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Autoimmune diseases
CENTRAL TOLERANCE IS INDUCED AND MAINTAINED IN THE BONE
MARROW AND THYMUS
Clonal deletion of self agressive B and T cell clones (not complete)
B AND T CELLS WITH SELF REACTIVITY ARE PRESENT IN THE
AVAILABLE PERIPHERAL T CELL REPERTOIRE
PERIPHERAL TOLERANCE
Maintenance of self tolerance of T-lymphocytes against tissuespecific self proteins which are not represented in the thymus
Active mechanisms at the level of CD4+ helper T-lymphocytes
AUTOIMMUNE DISEASES
Disturbance of tolerance
Misdirected adaptive immunity to healthy cells and tissues
PERIPHERAL TOLERANCE
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
PERIPHERAL TISSUES TOLERIZE THEMSELVES
AUTOIMMUNE DISEASES
• Chronic inflammatory conditions
• Repair mechanisms cannot compete with tissue destruction caused by
the immune system
• Variety of symptoms and of target tissues
• Mechanisms of recognition and effector functions are the same as
those acting against pathogens and environmental antigens
• Both genetic and environmental factors are involved in the predisposition to autoimmune diseases
– HLA class I and II and other genetic factors affect susceptibility
• Runs in families and varies between populations
• C1, C2 or C4 deficiency predisposes to systemic lupus erythematosus (SLE)
– Environmental factors
• Goodpasture’s syndrome – autoantibodies to type IV collagen,
glomerulonephritis, smokers develop pulmonary hemorrhage as well
• Symphathetic ophtalmia – provoked by damage
• Infection – Wegener’s syndrome – antibodies to proteinase-3 of neutrophil
granules results in destruction of small blood vessels primarily in the lung
Any infection can induce granulocyte activation and exposure of the autoantigen
ASSOCIATIONS OF HLA ALLOTYPE WITH
SUSCEPTIBILITY TO AUTOIMMUNE DISEASE
Disease
HLA
serotype
Relatív risk
Sex ratio
Women/male
Ankylosing spondylitis
B27
87.4
0.3
Acute anterior uveitis
B27
10.04
<0.5
Goodpasture’s syndrome
DR2
15.9
~1
Multiple sclerosis
DR2
4.8
10
Graves’s disease
DR3
3.7
4-5
Myasthenia gravis
DR3
2.5
~1
Systemic lupus erythematosus
DR3
5.8
10 - 20
DR3 and
DR4
3.2
~1
Rheumatoid arthritis
DR4
4.2
3
Pemphigus vulgaris
DR4
14.4
~1
Hashimoto thyroiditis
DR5
3.2
4-5
Insulin dependent diabetes
mellitus
Maximum 20% of predisposed people develop the disease
 environmental factors
Defective central tolerance:
Autoimmune PolyEndocrinopathy Candidiasis-Ectodermal Dystrophy (APECED),
AIRE deficiency (Finnish population)
Heterogenous disease:
Candida albicans infection
hypothyroidism
hypogonadism and infertility
vitiligo (depigmentation of the skin)
alopecia (baldness)
pernicious anemia
chronic active autoimmune hepatitis
TISSUE-SPECIFIC AUTOIMMUNE DISEASES
Endocrine glands I.
•
•
•
•
Tissue-specific proteins are not expressed in other cells
Vascularized tissues, secrete hormone to the blood
– Easy access to the immune system
Impaired function of a single type of epithelial cells
Thyroid gland
– Hashimoto’s thyroiditis
• no thyroid hormone production – hypothyroid
• CD4+ T cells and antibodies against thyroglobulin and microsomal
proteins
– Graves’ disease
• Antibodies to TSH receptor – hyperthyroid
• Negative feedback regulation is not functional
• CD4+ Th2 cells and antibodies against the muscle of eye – bulding eyes
STIMULATING ANTIBODIES IN GRAVES’ DISEASE
PITUITARY
PITUITARY
Tyroid stimulating
hormon
TSH
NEGATIVE FEED BACK
Tyroid hormons
T3 triiodine tyronin
T4 tyroxin
Tyroglobulin
Folliculus lumen
HYPERTYROSIS
Tyroid hormons
T3/T4
TISSUE-SPECIFIC AUTOIMMUNE DISEASES
Endocrine glands II.
