Basic Immunology

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Basic Immunology as it Relates to Allergy

• David Sloane, MD
• Allergy and Immunology
• Brigham and Womens Hospital
• NESA
• 5 April, 2013

2
Disclosures

• (Genentech Novartis) Unbranded Educational
  Talks on Asthma
• Contributor to the Mathematics Consortium Working
  Group

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Objectives

• 1) To review the biology of cells, antibodies,
  and mediator molecules in healthy immunity and
  dys-immunity germane to allergy.
• 2) To explore the rationale for therapeutic
  agents such as omalizumab in the treatment of
  allergic diseases
• 3) Participants will develop the skills needed to
  educate patients about those aspects of the
  immune system relevant to the patient's allergic
  or immunologic disease and its treatment

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Teleology

• Two theories of the purpose of the immune system
• (1) Defense against microbes (Janeway)
• (2) Defense against danger (Matzinger)
• What do you think the difference is between these
  two theories?

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Immune System as a Matter Processing Network
Inside Outside
Safe
Dangerous
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Reality Check
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The Whole Megilah Allergic Reaction System
Slide courtesy of Dr. Tse Wen Chang
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Components of the System

• Cells
• Dendritic Cells and other professional APCs
• T cells
• B cells
• Mast cells (and Basophils?)
• Eosinophils
• Antibodies What are they? What are they good
  for?
• IgE
• IgG4
• Mediator Molecules What are they? What are they
  good for?
• Interleukin (IL)-4
• IL-13
• Thymic Stromal Lymphopoetin (TSLP)

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Processing Stuff
Microbe
Antigen Presenting Cell (APC) DC
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Processing Stuff
APC
T cell
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The Whole Megilah A closer view
IL4, TSLP
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Wait a Minute!

• Why is this happening?
• Do the two theories of the purpose of the immune
  system help you?
• What is the hygiene hypothesis?

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Antibodies The Immune Systems Attacks Dogs
From Janeway et al. Immunobiology V. 2001.
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Antibodies The Various Species or Isotypes
From Janeway et al. Immunobiology V. 2001.
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The Role of IgE in Allergic Inflammation

• Necessary but not sufficient factor for
  antigenic stimulation of mast cells and
  basophils.
• Prausnitz (grass) and Küstner (fish) 1920s.
• Reagin identified as IgE in mid 1960s.

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IgE Structure

• Molecular Weight 190,000 kD
• Monomeric, two identical heavy chains, two
  identical light chains (k or l)

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IgE Synthesis

• B cells that undergo the isotype switch to Ce
  produce IgE
• Help from Th2 cells that express
• a) CD40L and
• b) IL-4, IL-13, TSLP

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IgE Circulation

• IgE circulates in the blood with a t½ 2-4 days
  (serum!)
• Normal serum concentration 0-0.002mg/mL (the
  lowest of all five isotypes)
• x IU 2.4x ng/mL (E.g., 125 IU 300ng/mL)

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IgE in Blood and Tissues

• In the blood, IgE binds to Basophils through the
  high affinity receptor for IgE, FceRI.
• IgE crosses from blood space into the
  extracellular space
• It binds to Mast Cells through FceRI
• FceRI is also expressed by monocytes,
  eosinophils, dendritic cells in peripheral blood,
  and Langerhans cells in skin.

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FceRI and FceRII

• FceRI Structure
• One a chain that binds the Fc portion of IgE
• One b chain with ITAM
• Two g chains, each with ITAM
• FceRII
• CD23
• Expressed on mature B cells, activated T cells,
  macrophages, eosinophils, follicular dendritic
  cells, platelets
• C-type lectin
• Antigen capture leading to processing and
  presentation to enhance immune responses.

