Transcript Therapy

AUTOIMMUNE DISEASES DISPLAYING
ORAL SYMPTOMS
AUTOIMMUNE POLYENDOCRINOPATHYCANDIDIASIS-ECTODERMAL DYSTROPHY (APECED)
• Anti-IL-17 specific
antibodies!
• AIRE deficiency
Therapy:
Rare disease, but more
Endocrine disorders – hormone replacement
frequently seen in inbred
populations
Antifungal treatment
(Finnish, Iranian Jews and
Immunosuppressive treatment
in the island of Sardine)
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.
SJOGREN’S SYNDROME
• Prevalence: cca 1:100
• Female: male ratio: cca 9:1
• Often shows up near the menopausal age
• Association with HLA-DR3 and HLA-B8, HLA-Dw3
• Hypergammaglobulinemia: anti-Ro(SSA), anti-La(SSB), anti-α-fodrin
• Systemic autoimmune disease, which tends to progress very slowly and affects
exocrine glands:
- Dry mouth, rapid development of dental caries, oral candidiasis
- Decreased production of tears, dry eyes, corneal ulceration
- Salivary gland enlargement (T cell accumulation)
SJOGREN’S SYNDROME
SJOGREN’S SYNDROME
• Systemic glandular (epithelial) symptoms:
pharyngitis, laryngitis, bronchitis, vaginitis sicca,
gastrointestinal, pulmonal, hepatobiliary symptoms
tyroid and renal abnormalitis
• Systemic extraglandular symptoms:
polyarthritis, Raynaud phenomenon, vasculitis, glomerulonephritis,
polyneuropathy, cytopenias
Therapy:
Moisture replacement therapies , NSAIDs, in severe cases patients
receive corticosteroids or disease-modifying anti-rheumatic drugs
(DMARDs) /methotrexate, azathioprine)/
Raynaud phenomenon
• Common in autoimmune diseases
• There are episodes of reduced blood flow in fingers due to
spasm of arteries.
• It has 3 phases:
– Initial pallor
– Cyanosis (blueing)
– Redness
BECHET’S DISEASE (Silk Road Disease)
Large number of various autoantibodies
/Anti-endothelial cell antibodies (AECAs) and autoantibodies targating retina/
Recurrent vasculitis
Prevalence/100,000
UK 0.64
Portugal 1.5
Germany 2.26
• Susceptibility genes: HLA-B51
• Infections (Str. sanguis, HSV) and exposure
to heavy metals increase relative risk
Japan 13.4
Italia 2.5
Turkey
80-370
Spain 7.5
• Mean Age: 25 – 30 years
Iran 16.7
Egypt 7.6
Saudi Arabia
20
Kuwait 1.2
China 14
SYMPTOMS OF BECHET’S DISEASE I
Oral aphthous ulcers and genital ulcers
SYMPTOMS OF BECHET’S DISEASE II
Skin and ocular lesions
Cardiovascular, neurological, and
gastrointestinal manifestations may appear
/bad prognostic signs/.
Therapy:
Local medication to relieve pain, anti-TNF drugs, systemic glucocorticoids
and immunosuppressive drugs
COMMON AUTOIMMUNE DISEASES
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.
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
shortness of breath
- coughing up blood, chest pain,
• Strong association with HLA-DRB1*15:01/*04
• Therapy: plasmapheresis, immunosuppression (prednisone, cyclophosphamide)
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: inhibition of 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
Temporary symptoms of antibody-mediated
autoimmune diseases can be passed from affected
mothers to their newborn babies.
TSHR, thyroid-stimulating hormone receptor
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:
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 - small
cytoplasmic ribonucleoprotein complex (Ro and La)
•
HLA-DR2: double-stranded DNA
• HLA-DR5:
spliceosome
ribonucleoprotein)
(U1
small
nuclear
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)
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 (during flares)
•
Cyclophosphamide: glomerulonephritis (other organ-damaging complications)
•
Chronic pain: NSAID
•
IVIG
•
Monoclonal Ab therapy
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
• 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
 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)
• 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 - hypothyroidism
• 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)
 Functions like a secondary lymphoid tissue BUT not encapsulated, lacks lymphatics
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
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
• Anti-IL6R, tocilizumab
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 on microglial cells (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
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.
• Autoantibodies attack the structural proteins of myelin. These
include myelin basic protein, proteolipid protein, and myelin
oligodendrocyte glycoprotein.
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
CELIAC DISEASE
• chronic T cell activation
• peptides presented by HLA-DQ8 or HLA-DQ2 molecules
• IgG and IgA antibodies against tissue transglutaminase
Therapy:
Gluten-free diet
Possible treatments for systemic autoimmune diseases
General precautions:
– Avoid intense UV light exposure
– Use of suncreams
– Avoid cold exposure
– Artificial tear
Drugs:
– Symptomatic treatment (NSAIDs, painkillers)
– Immunosuppressive drugs:
(Corticosteroids, cyclophosphamide, methotrexate, azathioprine,
cyclosporine A)
Biological therapies
- Monoclonal antibodies against TNF-α, IL-6R, CTLA4, CD20
Other possibilities
– IVIG, Plasmapheresis, Thymectomy (Myasthenia gravis, Hematopoietic
stem cell transplantation