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Lecture271109

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					AUTOIMMUNE DISEASES



     Martin Liška
Autoimmune disease

  Results from a failure of self-tolerance
  Immunological tolerance is specific
   unresponsiveness to an antigen
  All individuals are tolerant of their own
   (self) antigens
Autoimmunity
  is defined as an immune response against self
   antigens
  The principal factors in the development of
   autoimmunity are the inheritance of
   susceptibility genes and environmental
   triggers, such as infections
  Most autoimmune diseases are polygenic and
   are asssociated wih multiple gene loci, the
   most important of which are the MHC genes
  Infections may activate self-reactive
   lymphocytes, thereby triggering the
   development of autoimmune diseases
AUTOIMMUNE PATOLOGICAL
RESPONSE- ETIOLOGY
  the diseases are chronic and usually irreversible
  incidence: 5%-7% of population, higher frequencies in
   women, increases with age
  factors contribute to autoimmunity:

    - internal (HLA association, polymorphism of cytokine
   genes, defect in genes regulating apoptosis,
   polymorphism in genes for TCR a H immunoglobulin
   chains, association with immunodeficiency, hormonal
   factors)
    - external (infection, stress by activation of
   neuroendocrine‘s line and hormonal dysbalance, drug
   and ionization through modification of autoantigens)
CLINICAL CATEGORIES
  systemic
    - affect many organs and tissue

  organ localized
    - affect predominantly one organ
   accompanied by affection of other organs
   (inflammatory bowel diseases, celiac disease,
   AI hepatitis, pulmonary fibrosis)

  organ specific
    - affect one organ or group of organs
   connected with development or function
EXAMPLES OF SYSTEMIC
AUTOIMMUNE DISEASES

 examples
 autoantibodies
SYSTEMIC AUTOIMMUNE DISEASES

    Systemic lupus erythematosus
    Rheumathoid arthritis
    Sjögren‘s syndrome
    Dermatopolymyositis
    Systemic sclerosis
    Mixed connective tissue disease
    Vasculitis
SYSTEMIC LUPUS
ERYTHEMATOSUS
 chronic, inflammatory, multiorgan disorder


 autoantibodies react with nuclear material and attack
  cell function, immune complexes with dsDNA deposit
  in the tissue

 general symptoms: include malaise, fever, weight
  loss
 multiple tissue are involved including the skin,
  mucosa, kidney, joints, brain and cardiovascular
  system

 characteristic features: butterfly rash, renal
  involvement, CNS manifestation, pulmonary fibrosis
DIAGNOSTIC TESTS

  a elevated ESR (erythrocyte sedimentation rate), low
   CRP, trombocytopenia, leucopenia, hemolytic anemia,
   decreased levels of complement compounds (C4, C3),
   elevated serum Ig levels, immune complexes in serum
AUTOANTIBODIES

  Autoantibodies: ANA, dsDNA (double-
   stranded), ENA (SS-A/Ro, SS-A/La), Sm,
   against histones, phospholipids
RHEUMATOID ARTHRITIS

   chronic, inflammatory disease with systemic involvement
   characterized by an inflammatory joint lesion in the synovial
     membrane, destruction of the cartilage and bone, results in the
     joint deformation
   clinical features: arthritis, fever, fatigue, weakness, weight loss
   systemic features: vasculitis, pericarditis, uveitis, nodules under
     skin, intersticial pulmonary fibrosis
   diagnostic tests: elevated C- reactive protein
     and ESR, elevated serum gammaglobulin levels
    - autoantibodies against IgG = rheumatoid factor
      (RF), a-CCP (cyclic citrulline peptid), ANA
    - X-rays of hands and legs- show a periarticular
      porosis, marginal erosion
        SJÖGREN‘S SYNDROME


 chronic inflammatory disease affecting exocrine glands
 the primary targets are the lacrimal and salivary gland duct
  epithelium
 general features: malaise, weakness, fever
 primary syndrome - features: dry eyes and dry mouth, swollen
  salivary glands, dryness of the nose, larynx, bronchi and vaginal
  mucosa, involvement kidney, central and periferal nervous
  system, arthritis

