SBMS 308 Allergies aka Hypersensitivity reactions

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SBMS 308Allergies aka Hypersensitivity reactions

• These normally occur when the body recognises a
  particle such as a pollen grain or a protein
  modified by something like chromium as a bacteria
  or a virus.

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What can go wrong will

• 1) Hypersensitivity reactions occur when the
  immune responds in such a way to cause more harm
  than good to the hody.
• 2) Hypersensitivity reactions must involve
  inflammation. Hence IgA, which does not cause
  inflammation, is never implicated, all other
  classes of antibody and the cell-mediated Immune
  system may be.
• 3) Hypersensitivity reactions are classified into
  4 groups depending on which branch of the immune
  system is involved

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Why do some people get hyper-sensitivity reactions

• Between 10 and 20 of the population will suffer
  from some form of hypersensitivity reaction
  sometime in their life - but the majority do not.
• Type 1 and Type IV reactions are the most common
• Type 1 reactions vary from a mild tingle in the
  eyes to death.
• In an appreciable number of cases people with
  Type 1 hypersensitivity lose it as they get older

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What provokes hypersensitivity reactions

• Two groups of chemicals
• 1) High molecular weight materials - principally
  proteins and complex carbohydrates. Essentially
  the body treats these as though they were
  invading bacteria and mounts a humoral response
  involving IgG, IgM and IgE antibodies
• 2) Low molecular weight materials which bind to
  and modify the bodies proteins (eg chromate
  ions). The body tends to respond to these as
  though they were viruses and mounts a
  cell-mediated response

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Type 1 Hypersensitivity Reactions

• Type hypersensitivity reactions involve IgE
  antibodies
• IgE antibodies have two heavy (epsilon) chains
  and two light chains
• Little IgE antibody is found in serum, it
  functions by binding to mast cells through a high
  affinity receptor
• Mast cells are filled with granules which contain
  inflammatory mediators such as histamine. There
  are two variants but these are sufficiently
  similar we need not bother about the differences
• When antigen binds to the bound IgE antibody at
  at least two sites then calcium enters the cell.
  This results in two responses

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Mast Cells
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Mast Cell Degranulation
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Tissue Affected
The tissues most commonly affected are the skin,
the respiratory tract and the alimentary tract.
The results are at best uncomfortable (e.g. hay
fever, eczema, food allergy) at worst fatal
(asthma, anaphylaxis)
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The Immediate Reaction

• Mast cell granules contain a range of
  inflammatory mediators. Most important is
  histamine, which causes dilation of blood vessels
  and increases blood vessel permeability (but
  causes constriction of bronchial smooth muscle).
  The result is the four classic symptoms of
  inflammation (redness, swelling, heat and pain -
  in Latin rubor, tumor, calor, dolor)
• In addition the granules contain chemotactic
  factors, especially for eosinophils, and
  activating factors (eg for platelets)
• In addition to their direct effects factors in
  the mast cell granules activate the alternative
  pathway for complement fixation and the kinin
  system

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Inflammatory Factors from Mast Cells
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And the results
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The delayed response

• The swelling produced by the immediate response
  usually subsides in around an hour but, in severe
  reactions, a secondary response develops after a
  few hours and may persist for 1-2 days.
• This secondary response is characterised by
  infiltration of all classes of white blood cell
  especially eosinophils. This is probably
  associated with release of cytokines from the
  mast cells which act as chemoattractants. . On
  arrival the eosinophils, in particular, interact
  with the antibody-antigen complexes releasing
  their own granule contents which include
  chemoattractants

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Asthma in Pictures
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And Words

• Type 1 hypersensitivity reaction to inhaled
  allergens may lead to long term changes. The
  changes develop progressively
• Within minutes of exposure degranulation of the
  mast cells will lead to vasodilation (histamine)
  bronchoconstriction (PGD2) and mucus secretion
  (LTC4). This will be followed by cytokine and
  inflammatory cell infiltration leading to chronic
  inflammation
• Repeated stimulation of smooth muscle contraction
  and mucus production leads to hypertrophy of the
  muscle and mucus gland hyperplasia

