General Pathology: Hypersensitivity and Autoimmunity

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General PathologyHypersensitivity and
Autoimmunity

• Lorne Holland, M.D.
• Lorne.Holland_at_ucdenver.edu

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Hypersensitivity

• Exaggeration of normal immune response to foreign
  substances
• Broken into four types based on cells involved
  and mechanism of tissue injury

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Immediate Hypersensitivity (type I)

• Classic allergic reaction to food and insect
  bites as well as asthma
• IgE secreted by plasma cells is bound to the
  outside of mast cells via interaction of the Fc
  portion
• When two nearby IgE molecules are bound, signals
  mast cells to release inflammatory mediators
• Pre-formed mediators? rapid response histamine,
  chemokines, lysosomal enzymes
• Increased synthesis of prostaglandins and
  leukotrienes ? lasting response

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Immediate Hypersensitivity (type I)

• Recruitment of other inflammatory cells
  (eosinophils and lymphocytes)
• Major basic protein ? cytotoxic
• Eosinophil cationic protein ? RNAse
• Eosinophil peroxidase ? like neutrophils
• Eosinophil neurotoxin ? RNAse
• Severe response is called anaphylaxis and can be
  life-threatening

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Cell-bound Antigen (type II)

• Example of a hapten in action
• Classically, drugs or metabolites thereof stick
  to the cell membrane of normal cells
• Normal cell proteins plus hapten yeilds an
  immunologically foreign substance
• Antibodies bound to cell can trigger complement
  cascade, enhance phagocytosis and promote local
  tissue damage by neutrophils
• Classic example is drug-induced hemolytic anemia,
  thrombocytopenia, or leukopenia

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Cell-bound Antigen (type II)

• Antibodies can also be autoantibodies to normal
  cellular proteins
• Often after an infection
• Mechanism of damage for many autoimmune diseases
• Pemphigus ? antibody to dermal junction proteins
• Goodpastures ? antibody to glomerular and
  respiratory basement membrane

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Immune Complex (type III)

• Caused by deposition of circulating
  antibody-antigen complexes
• These complexes can activate complement
• Historically seen as serum sickness where
  people received repeated infusions of animal
  serum to neutralize toxic products (i.e. tetanus)
• Now mostly seen in cases where bacterial
  antigen-antibody complexes lodge in renal
  basement membrane (post-streptococcal
  glomerulonephritis) and lupus (more later)

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Delayed (type IV)

• Cause of many skin reactions such as tuberculin
  reaction and contact dermatitis
• T-cells in the skin have been previously exposed
  to an antigen
• Upon repeat exposure, a robust, but delayed
  reactions occurs
• Involves recruitment of more lymphocytes and
  macrophages

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Delayed (type IV)

• Typically limited course, antigen exposure is
  only temporary
• When exposure is not limited, chronic
  inflammation sets in (granuloma, more later)

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Autoimmunity

• Immune response to antigens which should not
  illicit an immune response
• Either a breakdown in the normal process of
  self-tolerance
• Something tricking the immune system into
  attacking self antigens

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Preventing Autoimmunity

• Many antigens are sequestered from entering the
  blood/lymph and so can not travel to lymph nodes
  and be taken up by APCs there
• Immature T-cells travel to thymus where they are
  negatively selected based upon too strong a
  response to self antigens
• T-cells in normal tissue may recognize self
  antigens, but resident APCs will not be activated
  and will not provide necessary costimulation ?
  anergy
• Small subset of suppressor T-cells which can
  secrete anti-inflammatory cytokines

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Breakdown of Tolerance

• When tissue damage occurs (trauma or
  inflammation) antigens previously sequestered may
  enter circulation
• Local inflammation may increase proteolytic
  activity which exposes/creates new antigens from
  self proteins
• APCs in tissue which is already inflamed may be
  induced to express costimulatory molecules
• Suppressor T-cells may be downregulated by other
  activated inflammatory cells
• One tolerance breaks down it is relatively easy
  for it to become self-sustaining

