lect 16 Flashcards
where is AIRE expressed
in lymphoid organs
thymic epithelial cells- positive selection
dendritic cells- negative selection
what results from the absense of AIRE in humans
autoimmune polyendocrine syndrome
APS-1
bc central tollerance missing
what are antigens that we have a tolerance to called
tolerogen or tolerogenic antigen
what are the mechanisms of central B cell tolerance
deletion- apoptosis
receptor editing
anergy
ignorance
B cell central tolerance +++ strength
apoptosis
B cell central tolerance + strength
anergic cell
B cell central tolerance +/- strength
mature B cell that is clonally ignorant
B cell central tolerance - strength
mature B cell
what happnes to the escapees of central tolerance
anergy due to no costimulatory singnal
deletion- FAS/FASL interactions - activates induced cell death
involves regulatory and supressor T cells
self rective B cells generated
druing immune reaction bc of SHM in gernal centre (affinity maturation)
what is the molecular basis of B cell anergy
B cells get only signal 1 from the antigen leading to anergy
follicular exclusion
what is follicular exclusion
cells excluded
from B-cell follicles in spleen &
LN; don’t receive survival signals
(die by neglect)
molecular basis of T cell anergy
only get one signla from Ag leading to anergy and no expression of IL2
Deletion of auto-reactive active T lymphocytes in the
periphery is due to
activation of the FAS receptor
ACID
activation induced cell death
anergic B cells also express Fas and can be eliminated this way
what disease results from mutated Fas
ALPS
autoimmune lymphoproliferative syndrome
mice with Fas and FasL mutations
lps and gld mice
autoimmune disease with increase numbers of lymphocytes
what initiates oral tolerance
encounter of food antigens with GALT- Ags enter circulation and presented by APC to T cell in absence of costiumulation by APC or B7
leads to T cell anergy
what plays an important role in oral toelrance
gut microbiome
what is the etiology of autoimmune diseases
genetic factors
environmental
interaction of genetic and environmental factors
drug and hormonal triggers
what are the genetic factors of autoimmunity
family clustering
- polygenic
-MHC(HLA) associated
-non HLA genes
what are the enviromental factors of autoimmunity
microbial and truama
what is associated genetically with autoimmune diseases
HLA types and Sex
environmental susceptibility types
sequestered Ags
molecular mimicry
polyclonal activation
innaproperiate expression class II MHC
what are the immunoprivelaged sites
eyes
testes
ovaries
placenta
dont develop a classical immune response
what sites are autoantigens protected
cartilage
neuronal antigens
what causes antigens to be released from immunoprivelaged sites
physical disruption OR infection
explain molecular mimmickry
a normally self reactive B cell wont activate from self antigen bc it wont have T cell help
if a B cell is reacting to microbial antigen that looks like our own, itll have T cell help and then produce antibodies that will react to our own antigens
explain polyclonal activation
Lypopolysaccharide (PAMPs) from a gran -ve bacteria interacts with activating receptors on B cells
this will lead to intracellular detection of pathogenic patterns of DNA
diabetes mellitis patients versus normal
Type 1 diabetes
B cells express class II and I MHC but they are only supposed to express class I
leads to activation of autoreactive CD4+ T cells
explain innaproperiate expression of class II MHC
Expression of class II MHC on cells
that do not normally express class II
MHC can activate autoreactive
CD4+ T cells
what causes the transfer of autoimmunity
tranfering CD4+ T cells
and a lack of T reg cells
what increases autoimmunity
specific HLA alleles
what is necessary to have an autoimmune reaction
interaction bw TCR and self peptide AND
MHC and self peptide
how do T regs supress autoreactive t h cells
they supress CD4+ t cells that interact with the same ppetide or different peptide if they are all intercating with the same APC
lleads to linked supression
what is an example of an immunosupressant
cyclosporin A
what can be used as treatment for autoimmune diseases
immunosupressive therapy:
immunosupressants
general anti inflamamtory drugs
depletion of CD4+ t cells using anti CD4 antibody
other treatment:
targetted therapies
oral tolerance
block only antigen activated T cells
does depletion of CD4 T cells using anti-CD4 antibody work
- Worked in mice
- Not successful in humans; timing of treatment?
*Humans diagnosed in later stages of disease compared to mouse models
what are some general targeted therapies for autoimmune treatment
anti cytokine antibodies or blockers
Rituximab
what is rituximab
mAb against B cell CD20 - promotes B cell apoptosis and ADCC
helpful for RA?
what are some anti cytokine antibodies and what do they do
block TNF-a
embrel
remicade
humira
what are anti cytokine antibodies used for
crohns disease
ankylosing spondyylitis
what is the advantage of blocking only ag activated T cells
overall immunity is not lowered
what is the challenge of blocking only ag activated T cells
target only activated T cells
- we can use mAb against IL2-R, a subunit
has promising resulst but BAD for T reg
- block specific asssociated TCR chains
what type of autoiimune is SLE
type 3
formation of immune complexes that lead to compliment activation and deposition in kidneys- inflammation
how is SLE distributed in sex
10:1 females to males
can be exacerbated during pregnancy
there is a genetic predisposition and an HLA association
what is the symptom and underlying cause of SLE
unknown ag
butterfly like rash and high levels of anti DNA abs
what is the visual symptom of hashimotos thyroiditis
goiter formation and hypothyroidism
what is the cuase of hashimotos thyroiditis
- Autoantibodies against microsomal &
thyroglobulin - Sensitized T H1 cells for thyroid antigen
- Intense infiltration of the thyroid gland
by mononuclear cells - Interfere with iodine uptake & leads to
decreased production of thyroid
hormones
what mediates MS
T cells
infiltrate the brain and cause inflammatory lesions
inflammatory lesions destroy myelin shief of CNS
autoreactive TH1 cells activate macrophages
-leads to inflammation
-inc macrophage, neutrophil, mast cells
-Fas mediated death of oligodendeocytes
what causes MS
not known
sequestered release of myelin Ags
mollecular mimicry following viral infection (EBV)
what is the gentic component of MS
HLA class II
DR15, DQ6
what cells are in type 1 IDDM
CD8+
TH1
Cytokines
what is the genetic component of type I diabetes
HLA Class II genes
HLA DQ2. DQ8 and non HLA genes
what occurs in Type I diabetes
destrction of insulin producing B islet cells of pancreas leads to autonatibodies formation
what cells are involved in rheumatoid artheritis
autoreactive CD4+ TH1 cells
CD4+ TH17 and cytokines lead to bone destruction
macrophages and fibroblasts cause a feed forward inflammation
what cytokines in RA
IFNY and IL17
genetic component of RA
some HLA DR4 alleles
what are the immune complexes in RA
rheumatoid factor ++
IgM antibody against Fc region of igG molecules
what is RA
chronic inflammation and ersion of synoviun and bone
