Download Auto Immune Diseases

Auto Immune
Diseases
Ch 4
(P 120 - 134 (
March. 7. 2016
Auto Immune Diseases
Autoimmunity is hard to classify as
strictly a B cell or T cell mediated
disease as multiple arms of the
immune system are involved
Auto Immune Diseases
Symptoms
• Initial diagnosis may be missed in patients as
diseases present with general symptoms
– Fever, muscle ache, fatigue, joint pain
• Disease specific manifests
– SLE – rash
– Sjogren’s – dry mouth, dry eyes
Diagnosis
• General tests
– C - Reactive Protein
– Autoantibody titers (anti DNA, anti phospholipids, etc)
– Presence of Rheumatoid Factor
• Disease specific tests
– Neurological exam – MS
– Fasting glucose - Diabetes
SLE
• A multisystem autoimmune disease.
• Most organ involve in the body; skin, kidneys, serosal
membranes, joints, & heart.
• Remitting and relapsing.
• autoantibodies, including (ANAs).
• Dx; demonstration of four or more of the criteria
• (F / M = 9 : 1)
• 2nd or 3rd decade of life.
SLE
•
•
•
•
•
•
Genetic
family
HLA-DR2, HLA-DR3
Low complement.
Environmental factors;
UV, Smoking, hormones, Drugs
The diagnosis is established by demonstration of four or more of the criteria during
any interval of observation.
SLE, SKIN
SLE, Glomerulous
Libman-Sacks vegetations
Libman-Sacks vegetations,
(Libman-Sacks endocarditis), are
on BOTH sides of the leaflet
LUPUS (SLE)
• Etiology: Abs directed against the patient’s own DNA
(ds DNA), HISTONES, NON-histone RNA, & NUCLEOLUS
(Sm), & phospholipids.
• Abs against Bl. Cells
• Abs against phospholipids.
• Pathogenesis: Immune complex disease, in skin,
joints, kidneys, vessels, heart, CNS
•
& Type II HR in Blood cells.
• Morphology: “Butterfly” rash, skin deposits, GN.
• Clinical expression: Progressive renal and vascular
disease, POSITIVE A.N.A.
Antinuclear Abs in Autoimmune Diseases
Antigen
Ab System
Many nuclear antigens Generic ANA
(DNA, RNA, proteins) (indirect IF)
SLE
DrugInduced
LE
SS—Diffuse
Sjögren
S—CREST Syndrome
>95
>95
70–90
70–90
50–80
Native DNA
Anti–doublestranded DNA
40–60
<5
<5
<5
<5
Histones
Antihistone
50–70
>95
<5
<5
<5
Core proteins of small
nuclear RNP particles
(Smith antigen)
Anti-Sm
20–30
<5
<5
<5
<5
RNP (U1RNP)
Nuclear RNP
30–40
<5
15
10
<5
RNP
SS-A(Ro)
30–50
<5
<5
<5
70–95
RNP
SS-B(La)
10–15
<5
<5
<5
60–90
<5
<5
28–70
10–18
<5
DNA topoisomerase I Scl-70
RNP, ribonucleoprotein;
Chronic Discoid Lupus Erythematosus.
•
•
•
•
•
•
disease with skin manifestations mimic SLE,
face and scalp are usually affected,
Only 5% to 10% of patients develop systemic dis.
35% of patients show a positive ANA test,
Abs to ds DNA are rarely.
skin biopsy show deposition of Ig and C3 at the
dermoepidermal junction similar to that in SLE.
Drug-Induced Lupus Erythematosus
• SLE –like syndrome may develop in patients
receiving hydralazine, procainamide, isoniazid,
and D-penicillamine,
• Positive ANAs,
• Negative ds DNA Abs are rare,
• HLA-DR4 allele are at a greater risk
• The disease remits after withdrawal of the
offending drug.
MORE SYSTEMIC AUTOIMMUNE
DISEASES
• RHEUMATOID ARTHRITIS
• SJÖGREN SYNDROME
• SCLERODERMA (SYSTEMIC SCLEROSIS)
↑
Destructive Rheumatoid
Synovitis
NORMAL Bi-Layered
Synovium
• Sjögren syndrome
• chronic auto imm. disease,
• dry eyes (keratoconjunctivitis sicca) and dry mouth
(xerostomia)
• CD4+T & Ab mediated reaction against epith. Cells of
lacrimal and salivary glands.
• primary form
• secondary form, associated with rheumatoid arthritis
SLE, polymyositis, scleroderma, vasculitis, mixed
connective tissue disease, or thyroiditis.
• Genetic & Environmental factors.
