Download Autoimmune diseases

AUTOIMMUNE DISEASES
Autoimmune Disease
• Autoimmunity: acquired immune
reaction, against self antigens
• Autoimmune diseases: the autoimmune
reaction induces lesions in tissues
• Auto-antibodies (Auto-Ab): Abs against
self Ags (usually IgG or IgM)
Autoimmune Reaction
• Natural – up to a point
• Needed to eliminate unwanted auto-Ags
(“old”, “non-efficient”, “alternated”), or to
reduce the immune response activated in
excess (“anti-idiotyp”)
• T ly, by linking to MHC  stimulate B ly to
secrete Auto-Abs (there are auto-Ab antialbumin etc)
Immune Tolerance
• This Immune tolerance induce either
deletion or inactivation of autoreactive T
ly
1. Central Tolerance : immature T and B ly
became tolerant to self Ags – clonally
deletion (takes place during the thymus
maturation, usually an irreversible
process. Its is followed by positive or
negative selection)
Immune Tolerance
• Induce deletion or inactivation of
autoreactive T ly
2. Peripheral Tolerance: takes place in
secondary lymphoid organs (Clonal
Anergy) – proliferative functions and
secretion one are inhibited by leak of
costimulitory mediators/signals
Immune Tolerance
• Induce deletion or inactivation of
autoreactive ly T
3. Activation of some suppressor
mechanisms : Ts ly act by inhibating
cytotoxic cells; idiotype – anti-idiotype
network or death of autoreactive cells)
Autoimmunity Hypothesis
• Theory of the hidden Ags (in Nervous
System, crystalline, thyroid, sperm cells,
bile)
• Theory of forbidden clone (some error
in deletion of autoreactive ly during fetal
life). Forbidden clones might appear also
after somatic mutation (normally they are
eliminated)
Autoimmunity Hypothesis
• Theory of clonal anergy: another form
of forbidden clones. Clones which
encounter the self Ag are not eliminated,
they are just temporally suppressed (they
recover at high quantities of Ags, or long
persistent of them)
Autoimmunity Hypothesis
• Theory of immune deficiency: there is
functional inhibition of suppressor cells
(CD8+ T ly) which do not block anymore
auto-aggressive phenomenon
Inverse Relation between the Incidence of Prototypical
Infectious Diseases (Panel A) and the Incidence of
Immune Disorders (Panel B) from 1950 to 2000
Bach, J.-F. N Engl J Med 2002;347:911-920
IL-4
GATA-3
Th2
TGF-b
FOXP3
Treg
Naive
IL-12
T-BET
Th1
IL-4
IL-5
CRTH2
IgE
Eosinophil
Immediate-type
responses
CD25
CTLA-4
IL-10
TGF-b
IgG4, IgA
Fibroblasts, epithelial cells
Regulatory and repair
responses
IFN-g
TIM-3
IgG1
Antigen-presenting cells
Inflammatory
responses
Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709–716
Treg
Th2
IL-4
IgE
Th1
IL-10
IgG4, IgA
IL-12
IgG1
Immune Recognition
• High organ Specificity
• Without organ Specificity (systemic
reactions)
Auto-Abs
• Anti-molecule
Immune Complexes (CI)
deposition in vessel, glomeruls
(colagenosis; SLE)
• Anti-cells (Ag in membranes)
cytotoxicity (C’ activation) or cell-mediated
cytotoxicity (CCAD) or phagocytosis
• Anti-receptor (cell receptor)
stimulation of function or neutralization of
receptor (myasthenia, hypertiroiditis)
Pathogenic Effects of Auto-Abs
• Cytotoxic (dependent of C’, mediated by
cells)
• Blocking, agglutination or masking (of
some cell function)
• Activation of phagocytosis (oposonization
and activation of macrophages)
Autoreactive T Lymphocytes
• Present in experimental encephalitis in
mice
• NK Cells – usually suppressed (they lose
their regulatory role of down-regulation of
immune responses)
Predisposing Factors
• Genetic Factors:
HLA-B27 with Ankylosis spondylitis
- in other diseases, the importance of
genetic factors is lesser
Association of the Autoimmune diseases and HLA
Autoimmune diseases
Gena HLA
Risc
Ankylosis spondylitis
B27
87.4%
Reiter’s Syndrome
B27
37%
Goodpasture’s Sd.
