

Question 31

describe the tuberculin type hypersensitvity

Answer 31

in sesnitised individuals - people who have encountered antigen before - memory Th1 cells circulating in blood are activated by APCs = IFN-y + TNF-a produced = macrophage activation = activate epithelial cells to upregulate adhesion molecules

Question 32

describe how upregulation of adhesion molcules on epithelial cells in Tuberculin-type hypersensitvity is helpful in inflammatory response

Answer 32

TNF-α and IL-1 prime the endothelium to become a gateway for immune cells by: 1. Increasing selectins (rolling) 2. Upregulating ICAM-1/VCAM-1 (firm adhesion) 3. Loosening junctions (permeability) 4. Supporting extravasation of leukocytes = allows immune cells to enter tissue/site of infection from blood via diapedisis

Question 33

how is tuberculin type hypersensitivity useful and name the test that is apart of this

Answer 33

test if an indiual has come into contact with antigen/pathogen before OR general measure of cell-mediated immunity 'Mantoux test' = inject antigens = swelling/hardening at site of injcetion

Question 34

what type of cell does chemokine CXCL8 recruit

Answer 34

neutophils in inflammatory response

Question 35

what is granulomatous hypersensitivity a result of

Answer 35

persistent intracellular pathogens or foreign substances that cannot be eradicated. = leads to chronic stimulation of T-cells and cytokine release leading to epitheliod granuloma development

Question 36

3 essential components of classic Th1 delayed type hypersensitivity

Answer 36

T cells with ⍺β TCR pro-inflammatory cytokines - IFN-𝜸 + TNF-⍺ chemokines

Question 37

why can mice defiecient in IFN-y + TNF-a not control tuberculosis infection

Answer 37

IFN-y + TNF-a is required to activate macrophages to kill bacteria and drives recruitment to form granuloma

Question 38

which out of TNF-a and IFN-y activate the macrophage and whicg one causes fusion of cells for granuloma

Answer 38

IFN-y = produced by Th1 to activate macrophage TNF-a = fusion of cells to form granuloma

Question 39

what percetage of human population is infected with TB

Answer 39

25% = contained in granulomas in lungs

Question 40

what are epitheliod cells

Answer 40

large elongated macrophages = differentaiute from immature macrophages on IFN-y stimualtion fuse together to form multinealted giant cells with TNF-a

Question 41

how do Th2 cells link to Type 1 /allergic response hypersensitivity

Answer 41

Th2 cells produce IL-4 to class switch from IgG --> IgE = primes eosinophils and basophils for re-introduction of allergen

Question 42

which cytokine promotes general T cell proliferation

Answer 42

IL-2