Lecture 1 Flashcards by Amy Ahern

What is the purpose of immunosuppression?

Prevention of organ transplant rejection
Treatment of autoimmune diseases

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What is autoimmunity?

An aberrant response to self-antigen (tolerance to self-antigen has broken down) - requires immunosuppressants to halt immune activation

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Why are immunosuppressants used to prevent organ transplant rejection?

Because transplantation of a donor graft requires the recipient’s immune system to see the graft as ‘self’ (immunosuppressants used to prevent immune responses to the graft)

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Autoimmunity can be classified into either __ or __ disease

organ-specific or systemic disease

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Examples of systemic autoimmune diseases

RA, scleroderma, SLE

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Examples of organ-specific autoimmune diseases

T1DM, Goodpasture syndrome, MS, Crohn’s disease, psoriasis, Grave’s disease

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Psoriasis is caused by…

autoreactive T cells against skin-associated antigens

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Rheumatoid arthritis is caused by…

autoreactive T cells and autoantibodies against antigens localised to joint synovium

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Grave’s disease is caused by…

autoantibodies against TSH receptor

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Hashimoto’s thyroiditis is caused by…

autoantibodies and autoreactive T cells against thyroid antigens

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SLE is caused by…

autoantibodies and autoreactive T cells against DNA, chromatin, proteins and ubiquitous ribonucleoprotein antigens

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Sjogren’s syndrome is caused by…

autoantibodies and autoreactive T cells against ribonucleoprotein antigens

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Crohn’s disease is caused by…

autoreactive T cells against intestinal flora antigens

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Multiple sclerosis is caused by…

autoreactive T cells against brain and spinal cord antigens

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Type 1 diabetes is caused by…

autoreactive T cells against pancreatic islet cell antigens

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What is central tolerance?

How the immune system learns to discriminate self from non-self (naive lymphocytes are essentially screened via positive and negative selection)

What is peripheral tolerance?

Preventing over-reactivity of the immune system

Heavy chains are composed of which regions?

V, D and J

Light chains are composed of which regions?

V and J

What causes junctional diversity?

Recombinational inaccuracies that cause differences in the amino acid sequence

What is insertional diversity a result of?

Terminal deoxynucleotide transferase activity (this enzyme adds nucleotides randomly at V-D and D-J junctions)

Decreased __ levels ensure allelic exclusion

RAG

B cells are negatively selected if…

they have a high affinity for self-antigen, or do not have a functional BCR to recognise its specific Ag (central tolerance)

Which TCR domain is nearest the cell membrane: constant or variable?

constant

What happens to thymocytes that do not successfully rearrange their β chain genes?

They die by apoptosis as they can not express the receptor

Successful synthesis of a rearranged β chain allows the production of a pre-T cell receptor that...

triggers cell proliferation and blocks further β chain gene rearrangement

Positive selection of T cells

Rescue DP cells from apoptosis, mature into SP (CD4+ or CD8+) that must recognise self-MHC (depends on engagement of CD4 with MHC II, and CD8 with MHC I)

What gives the TCR an intrinsic specificity for MHC molecules?

CDR1 & CDR2 loops of both α and β chains of TCR

Positive selection of T cells is mediated by __

cortical thymic epithelial cells (cTECs)

What transcription factor regulates negative selection of T cells?

AIRE (autoimmune regulatory element)

What cells express AIRE?

medullary thymic epithelial cells (mTECs)

What happens when AIRE is absent?

T cells reactive to tissue-specific antigens mature and leave the thymus

Peripheral tolerance aims to eliminate autoreactive T cells. What is the exception?

Some self-reactive T cells that are CD4+ will escape the thymus following central tolerance - regulatory T cells (FoxP3+, CD25hi)

How are Tregs important for peripheral tolerance and preventing autoimmunity?

Tregs are CD25+. CD25 is α chain of IL-2R. Tregs bind to any circulating IL-2, which prevents other T cells from utilising it and becoming autoreactive.

Tregs compete with Teff cells for...

IL-2 and MHC

Difference between natural Tregs and induced Tregs?

nTregs (from thymus) develop in response to stimulation by self-Ags iTregs are driven by TGF-β

'Immunologically privileged' sites

Brain, eye, testis, uterus

What immunosuppressive cytokine is produced in these immunologically privileged sites?

TGF-β