Immunology Test 4

Autoimmunity

Adaptive immune response against self proteins.

How can autoimmunity be mediated?

by B cells/antibodies and/or T cells

Can occur because?

self tolerance not working properly

Central tolerance

Tolerance in the location where lymph nodes develop. Thymus and bone marrow negative selection.

Peripheral tolerance

Anergy Only signal 1 on T cells : Treg: lack of antigen exposure

Genetic defects in central tolerance

can lead to autoimmunity: AIRE transcription factor- Without you can not het rid of self reacting T cells

Regulatory T cells

Fox3 transcription factor, lead to autoimmunity.

Where is autoimmunity more prevalent?

In females

Where are associations

Lots of associations between genetics and autoimmunity making HLA genes.

Organ specific autoimmunity

Type 1 diabetes, Hashimoto's thyroid-its, IBD, Crohn's/

Systemic

Systemic lupus erythematosus, Rheumatoid arthritis

Humoral autoimmunity

antibody secretion by self reactive B cells.

Rheumatoid arthritis

Auto-reactive T cells against antigens of joint synovium,

joint inflammation and destruction causes arthritis

Graves' disease

Autoantibodies against the thyroid stimulating hormone receptor

Hyperthyroidism- overproduction of thyroid hormone

Multiple sclerosis

Auto-reactive T cells against brain antigens

formation of sclerotic plaques in brain with destruction of myelin sheaths surrounding nerve cells axons, leading to muscle weakness, ataxia, and other symptoms

Type one diabetes

auto-reactive T cells against pancreatic islet cell antigens.

destruction of pancreatic islet Beta cells leading to non-production of insulin

Graves' Disease
Stimulating Auto antibodies

auto immunity- Example of type II hypersensitivity

Mother with Graves' Disease

* makes anti TSHR antibodies
* antibodies cross the placenta into the fetus
*newborn suffers from graves'
* Maternal anti TSHR antibodies are removed and cures the infants disease.

Cell mediated Autoimmunity

CD4 cells are necessary for most types of autoimmunity.
help is needed to optimally activate B cells and CD8 T cells.

Type one diabetes

Is caused by a loss of insulin producing cells. Beta cells. In the islets of the pancreas. Only appears when 70-80% beta cells are destroyed.

How does autoimmunity start?

* release of sequestered antigens

* Molecular mimicry - homology between tissue portions and portions in infectious tissue

* Polyclonal activation of B cells

* Danger signals/TLR regulation

Immune system

Prevent, control infection
prevent, control malignancies

Immunodeficiency

Primary or acquired

Inborn errors

Phenotypes:
Infections, Malignancy, Allergy, Autoimmunity, Auto inflammatory

10 categories of inborn errors

Cellular & humoral immunity

Combined immunodeficiency w/syndromic features

Predominat antibody deficiency

phagocyte defects

complement deficiencies

intrinsic and innate immune defects


Immune dysregulation

Auto-inflammatory disorder

bone marrow failure syndromes

"Phenocopies" of PID

Risk factors of autoimmunity

Recurrent infections

Neutrophil

= Granulocyte = polymorphonuclear leukocyte

white blood cell, very fast
faster than macrophages

early stimulus

many neutrophils come and will start clearing out infection then come in macrophages.

Phagocyte defects

early onset
Delay umbilical cord separation
Recurrent skin abscesses, adenitis, oral cavity infection

Bactria and fungi

Chronic Granulomatous Disease

Neutrophil - defect in gp91phox - inside the


neutrophil unable to kill along with macrophages making granulomas

Not able to make oxygen species

Complemnet deficiencies

Present at any age

very very rare

Susceptibility to Neisseria (C5-9)

Recurrent infections (C3, regulatory proteins)

IgG transfer Vs. Production

Before birth passive transfer of maternal IgG

6-9 months

SCID

Severe combined immunodeficiency

Numerous genetic etiologies
* X-linked: IL2R gamma
* related cytokine receptor/signaling pathways IL7R, Jak3

Impaired innate adaptive cross talk
MSMD
Impairs CD8 and NK cell function

What causes cancer

Acquired mutations
* carcinogens
* radiations
Inherited mutations
*BRCA1 and BRCA2
Infections
*HPV

Immune Surveillance Hypothesis

Cells of the immune system can detect and destroy tumor cells

T cell infiltration

Tumor infiltrated T cells correlates with prolonged patient survival

Elimination (best case)

* Equivalent to immune surveillance
* innate and adaptive immune cells contribute
* Provide selective pressure

Equilibrium

* Immune system can control tumors but can not eradicate them

Escape

Tumor cells can evade or tolerize the immune system

Tumor antigens

Tumor specific- neo antigens driven by mutations

Tumor associated

Self antigens

Evading- Low immunogenicity

Tumor cells do not express peptides for MHC to respond too.

T cells fail to detect and ignore the cancer cells.

Evading: Not views as foreign

cancer cells are nit viewed as foreign because they do not make up many neo antogens


Central tolerance and peripheral tolerance

Evade: Suppressive micro environment

Produce suppressive factors - TGF- beta, IL-10, or PD-L1

Treg
Suppressive macrophages
tumor reactive T cells are suppressed and less effective at killing tumor cells.

