Hypersensitivity (????)

1
Hypersensitivity (????)

• Jianzhong Chen
• Institute of Immunology
• Zhejiang University School Of Medicine
• chenjianzhong_at_zju.edu.cn

2
Type II hypersensitivity(cytotoxic type)

• Type II hypersensitivity reactions are mediated
  by IgG and IgM antibody binding to specific cells
  or tissues. The damage caused is thus restricted
  to the specific cells or tissues bearing the
  antigen.
• The antibodies damage cells and tissues by
  activating complement, and by binding and
  activating effector cells carrying Fc?R.

3
I. Pathogenic mechanisms

• Ags on the surface of target cells
• ?
• body?IgG, IgM
• ?
• 1. damage the target cell
• 1) activation of complement
• 2) opsonization FcR, C3bR
• 3) ADCC NK cells, M?
  
• 2. target cell dysfunction

4
(No Transcript)
5
NK cell
opsonization
6
Effector mechanisms of Ab-mediated diseases
In myasthenia gravis the Abs against Ach receptor
inhibit neuromuscular transmission and cause
paralysis
Graves disease
7
II. Clinical disease

• 1. Transfusion reactions

A????B???? B???????A??
??
A??
?? ?? ??
A????
??
??
?????
8
2. Hemolytic disease of the newborn
Mainly occurs when an Rh- mother gives birth to
an Rh infant. Prevention The administration of
anti-Rh Ab to an Rh- mother within 72 hours of
delivering an Rh infant will prevent
sensitization and problems with subsequent
pregnancies.
9
(No Transcript)
10
(No Transcript)
11

• ????IgG??????Rh????,????????????????

12
3. Autoimmune hemolytic disease Some drugs or
viruses stimulate Ab formation by changing the
erythrocyte surface components to form new
epitopes. The resulting Abs can cross react with
epitopes on unmodified RBCs.
13
Human antibody-mediated diseases
14
4. Drug-induced reaction to blood components

• These diseases have been associated with
  many different chemotherapeutics, such as
  penicillin, the sulfonamides. These drugs
  stimulate Ab formation by forming new epitopes
  with serum proteins, which then adsorb
  nonspecifically to the red blood cell surface so
  that its new epitopes are expressed.

15
5. Graves disease
The patients produce antibodies to
thyrotropin (thyroid stimulating hormone, TSH)
receptor. The end result is overproduction of
thyroid hormone and hyperthyroidism.
16
(No Transcript)
17
Type III hypersensitivity(immune complex type)

• Immune complexes (IC) deposit in basement
  membranes of small blood vessels in various
  organs.

18
I. Pathogenic mechanisms

• Ag?body?IgG, IgM, IgA
• 
  ?
• immune complexes (IC)
• ?
• soluble IC
• ?
• ICs are deposited from the
  circulation
• into vascular basement membranes
• ?? ?
  ?FcR
• activation of complement plat. and basophils
• ?
• C3a, C5a ?mast cell ? release of vasoactive
  amines
• ? basophils
• ? Neutrophils
  vasodilation
• ?
• lysosomal
  edema
• enzymes?damage the tissue

aggravate
19
(No Transcript)
20
IC are capable of triggering a variety of
inflammatory processes

• ICs interact with the complement system to
  generate C3a and C5a. These complement fragments
  stimulate the release of vasoactive amines and
  are chemotactic factors for mast cells and
  basophils, eosinophils and neutrophils.
• ICs interact directly with basophils and
  platelets (via FcR) to induce the release of
  vasoactive amines.
• Neutrophils exocytose their lysosomal enzymes
  onto the site of IC deposition and damage the
  underlying tissue.

21
Deposition of IC in tissues

• An increase in vascular permeability
• In general, complement, mast cells,
  basophils and platelets must all be considered as
  potential producers of vasoactive amines.
• Local high blood pressure and turbulence
• The blood pressure in the glomerular
  capillaries is approximately four times that of
  most other capillaries.

