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AUTOIMMUNE DISEASES

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Title: AUTOIMMUNE DISEASES


1
AUTOIMMUNE DISEASES
Martin Liška
2
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

3
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

4
AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY
  • the diseases are chronic and usually irreversible
  • incidence 5-7 of population, higher
    frequencies in women, increases with age
  • factors contributing to autoimmunity
  • - internal (HLA association, polymorphism
    of cytokine genes, defect in genes regulating
    apoptosis, polymorphism in genes for TCR and H
    immunoglobulin chains, association with
    immunodeficiency, hormonal factors)
  • - external (infection, stress by activation
    of neuroendocrinal axis and hormonal dysbalance,
    drug and ionization through modification of
    autoantigens)

5
Type II hypersensitivity reaction
  • IgM and IgG Ab promote the phagocytosis of cells
    which they bind, induce inflammation by
    complement and Fc receptor- mediated leukocyte
    recruitment , and may interfere with the
    functions of cells by binding to essential
    molecules and receptors.
  • Graves disease, Pernicious anemia, Myasthenia
    gravis, Acute rheumatic fever, Goodpastures
    syndrome, Pemphigus vulgaris, Autoimmune
    hemolytic anemia or thrombocytopenic purpura

6
Type III hypersensitivity reaction
  • Ab may bind to circulating antigens to form
    immune complexes, which deposit in vessels and
    cause tissue injury.
  • Injury is due mainly to leukocyte recruitment and
    inflammation.
  • Systemic lupus erythematosus, Polyarteritis
    nodosa, Poststreptococcal glomerulonephritis

7
Type IV hypersensitivity reaction
  • T cell- mediated diseases are caused by
    Th1-mediated delayed-type hypersensitivity
    reactions or Th17- mediated inflammatory
    reactions, or by killing of host cells by CD8
    CTLs (cytotoxic lymphocytes).
  • Diabetes mellitus (insulin-dependent), Rheumatoid
    arthritis, Multiple sclerosis, Inflammatory bowel
    disease

8
CLINICAL CATEGORIES
  • systemic
  • - affect many organs and tissue
  • organoleptic
  • - affect predominantly one organ accompanied
    by affection of other organs (inflammatory bowel
    diseases, coeliac disease, AI hepatitis,
    pulmonary fibrosis)
  • organ specific
  • - affect one organ or group of organs
    connected with development or function

9
EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES
  • examples
  • autoantibodies

10
SYSTEMIC AUTOIMMUNE DISEASES
  • Systemic lupus erythematosus
  • Rheumathoid arthritis
  • Sjögrens syndrome
  • Dermatopolymyositis
  • Systemic sclerosis
  • Mixed connective tissue disease
  • Vasculitis

11
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

12
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

13
AUTOANTIBODIES
  • Autoantibodies ANA, dsDNA (double-stranded), ENA
    (SS-A/Ro, SS-B/La), Sm, against histones,
    phospholipids

14
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

15
SJÖGRENS 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

16
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 erythematous, scaly eruption
occurring in symmetric fashion over the MCP and
interphalangeal joints
Heliotrope rash is a violaceous eruption on the
upper eyelids, often with swelling
17
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)

18
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

19
Immunological findings
  • ANA, ENA - anti-Scl-70 (fluorescence of
    nucleolus), anti-centromers

20
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)

21
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

22
Vasculitis
  • p- ANCA (myeloperoxidase) positivity
    (Polyarteritis nodosa, Churg- Strauss,
    Microscopic polyarteritis nodosa)
  • c- ANCA (serin proteinase) positive (Wegener
  • granulomatosis, Churg- Strauss syndrome)

23
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

24
EXAMPLES OF ORGANOLEPTIC AUTOIMMUNE DISEASES
  • diseases
  • autoantibodies

25
ORGANOLEPTIC AUTOIMMUNE DISEASES
  • Ulcerative colitis
  • Crohns disease
  • Autoimmune hepatitis
  • Primary biliary cirhosis
  • Pulmonary fibrosis

26
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

27
Crohns 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

28
  • 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

29
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
  • antimitochondrial
    autoantibodies (AMA)

30
ORGAN SPECIFIC AUTOIMMUNE DISEASES
  • Autoimmune endocrinopathy
  • Autoimmune neurological diseases
  • Autoimmune cytopenia

31
AUTOIMMUNE ENDOCRINOPATHY
  • Hashimotos thyroiditis
  • Graves-Basedow disease
  • Diabetes mellitus I. type
  • Addisons disease
  • Autoimmune polyglandular syndrome
  • Pernicious anemia

32
Hashimotos thyroiditis
  • thyroid disease result to hypothyroidism on the
    base of lymphocytes and plasma cells infiltrate
  • autoantibodies against thyroidal peroxidase
    (a-TPO) and/or against thyroglobulin (a-TG)

33
  • infiltrate of plasma cells and lymphocytes with
    germinal center formation is seen in this thyroid

34
Graves 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

35
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 ß-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

36
Polyglandular autoimmune syndrome
  • combination of several different AI
    endocrinopathies
  • autoantibodies appear in according with the
    connected disorders

37
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)

38
AUTOIMMUNE NEUROPATHY
  • Guillain-Barré syndrome (acute idiopathic
    polyneuritis)
  • Myasthenia gravis
  • Multiple sclerosis

39
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

40
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

41
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-oligodendrocyt
    e 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

42
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

43
IMMUNOSUPPRESSION
  • non-specific treatment
  • examples of drugs
  • indication
  • risks

44
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).

45
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.

46
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

47
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.

48
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

49
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

50
Monoclonal antibodies
  • Monoclonal antibodies are directed towards
    exactly defined antigens
  • Daclizumab - acts by binding the IL-2a receptor's
    a 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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