Transcript 19-20_Hypersensitivity

HYPERSENSITIVITY REACTIONS
Immune responses that are inadequately controlled,
inappropriately targeted to host tissues, or triggered by
commensal microorganisms or usually harmless
environmental antigens.
AN OVERVIEW OF HYPERSENSITIVITY
REACTIONS
Type I.
Type II.
„immediate”
Type III.
Type IV.
„late”
Antibody mediated
T cell mediated
Types of antibody mediated hypersensitivity reactions
FcRIα)
LIKE THE HYPERSENSITIVITY REACTIONS,
AUTOIMMUNE
DISEASES CAN BE CLASSIFIED ACCORDING TO
THE EFFECTOR
MECHANISM CAUSING THE DISEASE
Type II: Antibody against cell-surface or matrix antigens
Type III: Immune-complex diseases
Type IV: T-cell-mediated diseases
TYPE I HYPERSENSITIVITY REACTION
ALLERGY
Immune responses to nonmicrobial environmental
antigens that involve TH2 cells, immunoglobulin E,
mast cells, and eosinophils
Common allergic symptoms
Sequence of events in immediate hypersensitivity
reactions
TFH
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Sensitization to an inhaled allergen
Biochemical events of mast cell activation
Effector molecules released by mast cells
The physical effects of IgE-mediated mast-cell
degranulation vary with the tissue exposed to allergen
The acute response in allergic asthma leads to
TH2-mediated chronic inflammation of the airways
Defense against many helminthic infections is mediated
by IgE antibodies and activation of eosinophils
Systemic anaphylaxis is caused by allergens that reach the
blood stream
Normal larynx
Laryngeal oedema
Genetic/environmental predisposition to allergy
Genetic factors
chromosome 11q
FcεRβ chain gene
chromosome 11q
IL-3-5 IL-9, IL-13
GMCSF
HLAII DRB1*015
Inproper
immunregulation
Th1/Th2 inbalance
regulation of IgE synthesis
high eosinophil counts
allergy
Environmental
factors
lack of tolerance
The wheal and flare reaction in the skin
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Mediators and treatment of asthma
Antihistamines
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Monoclonal Anti-IgE
• Anti-IgE therapy represents a novel immunomodulatory approach that
targets an early point in the allergic inflammatory cascade.
• Omalizumab is a recombinant humanized monoclonal anti-IgE antibody
TYPE II HYPERSENSITIVITY
IgG or IgM antibodies bound to antigens
of particular cells or the extracellular matrix
Mechanisms of type II
hypersensitivity
reactions
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Examples of type II hypersensitivity
AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)
Idiopathic AIHA: 50%
Symptoms:
Warm-reactive antibodies:
limphoproliferative
diseases, SLE, RA
• pallor, fatique
Cold-reactive antibodies:
infections (mycoplasma,
viral pneumonia,
infectious mononucleosis)
• rapid pulse
Drug-induced (methyldopa,
penicillin, ceftriaxone)
• splenomegaly
Alloimmune hemolytic
anemia
• shortness of breath,
dizziness, headache,
• jaundice, yellowish color
of the skin (increased
bilirubin)
AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)
Mild cases may not require treatment
Treatment:
Treat underlying disease, infection
Immunosuppressive therapy, corticosteroids
Prednisone is thought to decrease monocytered cell interactions and decrease
autoantibody production.
Others: Azathioprine, Cyclophosphamid,
Chlorambucil
Surgery
Prednisone unresponsive patients:
splenectomy may be considered.
(Pneumococcus vaccine before treatment)
Immunotherapy, antibodies
IVIG
Anti-CD20 (rituximab)
Plasmapheresis
GOODPASTURE’S SYNDROME
•
Autoantibodies specific for α3 chain of type IV collagen; basement
membranes
•
Autoantibodies are deposited in the basement membranes of organs
•
High-pressure filtering of blood by renal glomeruli – most sensitive
•
Glomerulonephritis: IgG is deposited along the basement
membranes of renal glomeruli and renal tubules - inflammatory cells
accumulate - kidney failure
 Blood and protein in the urine, high blood pressure, unexplained
swelling of limbs or face
•
Pulmonary hemorrhage: only smokers - coughing up blood, chest
pain, shortness of breath
•
Strong association with HLA-DRB1*15:01/*04
•
Therapy:
plasmapheresis,
cyclophosphamide)
immunosuppression
(prednisone,
BULLOUS SKIN DISEASES
PEMPHIGUS VULGARIS
• The most severe and common form of pemphigus
• IgG4 autoantibodies against Dsg1 (skin lesion) and
Dsg3 (mucosal lesion)
• Affects the skin and mucous membranes
• Usually begins with painful erosions of the oral
mucosa (lasts for several months)
• Gradually followed by involvment of the skin
• HLA associaton: HLA DR4/14 haplotypes, Dsg3specific DLA-DR restricted Th2 cells
• Patients affected are usually in their fourth to sixth
decade of life
BINDING OF ANTIBODIES TO CELL-SURFACE
RECEPTORS CAUSES SEVERAL AUTOIMMUNE
DISEASES
Receptor agonist antibodies:
Mimic the natural ligand and cause the receptor to transduce activating
signals in the absence of its ligand
Examples of
organ- or tissuespecific
autoimmune
diseases
Examples of
systemic
autoimmune
diseases
Receptor antagonists antibodies:
Do not activate signaling on binding to the receptor and they block the
natural ligand from binding to the receptor
GRAVES’ DISEASE
Production
of
thyroid
hormones
(thyroxine (T4), triiodothyronine (T3)) is
regulated
by
thyroid-stimulating
hormone (TSH).