 secondary syndrome – is associated with others AI diseases
  (SLE, RA, sclerodermia, polymyositis, primary biliary cirhosis,AI
  thyroiditis)

 autoantibodies against ENA (SS-A, SS-B),
  ANA, RF
 The Schirmer test - measures the production
  of tears
  Systemic sclerosis

 sclerosis in the skin or other organs
 Diffuse scleroderma (progressive systemic
  sclerosis) is the most severe form,
   involves skin, will generally cause internal
  organ damage (specifically the lungs and
  gastrointestinal tract)
 The limited form is much milder
 The limited form is often referred to as
  CREST syndrome (CREST is an acronym
  for the five main features: Calcinosis,
  Raynaud's syndrome, Esophageal
  dysmotility, Sclerodactyly, Telangiectasia
Immunological findings

  ANA, ENA - anti-Scl-70 (fluorescence of
   nucleolus), anti-centromers
Mixed connective
tissue disease


  combines features of polymyositis, systemic
   lupus erythematosus, scleroderma, and
   dermatomyositis (overlap syndrome)
  Causes : joint pain/swelling, malaise,
   Raynaud phenomenon, muscle inflammation
   and sclerodactyly (thickening of the skin of
   the pads of the fingers)
  Distinguishing laboratory characteristics:
    a positive, speckled anti-nuclear antibody
   (ANA) and anti-U1-RNP antibody (ENA)
Dermatopolymyositis
• a connective-tissue disease related to polymyositis (PM) that is
characterized by inflammation of the muscles and the skin.




  Gottron's sign is an           Heliotrope rash is a violaceous
  erythematous, scaly eruption   eruption on the upper eyelids,
  occurring in symmetric fashion often with swelling
  over the MCP and
  interphalangeal joints
Dermatopolymyositis


  Elevated creatine phosphokinase (CPK)

  muscle biopsy (a mixed B- and T-cell
   perivascular inflammatory infiltrate,
   perifascicular muscle fiber atrophy)

  EMG (electromyogram)
  autoantibodies - ENA (Jo-1)
Vasculitis
  characterized by inflammatory destruction
   of vessels leading to thrombosis and
   aneurysms
  proliferation of the intimal part of blood-vessel
   wall and fibrinoid necrosis
  affect mostly lung, kidneys, skin

  diagnostic tests: elevated ESR, CRP,
   leucocytosis, biopsy of affected organ
   (necrosis, granulomas), angiography
Vasculitis

  p- ANCA (myeloperoxidase) positivity (Polyarteritis
   nodosa, Churg- Strauss, Microscopic polyarteritis
   nodosa)




  c- ANCA (serin proteinase) positive (Wegener
   granulomatosis, Churg- Strauss syndrome)
Classification
  Large vessel vasculitis (Takayasu arteritis,
   Giant cell (temporal) arteritis)
  Medium vessel vasculitis (Polyarteritis
   nodosa, Wegener's granulomatosis, Kawasaki
   disease)
  Small vessel vasculitis (Churg-Strauss
   arteritis, Microscopic polyarteritis, Henoch-
   Schönlein purpura)
  Symptoms: fatigue, weakness, fever,
   arthralgias, abdominal pain, hypertension,
   renal insufficiency, and neurologic dysfunction
EXAMPLES OF ORGAN-
SPECIFIC AUTOIMMUNE
DISEASES

 diseases
 autoantibodies
ORGANOLEPTIC AUTOIMMUNE
DISEASES


    Ulcerative colitis
    Crohn‘s disease
    Autoimmune hepatitis
    Primary biliary cirhosis
    Pulmonary fibrosis
Ulcerative colitis

 chronic inflammation of the large intestine
  mucosa and submucosa
 features: diarrhea, bloody and mucus stools
 extraintestinal features (arthritis, uveitis)
 autoantibodies against pANCA, a- large
  intestine
Crohn‘s disease