SLE
DR2
DR3
15.9%
15%
Diabetes mellitus
DR3/DR4
25%
Systemic Sclerosis
Grave’s Disease
Hashimoto’s Thyroiditis
Myastenia gravis
Rheumatoid Artritis
Psoriasis
DR2
DR3
DR3
DR3
DR4
DR4
5%
3.7%
3.2%
2.5%
4%
14%
Predisposing Factors
• Age: frequent in old age, but colagenosis
are seen in young people (SLE, RA)
• Sex: female (SLE – ratio F/M = 10/1;
Grave’s disease: 7/1; spondylitis – mostly
in male)
Predisposing Factors
• Infection (“antigenic mimetism”) :
virus (vi: Epstein-Barr, Cocksakie);
bacteria (mycoplasma, Klebsiella, Borrelia
burgdorferi etc)
• Drugs: procainamide, hidralazine
(phenomenon lupus-like)
With organ specificity
Autoimmune Diseases
Hashimoto’s Thyroiditis
Myasthenia gravis
Autoimmune atrophic Gastritis
Goodpasture’s Sd.
Pernicious Anemia
Diabetes
Addison’s disease
Autoimmune
hemolytic Anemia
Thrombocytopenia
idiopathic Purpura
Sjőgren’s Sd.
Ulcerative Colitis
Primitive Biliary Cirrhosis
Systemic Lupus
erythematous
Dermatomiositis
Sclerodermia
Rheumatoid Arthritis
Systemic
Hashimoto’s autoimmune
Thyroiditis
• Mechanism: humoral and cellular
• thyroid Cell
• Auto-Ab anti-tireoglobuline; - anti-
peroxidaza from thyroid
• La female (F/M = 5/1)
• 30-60 years
• Diffuse infiltration with ly, eosinophils,
atresia of parenchimatous cells
• Hypothyroidism
Grave’s disease
• Auto-Ab anti-receptor TSH (stimulatory hormone
of thyroid) - mechanism HS type II
• Hyperthyroidism
• Gointre (hyperplasic, diffuse)
• Extrathyroid signs (exophthalmia, peritibial
mixedema)
Myasthenia gravis
• Auto-Ab anti-receptor for acetylcholine
• Neuromuscular: post-synaptic block of
nervous influx transmition to motor plate
• Rare: incidence 2-6 cases in 1 million of
persons
• Muscular fatigue – very severe: ocular,
extension up to respiratory insufficiency)
• Treatment: extirpation of hypertrofiated
thymus (sometimes might work)
Myasthenia gravis:
- neuron-muscular junction Acetylcholin
e (Ach)
Auto-Ab anti
receptor for Ach
Receptors
for Ach
Other autoimmune disease - organ-spf
• Pancytopenia (H, L, Tr) autoimmune
• Anemia pernicious (Biermer) – intrinsec factor
• Diabetes (insulin-dependent) (B cells from
•
•
•
•
pancreas)
Addison’s Disease (receptors for ACTH and
microsoms)
Systemic Sclerosis (basic myelin protein from
brain, bown marrow)
Guillain-Barré Sd (peripheral nerves –
ganglioside)
Pemfigus – keratinocytes
SYSTEMIC LUPUS
ERITHEMATOUS
Diana Dumitrascu
Definition
• Affection with unknown etiology,
where the tissues are damaged by
Auto-antibodies and Immune
Complexes
Ethiology

Epidemiology
• 90% are Female, aged 20-30 years
• More frequent in blacks, followed by
Hispanic populations, and Asiatic
populations
• Prevalence 15-50/100,000 (SUA)
Pathology
• Lesions induced by AutoAb, IC
1. Hyperreactivity of T, B lymphocytes
2. Genetic Induce
3. Environment factors: viruses,
bacteria, drugs
Pathology
Genetic Induce :
- more frequent in monozigots (25 - 58%) vs dizigots
(0-6%)
- more frequent in families with one patients
- more frequent in pts with defects or deletion of allele of classes
III C4AQO (40-50% pts)
- more frequent in homozygote with defects of C’ (C1q,
C2, C4) (< 5% pts)
- haplotype B8.DR3.DQw2.C4AQO predispose to SLE
in population from north of Europe
•
Genetic Predisposition for SLE induce by drugs: dependence of
the acetilation of the drug
Pathology
-


Associated with HLA-DR2 or –DR3 (“gene for
autoimmunity”)
Cz 1 (1q23) has gene for FcγRIIA; and 1q4142 has poli gena (DNA-ribosil) polymerase
(PARP) and them may produce defects of the
way DNA is repaired and defects of apoptosis
AutoAb are associated with some symptoms in
SLE:
AutoAb to Ro/La (SS-A/SS-B) in sub acute SLE
normal Allele of FcγRIIA or FcγRIIIA which
bound to IgG2/IgG3 are more frequent in
nephritis (CI are not eliminated from
circulation)
Pathology
Immunological Factors: 
- IFN – type I (cz 9p21): -there are 13
-
isoforms of IFN-1 - they activate the
“program” of T ly for IFN-2 secretion (former