AGONIST autoantibodies
specific for
the TSH receptor
CHRONIC OVERPRODUCTION
OF THYROID HORMONES
The formation of autoantibodies
driven by a
CD4+Th2 response
Graves’ disease is associated with
HLA-DR3 (DR7 seems to be
protective)
GRAVES’ DISEASE
Hyperthyroid condition:
• Heat intolerance, rapid heart rate, nervousness,
irritability, warm moist skin, weight loss, and
enlargement of the thyroid
• Graves’ ophthalmopathy
 Autoantibodies made against a thyroid
protein cross-react with an eye-muscle
protein.
 Fibroblast – glycosaminoglycan release –
edema
• Dermopathy – TSH receptor expressing skin
fibroblasts
Therapy:
•
Short-term treatment: methimazole, propylthiouracil:
inhibit the production of thyroid hormones (inhibitor of
thyroperoxidase).
•
Long-term treatment: radioactive iodine or surgery destroy or remove the gland - need for lifelong use of
replacement of thyroid hormones
MYASTHENIA GRAVIS
Severe muscle weakness
ANTAGONISTIC autoantibodies bind to the acetylcholine
receptors on muscle cells - receptor endocytosis degradation
The loss of cell-surface acetylcholine receptors makes the
muscle less sensitive to neuronal stimulation - progressive
muscle weakening
Early symptoms: droopy eyelids and double vision
•
With time, other facial muscles weaken and similar
effects on chest muscles impair breathing susceptibility to respiratory infections, can even
cause death
Therapy:
•
Pyridostigmine:
inhibitor
of
the
enzyme
cholinesterase, which degrades acetylcholineincreases the capacity of acetylcholine to compete
with the autoantibodies
•
During crises of severe muscle weakening:
immunosuppressive drugs (azathioprine)
Myasthenia gravis is associated with HLA-DR3
TYPE III HYPERSENSITIVITY
Antibodies form immune complexes in the circulation,
and the complexes are subsequently deposited in
tissues, particularly in blood vessels, and cause injury
Immune complex–mediated tissue injury
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Tissue damage caused by deposited immune complexes
Frustrated
phagocytosis
Immune complexes activate the complement system, neutrophils, basophils and
thrombocytes
Examples of human immune complex–mediated diseases
Symptoms caused by type III hypersensitivity reactions
depend on the site of immunecomplex deposition
Arthus-reaction
• Localized Type III hypersensitivity
• Local vasculitis develops as a result of immune complex deposition
• Inhaled antigens (fungi, animal feces) may induce similar reaction in
the lung (Farmer’s lung and pigeon-breeder’s lung)
Localized deposition of immune complexes within a
tissue causes a type III hypersensitivity reaction
SYSTEMIC LUPUS ERYTHEMATOSUS
(SLE)
IgG is made against a wide range of cell-surface and
intracellular self antigens that are common to many cell
types.
The immune complexes formed by these antigens and
antibodies are deposited in various tissues, where they
cause inflammatory reactions resembling type III
hypersensitivity reactions.
The deposits can cause glomerulonephritis in the
kidneys, arthritis in the joints, and a butterfly-shaped
skin rash on the face.
SLE is particularly common in women of African or
Asian origin, 1 in 500 of whom has the disease.
