Transcript 39_Autoimmune diseases_LAx

AUTOIMMUNE DISEASES
ARPAD LANYI PhD
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 II AUTOIMMUNE DISEASES
Antibody against cell-surface or matrix antigens
AUTOIMMUNE/IDIOPATHIC THROMBOCYTOPENIC
PURPURA (A/ITP)
Autoimmun condition causing platelet destruction
General features
• Can be chronic (adults) or acute (children, after acut viral infection)
• MHC susceptibility genes are associated with chronic ATP (HLA DRB1*0410)
• A variety of infectious diseases are associated with ATP (H. pylori,
Hepatitis B,C, HIV)
• More common in women than in men (3:1)
Pathogenesis:
• Specific anti-platelet antibodies targeting platelet membrane glycoproteins

Usually IgG, but can be IgM or IgA

Cross the placenta, neonatal ATP

Antigen: platelet glycoprotein IIb-IIIa or Ib-IX complexes
• Autoantibodies bind to platelets resulting in clearance of the opsonized
platelets by the phagocytic cells (RES)
PHAGOCYTE IN
ACTION
Containing one intact platelet (P) and apparently
in the process of phagocytosing another
DOI: 10.1056/NEJM197709082971001
AUTOIMMUNE/IDIOPATHIC THROMBOCYTOPENIC
PURPURA (A/ITP)
Autoimmun condition causing platelet destruction
Clinical features:
• Thrombocytopenia
• Megathrombocytes
• Increased numbers of megakaryocytes in the bone marrow
• Some patients remain asymptomatic for years
• If the number of platelets falls below 109 per liter of blood, severe
spontaneous bleeding ensues
• Severe mucocutaneous bleeding
• Intracranial hemorrhage (rare)
THERAPY OF ATP
IVIG
Saturates Fcγ receptor sites
on macrophages, induces
increased expression of the
inhibitory receptor FcγRIIB,
which can contribute to the
inhibition of phagocytosis.
The abnormally high level
of circulating IgG has a
generally suppressive
effect on immunoglobulin
synthesis.
Less secere case: oral
prednisone, prednisolone
Severe case: dexamethasone,
methylprednisolone infusion
Remove existing
antibodies
Not recommended except in
an emergency
Rituximab:
monoclonal anti-CD20 Ab
Antibody-dependent
cellular cytotoxicity (ADCC)
and complement-dependent
cytotoxicity
CD40/CD40L interaction
IDEC131
Thrombopoietin receptor
agonists
Romiplostim (sc.):
thrombopoiesis stimulating
Fc-peptide fusion protein
Eltrombopag: orallyadministered agent
AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)
Idiopathic AIHA: 50%
Warm-reactive antibodies:
limphoproliferative diseases, SLE,
RA
Cold-reactive antibodies: infections
(mycoplasma, viral pneumonia,
infectious mononucleosis)
Drug-induced (methyldopa, penicillin,
ceftriaxone)
Alloimmune hemolytic anemia
Symptoms:
• pallor, fatique
• shortness of breath, dizziness,
headache,
• rapid pulse
• jaundice, yellowish color of the
skin (increased bilirubin)
• splenomegaly
AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)
Mild cases may not require treatment
Treatment:
Treat underlying disease, infection
Immunosuppressive therapy, corticosteroids
Prednisone is thought to decrease monocyte- red 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
AUTOIMMUNE NEUTROPENIA
• Leukocytes are less susceptible to complement-mediated lysis than erythrocytes.
• The main effect of complement fixation on leukocyte surfaces is opsonization.
• As the opsonized leukocytes circulate through the spleen they are removed and
degraded by the resident macrophages.
• Neutropenia: most common in infants and young children
Symptoms:
• Neutrophils are absent or reduced (less than 1.5X 109/L, or 1500/μl).
