Autoimmunity and Transplantation

Question 1

REMINDER: Central Tolerance

Answer 1

B-cells (bone marrow) T cells (thymus)
1. Building heavy and light chains (TCR, BCR)
2. Make sure they are not self-reactive (negative selection) -> for T-cells positive (does it bind MHC?) and negative selection happen simultaneously

Question 2

What is the function of Treg?

Answer 2

Arisen from T-cells binding self-antigens in an intermediate manner -> circulate and bind self -> release of anti-inflammatory cytokines for anti-inflammatory background signal

Question 3

Where does receptor editing occur for B-cells?

Answer 3

In the bone marrow, the mechanism is turned off once it is in the spleen

A second V gene segment is rearranged into the first rearrangement -> try another V and J light chain and try not to waste the heavy chain that has already been built

-T-cells undergo receptor editing to some degree but it is mainly the B-cells that do it

Question 4

What are the ways to deactivate self-reactive cells in the periphery?

Answer 4

-Apoptosis
-Anergy (deactivation)
-Treg

Question 5

How do T-cells determine if they probably interact with a self-antigen?

Answer 5

-Signal 2 is missing CD28 (T-cell) - B7 (APC)
-Signal 3 is missing -> if it is a pathogen there should be inflammatory cytokines

Question 6

How do Treg cells act anti-inflammatory?

Answer 6

-Still engaged with Ag-MHC-II
-Contact: replace CD28 with CTLA-4 -> binding to CD80
-No contact: secrete anti-inflammatory cytokines:
IL-10, TGF-ß, IL-35

Question 7

How do Treg cells act anti-inflammatory?

Answer 7

-Still engaged with Ag-MHC-II
-Contact: replace CD28 with CTLA-4 -> binding to CD80 or degrade CD8ß to turn off APC
-No contact: secrete anti-inflammatory cytokines:
IL-10, TGF-ß, IL-35, and shut off surrounding T-cells
(IL-12 f.e. would cause T-cells to become TH1)

Question 8

What is Bystander suppression or linked suppression?

Answer 8

Treg cells inhibiting T cells that bind to separate Ag-MHC-II on the same APC
->it will generate more Treg cells to keep that anti-inflammatory background as high as possible to prevent getting self-reactive T-cells

Question 9

How does Tolerogenic DC contribute to barrier immunity?

Answer 9

Tolerogenic DC reaches out through epithelial cells and looks for antigens -> as long as the environment is tolerogenic it will secrete IL-10 -> formation of Treg cells (also secrete IL-10 and TGF-ß) + formation of IgA-producing B-cells in Payers patch

-IgA against those antigens are going to the lumen to keep them outside (maybe it is a PAMP)

Question 10

What are other ways to collect antigens from the outside for barrier immunity?

Answer 10

-Intestinal cells, M-cells sampling Ag in the lumen and transfer it to lamina propia

-FcR cell receptors carrying IgA-Ag to lamina propia
-Goblet cells transferring soluble Ag to lamina propia

Question 11

Which TH cells promote what type of antibody response?

Answer 11

TH1 (intracellular, virus): IFN-gamma ->IgG for Antibody-dependent cytotoxicity

TH2 (extracellular, worms): IL-4, 5, 13 -> IgE for mast cells, neutrophils, basophils

Treg: IL-10, TGF-ß, IL-35 -> IgA

Question 12

Why does more inflammation occur when the microbiota is decreased?

Answer 12

Because less Treg that produces anti-inflammatory cytokines is formed

-Commensal microbes needed to build a proper MALT
-Firmicutes produce short fatty acids (SCFAs) and Bacteroides fragilis produce polysaccharide A to maintain Treg level

Question 13

Why does more inflammation occur when the microbiota is decreased?

Answer 13

Because less Treg that produces anti-inflammatory cytokines is formed

-Commensal microbes needed to build a proper MALT
-Firmicutes produce short fatty acids (SCFAs) and
Bacteroides fragilis produce polysaccharide A to maintain the Treg level

The IDEA is that when a pathogen comes around and wipe SCFAs or polysaccharide A away, it is recognized as a threat

Question 14

What stimulates the switch to an inflammatory rsponse?