 the granulomatous inflammation of whole
  intestinal wall with ulceration and scarring
  that can result in abscess and fistula
  formation
 the inflammation of Crohn's disease the most
  commonly affects the terminal ileum, presents
  with diarrhea and is accompanied by
  extraintestinal features - iridocyclitis, uveitis,
  artritis, spondylitis
 antibodies against Saccharomyces
  cerevisiae (ASCA), a- pancreas
  Primary biliary cirhosis

 autoimmune disease of the liver marked by the slow
  progressive destruction of the small bile ducts; can lead to
  cirrhosis
 AMA= antimitochondrial autoantibodies
     AUTOIMMUNE HEPATITIS
 type I – association with autoantibodies against
          smooth muscles SMA, ANA, ANCA, SLA

 type II – autoantibodies against microsomes LKM-1
             = liver-kidney microsomes

 type III – autoantibodies against SLA (solubile liver
              antigen)

 type IV – overlap syndrome with PBC –
           autoantibodies against mitochondries AMA
Pulmonary fibrosis




    is associated with SLE, RA, systemic
     sclerosis, polymyositis
    autoantibodies nonspecific- RF, ANA
    biopsy, lung function testing, X-ray
ORGAN SPECIFIC AUTOIMMUNE
DISEASES




  Autoimmune endocrinopathy
  Autoimmune neurological diseases
  Autoimmune cytopenia
AUTOIMMUNE ENDOCRINOPATHY



    Hashimoto‘s thyroiditis
    Graves-Basedow disease
    Diabetes mellitus I. type
    Addison‘s disease
    Autoimmune polyglandular syndrome
    Pernicious anemia
Hashimoto‘s thyroiditis
 thyroid disease result to hypothyroidism on the
  base of lymphocytes and plasma cells infiltrate

 autoantibodies against thyroidal peroxidase (a-
  TPO) and/or against thyroglobulinu (a-TG)
  Grave‘s disease

 thyrotoxicosis from overproduction of thyroid
  hormone (patient exhibit fatigue, nervousness,
  increased sweating, palpitations, weight loss,
   exophtalmus)



 autoantibodies against thyrotropin receptor,
  autoantibodies cause thyroid cells proliferation
Diabetes mellitus (insulin-
dependent)
 characterized by an inability to process sugars in
  the diet, due to a decrease in or total absence of
  insulin production
 results from immunologic destruction of the
  insuline- producing β-cells of the islets of
  Langerhans in the pancreas
 autoantibodies against GAD- glutamic acid
  decarboxylase = primary antigen),
  autoantibodies anti- islet cell, anti- insulin
 islets are infiltrated with B and T cells
Polyglandular autoimmune
syndrome

  combination of several different AI
   endocrinopathies

  autoantibodies appear in according with the
   connected disorders
Pernicious anemia
 the deficiency of the intrinsic factor results in
  inadequate and abnormal formation of
  erythrocytes and failure to absorb vitamin B12
 clinical feature- atrophic gastritis, macrocytic
  anemia
 autoantibodies against parietal cells of gastric
  mucose, against intrinsic factor (transportation
  of B12 vitamin)
AUTOIMMUNE NEUROPATHY


  Guillain-Barré syndrome (acute idiopathic
   polyneuritis)

  Myasthenia gravis

  Multiple sclerosis
Guillain-Barré syndrome


 inflammation demyelinates peripheral neuropathy
  that causes progressive muscle weakness and
  paralysis
 the cause is the loss of myelin

 occurs often 1-3 weeks after infection
  (Campylobacter jej.)

 features: progressive weakness and paresthesia of
  the lower and later upper extremitas and respiratory
  muscles, weakness can leads to paralysis and
  respiratory failure
 immunologic findings: autoantibodies against
  ganglioside membrane
Myasthenia gravis


  chronic disease with impaired neuromuscular
   transmission
  characterized by muscle weakness and fatigue
  the muscle weakness and neuromuscular
   dysfunction result from blockage and depletion
   of acetylcholine receptors at the myoneural
   junction
  immunological findings: autoantibodies against
   Ach receptors

  ptosis of the eye
Multiple sclerosis


 chronic demyelinizing disease with abnormal reaction T
  cells to myeline protein on the base of mimicry between a
  virus and myeline protein
 features: weakness, ataxia, impaired vision, urinary
  bladder dysfunction, paresthesias, mental abberations
 autoantibodies against MOG (myelin-oligodendrocyte
  glycoprotein)
 Magnetic resonance imaging of the brain and spine
  shows areas of demyelination