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Continued

• 3) Among factors released are eosinophils
  chemotactic factors. In addition release of
  factors such as NO tend to cause a predominance
  of Th2 cells which produce IL-5 and other factors
  which attract and activate eosinophils
• 4) Cytotoxic proteins and active oxygen
  intermediates are released. Eosinophils release
  eosinophil basic protein which causes bronchial
  hyperresponsiveness and is toxic to respiratory
  epithelial cells
• 5) The damage causes increased immigration of
  inflammatory cells and contributes to the . This
  increases responsiveness and leads to systemic
  effects. Bronchiolar contraction may become so
  strong that the patient suffocates. The damage
  is made worse by positive feedback loops which
  increase the formation of IgE

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Therapy

• Anti-asthma drugs attack all the steps in the
  genesis of the lesion
• 1) Sodium chromoglycate stabilises membranes and
  decreases Ca influx so inhibiting mast cell
  degranulation
• 2) Corticosteroids as general anti-inflammatory
  agents
• 3) Antihistamines for control of symptoms
• 4) Adrenaline - relaxes smooth muscle and
  decreases vascular permeability
• 5) Leukotriene, prostoglsmdin and
  phosphodiesterase antagonists
• 6) (Less usual) cetrizine - inhibits eosinophils

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Anaphylaxis

• In general the allergic reaction is confined to
  the tissue exposed to the allergen. Examples
  here are allergic rhinitis (eg hay fever) and
  eczema.
• Food allergies may result in local effects
  resulting on diarrhoea or vomiting.
  Alternatively the allergen may be carried to
  another site rich in mast cells resulting in
  asthmatic attacks or in atopic urticaria
• If the allergic reaction is severe enough
  inflammatory mediators will result inn systemic
  anaphylaxis. Vasodilation leads to a fall in
  blood pressure, pulmonary smooth muscle
  contraction which are both potentially lethal if
  not treated with adrenalin

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Type 2 Hypersensitivity reaction

• In this condition IgG or IgM antibodies are
  formed which react with surface proteins of the
  bodies own cells. The result in
  complement-mediated lysis of the cells
• The best example is haemolytic disease of the new
  born (Rhesus disease) where lgG antibodies
  transferred from the mother lyse the babies cells
• Rare, but serious, are cases where drugs or their
  metabolites bind to red cell or platelet
  membranes and induce antibody formation. This is
  found as a sporadic reaction with a range of
  drugs
• Complement mediated lysis may also be important
  in autoimmune disease

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Haemolytic disease of the new born
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And the result
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Type 3 Hypersensitivity Reactions

• Type 3 responses are typically observed several
  hours after exposure to the antigen. The
  reaction is associated with IgG antibodies
  binding to proteins and forming immune complexes
  which convert complement.
• The first condition involves formation of soluble
  immune complexes. These may arise from bacterial
  antigens in persistent disease (leprosy, malaria,
  trypanosomiasis etc. The term serum sickness is
  used because the condition was observed after
  passive immunisation.
• The second condition is observed when large
  amounts of antigen are inhaled or following
  injection of allergen. In this case the reaction
  occurs in the tissues and complement fixation
  results in general inflammation. The condition
  is termed the Arhus reaction

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Type 3 Reaction
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Serum Sickness

• Soluble immune complexes will eventually be lost
  from the circulation. This is encouraged when
  blood vessels take sharp bends as in the kidney
  which is a favoured site
• Other common sites of deposition are the joints
  and the skin
• Once the antibody is deposited then C3b can
  adhere to the underlying cell. This will result
  in complement dependent lysis. In the kidney
  this may lead to exposure of the basement
  membrane resulting in an autoimmune reaction
• Transfer of xenogeneic serum can provoke a
  spectacular form of reaction. It should be
  remembered that C3a and C5a are general
  inflammatory mediators

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Glomerular nephritis due to a) Reaction of
antibody with the glomerular basement membraneb)
Deposition of immune complexes
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Type 3 Hypersensitivity reactions and the lung

• Inhaled particles, if sufficiently immunogenic,
  can cause immune complex disease, in this case in
  the subepithelium of the lung
• Fungal proteins are by far the most common cause
• Examples are Farmers lung, Pigeon fanciers
  disease
• etc. etc.
• The mechanism probably involves reaction of
  complement with the immune complexes. This will
  result in general inflammation and in bystander
  damage as C3b reacts with neighbouring cells
• Injected antigen (eg an insect bite) may result
  in a Type I reaction followed 4-8h later by an
  Arhus reaction

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Type 3 reaction in the lungs
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Something quite different Type 4 or delayed
hypersensitivity