22
II. Clinical diseases

• 1. Arthus reaction
• An animal is immunized repeatedly until it
  has appreciable levels of serum Ab (mainly IgG).
  Following subcutaneous or intradermal injection
  of the antigen a reaction develops at the
  injection site, sometimes with marked edema and
  hemorrhage.

23
Nicolas Arthus 1862-1945
24
Arthuss reaction (1903)
?????????,???????????????????????????
25
(No Transcript)
26

• 2. Serum sickness
• Serum sickness is a complication of serum
  therapy, in which massive doses of anti-serum are
  given in conditions such as snake bite.

27
Serum sickness(???)
Clemens Pirquet 1874-1929
28
3. Postinfectious glomerulonephritis
???A??????????2-3??????????????????,??????????
29
Human immune complex disease
30
4. Rheumatoid arthritis

• Rheumatoid factor (RF) an immunoglobulin (mainly
  IgM but also IgG and IgA) with antibody
  specificity for the Fc portion of IgG.
• The joint synovial fluid contains IC consisting
  of RF-IgG-complement.
• Many patients with rheumatoid arthritis also have
  antinuclear antibodies.
• 5. Systemic lupus erythematosus (SLE)
• antinuclear antibodies
• hypergammaglobulinemia

31
RA,SLE
???????????????????,??????????????????
32
SLE
33
Type IV hypersensitivity(Delayed type
hypersensitivity)

• Delayed type hypersensitivity is initiated by
  sensitized T cells reacting with specific
  antigens. The reactions are manifest as
  inflammation at the site of antigen exposure,
  which usually peaks 24-72 hours after exposure.
• This reaction is independent of antibody and
  complement.

34
I. Pathogenic mechanisms

• Ag-MHC
• Antigen?APC?T cells
• co-stimulating factors?
• sensitized T cell
• ?
• effector and memory cells
• ?
  ?
• CD4T cell (Th1 type) CD8T cell
  (CTL)
• ? ?
• release of cytokines killing target cells
• ? by the
  release of
• inducing the inflammatory perforin and
  granzymes
• response or
  by the FasL-Fas pathway
• (primarily M? and T cells)

35
Mechanisms of T cell-mediated tissue injury
36

37
II. Clinical diseases

• 1. Infectious DTH
• In the infective process, intracellular
  parasitical bacteria (Mycobacterium tuberculosis,
  Mycobacterium leprae, Brucella), viruses and
  fungi cause T cell-mediated immune responses,
  which are referred to as infectious delayed type
  hypersensitivity.

38
??????
39
Tuberculin-type hypersensitivity

• The tuberculin skin test (OT) reaction
  principally involves M?
• tuberculin?body?T cells are activated
• ?
• 
  IFN-??M??TNF?, IL-1
• 
  ?
• endothelial cells
  in dermal blood vessels
• 
  ?express
• CAM
  E-selectin, ICAM-1, VCAM-1
• 
  ?
• 
  recruiting monocytes and T cells
• (Monocytes
  constitute 80-90 of
• 
  the total cellular infiltrate)

40
Tuberculin-like delayed type hypersensitivity
reaction are used practically in two ways.

• 1) To confirm past infection with M.
  tuberculosis, but not necessarily active disease.
• 2) To be a general measure of cell-mediated
  immunity.

41
2. Contact dermatitis

• Langerhans cells and keratinocytes acting as APCs
  have key roles in contact hypersensitivity.
• Keratinocytes produce a range of cytokines.
• A contact hypersensitivity reaction has two
  stages sensitization and elicitation.
  Sensitization produces a population of memory T
  cells and elicitation involves recruitment of
  CD4 lymphocytes and macrophages.

42
????
????
43

• Many important sensitizing allergens are organic
  chemicals, and some are metals such as nickel,
  chromate. It is assumed that they function as
  haptens.
• When allergen again penetrates the skin, these
  memory cells rapidly evolve into effectors that
  mediate a delayed-type hypersensitivity reaction
  at the site of penetration.

44
T cell-mediated diseases
45
Comparison of 4 types of hypersensitivity
46
Thanks for your attention!