γ)
Toll Receptors (role in innate immune sist
and allows the formation of acquired
immunity; stimulatory and inhibitory functions)
Dendritic plasmocitoide Cells (they secrete
IFN- 1) – receptors to identified BDCA-2 si
BDCA-4
Pathology
Environmental Factors: 
- UV-B and UV-A (70% pts have photosensitivity)
- Chemical Substances (hidralazine, isoniazide,
clorpromazin, D-penicilamin, practolol, metildopa,
quinidin, IFN-, hidantoine, etosuximide, contraceptive
oral)
-
Infections viruses/retroviruses 
Sexual hormones (female, in child bearing period)
Discoid Lupus
Histopathology
•
•
•
•
•
•
•
Lesions of basal membrane (epidermis)
Discontinuing of dermal-epidermal junctions
Infiltration with monocytes around the vessels
Hyperkeratosis
IgG and C’ deposits (80-100%) – may be
presents in normal tissues (50%)
Leucocytoclastic vasculitis
Glomerulonephritis - IC deposits or the might be
generated in situ in mesangium or in glomerular
basal membrane (if Ig and C’ deposits are out of
mesangium – severe prognostic)
Clinical forms
• Systemic lupus erithematous
• Discoid lupus erithematous – skin
lesions (skin atrophy) – 20%
• Subacute lupus erithematous – skin
lesions - vasculitis type
Symptoms
Onset
• One organ (after that  systemic)
• Systemic (most frequent: fatigue, malaise,
fever, anorexia, loss in weight)
Severity: mild
severe
Symptoms
• Muscular, joint, bone:
- mialgia, arthralgia (most of the pts):
 intermittent arthritis, usually symmetric:
small
joints: hand, foot, sometimes knee etc
 tenosinovitis
 inflammatory myopathy (or after treat: K ,
GCS, hidroxiclorochin)
 ischemic necrosis in the bone: pelvic joint,
knee, shoulder (post-GCS)
Symptoms
• Skin and mucosa:
-
-
-
Rash - “butterfly” on the face
without scarf lesion (only in discoid lupus)
Rare: urticaria, vesicles, erithema multiform,
lichen plan, paniculitis (= profound lupus)
Vasculitis lesions (SLE systemic, discoid,
subacute): purpura, subcutaneous nodules,
infarctation at nails, ulcers, vasculitic urticaria,
paniculitis, necrosis of fingers
Mucosa: Ulcer on oral, nasal mucosa
Symptoms
•Renal:
- ½ pts - glomerulonephritis (most of the
-
-
pts have Ig deposits in glomeruls)
Focal glomerulonefritis
renal
sclerosis
Without symptoms or nephrotic edema
haematuria, proteinuria, renal failure
Symptoms
• Neurological symptoms:
- meningitis, spine cord, central and peripheral
-
nerves
Unique or multiples
Associated with another organ lesions
Mild cognitive dysfunction (most frequent),
headache (migraine or unspecific headache),
muscular contraction
Rare: psychosis, acute confusion, cerebrovascular disease, aseptic meningitis, mielopathy,
mono or polineuropathy, Guillan-Barré
polineuropathy, depression, anxiety
Symptoms
• Vascular symptoms:
-
-
thrombosis in the vessel (anti fosfolipidic
antibodies: anticoagulant (LA),
anticardiolipid induce coagulation without
vasculitis)
Vasculitis
Cerebral embolus (Libman-Sacks
endocarditis)
Vascular and cerebral lesions - IC and
hyperlipidemia (induced by GCSs) – in
chronic disease
Symptoms
• Hematological:
- Anemia – chronic disease in most of the pts
-
- hemolytic anemia – rare, with
Coombs Test +
Low Leucocytes (and lymphocytes)
Low platelets (sometimes with purpura)
Seldom – Abs anti - factors for coagulation
(VIII, IX)
hemorrhage
Symptoms
• Heart and lungs:
-
Pericarditis
Myocarditis
dysrhithmias
Endocarditis (Libman-Sacks)
Pleuritis –
Lung involvement: most frequent
infections, lupic Pneumonitis, lung fibrosis,
PHT (rare)
Symptoms
• Gastrointestinal:
-
-
Nausea, diarrhea, abdominal pain
Peritonitis
Vasculitis
Pseudo-obstruction of the bowel
Lesion like scleroderma (motility
disorder)
Acute pancreatitis (disease, therapy with
corticosteroid, azathioprine)
High level of enzymes (ASAT, ALAT)
(without significant hepatic lesions)
Symptoms
• Eyes:
- Retinian vasculitis
- Conjunctivitis
- Episcleritis
- Optic nerve lesion
- Sicca sd.
