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1. Compare and contrast peripheral and central tolderance for B and T lymphocytesCentral tolerance refers to the negative selection that cocurs in the BM and the thymus for

B and t cells. In those lymphoid organs, precurosrs are exposed to self antigen:

Thymus:o Postiviie selection ensures that T cells responds to foregin peptides being

presented on MHCs and that TCRs, co-receptors (CD4/CD8) and MHC Class

1/II are matched.

o Negative slection ensures that cells whobind stoo tsronglyh to selfpeopeides are elmintaed

o Aire locus - responsible to expressing peripheral self antigens in emduallaryepithelical cells and providing the appartatus for effective antigen

presentation, thereby ensuring effacing pruing of self reactive T cels

Small minority of cells untiately become nave T cells or T regs (which expressCD4+CD25+; T regs recognize self-antignes). It is unclear as to what incudes

negative selction verus Treg expression

o The aiire locus is the key influencer of negative selction of T cellso Mutation s in the aire locus result in multi organ autoimmune disease now

as APECED

o Extrathymic aire-expressing cells eist outside fo the thymus and may act tohelp elmiante autoimmune cells

BONE MARROW: immature B cells that interact strongly with self antignes in theBM are eliminated (clonally deleted ) from the repertoire. This process of negative

selction is simulator to that of immature T cells, except there are no MHC molecule

involved

o B cells can also undergo recetpor editing, where B cells can alter theirrecetpor sepcifcicity be expressing a new ligh chaing , producing a new

recetport that doesn't interact with self antigen .

The primary distinction between BM and thymus - BM continually turns over the B cell

repertorie whiel the thymus principally workds during youth. People must accumulate arepertorie of T cells when they are young and T cells are used throughout life.

Why does T cell involution happen in old people? 5 theories:

1. anive and memory T cells are long lived2. continuous thombobobpopeieis is inefficient and potentially dangerious

(autoimmunity)

3. thymus evoled before modern medicine4. thymus evolved before air travel5. consequences occur in post reproductive dadults - may not be useful to vaccinate

older people who have no thymus

Peripehral tolderance: induced when mature nave B and T cells regonize slef antigens in

peripheral tissues. They are inactivated (angery) killed or suppressed by T regs.

2. Describe anergy in peripheral B and T lymphocytesAnergy in T cells- occurs in 2 wyas

When a TCR on a T cell binds to a MCH that does not express costimulatorymolecule B7, the T cells become anergic. IN other wrods, T cell meets an APC that is

constimulator deficient

When a T cell engages in a CTLA-4:B7 interacton, it becomes angeric. CTLAdownregulates the wimmune response

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Anergic cells cannot express IL-2 and are unable to stimulate their own

proliferation and ifferentaion,

Angery in B cells: when GB cells encounter self antign in peripheral lymphoid tissues, they

come anergic

Anergic B cells express high IgD and low igM. They also develop a paratial block insignal transduction, migrate to the periphery and rapidly lost in competition with other

B cells

3. what is activation induced cells deathRepeated stimulation of a T cell without costimuation will actually kill off the cell

(instaed of just anergy). This is known as actiavation induced cell death., whcere leack

of costimuation results in the xpression of Fas and FasL, which induces 2 T cells to

intitatie the apoptosis of each other

4. why are T regs important Fuction: T regs mediate tolderance by inhibiting surrounding autoreactive cells What they do: T regs arise fro mteh thymus as well as peripheral lymphoid organs in

roespnse to strong recognition of self antigens. These cells can hinbigibt the activation

and andifferenatiaon of aniive T Cells by contact dependent mechanisms or by

secreting cytokines that inhibit T cell profilerations

Antigens: T regs express CD4 and CD25 on their surfaces, and FOX P3 transcriptionfactor within

Mutatiions in FOXP3 result in IPEX, a severe autoimmune diease resulting in diarrheain infancy, dermatitis, autoimmune endocrinopathies, and death in frist 2 years of life.

Imprornat because they have applications to cancer, transplant rejection, infection andallergy

Immune privilege: immune repsones in immunologicaly privileged sigtes are tightly regulated

and have anti inflammatory profiles. They include the brain (BBB), eyes(blood-retianl

bbarreir), testis, and fetus( the placenta sequesters the fetus from the mtohers T cells, which

would otherwise go asints the fathers froeign MHC molecules)

- disavanatage of hainvg immune privielege is the the issues have lmited capacitiy for

regeneration (like brain damage( and imue mediated inflammation can hae devasting

conseuqensces