AUTOIMMUNE DISEASES

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AUTOIMMUNE DISEASES
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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)

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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 anti-albumin
  etc)

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Immune Tolerance

• This Immune tolerance induce either deletion or
  inactivation of autoreactive T ly
• 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)

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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

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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)

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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)

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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)

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Autoimmunity Hypothesis

• Theory of immune deficiency there is functional
  inhibition of suppressor cells (CD8 T ly) which
  do not block anymore auto-aggressive phenomenon

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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 2002347911-920
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IgE Eosinophil Immediate-type responses
IL-4 IL-5 CRTH2
IL-4
GATA-3
Th2
Naive
IgG1 Antigen-presenting cells Inflammatory respons
es
IFN-g TIM-3
IL-12
T-BET
Th1
Schmidt-Weber, Blaser Curr Opinion Immunol 2004
16709716
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Treg
Th2
Th1
IL-4
IL-10
IL-12
IgG4, IgA
IgE
IgG1
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Immune Recognition

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

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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)

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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)

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Autoreactive T Lymphocytes

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

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Predisposing Factors

• Genetic Factors
• HLA-B27 with Ankylosis spondylitis
• - in other diseases, the importance of genetic
  factors is lesser

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Association of the Autoimmune diseases and HLA
Autoimmune diseases Gena HLA Risc
Ankylosis spondylitis B27 87.4
Reiters Syndrome B27 37
Goodpastures Sd. DR2 15.9
SLE DR3 15
Diabetes mellitus DR3/DR4 25
Systemic Sclerosis DR2 5
Graves Disease DR3 3.7
Hashimotos Thyroiditis DR3 3.2
Myastenia gravis DR3 2.5
Rheumatoid Artritis DR4 4
Psoriasis DR4 14
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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)

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Predisposing Factors

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

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Autoimmune Diseases
With organ specificity
Hashimotos Thyroiditis Autoimmune atrophic
Gastritis Pernicious Anemia Addisons disease
Myasthenia gravis Goodpastures Sd. Diabetes
Autoimmune hemolytic Anemia Thrombocytopenia
idiopathic Purpura
Sjogrens Sd. Ulcerative Colitis Primitive
Biliary Cirrhosis
Systemic Lupus erythematous Dermatomiositis Sclero
dermia Rheumatoid Arthritis
Systemic
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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

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Graves disease

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

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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)

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Myasthenia gravis - neuron-muscular junction
-
Acetylcholine (Ach)
Auto-Ab anti receptor for Ach
Receptors for Ach
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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-Barré Sd (peripheral nerves
  ganglioside)
• Pemfigus keratinocytes

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SYSTEMIC LUPUS ERITHEMATOUS

• Diana Dumitrascu

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Definition

• Affection with unknown etiology,
• where the tissues are damaged by
• Auto-antibodies and Immune
• Complexes

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Ethiology

• ?

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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)

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Pathology

• Lesions induced by AutoAb, IC
• Hyperreactivity of T, B lymphocytes
• Genetic Induce
• Environment factors viruses, bacteria, drugs

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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) (lt 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

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Pathology

• Associated with HLA-DR2 or DR3 (gene for
  autoimmunity)
• Cz 1 (1q23) has gene for Fc?RIIA 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 Fc?RIIA or Fc?RIIIA which bound
  to IgG2/IgG3 are more frequent in nephritis (CI
  are not eliminated from circulation)

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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

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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)

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Histopathology
Discoid Lupus

• 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)

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Clinical forms

• Systemic lupus erithematous
• Discoid lupus erithematous skin lesions (skin
  atrophy) 20
• Subacute lupus erithematous skin lesions -
  vasculitis type

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Symptoms

• Onset
• One organ (after that ? systemic)
• Systemic (most frequent fatigue, malaise, fever,
  anorexia, loss in weight)
• Severity mild severe

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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)

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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

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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

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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,
  cerebro-vascular disease, aseptic meningitis,
  mielopathy, mono or polineuropathy, Guillan-Barré
  polineuropathy, depression, anxiety

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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

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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

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Symptoms

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

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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)

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Symptoms

• Eyes
• Retinian vasculitis blindness
• Conjunctivitis
• Episcleritis
• Optic nerve lesion
• Sicca sd.

