Transcript 34_Development of autoimmunityx

DEVELOPMENT
OF
AUTOIMMUNITY
CENTRAL AND PERIPHERAL TOLERANCE
TO SELF ANTIGENS
Central tolerance:
Elimination of self-reactive clones.
BUT!!! Some clones escape.
Peripheral tolerance:
Elimination of „fugitive” or
altered clones is an important
role for regulatory T-cells.
IMMUNE RESPONSES ARE NOT INITIATED IN
THE PERIPHERY
Normal tissue cells do not express MHC class II
NO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules
and do not produce T-cell differentiating cytokines
NO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limited
Antigen presenting cells are not activated in normal tissues
UNDER NORMAL CIRCUMSTANCES PERIPHERAL
TISSUES ARE PROTECTED FROM IMMUNE
RESPONSE
GENERAL FEATURES OF AUTOIMMUNE DISORDERS
Autoimmune diseases may be either systemic or organ specific,
depending on the distribution of the autoantigens that are
recognized.
• Circulating immune complexes – SLE
• Autoantibodies or T-cell responses against self antigens with
restricted tissue distribution - Type 1 diabetes
Various effector mechanisms are responsible for tissue injury in
different autoimmune diseases.
• Autoantibodies
• Immune complexes
• Autoreactive T lymphocytes
All autoimmune diseases involve breaking T-cell tolerance.
AUTOANTIBODY PRODUCTION IS DEPENDENT ON THE
AVAILABILITY OF AUTOREACTIVE T-CELLS
Practically all autoimmune diseases
involve some T-cell defects
In the absence of T-cell help autoreactive
B-cells are retained in the T-cell zone and
die by apoptosis
SINGLE GENE MUTATIONS CAUSE
AUTOIMMUNITY
• AIRE - Failure of central tolerance - APECED
AUTOIMMUN REGULATOR (AIRE)
A transcription factor expressed by thymic medullary epithelial cells
and induces expression of many tissue-specific genes
Deficiency in establishing central T-cell tolerance
allows too many
self reactive T-cell clones to leave the thymus
AUTOIMMUNE POLYENDOCRINOPATHYCANDIDIASIS-ECTODERMAL DYSTROPHY
(APECED)
Rare disease, but more frequently seen in inbred
populations
Finnish, Iranian Jews and in the island of Sardine
SYMPTOMS OF APECED
• Anti-IL-17 specific
antibodies!
• Role of Th17 discovered by
studying a rare
immunodeficiency
• https:///jimneydandme.wordp
ress.com/james-story
SINGLE GENE MUTATIONS CAUSE
AUTOIMMUNITY
• AIRE - Failure of central tolerance - APECED
• FOXP3 – Deficiency of functional regulatory T cells - IPEX
• CTLA4 - Failure of anergy in CD4+ T cells; defective
function of regulatory T cells - several autoimmune disorders
• CD25 - Defective development, survival, or function of
regulatory T-cells – IPEX-like
• C4 - Defective clearance of immune complexes; failure of B
cell tolerance – SLE
• FAS/FASL - Defective deletion of anergic self-reactive B
cells; reduced deletion of mature CD4+T cells - Autoimmune
lymphoproliferative syndrome (ALPS)
These genes are associated with rare autoimmune diseases, their identification
has provided valuable information about the importance of various molecular
pathways in the maintenance of self-tolerance.
MOST AUTOIMMUNE DISEASES ARE
COMPLEX
POLYGENIC TRAITS
MULTIPLE INHERITED GENETIC POLYMORPHISMS
CONTRIBUTE TO
DISEASE SUSCEPTIBILITY
HLA IS THE DOMINANT GENETIC
FACTOR AFFECTING SUSCEPTIBILITY
TO AUTOIMMUNE DISEASE
Family studies reveal that HLA type
correlates
with susceptibility to type 1 diabetes
Haplotype is a group of genes within an
organism that was inherited together
from a single parent
Similar results are seen for many
autoimmune diseases
ASSOCIATIONS OF HLA ALLOTYPES WITH
AUTOIMMUNE DISEASE
HLA associations reflect the
importance of T-cell
tolerance in preventing
autoimmunity
Many more autoimmune
diseases are associated with
HLA II than with HLA I
indicating that CD4+T-cells are
inherently more likely
to lose tolerance to a self antigen
than are CD8+T-cells
PREFERENTIAL ALLELE ASSOCIATIONS:
LINKAGE DISEQUILIBRIUM
Particular alleles of the different polymorphic genes are
combined in HLA haplotypes at frequencies higher
than expected by chance
A1–B8–DR3–DQ2 haplotype, which includes alleles for
HLA-A, -B, -C, -DR, and -DQ is characteristic of
Caucasian populations (up to 11%).
