AUTOIMMUNE DISEASES

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AUTOIMMUNE DISEASES
Martin Liška
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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

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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

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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)

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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

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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

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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

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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

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EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES

• examples
• autoantibodies

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SYSTEMIC AUTOIMMUNE DISEASES

• Systemic lupus erythematosus
• Rheumathoid arthritis
• Sjögrens syndrome
• Dermatopolymyositis
• Systemic sclerosis
• Mixed connective tissue disease
• Vasculitis

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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

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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

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AUTOANTIBODIES

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

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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

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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

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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
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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)

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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

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Immunological findings

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

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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)

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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

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Vasculitis

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

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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

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EXAMPLES OF ORGANOLEPTIC AUTOIMMUNE DISEASES

• diseases
• autoantibodies

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ORGANOLEPTIC AUTOIMMUNE DISEASES

• Ulcerative colitis
• Crohns disease
• Autoimmune hepatitis
• Primary biliary cirhosis
• Pulmonary fibrosis

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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

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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

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• 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

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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)

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Pulmonary fibrosis

• is associated with SLE, RA, systemic sclerosis,
  polymyositis
• autoantibodies nonspecific- RF, ANA
• biopsy, lung function testing, X-ray

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ORGAN SPECIFIC AUTOIMMUNE DISEASES

• Autoimmune endocrinopathy
• Autoimmune neurological diseases
• Autoimmune cytopenia

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AUTOIMMUNE ENDOCRINOPATHY

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

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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)

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

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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

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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

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Polyglandular autoimmune syndrome

• combination of several different AI
  endocrinopathies
• autoantibodies appear in according with the
  connected disorders

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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)

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AUTOIMMUNE NEUROPATHY

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

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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

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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

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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

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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

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IMMUNOSUPPRESSION

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

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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).

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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.

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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

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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.

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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

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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

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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