lecture 1 exam 2 Flashcards by Morgan Thomas

function of primary lymphoid tissues

site of T and B lymphocyte development and training
provide collection of T and B w receptors specific for diverse antigens for secondary lymphoid tissues
central tolerance: KILL T and B cells tolerant to self antigens (- selection?)

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primary lymphoid tissue examples

thymus - T
bone marrow - B
intestine (ruminants and horses) - ileal peyers patches (B cells)
bursa (birds B cells)

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secondary lymphoid tissue examples

bone marrow
spleen
lymph nodes
urogenital system
intestine (GALT - jejunal peyers patches)
mammary glands
respiratory tract
tonsils
MALT - mucosa associated lymphoid tissue

sites of foreign antigen interaction and proliferation through bathing from blood over immune cells

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source of stem cells

fetal yolk sac -> fetal liver (B cell!) -> bone marrow

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lymphocyte origin

hematopoietic cells are made in bone marrow
-B1 subset are in fetal liver
from bone marrow they will develop into B cells in the bone marrow or migrate to thymus to develop into T cells

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B cell development in bone marrow

prepro B cell -> pre B cell (+ selection - functional B cell) -> immature B cell (- selection) -> delete if self reactive or leave bone marrow as mature but naive B cell

V(D)J rearrangement happens from preproBcell on

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BCR

2 binding sites - 2 heavy chains (VDJ) 2 light chain (VJ), linked by disulfide bond
most important event in development of lymphocyte is the generation of an antigen receptor
membrane bound immuoglobulin (Ig)

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BCR structure development

hallmark of humoral immunity is specificity of immune response due to gene rearrangement and somatic hypermutation

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gene rearrangement

occurs in primary lymphoid organs (bone marrow, peyers patch, bursa)
random selection of gene segments resulting in genetic diversity of BCR (and TCR)

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somatic hypermutation

occurs in secondary lymphoid organs (germinal centers - lymph nodes, spleen, tonsil, GALT, MALT etc)
high frequency mutation in variable region of Ig genes after B cell activation (when find antigen) resulting in increased affinity for antigen

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types of peyers patches

ileum - continuous - involutes by 25 months - B - primary for ruminants and horses
jejunum - discontinuous - life long (30%. T cell - 70% B cell) - secondary

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ileum peyers patches

sites of rapid B cell proliferation for ruminants and horses
most ells undergo apoptosis (- selection)
survivors (2-5%) released into circulation
reach maximal size and maturity before birth

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bursa of fabricius

found only in birds
round sac above cloaca
hollow sac with folds of epithelium containing lymphoid follicles
greatest size 1-2 wks after hatchign then shrinks

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bursa structure and function

generate BCR diversity!
lymphoid folloicles w cortex and medulla
CORTEX: B cells proliferate and genes rearrange
MEDULLA: stromal cells present self-antigens to B cells, negative selection of self reactive b cells - central tolerance

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central tolerance

negative selection of self reactive B cells - occurs in medulla of germinal centers in lymph nodes or bursa follicles

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percentage of b lymphocytes in blood

on average - 20%

bursectomy or removal of ileal pp

total circulating lymphocyte pool SLIGHTLY decresed

humoral immunity - antibody concentration REALLY decreased

thymus

epithelial outgrowth of third pharyngeal pouch - thymic epithelial reticulum
- located in anterior mediastinum over heart
lymphoid progenitors from bone marrow migrate to thymus and become thymocytes (naive T cells)
mature to T lymphocytes

rich in lymphocytes in cortex (dark)

maturation of T cells in thymus

develop t cell receptor (TCR)
become class restricted (MHC)
tolerized to self

TCR generation

1 binding site for antigen - heterodimer of 2 chains
gamma delta (ruminants)
alpha beta (most numerous
CD3 - TCR co receptor required for signal transduction
beta delta chains have variable (V), diversity (D), junctional (J) and constant (C) genes
alpha gamma chains have variable (V), junctional (J), constant (C) genes (NO D)

generated by somatic recombination (gene rearrangement)

CD3 required for what

TCR co receptor for signal transduction

can flow cytometry or immunohistochemistry for CD3 to tell how many T cells

gene rearrangement for TCR

occurs in each lymphocyte during development
RANDOM - like shuffling cards
gene splicing of diverse (VDJ) genes make heterodimer alpha beta TCR on surface of thymocyte (which enters thymus from bone marrow)
requires looping out of genes by RECOMBINASE ENZYMES

recombinase enzyme

contributes to looping out (removal of gene thorugh splicing)
occurs in TCR rearrangement

defect VDJ recombination can lead to

SCIDS - severe combined immunodeficiency: cannot develop B or T cells

T cell development

proliferation and rearrangement of TCR genes gamma delta & alpha beta compete for expression -gamma delta win? - these cells leave thymus -alphabeta win? - surface molecules are expressed on developing thymocytes >CD3, CD4, CD8 (double positive)

CD4 on alpha beta Tcell

for T helper T cells - class switching! IgG -> IgA

CD8 on alpha beta Tcell

kills cells that are infected with pathogen (CTL)

thymus location for T cell development

``` CORTEX: positive selection and class restiction - express alpha beta, CD3, 4, 8 - proliferation and development MEDULLA: negative selection/self tolerance - has dendritic cells and macrophages and hassalls corpuscles ```

positive selection in thymus

class restriction: recognize antigens presented by thymic epithelial cells on either MHC 1 or MHC 2 molecules cells w TCR can bind MHC ag complex and are POSITIVELY SELECTED in thymus (if lacking TCR capable of binding MHC ag - apopotosis) huge diversity of TCRs are possible and only small proportion bind to self MHC (negative selection) - approx 98% of T cells die in thymus

if TCR cell binds to self MHC 1 self peptide on thymic epithelial cell

double positive development of CD8+ T cell will downregulate expression of more CD4 on same T cell

if TCR cell binds to self MHC 2 self peptide on thymic epithelial cell

double positive development of CD4+ T cell will downregulate expression of more CD8 on same T cell

single positive thymocytes

CD8 Tcell -> cytotoxic CTL CD4 Tcell -> helper to negative selection! exception - pigs possess up to 60% CD4+ CD8+ in circulation - so double positive leave thymus in pigs but not in other animals

negative selection in thymus

medulla get exposed to self antigens to see if they respond -> if they bind to MHC + self ag then they are negatively selected and deleted by apoptosis (like self tolerance in B cells) cells that successfully survive emerge from thymus as self tolerant

AIRE genes

autoimmune regulator gene - controls >400 tissue specific proteins (antigens) genes that encodes for self peptides (insulin, thyroid hormones, collagen etc) involved/displayed on medullary thymic epithelial cell MHC for TCR to see if it is self tolerant or not if lacking AIRE gene = autoimmune polyendocrinopathy -> no prevention of self antigen reaction

percentage of T cells in blood of adult animals

average 50-65%

thymus involution

occurs within 3 weeks for mice puberty for humans the involuted thymus is replaced by fat byt small amounts of functional lymphoid tissue remains

no thymus results in

``` susceptible to infection no growth nude mice no T cells in secondary lymphoid tissues no T cells in circulation defective rejection of graft tissue defective T cell mediated immunity IgM levels OK but IgG and IgA are decreased -IgG are first responders, IgM are blood borne ```