Association with several common autoimmune
diseases: type 1 diabetes, SLE, myasthenia gravis,
autoimmune hepatitis, primary biliary cirrhosis.
COMBINATIONS OF HLA CLASS II
ALLOTYPES CONFER
SUSCEPTIBILITY TO TYPE 1 DIABETES
Common Caucasian HLA haplotypes that encode
either the DQ2 or the DQ8 allotype confer
susceptibility to type 1 diabetes.
Heterozygous individuals are more susceptible to
diabetes.
This augmented susceptibility is due to a novel
HLA-DQ heterodimer consisting of the DQ8 αchain and the DQ2 β-chain.
POLYMORPHISMS IN NON-HLA GENES ASSOCIATED WITH
AUTOIMMUNITY
GENETIC PREDISPOSITION IS NOT EQUAL
TO AUTOIMMUNE DISEASE
INDIVIDUALS WITH GENETIC PREDISPOSITION
DEVELOP AUTOIMMUNE DISEASE
WITH A MAXIMUM FREQUENCY OF 20%
ENVIRONMENTAL FACTORS PLAY A
ROLE
IN DEVELOPING OF AUTOIMMUNITY
DRUG INDUCED HEMOLYTIC ANEMIA
• Alpha methyldopa therapy results in the formation of red blood cell
autoantibodies in 10-20% of patients taking the drug for longer than 4
months.
 True autoantibodies: directed against an autoantigen on the red blood
cell membrane, not against the drug
 The target membrane antigen is usually within the Rhesus system
• Drug-dependent Abs
 Penicillin, cefotetan: covalently bind to rbc membrane proteins.
o Anti-drug Ab (usually IgG) - attaches to the drug-coated RBCs clearance by macrophages
 Ceftriaxone: binds non-specifically to RBC membrane proteins
o Abs are formed to the combined membrane-drug (hapten) complex,
can be IgM or IgG, and often activate complement - acute rapid
intravascular hemolysis
SMOKING
Smoking damages the mucosa of the airways and
exacerbates many diseases.
All patients with Goodpasture’s syndrome develop
glomerulonephritis, but only those who habitually smoke
cigarettes develop pulmonary hemorrhage.
In nonsmokers, the basement membranes of lung alveoli
are inaccessible to antibodies.
In smokers the lack of integrity gives circulating
antibodies access to the basement membranes.
PHYSICAL TRAUMA
INFECTIONS:
ENVIRONMENTAL FACTORS
THAT CAN TRIGGER
AUTOIMMUNE DISEASE
ROLE OF INFECTIONS IN THE DEVELOPMENT
OF AUTOIMMUNITY
MOLECULAR MIMICRY MAY LEAD TO
SEVERE AUTOIMMUNE
REACTIONS
INFECTIONS ASSOCIATED WITH THE START OF
AUTOIMMUNITY
ANTIBODIES AGAINST STREPTOCOCCAL CELL-WALL ANTIGENS
CROSS-REACT WITH ANTIGENS ON HEART TISSUE
INDUCTION OF HLA CLASS II EXPRESSION
ON TISSUE CELLS
FACILITATES AUTOIMMUNITY
• In
response
to
IFN-γ
MHCII
expression is induced on thyroid cells (on
the β cells of the pancreas as well as on
microglia).
• Insufficient for the activation of naive
T-cells (not normally present in the
periphery anyway), BUT effector T-cells
cross-reacting with autoantigens may be
activated.