• Mucocutaneous infections
• Elevated IgG, myeloid hyperplasia with diminished number of mature cells
Therapy:
• Corticosteroids to reduce autoantibody production
• Antibiotics to prevent infection
• G-CSF
 Stimulates proliferation and maturation
 Release mature cells into the bloodstream
 Stimulates phagocyte function
 Reduces neutrophil apoptosis
 Raises levels of soluble FcγRIIIb, sequestering autoantibodies
• Splenectomy: opsonized leukocytes survive longer in the circulation (opsonized
leukocytes are still functional)
• IVIG
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
shortness of breath
- coughing up blood, chest pain,
• Strong association with HLA-DRB1*15:01/*04
• Therapy: plasmapheresis, immunosuppression (prednisone, cyclophosphamide)
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, Dsg3-specific DLA-DR
restricted Th2 cells
• Patients affected are usually in their fourth to sixth decade of life
BULLOUS SKIN DISEASES
PEMPHIGUS FOLIACEUS
• IgG4 autoantibodies against Dsg1 (EC5 – EC1/EC2
– intramolecular epitope spreading)
• Affects skin only, superficial blisters, exfoliative
erythroderma
• Drug-induced pemphigus: penicillamine
Pemphigus foliaceus with
large scaly and crusted
erosions over the trunk
giving a ‘corn flakes’
appearance
Pemphigus foliaceus
characterised by
exfoliative erythroderma
DOI: 10.5772/56423
BULLOUS SKIN DISEASES
THERAPY
• Corticosteroids (prednisone); adjuvant therapy:
spearing agents (cyclophosphamide, methotrexate)
steroid
• The mortality rate has been reduced to less than 10%
• Complictions: osteoporosis, diabetes, hypertension, obesity
• Patient resistant to steroids: plasmaferesis, IVIG
• Rituximab: anti-CD20 mAb
Nine months after
treatment with
rituximab, the
patient’s clinical
condition remained
stable
Med J Aust 2008; 189 (5): 289-290.
ACUTE RHEUMATIC FEVER
Group A streptococci, Steptococcus pyogenes
Cross reactivity with self antigens present in heart, joint, kidney
(M-protein shows sequence similarity with myosin.)
Main symptoms:
•Pancarditis, cardiac murmur, mitral valve insufficiency
•Polyarthritis (joints become hot, red, swollen)
•Sydenham’s chorea
•Erythema marginatum (rash)
Aschoff body: rheumatic granuloma, fibrinoid necrosis surrounded
by
Aschoff (multinucleated giant cells)/Anitschkow (enlarged
macrophages) cells, infiltrated lymphocytes.
However only 3% of all patients with untreated Streptococcal
pharingytis develop rheumatic fever. Likely that genetic factors
contribute to the development of the disease !!!
Association between different HLA class II antigens and RF has
been found in several populations (USA: DR4, DR9; South Africa:
DR1, DR6, Brazil: DR7, DR53 etc.)
Therapy: antibiotics, arthritis: salicylates, NSAID
During 2nd world war young recruits treated with pencillin within 10
days of strep throat did not get rheumatic fever.
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 tissue-specific
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 thyroidstimulating 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 acetylcholine- increases the capacity of
acetylcholine to compete with the autoantibodies
• During
crises
of
severe
muscle
immunosuppressive drugs (azathioprine)
Myasthenia gravis is associated with HLA-DR3
weakening:
TYPE III AUTOIMMUNE DISEASES
Immune-complex diseases
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)
Initiating event: Loss of T-cell tolerance
The antibodies specificities depend on the HLA class
II type
• HLA-DR3: the greatest susceptibility
cytoplasmic ribonucleoprotein complex
•
-
small
HLA-DR2: double-stranded DNA
• HLA-DR5: spliceosome (nuclear ribonucleoprotein
complex)
Immune complex deposition - Tissue disruption –
Release cellular antigens - Further inflammatory reactions
Once an antibody has been made against one component of a
particle, that antibody can deliver the particle to cells and
facilitate the development of antibodies against the other
components.
Ever-increasing and uncontrolled destruction
can affect every tissue of the body!
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Stroke from blood vessel clots
Neuropathia, paralysis
Persistent headache, memory loss, confusion
Reversible blindness, retinal exudates
Mucosal ulcers (oral, vaginal, nose)
Photosensitivity, exudative erythema, discoid, butterfly rash
Pericarditis, myocarditis, endocarditis, pleuritis, peritonitis,
pneumonia
Glomerulonephritis, hematuria, proteinuria,
Bleeding, nausea, vomiting, diarrhea,
Menorrhagia, amenorrhoea, prematurity, spontaneous abortion
Hemolytic anemia, thrombosis, thrombocytopenia
Arthritis (90%), painfull swollen joints, myalgia
Outbreaks of intense inflammation alternate with periods of relative calm.
Many patients die of the disease because of failure of vital organs such as the brain or the kidneys.
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Deposition of immune complexes in the kidney glomeruli
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
THERAPY
No cure is available for SLE but there are many treatments for
the disease
•
Disease-modifying antirheumatic drugs (DMARDs): reduce the incidence of
flares (methotrexate, azathioprine)
•
Corticosteroids (flares)
•
Cyclophosphamide: glomerulonephritis (other organ-damaging complications)
•
Chronic pain: NSAID
•
IVIG
TYPE IV AUTOIMMUNE DISEASES
T-cell-mediated diseases
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
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
• The β-cells comprise about two-thirds of the islet cells; as they die, the architecture of the islet
degenerates.