SYSTEMIC LUPUS ERYTHEMATOSUS
(SLE)
Deposition of immune complexes in the kidney glomeruli
TYPE IV HYPERSENSITIVITY REACTION
T lymphocytes injure tissues either by triggering
inflammation or by directly killing target cells
Type IV hypersensitivity reactions
Mechanisms of T cell–mediated hypersensitivity reactions
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Tuberculin skin test
Introduction of Ag
Ag = antigen
Purified protein derivate (PPD)
Most type IV hypersensitivity reactions are
orchestrated by the cytokines released by TH1 CD4
cells in response to antigen
DTH as a result of a contact-sensitizing agent*
CONTACT DERMATITIS
*a contact-sensitizing agent is usually a small molecule that penetrates
the skin then binds to self-proteins, making them “look” foreign
CONTACT DERMATITIS
Poison ivy
Anacardiaceae (family), Toxicodendron (genus)
Toxicodendron radicans or Rhus toxicodendron
Physical contact with
poison ivy transfers
pentadecacatechol,
which causes dermatitis
CELIAC DISEASE
Delayed-type hypersensitivity
TYPE 1 DIABETES
Selective autoimmune destruction of the insulin-producing cells
of the pancreas
• T-cell and antibody responses
 Antigen-specific CD8+T-cells are believed to mediate β-cell destruction
 CD4+Th1 cells
 Insulin, glutamic acid decarboxylase, and other specialized proteins of
the pancreatic β-cell
Insulitis:
infiltration of
lymphocytes
from the
islet
periphery
toward the
center
Comparison of histological sections of a pancreas from a
healthy person and a patient with type 1 diabetes
HASHIMOTO’S DISEASE
•
Caused by a CD4 Th1 response
•
Effector CD4+T-cells and antibodies specific for thyroid antigens (thyroglobulin,
thyroid peroxidase, TSH receptor, thyroid iodide transporter)
•
Lymphocytes infiltrate the thyroid, causing a progressive destruction of the
thyroid tissue
 Loss of the capacity to make thyroid hormones - hypothyroid
•
Ectopic lymphoid tissues: a characteristic feature of Hashimoto’s disease:
immune cells infiltrating the thyroid gland become organized into structures lymphoid neogenesis - driven by lymphotoxin
 Resembling the typical microanatomy of secondary lymphoid organs (Tcell and B-cell areas, dendritic cells, follicular dendritic cells,
macrophages)
 Not encapsulated, lacks lymphatics
RHEUMATOID ARTHRITIS
The most common rheumatic disease (1–3% in US)
•
Chronic and episodic inflammation of the joints.
•
The synovium of an arthritic joint is infiltrated:
 CD4 and CD8 T-cells, B-cells, lymphoblasts,
plasma cells neutrophils, macrophages
•
Pro-inflammatory cytokines: IFN-γ, IL-17, IL-1 , IL-6,
TNF-a
•
Prostaglandins, leukotrienes, lysosomal enzymes:
tissue damage, synoviocyte activation
•
Fibroblasts activated by cytokines produce matrix
metalloproteinases (MMPs), which contribute to
tissue destruction.
•
Proteinases and collagenases: cartilage, ligaments,
tendons
•
The TNF-family cytokine RANK ligand (T-cells,
fibroblasts): primary activator of bone-destroying
osteoclasts
•
Rheumatoid factor: IgM, IgG, and IgA antibodies
specific for the Fc region of human IgG (80%)
•
ACPA: HLA DR4, smoking
RHEUMATOID ARTHRITIS
The most common rheumatic disease (1–3% in US)
X-ray of the right hand of a patient with
rheumatoid arthritis. It shows extensive
destruction and dislocation of the
metacarpophalangeal joints.
Inflamed joints in the hand of a patient with
rheumatoid arthritis
MULTIPLE SCLEROSIS
a4:B1 integrin
- VCAM
Pathogenesis
Sclerotic plaques of
demyelinated tissue
in the white matter of
the central nervous
system
T-cells reencounter antigen: microglia: phagocytic macrophage-like
cells of the innate immune system resident in the CNS
Inflammation, IFN-γ, IL-17, increased vascular permeability: T -cell, B-cell, macrophage, dendritic
cell infiltration, mast cells: histamine
Oligoclonal IgG: structural proteins of myelin
MULTIPLE SCLEROSIS
•
A variety of nervous symptoms:
 Muscle weakness, impaired vision, ataxia, spasticity (excessive contraction of
muscles), paralysis of limbs, urinary incontinence
•
It can alternate between acute attacks of exacerbating disease and periods of
gradual recovery.
•
The disease is 10 times more frequent in women than in men and is associated
with HLA-DR2.
•
Therapy:
 Regular subcutaneous injection of IFN-β1 reduces the incidence of disease
attacks and the appearance of plaques.
 Disease attacks: immunosuppressive drugs, corticosteroids
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
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 selfreactive 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.
AUTOIMMUN REGULATOR (AIRE)
A transcription factor expressed by thymic medullary
epithelial cells and induces expression of many tissuespecific 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-Th17
specific
antibodies!!!!!
•
Role of Th17
discovered by
studying a rare
immunodeficiency
•
https:///jimneydandme
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
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 drugcoated 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
ROLE OF INFECTIONS IN THE DEVELOPMENT
OF AUTOIMMUNITY
MOLECULAR MIMICRY MAY LEAD
TO SEVERE AUTOIMMUNE
REACTIONS
BODIES AGAINST STREPTOCOCCAL CELL-WALL ANTI
CROSS-REACT WITH ANTIGENS ON HEART TISSUE
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
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