•
•
Islets of Langerhans in pancreas
– Insulin-dependent diabetes
• T cells against insulin, glutamic acid decarboxylase GAD
– Insulin-resistant diabetes
• Antagonistic antibodies to insulin receptor
Adrenal gland
– Addison’s disease – chronic adrenal gland hypofunction (21 hydroxilase)
BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS
NEURO-MUSCULAR JUNCTION
MYSTENIA GRAVIS
Nerve
impulse
Nerve impulse
Acetilcholin receptor
Muscle
Internalization
NO Na+ influx
NO muscle contraction
MECHANISM OF AUTOREACTIVITY IN INSULIN-DEPENDENT
DIABETES
Type IV hypersensitivity
AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING βCELLS
Insulin
a cell a cell b cell
glucagon
b cell
108 insulin secreting
cells
Pancreatic islet cells
d cell
d cell
Somatostatin
SYSTEMIC AUTOIMMUN DISEASES I.
Autoreactivity against common components of human cells
• Systemic lupus erythematosus SLE
– Type III hypersensitivity
– Autoantibodies against cell surface, cytoplasmic,
nuclear proteins, nucleic acid, nucleoprotein particles
induce tissue demage
– Comon nucleoprotein particles
• Nucleosome
• Splicosome
• Small cytoplasmic ribonucleoprotein complex – Ro, La
– Soluble cellular antigens bind antibodies and form
soluble immune complexes – released form dying,
dead cells
– Immune complexes are deposited to blood
vessels,kidneys, joints and other tissues
MANIFESTATION OF TYPE III HYPERSENSITIVITY IN SLE
Facial, malar "butterfly" rash with
characteristic shape across the cheeks.
Discoid lupus erythematosus (DLE)
involves mainly just the skin, it is
relatively benign compared to systemic
lupus erythematosus (SLE). In either case,
sunlight exposure accentuates this
erythematous rash. A small number (5 to
10%) of DLE patients go on to develop SLE
(usually the DLE patients with a positive
ANA).
Here is a more severe inflammatory
skin infiltrate in the upper dermis of a
patient with SLE in which the basal
layer is undergoing vacuolization
and dissolution, and there is purpura
with RBC's in the upper dermis
(which are the reason for the rash).
DEPOSITION OF IMMUNE COMPLEXES IN THE SKIN OF SLE
PATIENTS
If an immunofluorescence stain with
antibody to complement or
immunoglobulin is performed, then one
can see the brightly fluorescing band
along the dermal epidermal junction
that indicates immune complex deposits
are present.
Immunofluorescence staining pattern with
antibody to IgG showing evidence for
immune complexes at the dermalepidermal junction. If such a pattern is
seen only in skin involved by a rash, then
the diagnosis is probably DLE, but if this
pattern appears even in skin uninvolved
by a rash, then the diagnosis is SLE.
RENAL FAILURE IN RHEUMATIC DISEASES
One of the feared complications of the
rheumatic diseases is renal failure. This
is most likely to occur with SLE. Here is
a glomerulus in which the capillary
loops are markedly pink and thickened
such that capillary lumens are hard to
see. This is lupus nephritis.
Here is a glomerulus with
thickened pink capillary loops, the
so-called "wire loops", in a patient
with lupus nephritis. The
surrounding renal tubules are
unremarkable.
SYSTEMIC AUTOIMMUN DISEASES II.
• Rheumatoid arthritis
– Type IV hypersensitivity
– Cellular response to synovial membrane
• CD4+ and CD8+ T cells, B cells, plasma cells,
neutrophils, macrophages
• Production of rheuma factors – antibodies to IgGFc