Boli autoimune

Document Sample
Boli autoimune Powered By Docstoc
					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 anti-
  albumin 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
                                                                   IgE
                                                          IL-4
              IL-4           GATA-3                                Eosinophil
                                                          IL-5
                                                                   Immediate-type
                                                          CRTH2
                                                 Th2               responses


                                                          CD25     IgG4, IgA
             TGF-b            FOXP3                       CTLA-4   Fibroblasts, epithelial cells
                                                          IL-10    Regulatory and repair
Naive                                            Treg     TGF-b    responses




             IL-12            T-BET                       IFN-g    IgG1
                                                          TIM-3    Antigen-presenting cells
                                                 Th1               Inflammatory
                                                                   responses




Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709–716
           Treg
Th2                         Th1




IL-4   IL-10   IgG4, IgA   IL-12
IgE                        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.         DR2        15.9%
 SLE                       DR3        15%
 Diabetes mellitus         DR3/DR4    25%
 Systemic Sclerosis        DR2        5%
 Grave’s Disease           DR3        3.7%
 Hashimoto’s Thyroiditis   DR3        3.2%
 Myastenia gravis          DR3        2.5%
 Rheumatoid Artritis       DR4        4%
 Psoriasis                 DR4        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
                                                    Sjőgren’s Sd.
                     hemolytic Anemia
                                                    Ulcerative Colitis
                     Thrombocytopenia
                     idiopathic Purpura             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 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)
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, cerebro-
    vascular 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   blindness

- Conjunctivitis

- Episcleritis

- Optic nerve lesion
- Sicca sd.
                Acut Lupus




                    Lupus Paniculitis
Discoid lupus
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      Ag      Clinical significance
Antinuclear 98%        nucleus    diagnostic
Anti-ADN    70%        ADN        Spf, renal les.,
                       (ds)       activity index

Anti-Sm    30%         Prot.      spf
                       Cuplated
                       to nucl.
                       ARN
Anti-RNP   30%         Prot.      In Overlap sd. with SLE,
                       Bond to    polimyositis,
                                  scleroderma, mixt conj.
                       U1ARN      tis. disease
                                  May protect for Renal
                                  les.
Auto-Abs
          Incidence       Ag      Clinical
                                  significance
Anti-Ro   30%         Prot. Bond Sjögren Sd., subacut
(SS-A)                to y1-y5   lupus, deficiency of
                                 C’, lupus with ANA-
                      ARN
                                  neg, renal Les.

Anti-La   10%         Fosfopro-   Always Associated
                      tein        with Anti-Ro,
(SS-B)
                                  Sjögren Sd.
                                  Rarely in nephritis

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

              Incidence       Ag       Clinical
                                       significance
Anti-         60%         Suprafata    Lez. diffuse of CNS
neuronali                 neurons si a at high values
                          ly
Anti-         20%         Ribosomal CNS les., psychosis,
ribosomal P               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 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
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

•    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
Test

•    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

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:112
posted:3/22/2012
language:Latin
pages:78