• This is a blanket term which covers what appears
  to be three distinct phenomena
• 1) Contact hypersensitivity-as its name implies
  there is simply contact with the outer surface of
  the skin
• 2) Tuberculin type hypersensitivity-observed
  when allergen passes into the dermis-as in
  testing for Tb immunity
• 3) Cutaneous basophil hypersensitivity. This is
  also associated with injection into the dermis
  but in this case the cellular infiltrate is rich
  in basophils

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Contact Hypersensitivity - priming the response

• The first key cell here is the Langehans cells.
  These are antigen-presenting cells which are
  normal skin residents
• In addition the main cell type of the skin, the
  keratinocyte, plays an important role. Binding
  of hapten to these results in formation of
  cytokines
• (IL-1 beta seems to play an important role).
  These activate the Langehans cells which
  emigrate from skin to lymph nodes)

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Continued

• In the lymph nodes the Langehans cells interact
  with CD8 T cells (there has been argument on
  this but MHC Class 1 deficient mice do nor show
  CHS, Class 2 deficient mice may even show an
  exaggerated response)
• Sensitised T cells emigrate from the lymph nodes
  and begin the normal circulation.
• Further interactions involving Th1 and Th2 cells
  may regulate the response

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Continued
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Contact hypersensitivity
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Mechanisms, what mechanisms

• The old idea was that Tc cells patrolled the skin
  and attacked and killed cells which presented
  hapten. This is now in doubt
• What is left behind is a horrible muddle. The
  primary response seems to involve CD8 cells but
  adoptive transfer suggests a CD4-CD8- population
  recognise the antigen and are helped by a CD4
  cell which is MHC restricted but antigen
  non-specific. Gamma-Delta T cells may also get
  in on the act

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Other delayed type hypersensitivity reactions

• The tuberculin reaction is MHC-class 2 restricted
  and appears to involve stimulation of production
  of Th1 cells
• I have found no details on the mechanism of
  Cutaneous Basophil Hypersensitivity. This used
  to be called Jones-Mote if you look at old texts
  or in Ivan Roitts book.

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Why do we get hypersensitivity reactions

• Because of defects in the regulatory system.
  This is immensely complex and involves several
  distinct systems. These systems involve both
  regulation of whether antibody is produced at all
  (clonal deletion, clonal anergy) or regulation of
  which type of response should be mounted
  (humoral, cell mediated, secretory). We will
  look briefly at the latter topic

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Regulation of the Immune Response

• The immune system lives on a knife edge. Too
  small a response will result in pathogens
  entering the body while too large a response will
  result in hypersensitivity reactions
• The response is controlled by signalling between
  the different classes of T cell and also between
  T cells and effector cells, especially
  macrophages, mast cells and NK cells.

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Atopy runs in families
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Initiation of an Humoral Response

• The primary reaction to a potential allergen will
  result in naïve B cells forming IgM and IgD.
• In the germinal centres cells will be selected
  for their ability to bind antigen and to interact
  with a CD4 TH cell (if not they die)
• These differentiated cells now differentiate
  either into plasma cells or memory cells and, in
  the process class switch. The control of this is
  an immensely complex topic but essentially
  cytokines secreted by TH cells will determine the
  class of antibody to be formed. Actual contact
  between B and T cell, mediated by CD40 and CD40L,
  is needed

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What commands what

• Stimulation by IFN-gamma (produced by TH1 cells)
  leads to the formation of IgG2a and IgG3 plasma
  cells and to delayed hypersensitivity reactions
• TGF-beta (produced by a subset of TR cells)
  stimulates the formation of IgA or IgG2b plasma
  cells.
• IL-4 (produced by TH2 cells) stimulates the
  formation of IgE or IgG1 plasma cells
• IL-1, IL-4 and IL-5 stimulate the formation of
  IgM plasma cells.
• As mentioned earlier these these cytokines are
  secreted by TH cells, a markedly heterogeneous
  group of cells, and also by effecter cells such
  as macrophages

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TH subclasses

• TH cells can be divided into several different
  classes. Best characterised are
• TH1 cells which secrete IL-2, IFN-gamma, TNF-beta
  and GM-CSF inter-alia. These cells stimulate
  cell mediated responses and the formation of
  opsonising IgG molecules.
• TH2 cells secrete IL3,4,5,10 and 13 and stimulate
  IgE responses and eosinophil proliferation
• Regulatory TH cells (TRCells) secrete TNF-beta
  limit the response.
• TH0 cells are a poorly characterised group which
  may be precursors of the other subgroups