Evade: physical barriers

Molecules that physically block T cells form accessing the tumor and have altered vasculature

collagen

Evade: Metabolic competition

They do what they can to survive, adapting to new environments and fermentation to metabolize glucose.

preventative vaccine

HPV vaccine

Monoclonal antibody therapies (mAb)

directly target cancer cells
manipulate

manipulate the immune system

transfer of genetically engineered T cells

chimeric antigen receptor (CAR) T cells

Oncolyic viru

virus injected directly into the tumor

mAbs

can directly target the cancer or be used to interfere with immosuppssive target

How to mAbs interfere with cancer cell growth?

1. ADCC
2. Complement
3. Apoptosis
4. Anti- proflierative efect
5. Conjunctive to a toxin or radiosotype

CAR

is engineered expressed in T cells.
bypass peptide MHC recognition no need for TCR
No worry of rejection because these are your own cells

Making CAR calls.

1. T cells isolated from patients
2. t cells are engineered to express CARs that recognize caner cells
3. modified T cells are grown and expanded in culture
4. Modified T cells are infused into patient

But only in liquid cancers

HIV

Human immunodeficiency virus, chronic infection, elimination of CD4 T cells over time

HIV receptors

CD4
Chemokine receptors- CCR5- CXCR4

HIV life cycle

Integrate into host genome then sleep

Why are anti-pathogen vaccines effective?

They are effective at interfering with infectious process because they generate antibodies

Antibodies are what?

main mediator of protection

What happens if Ab titer drops?

you lose anti pathogen efficacy, this is why you need a booster.

Natural immunity

Expresser to pathogen itself: typically best way to get immunity if it doesn’t kill you

Live attenuated vaccines and virus based vaccines

VSV used for ebola, usually very good, Adenovirus used for SARS-Cov V2 is
subunit vaccine
RNA vaccines
DNA vaccines

Barriers to successful transplantation

Rejection, and graft Vs. Host disease.

Rejection

Host fights graft

Graft Vs. host disease

graft fights host

What is major antigen in transplantation

MHC which is called HLA- Major Histocompatibility complex

Minor antigens

Are any other protein in your body

can cause rejection

Matching

You need to have clinical Histocompatibility HLA type, Antibodies, HLA type

What causes Antibody formation?

Previous rejected organ allograft

previous pregnancy

Whole blood/blood component transfusion

Anti-HLA antibodies

May be directed against HLA class I antigens, class II antigens or both.

Can be of IgM, IgG, IgA isotopes.

Immediate rejection

Is from pre formed antibodies results in hyper acute graft rejection.

Activate complement, and clotting cascades

Antibodies are?

Antibodies are the main mediators of protection

What happens when you Ab titter drops?

you lose anti-pathogen efficacy and this is when you need a booster.

"Natural" Immunity or exposure to pathogen itself

Typically best way to get immunity IF it doesn't kill or hurt you

some natural immunity is not the best

best vaccines

Live attenuated vaccines

Rejection

Host fight graft

Graft vs. Host disease (GVHD)

Graft fights host

MHC is the...

major antigen

is called HLA

HLA is....

Human Leukocyte Antigen.

Minor antigens also exist

This can also cause rejection

Oran rejection

caused by antibodies, very quick rejection

can be caused by T cells, takes longer

Allograft

graft from MHC mismatched person

Isograft

graft from identical person (Twin)

Autograft

Graft from yourself

Xenograft

graft from different species

Clinical Histocompatibility testing

This is matching:
Recipient: HLA Type
ABO compatible donnor: HLA type
Panel-Reactive Antibody: Determine if donor specific Anti-HLA antibody exist in recipient
Lymphocyte Crossmatch

Cause of antibody formation:

Previous rejection
Previous pregnancy
Whole blood/blood componet transfusion

Anti-HLA antibodies

May be directed against HLA class I antigens, Class II antigens or both

can be IgM, IgG, isotopes

panel reactive Antibody test

PRA is a c compatibility test between patients serum and a panel of HLA phenotypes representative of the potential donor population.

Expressed as a specific antigens

There are the specific antigens that the recipient has antibodies against

Graft rejection

Immediate rejection form pre-formed antibodies result in hyper-acute graft rejection

Graft rejection activates

Activation of compliment and clotting cascade

Graft recipients are not prescreened for donor specific antibodies

How is rejection initiated....

By direct recognition of donor APC by T cells.

or

By recipient APC APC that has taken up graft proteins

What is used to prevent/suppress lymphocyte activity and graft rejection.

They require longterm treatment with immunosuppressive drugs.

Long term immunosuppressive drugs

long term immunosuppressive drugs can lead to grater risk of cancer and infections

Graft V. Host disease

Due to donor lymphocytes in the transplanted organ which leave the graft and become activated by host antigens, and cause damage to the host

Graft Vs. Tumor

donor derived lymphocytes can and are intended to identify and attach host tumor cells.

Some malignancies need this.

Red queen hypothesis

Host pathogen interactions favor sexual reproduction of the host to increase reproduction

RNA hypothesis

Processors to RNA viruses
First immune systems targeted RNA

Viruses Next pathogen:

DNA revolved and was plagued by transposable elements.

Euk needs to protect itself from viruses, fungi, bacteria, and cancers.

Toll-like receptors