 The cerebrospinal fluid is tested for oligoclonal bands,
  can provide evidence of chronic inflammation of the
  central nervous system
AUTOIMMUNE CYTOPENIA


  AI hemolytic disease- autoantibodies
   against membrane erythrocyte antigens

  AI trombocytopenia - autoantibodies against
   trombocyte antigens (GPIIb/IIIa)

  AI neutropenia - autoantibodies against
    membrane neutrofil antigens
IMMUNOSUPPRESSION



 non-specific treatment
examples of drugs
indication
risks
Immunosuppressants

 Drugs that inhibit or prevent activity of the immune
  system
 They are used in immunosuppressive therapy to:
 Prevent the rejection of transplanted organs and
  tissues (bone marrow, heart, kidney, liver)
 Treat autoimmune diseases or diseases that are
  most likely of autoimmune origin (rheumatoid arthritis,
  multiple sclerosis, myasthenia gravis, systemic lupus
  erythematosus, Crohn's disease, pemphigus,
  ulcerative colitis).
 Treat some other non-autoimmune inflammatory
  diseases (allergic asthma, atopic eczema).
Glucocorticoids

  suppress the cell-mediated immunity- act by
   inhibiting genes that code for various cytokines
   (e.g.IL-2)
  decrease cytokine production reduces the T
   cell proliferation.
  suppress the humoral immunity, causing B
   cells to express smaller amounts of IL-2 and
   IL-2 receptors- this diminishes both B cell clone
   expansion and antibody synthesis.
Glucocorticoids
  leads to diminished eicosanoid production,
   suppression of the cyclooxygenase expression
  Glucocorticoids also stimulate the lipocortin-1
   escaping to the extracellular space, where it
   binds to the leucocyte membrane receptors
   and inhibits : epithelial adhesion, migration,
   chemotaxis, phagocytosis, respiratory burst,
   and the release of various inflammatory
   mediators from neutrophils, macrophages, and
   mastocytes.
  side-effects: hypertension, dyslipidemia,
   hyperglycemia, peptic ulcers, osteoporosis,
   disturbed growth in children
Drugs affecting the proliferation
of both T cells and B cells

  Cyclophosphamide -very efficient in the
   therapy of systemic lupus erythematosus,
   autoimmune hemolytic anemias
  high doses cause pancytopenia and
   hemorrhagic cystitis
  Methotrexate is a folic acid antagonist, acts
   during DNA and RNA synthesis, and thus it is
   cytotoxic during the S-phase of the cell cycle;
   used in the treatment of autoimmune diseases
   (RA, Crohn's disease) and in transplantations.
Drugs affecting the proliferation
of both T cells and B cells
  Azathioprine is a purine synthesis inhibitor,
   inhibiting the proliferation of cells, especially
   leucocytes; SLE, RA, sclerosis multiplex,
   transplantation


  Mycophenolate mofetil – affects the enzyme
   that controls the purine synthesis
  Used in transplantation of solid organ
Drugs blocking the activation
of lymphocytes
 Tacrolimus - prevents the cell from transitioning from
  the G0 into G1 phase of the cell cycle
 Used to prevent rejection reactions, atopic eczema

 Cyclosporin A- inhibits calcineurin, which is
  responsible for activating the transcription of
  interleukin-2; inhibits cytokines production and
  interleukin release
 Used to prevent rejection reactions

 Side effects: nephrotoxicity, neurotoxicity,
  hypertension, dyslipidemia, hyperglycemia
Monoclonal antibodies

  Monoclonal antibodies are directed towards
   exactly defined antigens
  Daclizumab - acts by binding the IL-2a
   receptor's α chain, preventing the IL-2 induced
   clonal expansion of activated lymphocytes and
   shortening their survival
  used in the prophylaxis of the acute organ
   rejection after the bilateral kidney
   transplantation

				
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posted:4/15/2011
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