lecture 1 exam 2 Flashcards
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?)
primary lymphoid tissue examples
thymus - T
bone marrow - B
intestine (ruminants and horses) - ileal peyers patches (B cells)
bursa (birds B cells)
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
source of stem cells
fetal yolk sac -> fetal liver (B cell!) -> bone marrow
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
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
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)
BCR structure development
hallmark of humoral immunity is specificity of immune response due to gene rearrangement and somatic hypermutation
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)
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
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
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
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
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
central tolerance
negative selection of self reactive B cells - occurs in medulla of germinal centers in lymph nodes or bursa follicles
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
