T-cell maturation / immuno week 6 Flashcards
What is the first step of T-cell maturation when the cell reaches the thymus?
rearrange TCR genes (specifically beta chain)
after beta chain rearranges, you make pre-TCR
What does pre-TCR signal?
starts proliferation / double positive expression on T-cells
What happens after proliferation in the thymus?
positive selection
T-cells express both CD8 and CD4
occurs in thymic cortex
*make sure TCR recognize antigens presented by MHCs
What happens after positive selection?
negative selection at the cortex-medullary boundary (medullary more)
cells only positive for CD8 OR CD4
selects for TCR that attacks MHC + self with a low binding affinity (never receive a signal for apoptosis)
MHC-restricted
T-cells are MHC-restricted after they pass positive and negative selection
can only bind to peptide antigens in the context of the MHC molecules presented by their hosts
Where do T-cells go after the thymus?
to secondary lymphoid organs (lymph nodes + spleen)
Immune tolerance
refers to the ability of immune system to recognize a wide variety of potentially pathogenic microorganisms and react to self-structures
need to discriminate self from not-self
Central tolerance
tolerance to self antigens that is established in lymphocytes during development in primary lymphoid organs (thymus or bone marrow)
removes strongly autoreactive lymphocytes
Peripheral tolerance
tolerance to antigens encountered by mature lymphocytes in peripheral tissues
AIRE
involved in self-tolerance
transcription factor
turns on expression of self proteins in the thymus
APECED
a severe and fatal autoimmunity causes by mutations in the AIRE gene
What happens if an antigen binds strongly to self-cell presented by AIRE transcription factors?
the T-cell is deactivated
What happens if a T-cell binds moderately to self-antigen?
cells develop into regulatory T-cells (Tregs)
What transcription factor is essential for Treg development and function?
Foxp3
Where does B-cell central tolerance occur?
in the bone marrow
List the 4 peripheral tolerance mechanisms
Anergy
Activation induced cell death (AICD)
Suppression by regulatory Treg and Breg
Immune privilege
Anergy
state of non-responsiveness to antigen
peripheral tolerance mechanism
IPEX Syndrome
mutation in Fox3p gene
leads to multiple autoimmune diseases in infancy
no Tregs
How do Tregs work?
they can regulate overactive T-cells
secrete anti-inflammatory cytokines that inhibit T-cells or other immune cells
immunologically privileged sites
sites in the body where the immune system is dampened down
Examples of immunologically privileged sites
brain, eye, testis, uterus
3 ways immune privileged sites work”
- not surrounded by conventional lymphatics + tissue barriers
- use non-inflammatory Th2 responses
- expression of Fas ligand by tissues of privilege. induce apoptosis in Fas-bearing lymphocytes that try to enter these sites
What do you need to develop an autoimmune disease?
combination of genes and environment
Are autoantibodies always cause of disease?
no, sometimes they are the symptoms of a disease
How are MHC genes involved in autoimmunity?
mutated MHCs will present self-peptides more
What are the two major forms of autoimmune disease?
organ specific and systemic (lupus)
Polymorphism
multiple genes produce autoimmunity
allelic mutations in genes that control immune activation
What major groups of genes are implicated in autoimmunity
MHC
cytokine + signaling pathways
sex differences
PTPN22
gene that controls immune activation
associated with rheumatoid arthritis
What 2 mechanisms can lead to activation of self-reactive T-cells? (mechanisms that leads to autoimmunity)
molecular mimicry
bystander activation through APC maturation
Examples of molecular mimicry (2)
M protein of GAS strep is similar to myosin and causes rheumatic heart disease
Herpes virus can resemble a corneal protein (herpes stromal keratitis) (HSV1 UL6)
Bystander activation
tissue damage can lead to release of sequestered antigens
co-factors are present to activate immune response to tissues
Example of bystander activation
Sympathetic opthalmia
one eye is damaged
antigens are released and travel to the lymph node where T cells activate
T cells can then travel to both eyes and cause damage
How can antibodies be pathogenic?
directly kill cells
recruit innate cells to kill
activate receptor
block receptor
IgM
type of antibody
complement activation
IgG
most common circulating antibody in blood
neonatal immunity through placenta transfer
IgE
type of antibody
allergy and inflammation
IgA
type of antibody
mucosal immunity
Autoimmune hemolytic anemia
antibodies by antigen on RBC
directly kill RBCs
Graves’ disease
antibodies bind TSH receptors
leads to constant activate to produce thyroid hormones
Goodpasture’s syndrome
antibodies recognize collage (type IV) in basement membrane
bind to basement membrane in glomerulus or alveoli
cause inflammation of alveoli and Glomerulonephritis/kidney failure
Myasthenia gravis
antibodies bind to acetylcholine receptor
block ability for acetylchoine to bind
causes muscle weakness + ptosis
Graves vs. Hashimoto
Graves causes hyperthyroidism by antibodies activating the TSH receptor
Hashimoto causes hypothyroidism by antibodies binding directly to follicular cells and causing cell death