GENETIC AND ENVIRONMENTAL FACTORS
ACT TOGETHER
TO CAUSE AUTOIMMUNITY
RHEUMATOID ARTHRITIS IS INFLUENCED
BY GENETIC AND ENVIRONMENTAL FACTORS
Smoking is the major
environmental factor
associated with
rheumatoid arthritis
Smoking, HLA-DR4
and an immune
response to
citrullinated
proteins are all tied
together in the
same diseasecausing mechanism
ACPA+: strong
association with HLADR4 and smoking
smokers
APCA-: no association
nonsmokers
Basic residues in the
peptide-binding groove of
the DRβ*04 chain are
necessary to confer
susceptibility to
rheumatoid arthritis
INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS:
CELIAC DISEASE
Strong genetic predisposition:
DQ2, DQ8 allotypes – celiac disease - 80% DQ2 (the
same DQ allotypes that predispose to type 1 diabetes)
Caucasian populations
•
•
•
•
bread: staple
DQ2:30%
Celiac disease: 0.5-1%
The concordance rate in monozygotic twins: 75-80%
Environmental factors:
•
•
•
•
Antibodies, memory T-cells – cross-reaction
Repeated infections with rotavirus
IFN-γ therapy (hepatitis)
Gluten introduction – maternal IgA
ROLE OF THE GUT MICROBIOTA IN AUTOIMMUNITY
doi:10.1038/nri3430
doi:10.1038/nri3430
ROLE OF THE GUT MICROBIOTA IN AUTOIMMUNITY
doi:10.1038/nri3430
doi:10.1038/nm0911-1055
ROLE OF OTHER INTRINSIC FACTORS
IN AUTOIMMUNITY
HORMONES
Most autoimmune diseases are more prevalent
in women than men.
Conservative estimates indicate that nearly 80% of
individuals with autoimmune diseases are women.
Ankylosing spondylitis occurs more frequently in
men.
SENESCENCE OF THE THYMUS
AND THE T-CELL POPULATION
CONTRIBUTES TO
AUTOIMMUNITY
T-cell populations are dynamic:
• T-cells must divide periodically to survive.
• 1% of the body’s T-cells being replaced each day.
Once the thymus can no longer fulfill the demand
for naive T-cells, the immune system compensates:
• expanding the size of existing T-cell clones
• altering the properties of T-cells - make them
more resistant to apoptosis; CD28 - KIR
RA: large clones of expanded autoreactive CD4 T-cells
• lack of CD28
• express NK-cell receptors - KIR2DS2
• produce large amounts of IFN-γ
• not anergic
AUTOIMMUNE DISEASES TEND TO BE
CHRONIC, PROGRESSIVE AND SELFPERPETUATING
Self antigens are persistent, and once an immune response starts,
many amplification mechanisms are activated that perpetuate the
response
Tissue injures result in the release and alterations of other tissue
antigens, activation of lymphocytes specific for these other antigens,
and exacerbation of the disease
MECHANISMS OF CHRONICITY OF AUTOIMMUNE DISEASES
INTRAMOLECULAR EPITOPE SPREADING
PEMPHIGUS FOLIACEUS
INTERMOLECULAR EPITOPE SPREADING IN SLE
DYSFUNCTION OF REGULATORY T-CELLS
LOSS OF REGULATION OF AUTOREACTIVE T-CELLS
RESULTS IN AUTOIMMUNITY
FOXP3 deficiency: IPEX
CTLA-4 haploinsufficiency: autoimmunity
)
IL-10: severe colitis
IL-6 mediated resistance in psoriasis
Autoimmunity in Dry Eye:
qualitative Treg defect – resistance Th17 cells
doi:10.1038/nri2889
IL-6 MEDIATED RESISTANCE IN PSORIASIS
IL-6 is overexpressed in
IL-6 is necessary and
lesional psoriatic skin
sufficient for reversal
of Treg suppressive
function
Immune cell subsets including DCs, as well as CD31+ endothelial cells, represent major sources of IL-6 in
lesional psoriatic skin
Average Pixel
Average Pixel
Fold Increase
Density within
Density within
over
Indicated Cellsa
Keratinocytesa
pb
Keratinocytesc
CD11c
CD3
+
+
Mac387
CD31
+
+
966.5 ± 30.3
587.1 ± 30.6
0.039
1.98 ± 0.37
914.1 ± 35.7
676.2 ± 21.3
0.0044
1.38 ± 0.09
1014.0 ± 38.4
958.9 ± 28.7
0.4056
1.08 ± 0.06
1495.2 ± 81.2
832.3 ± 36.3
0.0015
1.87 ± 0.23
10.4049/jimmunol.0803721
AUTOIMMUNITY IN DRY EYE:
DEFECT IN TREGS IS QUALITATIVE NOT QUANTITATIVE
doi: 10.4049/jimmunol.182.3.1247