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Regulation of IgE production

• Incubation of LPS with normal unprimed B cells
  results in 2 of cells expressing membrane IgG1
  and only 0.05 expressing IgE. These percentages
  rose to 40-50 and 15-25 if IL4 was present
• IL4 knockout mice cannot mount an IgE response
• Co-culture of allergen specific T cells from
  atopic individuals with autologous B cells
  results in IgE production, T cells from
  non-atopics does not,
• Allergen specific T cells were predominately TH2,
  from non-atopics TH1from non-atopics
• Gamma interferon, secreted by TH1 cells inhibits
  IgE production

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How differences in the type of response affect a
disease

• Infection by mycobacterium leprae results in two
  distinct forms of the disease
• In tuberculoid leprosy a cell mediated response
  results in destruction of the organisms or their
  sequestration in granulomas. The result is a
  slowly developing disease with only limited
  damage to skin or nerves.
• In lepromatous leprosy humoral response results
  in massive uptake of the organisms into
  macrophages and a rapidly spreading disease.
• Examination of cytokine levels in patients shows
  that in the 1st case there is a TH1 type
  response, in the 2nd a TH2 type

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Damage limitation

• In the immune system there must be a fine balance
  between efficiency of removal of invading
  microorganisms and of induction of damaging
  hypersensitivity reactions.
• This problem is especially severe in the gut as
  there is extensive exposure to food proteins and
  to resident microorganisms.
• There are several mechanisms for damage
  limitation
• As seen earlier there are a variety of possible
  responses
• At high doses the TH cells mediating the response
  may be deleted

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Continued

• 3) The response may be suppressed. The active
  suppression is partly associated with a subset of
  Tr cells which secrete TGF-beta.
• These cells are found in large numbers in the
  Peyers patches. They act as helper cells for an
  IgA response and they appear to suppress TH1 and
  2 mediated responses. IL-10 appears to play a
  major role in this suppression
• This has lead to suggestions that oral
  administration of antigen may be beneficial in
  autoimmune disease and studies have taken place
  both in humans and in experimental animals

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To respond or suppress

• At one time it was thought that initiation of an
  IgA response was associated with suppression of
  Th1 and Th2 mediated responses. This now seems
  less likely . It is, for example, rare to find
  food specific IgA antibodies
• It has also been suggested that soluble antigens
  which can penetrate the epithelial layer intact
  may tend to produce tolerance whereas
  particulates such as bacteria, which require
  processing in the Peyers patches tend to give an
  immune response

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Oral Tolerance and Breakdown

• It has long been known that oral administration
  of an antigen can remarkably reduce a later
  response following parenteral administration.
  Furthermore while we tolerate our own gut flora
  we may react vigorously to strains derived from
  other people and we do not react to foods
  although these may contain potent allergens.
• This may break down producing
• Food allergies
• Inflammatory bowel disorders such as ulcerative
  colitis

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Atopy

• Some people show marked immmune reactions afainst
  a wide range of antigens. There is a clear
  genetic element in the response - children of
  atopic patients are likely to be atopic
  themselves.
• Atopics tend to have higher IgE levels than
  non-atopics, but serum IgE levels are very
  variable in any individual
• There is a strong association between atopy and
  IL4 production which seems to be genetically
  determined IL3, IL5 and IL13 also seem to have
  roles

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More evidence

• The incidence of asthma is rising - about
  one-third of children seen by accident and
  emergency departments are there because of this
  problem
• Innumerable correlations have been made - but
  without much agreement. For example a study on
  7000 children in Germany showed a correlation of
  house dust allergy with exposure - yet overall
  houses have got cleaner
• There is some evidence that particulates may act
  as adjuvents - but it is far from conclusive

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Spontaneous and deliberate hypo-sensitisation

• Type 1 reactions may disappear with age
• In some cases injecting increasing dose of
  allergen reduces or abolishes the response. This
  does good in about 60 of cases, has no effect in
  30 and makes things worse in 10
• The hope is that as we understand more about
  control of the immune response by cytokines so we
  will be able to modulate the response. However
  the complexity of the control of immune responses
  is likely to make this a rather hit and miss
  affair