Download development of autoimmunity

DEVELOPMENT
OF
AUTOIMMUNITY
AUTOIMMUNE REACTIONS
• During an autoimmune response, the immune system attacks
healthy cells and tissues.
• Mechanisms of recognition and effector functions are the same
as those acting against pathogens and environmental antigens.
• These chronic diseases can be potentially fatal (for example
autoimmune type 1 diabetes or pernicious anemia).
• They cause serious, progressive inflammatory symptoms and
induce tissue damages.
• Diseases caused by them require life-long treatments.
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 (self antigen + autoantibody)
• 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
FOXP3 DEFICIENCY:IPEX
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked
syndrome
 Polyendocrinopathy: multiple disorders of the endocrine glands
 Type 1 diabetes mellitus (most common) develops within the first few months of life
 Autoimmune thyroid disease (hypo- or hyperthyroidism)
 Enteropathy: severe diarrhea, usually the first symptom, failure to thrive
 Dermatitis
 Autoimmune blood disorders are common; about half of affected individuals have anemia,
thrombocytopenia, neutropenia
 Most patients with IPEX are males and most of them die within the first 2 years of life
without treatment (a few with a milder phenotype have survived into the second or third
decade of life)
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
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
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
Focal infections
• A local chronic infection affecting a small area of the body can lead
to subsequent symptoms in other parts of the body due either to
the spread of the infectious agent itself or toxins produced from it.
A focus of infection may be described as a circumscribed area of
tissue infected with pathogenic organisms.
• The pathogenesis of focal diseases has been classically attributed
to dental infections.
• Chronic periodontitis may be a causal
factor in the pathogenesis of
rheumatoid arthritis.
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
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
PHYSICAL TRAUMA
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.
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
GENETIC AND ENVIRONMENTAL FACTORS
ACT TOGETHER
TO CAUSE AUTOIMMUNITY
HORMONES ALSO AFFECT THE
DEVELOPMENT OF AUTOIMMUNITY
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.
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
SIMILARLY TO HYPERSENSITIVITY REACTIONS,
AUTOIMMUNE DISEASES CAN ALSO BE GROUPED
BY THEIR EFFECTOR MECHANISM