Introduction to Autoimmunity and Autoimmune Diseases Flashcards
autoimmune disease is a breakdown in
immunological tolerance
most mechanisms of peripheral tolerance focus on
t cells
all antibody responses are ___ dependent
t cell
if you silence t cells you also take care of
autoreactive b cells
breakdown in self tolerance is
autoimmune disease
immunopathologies
diseases where pathology is mediated by the immune response
ex of immunopathologies
HSR and autoimmunity
all autoimmune diseases are
chronic
autoimmune diseases are chronic b/c they are driven by
antigen
define chronic autoimmune disease
Chronic diseases with evidence of active immune responses but no active infection
you can never get rid of antigen in autoimmune disease b/c
it is part of yourself
autoimmunity is a problem of self vs.
non self discrimination
autoimmunity is caused by ____ ___ ______ processes that normally protect the host from the action of self-reactive lymphocytes
failure of tolerance
two different kinds of tolerance
central or peripheral
just b/c you detect autoantibodyt does not mean that antibody plays role in
pathology
autoantibodies can be
diagnostic or pathogenic, they don’t have to all be both
how can antibodies not necesarilly be pathology
autoimmune disease causes destruction of cell - so there are antibodies against the inside of cell proteins but the intracellular cells are not what is causing the pathology
what happens regarding selection of b cell in bone marrow
clonal deletion of b cells in bone marrow
expression of tissue-specific proteins in the thymus so that they participate in negative selection of t cells is made possibel by
Aire
what kind of selection of t cells in thymus
negative
central tolerance
mechanisms that happen in central or primary lymphoid orangism
peripheral tolerance
mechanisms outside of central lymphoid organs
what tissues are immune privileged sites
brain, eye, testis
exclusion of lymphocytes from certain peripheral tissue is known as
peripheral ignorance
anergy can happen where
peripheral circulation & bone marrow
when is anergy likely to happen in bone marrow
immature b cell recognizes soluble antigen
suppression of autoimmune responses by
regulatory t cells
regulatory t cells are generated
in thymus and outside of thymus
what is needed for t reg
Foxp3
AIRE does what
allows deletion of autoreactive thymocytes - what is normally not expressed in thymus can now be exprssed, so can show proteins from around the body
review pg 8
pg 8
AIRE allows for
negative selection of thymocytes
selection and deletion in thymus is governed by
how MHC binds self peptie
if t cell binds to MHC with low affinity what happens
differentates to CD4+ or CD8+
if MHC binds self peptide with high affinity what happens
apoptosis
if MHC binds self peptide with intermediate affinity what happens
Treg
what is Treg positive for
CD4, CD25, Foxp3
aire deficiency results in
multi-system autoimmune diseases
not all self reactive cells are deleted in the
thymus
how do we silence reactive cells outside of the thymus
peripheral tolerance
peripheral tolerance:
Prevent autoreactive cells that have escaped deletion from causing pathology
mechanisms of peripheral tolerance:
Inactivated (anergy)
Suppressed by regulatory T cells (Tregs)
Kept immunologically ignorant
naive t cell requires ___ signals to be activated
2
what are the two signals to activate naive t cell
TCR CD3
CD28 CD80
in absence of signal 2, naive t cell will
become anergic - shut down permanently
where are Treg cells generated
thymus and periphery
in absence of Foxp3+ what happens
autoimmune disease - don’t get Treg
cytokines secreted by Treg:
TGF beta and IL-10
TGF beta direct affect on
T cell proliferation and differentiation
IL-10 does what to APC
makes them incapable of delivering signal 2
Foxp3 is encoded where
x chromosome
IPEX syndrome is result of
inactivating mutation or deletion of FRoxp3
what does IPEX syndrome stand for
Immune dysregulation, Polyendocrinopathy (diseases affecting multiple endocrine glands), Enteropathy (disorder of the intestines), X-linked syndrome
treatment of IPEX
Hematopoietic stem cell transplantation within the first year of life.