Answer 14

Once Tolerogenic DCs don’t sense commensal microbes, they get activated and -> activation of TH1 and TH17 -> they secrete IFN-gamma, TNF-alpha, IL-17 -> generate an inflammatory response

Question 15

What stimulates the switch to an inflammatory response?

Answer 15

Once Tolerogenic DCs don’t sense commensal microbes, they get activated and -> activation of TH1 and TH17 -> they secrete IFN-gamma, TNF-alpha, IL-17 -> generate an inflammatory response

Question 16

What does Dysbiosis mean?

Answer 16

Disruption of a healthy microbiome: Factor in Inflammatory Bowel Disease (IBS)
-> Crohn’s Disease - inappropriate TH1 response
-> Ulcerative colitis - inappropriate TH2 response
both inflammatory

Question 17

What is Celiac disease?

Answer 17

Celiac disease is an autoimmune disorder
triggered by an immune response to gluten
-> triggers TH1 response, NK, and B-cell activity
-> ILEs activated -> epithelial cell death

Question 18

Other Regulatory Cells

Answer 18

-Regulatory CD8+ T cells: in the periphery and uses a range of mechanisms -> Lysis and inhibition of APCs showing self-peptide and regulation of effector cells binding the same Ag

-Regulatory B cells (BREG): producing IL-10
-Myeloid-derived suppressor cells (MDSC) - produce IL-10

Question 19

What can cause Autoimmune disorders?

Answer 19

failure in tolerance process -> often multifactorial, a combination of multiple triggers

-Infections and molecular mimicry (antigen looking close to self)
-Infections that induce genetic changes (infected cells, or cancer)
-sequestered Ag: eyes have their own sequestering system, eye proteins are not exposed to T cells -> when eye proteins get to the periphery Tcells start to react
-Food-altering (or stress) gut microbiota

Question 20

Two examples of systemic autoimmunity:

Answer 20

-(APS-1) caused by mutations in the AIRE gene -> AIRE expresses tissue-specific antigens of other tissues than the thymus -> in round 2 of negative selection of T-cells in the Thymus -if this process doesn’t work well, it can cause self-reactive T-cells

-(IPEX) syndrome, caused by mutations in the FoxP3 gen: Master regulator that converts the polarizing signal into the conversion of the T-cell -> MUTATION in Foxp3 means no formation of Treg cells -> no turning off of self-reactive T cells and low anti-inflammatory background signal

Question 21

Typ 1 diabetes mellitus:

Answer 21

-an autoimmune attack against insulin-producing beta cells in the pancreas

-CTLs infiltrate the pancreas and activate
macrophages
-cytokine release and production of autoantibodies -> activate complement or ADCC activities by NK cells

Question 22

Which two pathways activate cytotoxicity by caspase?

Answer 22

FasL and Granzyme B (Perforin will let Granzyme B in)

Question 23

What is Myasthenia gravis?

Answer 23

-Autoantibodies produced against acetylcholine receptors on muscle -> BLOCKING -> muscle cant move

Question 24

What is Myasthenia gravis?

Answer 24

-Autoantibodies produced against acetylcholine receptors on muscle -> BLOCKING -> muscle cant move (weakening of skeletal muscle)

-Treatment: increase ACh, decrease Ab production (create ideotype Ab against those B-cells), remove Ab

Question 25

Explain Systemic lupus erythematosus (SLE):

Answer 25

Ab against DNA or histones, other self structures
-patients serum (with secondary Ab) is tested on human cells detected by immunofluorescence

-Symptoms caused by Auto-Ab wide range, depending on where it is acting: Fever, weakness, arthritis, skin rashes, kidney dysfunction

Question 26

Explain Rheumatoid arthritis:

Answer 26

-Ab against Fc region of own IgG Ab forming immune complexes (agglutination) and activate complement

-major symptom: joint inflammation
-Treatment: nonspecific anti-inflammatory drugs and corticosteroids (shut down autoimmune response -> but vulnerable to infections)

Question 27

What are the ways to treat Autoimmune disorders?