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Acut Lupus
Lupus Paniculitis
Discoid lupus
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Investigation

• Antinuclear antibodies (ANA) human substrate
  (WIL-2 or Hep-2) - on gt 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.

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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)

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Auto-Abs
Incidence Ag Clinical significance
Antinuclear 98 nucleus diagnostic
Anti-ADN 70 ADN (ds) Spf, renal les., activity index
Anti-Sm 30 Prot. Cuplated to nucl. ARN spf
Anti-RNP 30 Prot. Bond to U1ARN In Overlap sd. with SLE, polimyositis, scleroderma, mixt conj. tis. disease May protect for Renal les.
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Auto-Abs
Incidence Ag Clinical significance
Anti-Ro (SS-A) 30 Prot. Bond to y1-y5 ARN Sjögren Sd., subacut lupus, deficiency of C, lupus with ANA- neg, renal Les.
Anti-La (SS-B) 10 Fosfopro-tein Always Associated with Anti-Ro, Sjögren Sd. Rarely in nephritis
Anti-histon 70 Histon SLE induce by drugs
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Auto-Abs
Incidence Ag Clinical Significance
Anti-Phospholipids 50 Phospholipids 3 type lupus-Anticoagulant (LA) Anticardiolipin (aCL) False syphilis (BFP)
Anti-erythrocyte 60 Erythrocyte Hemolisis (nu to all)
Anti-platelets 30 Pl Surface and cytoplasm Low Pl (15)
Anti-lymphocyte 70 Ly. Surface Low Leukocyte, T ly abnormality
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Auto-Abs
Incidence Ag Clinical significance
Anti-neuronali 60 Suprafata neurons si a ly Lez. diffuse of CNS at high values
Anti-ribosomal P 20 Ribosomal Prot. P CNS les., psychosis, depression
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Diagnostic

• Diagnostic Criteria ARA (1997)
• 4 criteria (dg. 98 spf and 97
  sensib.)
• Rash one face
• Discoid Rash
• Photo sensibility
• Oral Ulcers
• Arthritis
• Serositis
• Renal lesion
• Neurological involvement
• Hematological Abnormalities
• Immunologic Abnormalities
• Antinuclear Antibodies

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Differential Diagnostic

• Rheumatoid Arthritis
• Other autoimmune diseases
• Dermatitis
• Neurological Diseases systemic sclerosis
• Psychiatric Diseases
• Hematological Diseases idiopathic purpura with
  low platelets

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Progression of the disease

• Remission rarely
• 25 have a mild form of SLE - no lethal risk
• With activity and remission periods

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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)

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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

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Treatment

• Severe Form (renal, cardiac etc)
• To Reduce side effects of GCS
• vaccine
• supplement Vit D, Calcium, Calcitonin,
• Biphosphonats
• association with other therapy

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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)

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Treatment

• Severe Form (renal etc)
• Anticoagulants (warfarina)
• Ig iv
• renal transplant - allograph (high risk of
• rejection)
• plasmaferesis (associated with
• cytotoxicity)
• cyclosporine

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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

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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

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Sjögren Sd.

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

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Sjögren Sd.

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

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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)

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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)

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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

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Jacob Jordaens (1593-1678) The Artist Family
Prado, Madrid
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David Teniers, young (1610-1690) The Temptation
of Saint Anthony
Antwerpen
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Test

• Which are arguments for SLE
• 25 years old Man
• Polyserositis
• High circulate immune complexes
• High IgE
• Radiology signs at sacroiliac joints

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Test

• Which are arguments for SLE
• 25 years old Man
• Polyserositis
• High circulate immune complexes
• High IgE
• Radiology signs at sacroiliac joints