 108 β-cells - disease symptoms do not manifest until years
• Disease symptoms usually manifest themselves in childhood or adolescence
 Polyuria (excessive urination), polydipsia (increased thirst), xerostomia (dry mouth), polyphagia
(increased hunger), fatigue, weight loss
 Diabetic ketoacidosis: xeroderma (dry skin), rapid deep breathing, drowsiness, abdominal pain,
vomiting
• Treatment: daily injection with synthetic human insulin; (coma, death)
 Treg cell therapy
• Type 1 diabetes principally affects populations of European origin, 1 in 300.
 DQ2, DQ8 allotypes confer susceptibility to type 1 diabetes.
 DQ6 allotype confers strong resistance to 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 (T-cell and B-cell
areas, dendritic cells, follicular dendritic cells, macrophages)
 Not encapsulated, lacks lymphatics
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 (T-cell and B-cell
areas, dendritic cells, follicular dendritic cells, macrophages)
 Not encapsulated, lacks lymphatics
 Functions like a secondary lymphoid tissue
o T- and B-cells are stimulated by antigen to give effector cells, germinal center
reactions: isotype switching, somatic hypermutation
HASHIMOTO’S DISEASE
Most common symptoms:
• Fatigue, weight gain, feeling cold, joint and muscle pain, depression, panic
disorder, slowed heart rate, irregular periods, problems getting pregnant and
maintaining pregnancy
HLA DR4 association (protective: DR13)
Treatment:
• Replacement therapy with synthetic thyroid hormones taken orally on a daily
basis.
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
RHEUMATOID ARTHRITIS
The most common rheumatic disease (1–3% in US)
• Rheumatoid arthritis is a chronic, painful, and debilitating disease, which
patients can suffer for many decades of their lives (usually starting between
20 and 40 years of age).
• Therapy:
• Physiotherapy with anti-inflammatory and immunosuppressive drugs,
glucosamine, chondroitin
• Rituximab: anti-CD20 mAb
• Anti-TNF-α antibodies: infliximab (chimeric), adalimumab
MULTIPLE SCLEROSIS
Pathogenesis of multiple sclerosis
• CNS is a relatively immunologically privileged site from which antigens do not normally reach
the lymphoid tissues.
• In MS, an unknown injurious event is presumed to provoke the release of CNS antigens and
their presentation to lymphocytes in the peripheral lymphoid organs.
• This results in the expansion of clones of autoreactive T-cells and their differentiation into
Th1, Th17 cells, which home to the CNS and initiate inflammation.
MULTIPLE SCLEROSIS
a4:B1 integrin VCAM
Pathogenesis of multiple sclerosis
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
THANK YOU
AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)
Idiopathic AIHA: 50%
Warm-reactive antibodies:
limphoproliferative diseases, SLE,
RA
Cold-reactive antibodies: infections
(mycoplasma, viral pneumonia,
infectious mononucleosis)
Drug-induced (methyldopa,
penicillin,ceftriaxone)
Alloimmune hemolytic anemia
Symptoms:
• pallor, fatique
• shortness of breath, dizziness,
headache,
• rapid pulse
• jaundice, yellowish color of the
skin (increased bilirubin)
• gallstones
• splenomegaly
ACUTE RHEUMATIC FEVER
Group A streptococci, Steptococcus pyogenes
Cross reactivity with self antigens present in hart, joint, kidney
(M-protein shows sequence similarity with myosin.)
Main symptoms:
•Pancarditis, cardiac murmur, mitral valve insufficiency
•Polyarthritis (joints become hot, red, swollen)
•Sydenham’s chorea
•Erythema marginatum (rash)
Aschoff body: rheumatic granuloma, fibrinoid necrosis surrounded
by
Aschoff (multinucleated giant cells)/Anitschkow (enlarged
macrophages) cells, infiltrated lymphocytes.
However only 3% of all patients with untreated Streptococcal
pharingytis develop rheumatic fever. Likely that genetic factors
contribute to the development of the disease !!!
Association between different HLA class II antigens and RF has
been found in several populations (USA: DR4, DR9; South Africa:
DR1, DR6, Brazil: DR7, DR53 etc.)
Therapy: antibiotics, arthritis: salicylates, NSAID
During 2nd world war young recruits treated with pencillin within 10
days of strep throat did not get rheumatic fever.
GRAVES’ DISEASE
Production of thyroid hormones (thyroxine (T4),
triiodothyronine (T3)) is regulated by thyroidstimulating hormones (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)
MULTIPLE SCLEROSIS
a4:B1 integrin VCAM
Pathogenesis of multiple sclerosis
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