B cells can be anergized if they id to
monivalent or soluble self antigen in bone marrow
if b cell bind to self surface antigen
cross link BCR
default pathway if immature b cell binds to self
editing
what is re-expressed to edit B cell
RAG 1 and RAG2
what is edited in b cell if it binds to self surface antigen
replace light chain with alternative light chain
rearrangement of light chains in B cells, what genes are rearranged
V,J
if B cells cannot edit to make a non-self reactive what happens
apoptosis
immature b cell vs. mature b cell
mature b ells express IgM and IgD as BCR, only constant region of heavy chain will be different b/w the two
most people have autoreactive
b cell
without help from ___ there will not be an issue with autoreactive be cell
t cell
as we age we lost t cell mediated regulation and have increased chance of
autoantibodies
majority of autoimmune diseases are more prevelant in
females than males
most autoimmune diseases have association with particular
class I or II alleles (HLA)
disease associated alleles differ in non disease associated only in
amino acid residues that line the peptide binding groove
ankylosing spondylitis 95% of ppl with it express what HLA
B27
what diseases are associated with HLA: B27
PAIR: Psoriatic arthritis, ankylosing spondylitis, ifnlammatory bowel dise, reiter’s dsyndrome
B27 is highly associated with
anklyosing spondylitis
they don’t flly understand how B27 is associated with ankylosing spondyitis
:(
what disease has high incidence of DQ2 and DQ8 HLA?
celiac disease & Type 1 diabetes
why is there higher association with heterozygous DQ2 and DQ8 for celiac and type 1 diabetes
MHC II can mix and match their alpha and beta chain - good evidence that the susceptibility allele is not DQ2 or DQ8 but a hybrid of alpha chain of DQ8 with beta of DQ2
autoimmune disease needs 3 components:
MHC molecules which are able to efficiently present self antigens
A failure to delete or functionally inactivate self-reactive lymphocytes
Breakdown in Immunological Tolerance
review pg 25
25
disruptino of tissue or cell barrier by infection or traumatic injury allows the release of
previously unseen antigens
the release of antigens can go to t cells via injury can result in what disease
sympathetic opthalmia
sympathetic ophthalmia is usually due to
eye injury
one eye is damaged and causes sympathetic opthalamia, and eventually
the other eye is attacked
if somebody gets traumatic eye injury they are put on what immediately
immunosuppressants
what enviornmental factors have been associated with autoimmunity
infectious agents
group A streptococcus can give rise to
rheumatic fever
coxsackie virus and rubella can give rise to what autoimmune disase
type 1 diabetes
how can previous infections give rise to autoimmune disease? describe molecular mimicry hypothesis
Immunological crossreactivity between epitope on pathogen and self antigen
disease with strong evidence for pre-existing infection giving rise to autoimmune disease is
rheumatic fever
how infections agents might break self tolerance (like rheumatic fever causing autoimmune disease)
t cells are cross reactive with t cells
activated effector cells secreting antibody
molecular mimicry mediated by t cells
pathogen peptide that resembles self peptide
generate effector t cells that react against bacterial peptide presented on MHC
once bacteria cleared, left with activated effector cells cross reactive against self antigen
why wouldn’t t cells be activated by the self peptide, why does the virus or bacteria cause the activation
naive t cells require higher level of antigen to become activated
Ab mediated molecular mimicry
genrate antibody against surface antigens on bacteria, they cross creact witha ntigen expressed in our tissue
in vast majority of cases, for autoimmune diseases, we really don’t know what antigen is that triggers
autoimmune disease
by the time autoimmune disease presents, body has gone on to
recognize many antigens
the autoantibodies you detect during autoimmune disease may not be
pathogenic - may just be diagnostic
epitope spreading, what is it
immune response recognizes different antigens later on in immune response than it did earlier (the immune response is spreading, not the epitope).
