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

IL-4 IL-5 CRTH2

IgE Eosinophil Immediate-type responses

TGF-b Naive

FOXP3 Treg

CD25 CTLA-4 IL-10 TGF-b

IgG4, IgA Fibroblasts, epithelial cells Regulatory and repair responses

IL-12

T-BET Th1

IFN-g TIM-3

IgG1 Antigen-presenting cells Inflammatory responses

Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709716

Treg
Th2 Th1

IL-4

IL-10

IgG4, IgA

IL-12 IgG1

IgE

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
Ankylosis spondylitis

Gena HLA
B27

Risc
87.4%

Reiters Syndrome
Goodpastures Sd.

B27
DR2

37%
15.9%

SLE Diabetes mellitus Systemic Sclerosis Graves Disease Hashimotos Thyroiditis Myastenia gravis Rheumatoid Artritis Psoriasis

DR3 DR3/DR4 DR2 DR3 DR3 DR3 DR4 DR4

15% 25% 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;

Graves 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
Hashimotos Thyroiditis Autoimmune atrophic Gastritis Pernicious Anemia Addisons disease Autoimmune hemolytic Anemia Sjgrens Sd. Myasthenia gravis Goodpastures Sd. Diabetes

Thrombocytopenia idiopathic Purpura

Ulcerative Colitis
Primitive Biliary Cirrhosis Systemic Lupus erythematous Dermatomiositis Sclerodermia Rheumatoid Arthritis

Systemic

Hashimotos 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

Graves 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) Addisons Disease (receptors for ACTH and microsoms) Systemic Sclerosis (basic myelin protein from brain, bown marrow) Guillain-Barr 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 FcRIIA; 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 FcRIIA or FcRIIIA 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 ) 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:
-

- 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-Barr 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
blindness

- Conjunctivitis
- Episcleritis - Optic nerve lesion - Sicca sd.

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%

Ag nucleus ADN (ds)

Prot. Cuplated to nucl. ARN Prot. Bond to U1ARN

Clinical significance diagnostic Spf, renal les., activity index

spf

Anti-RNP

30%

In Overlap sd. with SLE, polimyositis, scleroderma, mixt conj. tis. disease May protect for Renal les.

Auto-Abs
Incidence

Ag

Clinical significance

Anti-Ro (SS-A) Anti-La (SS-B)

30%

Prot. Bond Sjgren Sd., subacut lupus, deficiency of to y1-y5 C, lupus with ANAARN
neg, renal Les.

10%

Fosfoprotein

Always Associated with Anti-Ro, Sjgren Sd. Rarely in nephritis SLE induce by drugs

Antihiston

70%

Histon

Auto-Abs
Incidence

Ag

Clinical Significance

Anti50% Phospholipi ds
Anti60% erythrocyte Anti30% platelets Anti70%

Phospholipid 3 type: lupuss Anticoagulant (LA) Anticardiolipin (aCL) False + syphilis (BFP) Erythrocyt Hemolisis (nu to all)

Pl Surface and cytoplasm Ly. Surface

Low Pl (15%)

Low Leukocyte, T ly

Auto-Abs
Incidence Clinical significance Suprafata Lez. diffuse of CNS neurons si a at high values ly Ribosomal CNS les., psychosis, Prot. P depression

Ag

Antineuronali Antiribosomal P

60% 20%

Diagnostic

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

Diagnostic Criteria ARA (1997):

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

 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

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

Sjgren Sd.
Female (F/M = 9/1) Young age HLA-B8, HLA-DR3 modified Ags (viral retrovirusuri?) lymphoid infiltration

Sjgren 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