blindness
Acut Lupus
Discoid lupus
Lupus Paniculitis
Investigation
• Antinuclear antibodies (ANA): human
substrate (WIL-2 or Hep-2) - + on > 95%
(there are false + in normal subjects,
other immune disease, viral infections,
chronic infections, drugs). Negative ANA
does not exclude, but is less probable
• Ab anti –ADN double strain (Ab anti –
dsDNA) and anti Sm - +, but not specific.
Investigations
•
•
•
•
•
•
•
C’ low (= activity of disease)
CH50 – total hemolytic function of C’
C3, C4 – low
CH50 very low + C3 normal = innate deficiency of
C’ (associated frequent with SLE - ANA neg)
Anemia (normochrom, sometimes hemolytic),
low leucocytes, low lymphocytes, low plattelets
ESR – is correlated with activity of disease
(sometimes)
Proteinuria, hematuria, creatinin may be 
(periodic renal control to all pts)
Auto-Abs
Incidence
Antinuclear 98%
Anti-ADN
70%
Anti-Sm
30%
Anti-RNP
30%
Ag
nucleus
ADN
(ds)
Clinical significance
Prot.
Cuplated
to nucl.
ARN
Prot.
Bond to
U1ARN
spf
diagnostic
Spf, renal les.,
activity index
In Overlap sd. with SLE,
polimyositis,
scleroderma, mixt conj.
tis. disease
May protect for Renal
les.
Auto-Abs
Incidence
Anti-Ro
(SS-A)
30%
Ag
Clinical
significance
Prot. Bond Sjögren Sd., subacut
lupus, deficiency of
to y1-y5
C’, lupus with ANAARN
neg, renal Les.
Anti-La
(SS-B)
10%
Fosfoprotein
Always Associated
with Anti-Ro,
Sjögren Sd.
Rarely in nephritis
Antihiston
70%
Histon
SLE induce by drugs
Auto-Abs
Ag
Incidence
Anti50%
Phospholipi
ds
Anti60%
erythrocyte
Anti30%
platelets
Anti-
70%
Clinical
Significance
Phospholipid 3 type: lupuss
Anticoagulant (LA)
Anticardiolipin (aCL)
False + syphilis
(BFP)
Erythrocyt Hemolisis (nu to all)
e
Pl Surface
and
cytoplasm
Ly. Surface
Low Pl (15%)
Low Leukocyte, T ly
Auto-Abs
Incidence
Antineuronali
60%
Antiribosomal P
20%
Ag
Clinical
significance
Suprafata
Lez. diffuse of CNS
neurons si a at high values
ly
Ribosomal CNS les., psychosis,
Prot. P
depression
Diagnostic
•
Diagnostic Criteria ARA (1997):
4 criteria (dg. + 98% spf and 97% sensib.)
1. Rash one face
2. Discoid Rash
3. Photo sensibility
4. Oral Ulcers
5. Arthritis
6. Serositis
7. Renal lesion
8. Neurological involvement
9. Hematological Abnormalities
10. Immunologic Abnormalities
11. Antinuclear Antibodies
Differential Diagnostic
• Rheumatoid Arthritis
• Other autoimmune diseases
• Dermatitis
• Neurological Diseases: systemic sclerosis
• Psychiatric Diseases
• Hematological Diseases: idiopathic
purpura with low platelets
Progression of the disease
• Remission – rarely
• 25% have a mild form of SLE - no lethal risk
• With activity and remission periods
Treatment
• No curative treatment
• Mild Form:
• better without glucocorticosteroids (GCS)
• NSAD • COX-2 inhibitors
• Antimalarics: hidroxiclorochin (400 mg/day)
• UV protection oigments
• Topic or intralesional: GCS, quinacrin,
retinoids, dapson
• for drug induce – withdraw the drug (rarely
short term GCS)
Treatment
• Severe Form (renal, nervous system
etc):
• Gluco-Corticosteroids:
- 1-2 mg/kg/day (in 2-3 dose, at
8-12 hours; pulse therapy with
metilprednisolon 1000 mg/day iv, 2-5 days)
- after that in the morning, in alternative
days with GCS with short action:
prednisone, prednisolon, metilprednisolon
with maintenance doses: lowest dose
without symptoms
Treatment
• Severe Form (renal, cardiac etc):
To Reduce side effects of GCS:
• vaccine
• supplement: Vit D, Calcium,
Calcitonin,
Biphosphonats
• association with other therapy
Treatment
• Severe Form (renal, etc):
• Cytotoxic Agent (immunosuppressive): Azathioprin
2-3 mg/kg/day p.o., Clorambucil, Ciclofosfamid 10 -15
mg/kg/day iv for 4 weeks and 1,5-2,5 mg/kg/day p.o.,
Methotrexat 5-20 mg/day, once/week, p.o. or s.c.,
Mofetil Micofenolate –[CellCeptR, cp 500mg] - 1-2,5
g/day, p.o.)
