Download 35_Organ-specific autoimmune diseases

ORGAN-SPECIFIC AUTOIMMUNE
DISEASES
In organ-specific diseases, autoantigens from
one or a few organs are targeted, and disease
is limited to those organs
AUTOIMMUNE ENDOCRINE 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
• 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.
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
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.
AUTOIMMUNE ADRENOCORTICAL FAILURE,
OR ADDISON'S DISEASE
• It develops as a consequence of autoimmune destruction of steroidproducing cells in the adrenal gland.
• A major autoantigen is 21-hydroxylase (21OH), which is involved in
the biosynthesis of cortisol and aldosterone in the adrenal cortex .
• Female: Male ratio: 4 : 1
• Susceptibility genes: HLA-DR3
• T cell-mediated injury is likely to be central to pathogenesis. Adrenal
autoantibodies may have a pathogenic role, as yet unclear, or could arise
secondary to T cell-mediated tissue damage
Symptoms & treatments in Addison's disease
•
•
•
•
•
•
Weakness
Weight loss
Poor appetite
Hyperpigmentation
Hypotension
Weak pulses
Treatment: Hormone replacement
• Cortisol is replaced with a corticosteroid
such as hydrocortisone, dexamethasone, or
prednisone, and is taken orally one to three
times a day.
• Aldosterone is replaced with a
mineralocorticoid called fludrocortisone
acetate taken orally once or twice a day.
SKIN AND MUCOSAL MEMBRANES
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.
BLOOD DISORDERS
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
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
• 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,
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 severe 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
IDEC-131 (mAb to CD40-ligand)
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.
Surgery
Prednisone unresponsive patients: splenectomy may
be considered. (Pneumococcus vaccine before
treatment)
Immunotherapy, antibodies
IVIG
Anti-CD20 (rituximab)
Plasmapheresis
KIDNEYS AND LUNGS
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)
MUSCLE CELLS
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:
CENTRAL NERVOUS SYSTEM
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