this is normal phenomenom in immune response
immune resopnse can spread so that different
epitopes are reocgnized at different stages of disease
intermolecular epitope spreading:
Response spreads to epitopes on different antigens
intramolecular epitope spreading:
Response spreads to different epitopes on the same antigen
intermolecular epitope spreading, why does it happen
death of cells, so get other antigens released from those dead cells
intramolecular epitope spreading, how does it happen
early on in disease process, get autoantibodies (not pathogenic)
later on get autoantibodies against membrane distal epitopes to it that you give rise to, for example, blistering skin disease
pg 38
intramolecular epitope spreading is a feature of what disease
pemphigus
why would resposne spread on an epitope
exhaustion or deletion of t cells reactive against dominant epitope early in disease
or autoantibody generated early on proximal domain block the membrane proximal domain and can no longer get stimulation of b cells specific for AKA binding of autoantibodies masks epitope allowing production of Abs against other epitopes
review pg 39
39
for most autoimmune diseases, concordance is higher in
monozygotic twins vs. dizygotic twins
for most autoimmune diseases, concordance is higher in, this means that
there is strong genetic component for many autoimmune diseases
concordance rate for monozygotic twins are never
100%
APCED what gene is inactivated
aire
in IPEX what gene is inactivated
FOXP3
inactivattion of CTLA4 can lead to
T cell anergy
inactivation of Fas can lead to
no check on proliferation of autoreactive t cells - so autoreactive t cells accumulate
ALPS is inactivation of
Fas
usually a single gene mutation will not give rise to autoimmune diseases, most
autoimmune diseases do not have pin-poinaable gene, it is very complicated
polymorphisms leading to overexpression of what in many autoimmune diseases
pro-inflammatory cytokines
polymorphisms leading to underexpression fo anti-finfalmmatory cytokines leads to
many autoimmune diseases
reivew pg 45
45
how does gender predispose to autoimmune diseases
female more likely to get disease
how is aging associated with autoimmune diseases
the older you get the more likely you are to have autoimmune disease
why does aging increase autoimmunity
erosion of self-tolerance of t cells (thymic atrophy)
frequency 9of autoantibodies increases
altered t cell and b cell function in elderly - immune senescence
what is immune senescence
Aging-associated increase in autoantibody production has been attributed to altered T cell and B cell function in the elderly
by what age, most of thymus is replaced by fatty tissue
7 years
what is thymic involution
it gets smaller and more fatty as you age
thymic involution impairs
negative selection
smoking can induce the production of what enzyme to increase autoimmunity
PAD
what does PAD stand for
peptidyl arginine deiminase
what does PAD do
converts Arg into citrulline
what are first cell to infiltate site of acute inflammation
neutrophil
when neutrophil exhausts itself what happens
it dies by apoptosis
if you have chronic infection, how else can neutrophil die besides apoptosis
NETosis
netosis
explosive material from neutrophils - looks like net
when neutrophils die by netosis it basically
forms a trap - so it essentially explodes, extruding DNA, chromatin, all the proteins with it, and the net traps bacteria and makes it easier for monocytes and macrophages to deal with
peptidyl arginine deiminase is released ruing
Netosis (death by neutrophil)
peptidyl arginine deiminase what does it do when released via netosis
cittrilate proteins (like same way that cigarettes do)
netosis shows that there may be link b/w autoimmune disease and infection, doesn’t have to be
specific infection
NETs contain autoantigens that are reocnigzed in many
rheumatic autoimmune diseases
once we have autoreactive t cells or b cells how does the rxn proceed
type II, III, or IV HSR
most joint damage is mediated by what HSR in autoimmune disease
IV
review pg 58
58
most autoimmune diseases classified by:
organ specificity and systemic (multiple organs targeted)
type II and IV HSR determiend by
localization of auto-antigen
type III HSR are what kind of autoimmune
systemic
type III HSR not dependent on
anigen
example organ specific autoimmune disease
Type 1 diabetes mellitus
goodpasture’s syndrome
Multiple sclerosis
grave’s disease
type 1 diabetes mellitus is what classification of autoimmune disease
organ specific
rheumatoid arthritis is what Classification of Autoimmune Disease
systemic
systemic means
multiple organs affected
will never get organ specific autoimmune disease mediated by
type III HSR
fastest form of rejection is mediated by what/ and what type HSR?
pre-existing antibody
type II
autoimmune hemolytic anemia is mediated by
IgG autoantibody that binds to surface or RBC
autoimmune hemolytic anemia is what HSR
II
systemic lupus erythematosus is mediated by
immune complexes
systemic lupus erythematosus is what HSR
III
type I diabetes is what HSR
IV
REVIEW PG 62
62
autoimmune diseases mediated by immune complex are what type HSR
III
joint damage in RA is mediated by what HSR
type IV