• reduce the GCS dose: two even 3 drugs (ciclofosfamid +
azathioprina)
• in renal lesions (GCS + ciclofosfamida iv – most efficient, but
very toxic)
• try to reduce doses when the disease is controlled, (even
withdraw them)
Treatment
• Severe Form (renal etc):
• Anticoagulants (warfarina)
• Ig iv
• renal transplant - allograph (high risk
of
rejection)
• plasmaferesis (associated with
cytotoxicity)
• cyclosporine
New Treatments
• Mild Forms: dihidroepiandrosteron
• Rituxan (Mo Ab anti B Ly - anti CD20)
• Blocking the activity of B ly with antiBlys (member of TNF superfamily
molecules)
• induce tolerance to ADN
• MoAb anti - TNF - disappointment
Prognostic
• Prognostic is good in drug induced lupus (those drugs
•
•
•
•
•
may be administered in pts with SLE)
Remission (frequent, but short period) – la 20%
Survival
at 2 years: 90-95%
at 5 years: 71-80%
at 10 years: 63-75%
Prognostic is sever for renal involve. (mortality 50% at
10 years), CNS les.
Prognostic is severe when C’ is very low, or platelets are
low
Death: either from active disease, either infections in
first prima 10 years, or thrombembolism in next 10-20
years
Sjögren Sd.
• Female (F/M = 9/1)
• Young age
• HLA-B8, HLA-DR3
• modified Ags (viral – retrovirusuri?)
• lymphoid infiltration
Sjögren Sd.
• oral involvement (xerostomia)
• ocular involvement (kerato-conjunctivitis)
• exocrine glandular involvement
• extra glandular symptoms
• Many Auto-Abs: RF, anti-nuclear Abs, etc
Therapy
• NSAID
• GCS
• Immunomodulation (cytostatic:
methotrexat, ciclofosfamid, azathioprin)
• Immunomodulation (cyclosporine,
tacrolimus)
• Mo Ab (anti-CD3, -CD2, -CD4, CD7, -CD8,
CD25, -CD20; anti-TNF, anti-IL-6, anti-IL-8)
RHEUMATOID ARTHRITIS
•
•
•
•
•
•
•
•
1859 Sir Alfred Garrod - Rheumatoid Arthritis
1893 W.A. Lane – surgical therapy
1897 - acetil salicic Acid
1929 – Gold Salts
1939 - Sir McFarlane Burnet - Autoimmune Theory
1948 - Philip Hench & E. C. Kendall - antiinflamatory
effect of steroid hormons
1955 – prednison was use for the first time
‘90 – immunomodulatory effects of Mo Ab anti TNF
(Infliximab - RemicadeR)
RHEUMATOID ARTHRITIS
• 4500 b.h. – indian scheleton in Tenesseee
• 123 a.h. - Carata Samhita: tumefaction,
•
•
pain of joints, initial at hand and legs, and
after, extension in hole body, losing
appetite, occasionaly fever
1591 - Guillaume de Baillou – first book
abou arthritis : - RA + fibromialgy
1763 – first treatments with willow
extracts
Jacob Jordaens (1593-1678) The Artist
Family
Prado, Madrid
David Teniers, young (1610-1690)
The Temptation of Saint Anthony
Antwerpen
Test
•
1.
2.
3.
4.
5.
Which are arguments for SLE:
25 years old Man
Polyserositis
High circulate immune complexes
High IgE
Radiology signs at sacroiliac joints
Test
•
1.
2.
3.
4.
5.
Which are arguments for SLE:
25 years old Man
Polyserositis
High circulate immune complexes
High IgE
Radiology signs at sacroiliac joints