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Mast Cells (and Basophils)
FceRI
IgE
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Mast Cells

• Live in
• mucosal layers (gut, lung)
• submucosal layer
• dermis
• Mediators
• Preformed (histamine, tryptase)
• Rapidly synthesized (PGD2, LTC4)
• Not so rapidly synthesized (cytokines)

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Measurement of Total Serum IgE Why bother?
Burrows B, Martinez FD, Halonen M, Barbee RA, and
Cline MG. Association of Asthma with Serum IgE
Levels and Skin-Test Reactivity to Allergens.
NEJM 1989320(5)271-277.
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Mast Cells and IgE
IgE
FceRI
Allergen
Mediator Release
Mast cell granules
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Wait a Minute!

• Where is IgE acting?
• Where do we measure IgE?

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So What?
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How do we treat Allergic Inflammation?

• Avoid the allergenic trigger (I cant eat that)
• Antagonize the mast cell mediators (Wheres my
  antihistamine?
• Throw a monkey wrench into the response system
  (The story of the yetzer harah)
• Try to teach the immune network not to attack
  (Stay.staaaaay. Good dog!)

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The binding specificities of a therapeutic
anti-IgE
Slide courtesy of Dr. Tse Wen Chang
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IgEanti-IgE complexes
3 IgE3 anti-IgE the largest Soluble and no
immune complex problems
T1/2 anti-IgE ca. 20 days, IgE 1-2 days,
IgEanti-IgE ca. 20 days Immune complexes
accumulate rapidly.
Could IgEanti-IgE complexes be beneficial? They
may serve as antigen sweepers, blocking antigens
to access receptors on inflammatory cells.
Slide courtesy of Dr. Tse Wen Chang
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Down regulation of FceRI in patients

• FceRI density on basophils falls by 97 in 3
  months.
• FceRI on basophils decreases with a half life of
  about 3 days.
• FceRI on dendritic cells are decreased
  substantially in two weeks.

From MacGlashan DW et al., J. Immunol. 1581438
(1997)
Slide courtesy of Dr. Tse Wen Chang
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Down regulation of FceRI in patients (cont.)
From MacGlashan DW et al., J. Immunol. 1581438
(1997)
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Allergy Immunotherapyteaching an old dog a new
trick, or teaching it not to do an old trick

• Introduce allergen in a non-threatening manner
  and context
• Elicit an IL-10 response from Treg cells instead
  of an IL-4 and TSLP response from Th2 cells.
• Thus, lead B cells to make the isotype switch to
  IgG4.
• IgG4 binds to mast cell inhibitory receptors and
  blocks activation.

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Mast Cells post Immunotherapy
IgE
FceRI
Allergen
IgG4
NO Mediator Release
FcgRIIb
Mast cell granules
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Question 1

• Which of the following cells is thought to be the
  primary effector cell in anaphylaxis?
• A. Eosinophils
• B. Basophils
• C. CD8 T cells
• D. Mast cells
• E. Th17 cells

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Question 1

• Which of the following cells is thought to be the
  primary effector cell in anaphylaxis?
• A. Eosinophils
• B. Basophils
• C. CD8 T cells
• D. Mast cells
• E. Th17 cells

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Question 2

• Which of the following cells promotes B cells to
  undergo an isotype switch to make IgE?
• A. Th1 cells
• B. Th2 cells
• C. Th17 cells
• D. Treg cells
• E. NKT cells

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Question 2

• Which of the following cells promotes B cells to
  undergo an isotype switch to make IgE?
• A. Th1 cells
• B. Th2 cells
• C. Th17 cells
• D. Treg cells
• E. NKT cells

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Question 3

• Fill in the blanks to make this statement
  correct A major hypothesis on how allergy
  immunotherapy works is the belief that ____
  promotes B cells to make ____.
• A. IL-4.... IgE
• B. IL-13.... IgA
• C. IL-10.... IgG4
• D. IL-18.... IgD
• E. Fractalkine.... Thymic Stromal Lymphopoetin
  (TSLP)

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Question 3

• Fill in the blanks to make this statement
  correct A major hypothesis on how allergy
  immunotherapy works is the belief that ____
  promotes B cells to make ____.
• A. IL-4.... IgE
• B. IL-13.... IgA
• C. IL-10.... IgG4
• D. IL-18.... IgD
• E. Fractalkine.... Thymic Stromal Lymphopoetin
  (TSLP)