SJÖGREN SYNDROME
SJÖGREN SYNDROME
• SYSTEMIC SCLEROSIS (SCLERODERMA)
• 1. chronic inflammation
• 2. widespread damage to small bl ves.
• 3. progressive fibrosis in skin & organs
• Two types;
a. Diffuse type, SS
b. Limited “CREST”
• Two ANAs ;
a. Anti DNA topoisomerase I (anti-Scl 70), highly
specific. systemic sclerosis.
• anticentromere Ab, in CREST or limited sclerosis.
Possible mechanisms leading
to systemic sclerosis.
Scleroderma
Scleroderma
(Collagen Vascular Disease)
SYSTEMIC SCLEROSIS
(SCLERODERMA)
Systemic sclerosis. A, Normal skin. B, systemic sclerosis. Note the extensive deposition of
dense collagen in the dermis with virtual absence of appendages &foci of inflammation
(arrow).
PAN
IgG4-RD (Fibroiflammatory disease).
• Inflamm.
• Fibrosis
• Obliterative phlebitis.
Amyloidosis
Pathogenesis of Amyloidosis
• Amyloidosis - abnormal folding of pr., which are
deposited as fibrils in EC tissues and disrupt
normal function.
• The Pr. that form amyloid fall into two general
categories:
• (1) Normal proteins that have an inherent
tendency to fold improperly, and do so when
they are produced in increased amounts; and
• (2) mutant proteins that are prone to misfolding
and subsequent aggregation
 Physical Nature of Amyloid
• nonbranching fibrils, 7.5 - 10 nm.
• cross-β-pleated sheet conformation
Chemical Nature of Amyloid
• 95% of amyloid material consists of fibril pr,
• (1) AL (amyloid light chain) is derived from Ig light
chains produced in plasma cells;
• (2) AA (amyloid-associated) is derived from a unique
non-Ig protein synthesized by the liver; and
• (3) Aβ amyloid is produced from β amyloid precursor
protein and is found in the cerebral lesions of Alzheimer
disease.
Classification of Amyloidosis
• Primary
• Secondary
• systemic
• Localized
• Congenital
• Acquired
Primary Amyloidosis
Secondary (Reactive) Amyloidosis
• AA protein.
• Systemic amyloidosis,
• TB, bronchiectasis, ch. Osteomyelitis.
• Rh arthritis, other CT disorders such as ankylosing
spondylitis, and IBD.
• Heroin abusers
• renal cell carcinoma
• Hodgkin lymphoma.
Pathogenesis of amyloidosis
Clinicopathologic Category Associated Diseases
SYSTEMIC (GENERALIZED) AMYLOIDOSIS
(primary amyloidosis)
Multiple myeloma and
Major Fibril Protein
Chemically Related Precursor
Protein
AL
Immunoglobulin light chains,
(secondary amyloidosis)
Chronic inflammatory
conditions
AA
SAA
Hemodialysis-associated
amyloidosis
Chronic renal failure
Aβ2m
β2-microglobulin
AA
SAA
Familial amyloidotic
neuropathies (several types)
ATTR
Transthyretin
SYSTEMIC SENILE
AMYLOIDOSIS
LOCALIZED AMYLOIDOSIS
Senile cerebral
Endocrine
Medullary carcinoma of
thyroid
Islets of Langerhans
ATTR
Transthyretin
Ab
A Cal
AIAPP
APP
Calcitonin
Islet amyloid peptide
AANF
Atrial natriuretic factor
HEREDITARY AMYLOIDOSIS
Familial Mediterranean fever
Alzheimer disease
Type 2 diabetes
Clinical Features.
• Renal involvement proteinuria, nephrotic syndrome.
renal failure and uremia.
• Cardiac amyloidosis ____congestive heart failure.
• Gastrointestinal amyloidosis, Amyloidosis of the
tongue.
• Depositions in the stomach and intestine may lead to
malabsorption, diarrhea, and disturbances in digestion.
• Diagnosis of amyloidosis
• Biopsy: rectal or gingival tissues in patients
suspected of having systemic amyloidosis.
• Examination of abdominal fat
• kidney, when renal manifestations are present
• Congo red.
• serum and urine protein electrophoresis.
• Bone marrow aspirates show monoclonal
plasmacytosis,
• Radiolabeled serum amyloid P (SAP) binds to
the amyloid deposits and reveals their presence.
• The prognosis for individuals with
generalized amyloidosis is poor.
• New therapeutic strategies aimed at
correcting protein misfolding and inhibiting
fibrillogenesis are being developed.
Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated
by the massive accumulation of amyloid.
Liver Amyloidosis
Liver Amyloidosis
Liver Amyloidosis
Skin Amyloidosis