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)

• 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)

• 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)

• 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

• 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)

• 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)

• 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)

• 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

Naive
IL-4 GATA-3
TGFb FOXP3
Th2
IL-4
IL-5
CRTH2
T reg
CD25
CTLA-4
IL-10
TGFb
IL-12 T-BET
Th1
IFNg
TIM-3
IgE
Eosinophil
Immediate-type responses
IgG4, IgA
Fibroblasts, epithelial cells
Regulatory and repair responses
IgG1
Antigen-presenting cells
Inflammatory responses
Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709–716

Th2
IL-4
IgE
T reg
Th1
IL-10 IgG4, IgA IL-12
IgG1

• High organ Specificity
• Without organ Specificity (systemic reactions)

• 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)

• Cytotoxic (dependent of C’, mediated by cells)
• Blocking, agglutination or masking (of some cell function)
• Activation of phagocytosis (oposonization and activation of macrophages)

• Present in experimental encephalitis in mice
• NK Cells – usually suppressed (they lose their regulatory role of down-regulation of immune responses)

• 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
Reiter’s Syndrome
Goodpasture’s Sd.
SLE
Diabetes mellitus
Systemic Sclerosis
Grave’s Disease
Hashimoto’s Thyroiditis
Myastenia gravis
Rheumatoid Artritis
Psoriasis
B27
B27
DR2
DR3
DR3/DR4
DR2
DR3
DR3
DR3
DR4
DR4
87.4%
37%
15.9%
15%
25%
5%
3.7%
3.2%
2.5%
4%
14%

• 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)

• Infection (“antigenic mimetism”) : virus (vi: Epstein-Barr, Cocksakie); bacteria (mycoplasma, Klebsiella, Borrelia burgdorferi etc)
• Drugs: procainamide, hidralazine
(phenomenon lupus-like)

With organ specificity
Hashimoto’s Thyroiditis
Autoimmune atrophic Gastritis
Pernicious Anemia
Addison’s disease
Myasthenia gravis
Goodpasture’s Sd.
Diabetes
Autoimmune hemolytic Anemia
Thrombocytopenia idiopathic Purpura
Sjőgren’s Sd.
Ulcerative Colitis
Primitive Biliary Cirrhosis
Systemic Lupus erythematous
Dermatomiositis
Sclerodermia
Rheumatoid Arthritis
Systemic

• Mechanism: humoral and cellular
• thyroid Cell
• Auto-Ab anti-tireoglobuline; - antiperoxidaza from thyroid
• La female (F/M = 5/1)
• 30-60 years
• Diffuse infiltration with ly, eosinophils, atresia of parenchimatous cells
• Hypothyroidism

• Auto-Ab anti-receptor TSH (stimulatory hormone of thyroid) - mechanism HS type II
• Hyperthyroidism
• Gointre (hyperplasic, diffuse)
• Extrathyroid signs (exophthalmia, peritibial mixedema)

• 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)

Acetylcholin e (Ach) Auto-Ab anti receptor for Ach
Receptors for Ach

• 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

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
G enetic 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 1q41-
42 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)

• 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
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-Barr é polineuropathy, depression, anxiety

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
•
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
•
Pericarditis
Myocarditis dysrhithmias
Endocarditis (Libman-Sacks)
Pleuritis –
Lung involvement: most frequent infections, lupic Pneumonitis, lung fibrosis,
PHT (rare)

Symptoms
•
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
•
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)
• CH
• C3, C4 – low
• CH
50
– total hemolytic function of C’ very low + C3 normal = innate deficiency of
• 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 Clinical significance nucleus diagnostic
ADN
(ds)
Prot.
Cuplated to nucl.
ARN
Spf, renal les., activity index spf
Prot.
Bond to
U1ARN
In Overlap sd. with SLE, polimyositis, scleroderma, mixt conj. tis. disease
May protect for Renal les.

Auto-Abs
Incidence
Anti-Ro
(SS-A)
Ag Clinical significance
30% Prot. Bond to y
ARN
1
y
5
Sj ö gren Sd., subacut lupus, deficiency of
C’, lupus with ANAneg, renal Les.
Anti-La
(SS-B)
10% Fosfoprotein
Always Associated with Anti-Ro,
Sj ö gren Sd.
Rarely in nephritis
Antihiston
70% Histon SLE induce by drugs

Auto-Abs
Anti-
Phospholipi ds
Antierythrocyte
Antiplatelets
Antilymphocyte
Incidence
50% Phospholipid s
Ag Clinical
Significance
3 type: lupus-
Anticoagulant (LA)
Anticardiolipin (aCL)
False + syphilis
(BFP)
Hemolisis (nu to all) 60% Erythrocyt e
30% Pl Surface and cytoplasm
Low Pl (15%)
70% Ly. Surface Low Leukocyte, T ly abnormality

Auto-Abs
Antineuronali
Antiribosomal P
Incidence
60%
20%
Ag
Suprafata neurons si a ly
Ribosomal
Prot. P
Clinical significance
Lez. diffuse of CNS at high values
CNS les., psychosis, 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
(renal, etc) :
• Cy totoxic Agent (immunosuppressive) : Azathioprin
2-3 mg/kg/day p.o., Clorambucil , Ciclofosfamid mg/kg/day iv for 4 weeks and 1,5-2,5 mg/kg/day p.o.,
10 -15
Methotrexat 5-20 mg/day, once/week, p.o. or s.c.,
Mofetil Micofenolate –[CellCept R , 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 of
• renal transplant - allograph (high risk 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 anti-
Blys (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

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

• oral involvement (xerostomia)
• ocular involvement (kerato-conjunctivitis)
• exocrine glandular involvement
• extra glandular symptoms
• Many Auto-Abs: RF, anti-nuclear Abs, etc

• 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)

• 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 - Remicade R )

• 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

• Which are arguments for SLE:
1.
25 years old Man
2.
Polyserositis
3.
High circulate immune complexes
4.
High IgE
5.
Radiology signs at sacroiliac joints

• Which are arguments for SLE:
1.
25 years old Man
2.
Polyserositis
3.
High circulate immune complexes
4.
High IgE
5.
Radiology signs at sacroiliac joints