Answer 27

General or pathway-specific immunosuppression

-Treat symptoms: Typ-1-D -> give Insulin, Rheumatoid arthritis -> treat inflammation

-strong anti-inflammatory drugs: inhibit lymphocyte proliferation or kill the cells
but: vulnerable to infections, and cancer cells (by shutting off NK and anti-tumor T-cells)

Better:
-Antigen-specific immunotherapy target sell-reactive B-cells

-stimulate tolerance to the auto-Ag, restore balance

-Glatiramer acetate to treat multiple sclerosis (myelin basic protein) -> expose that self-reactive-protein to Treg in an anti-inflammatory environment
-same with Typ-1-D self protein proinsulin coated with nanoparticles -> tolerogenic shifting by exposure in anti-inflammatory envirnment

Question 28

What are the ways to treat Autoimmune disorders?

Answer 28

General or pathway-specific immunosuppression

-Treat symptoms: Typ-1-D -> give Insulin, Rheumatoid arthritis -> treat inflammation

-strong anti-inflammatory drugs: inhibit lymphocyte proliferation or kill the cells
but: vulnerable to infections, and cancer cells (by shutting off NK and anti-tumor T-cells)

Better:
-Antigen-specific immunotherapy target sell-reactive B-cells

-stimulate tolerance to the auto-Ag, restore balance

-Glatiramer acetate to treat multiple sclerosis (myelin basic protein) -> expose that self-reactive-protein to Treg in an anti-inflammatory environment
-same with Typ-1-D self-protein proinsulin coated with nanoparticles -> tolerogenic shifting by exposure in anti-inflammatory environment

Question 29

What are the different ways to receive a transplantant?

Answer 29

-Autograf: one part of the body to another (self-self): rejection often not immune-based, inflammation can occur

-Isograft: between genetically identical individuals (monozygotic twins, an inbred strain)

-Allograft: a different member of the same species (2 different humans): concern of MHC compatibility

-Xenograft: members of different species (pig to human): non-carbonhydrates antigens on the surface cause IgM rejection

Question 30

Histocompablities and rejections:

Answer 30

-Graft rejections
-AB0 blood group matching
-MHC matching: family members are the first choice

-Crossmatching: determine recipient Ab generated against donor MHC

Question 31

How do rejections occur in transplantations?

Answer 31

Indirect recognition: Donor proteins are presented on the host MHC by the host APC
these proteins may contain mutations

Direct recognition: Host TCR binds to donor MHC within donor APC
-> MHC might be different and show different peptides (same sequence)

Question 32

How fast are transplants rejected?

Answer 32

-Hyperacute rejection by preexisting antibody
preexisting Ab from a blood transfusion or other exposure -> graft rejection within 24 hr

-Acute rejection: by new T-cells after 7-10 days
Experiment shows that memory Ab after first exposure cause faster rejection of the second graft or faster rejection after transferring Anti-graft T-cells -> on the other hand T-cell depletion protects the graft

Question 33

What does the immune response in transplant rejections look like?

Answer 33

-CTL target graft cells
-Anti-graft Ab induce complement and ADCC (NK cells)

-Chronic rejection phase develops months or years
after acute rejection -> but if the body can keep the graft long enough it eventually gets used to it and can keep it by shifting with Treg cytokines (can be turned around by infection)

Question 34

Transplantation Immunotherapy

Answer 34

-Total lymphoid irradiation to eliminate lymphocytes -> often in graft-versus-host diseases: donor lymphocytes target host tissue

-receive donor stem cells treated with X-ray exposure to the thymus, and spleen -> destroy own immune cells so that the donor stem cells can create a new immune system

Question 35

Further Immunotherapies

Answer 35

-mAb to CD3 depletes T-cells before transplantation or mAb for IL-2 to block T-cell proliferation

-mAb to CD20 to deplete mature B-cells

-soluble CTLA-4 binds to CD80/86 preventing Signal 2 (costimulation) and inducing T-cell anergy

Question 36

Examples of successful Transplantation routes:

Answer 36

-lack alloantigens (e.g., cartilage or heart valves)
-tissue is grafted to a so-called privileged site (eye), protected from the immune system
-tolerance induced before transplantation -> Mixed hematopoietic chimerism -> take hematopoieteic stem cells from the donr and put it in the the recipients thymus and generate tolrtance?