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Molecular Mimicry

• Proteins from various bacteria and viruses may
  bear some resemblance to self antigens
• When an immune response is mounted against these
  microbial proteins, there is a small amount of
  cross-reactivity
• As before, in the context of an already
  pro-inflammatory environment (from the microbial
  invasion) this cross-reactivity can be
  self-sustaining/self-propagating

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Predisposition to Autoimmunity

• Genetics undoubtedly plays a role in some
  diseases with HLA type being the classic example
• HLA B27 ? ankylosing spondylitits, Reiters
  syndrome
• DR2 ? Goodpastures syndrome
• DR3 ? Hashimotos thyroiditis, myasthenia gravis
• DR4 ? Type I diabetes

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Predisposition to Autoimmunity

• Environmental factors are even more likely to
  contribute to autoimmunity
• Most autoimmune diseases are more prevalent in
  females (estrogen)
• Infection creates a pro-inflammatory state and
  can cause autoimmunity due to molecular
  mimicryat the same time conditions which are too
  aseptic promote autoimmune disease
• Certain drugs can act as haptens with self
  antigens
• UV radiation can alter (skin) self antigens
  and/or increase expression of some proteins

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Systemic Lupus Erythematous

• Systemic autoimmune disorder which can affect
  almost any organ
• Basically, a Type III hypersensitivity reaction
  to self antigens
• Special predilection for skin, kidney, serosal
  surfaces, joints and heart
• Onset typically in adolescence or early adulthood
• Women and AA are especially at risk, 1245 for AA
  women of child bearing age

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Systemic Lupus Erythematous

• Exact cause is unknown, but there is a breakdown
  of both T-cell and B-cell tolerance
• Genetic component
• 25 concordance in monozygotic twins
• 20 of family members who are clinically silent
  have detectable autoantibodies
• Environmental component
• UV exposure increases severity of skin lesions
• Drugs (procainamide, hydralazine) can induce
  lupus symptoms which eventually cease when drug
  is stopped

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Systemic Lupus Erythematous

• A variety of autoantibodies can be formed, but
  all are collectively called antinuclear
  antibodies
• Native (coiled) DNA
• Histones
• Other proteins bound to nucleic acids
• Nucleolar antigens

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Autoimmune Immunofluoresence
Diffuse- condensed DNA, histones, ds-DNA
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Systemic Lupus Erythematosus

• Autoantibodies to red cells, platelets and/or
  lymphocytes due to DNA and related proteins stuck
  to membranes (like Type II hypersensitivity)
• Hemolytic anemia, thrombosis thrombocytopenia,
  lymphopenia
• Antiphospholipid antibodies
• a.k.a lupus anticoagulant
• In lab, prolongs coagulation tests results
• In patient, predisposes to thrombosis

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Systemic Lupus Erythematosus

• 1997 Revised Criteria, at least 4 of 11
• Malar rash
• Discoid rash
• Photosensitivity
• Oral ulcers
• Arthritis of 2 or more peripheral joints
• Pleuritis or pericarditis
• Persistent proteinuria or casts
• Unexplained seizures or psychosis
• Hemolytic anemia, leukopenia, lymphopenia or
  thrombocytopenia
• Anti-DNA, Anti-Sm or antiphospholipid antibodies
• Antinuclear antibody

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Systemic Sclerosis

• A seronegative spondyloarthropathy because of
  lack of rheumatoid factor
• a.k.a scleroderma
• Excess deposition of collagen in skin and organs
  (GI tract, joints, lungs, kidneys, heart)
• Typical patient is a 50-60 y/o female
• CREST (calcinosis, Raynauds phenomenon,
  esophageal dysmotility, sclerodactyly,
  telangiectasia) syndrome is a more mild form

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Systemic Sclerosis

• Autoantibodies to specific proteins
  (topisomerase/anti-Scl-70), but they seem to play
  little role in symptoms of disease
• Similar to Type IV hypersensitivity reaction
• Lymphocytes recognize autoantigens in skin and
  connective tissue
• Recruit more lyphocytes and macrophages
• Recruited cells release cytokines which
  stimulated local fibroblast to make too much
  collagen (scar tissue)

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Questions?