Immunology pdf - د.أحمد الحربي

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Hyper sensitivity reactions (Type II, III, and IV)

Objectives:

The main objectives of this lecture are to:

 Understand the mechanism of TYPE II, III, and type IV HSR

 Explain examples for diseases caused by the above 3 types of HSR.

Type II Hyper sensitivity reaction: (Tissue-specific,
or Cytotoxic hypersensitivity).

Mechanism of Type II HSR includes:

Antibodies produced by the immune response bind to the antigens on the patient’s own cell

surfaces such as circulating red blood cells, and extracellular materials (basement membrane).

 The resulting Ag-Ab complexes

EITHER:

Activate complement (via the classical pathway), leading to cell lysis or extracellular tissue

damage, OR opsonization of the target cell via C3b.

In this diagram, a red blood cell has
antigen  fixed  on  its  surface  to
which  antibody  attaches.  The
attached  antibody  activates  the
complement  cascade,  which  ends
with  the  formation  of  the
"Membrane Attack Complex“ MAC
of  C5-9  which  causes  lysis  of  the
cell.

Other

complement

components may be generated,
such as the opsonin C3b Induces
phagocytosis (1).

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Diseases under this category include:

• Transfusion reactions: incompatibility reaction.

• Autoimmune hemolytic anemia: antibodies made against one's own RBC's.

• Erythroblastosis fetalis: due to Rh incompatibility between maternal and fetal blood.

• Goodpasture's syndrome: due to presence of anti-glomerular membrane antibodies.

The Ab-Ag reaction be independent from complement activation and dependent on cellular

activation and called (Antibody-dependent cell-mediated cytotoxicity (ADCC)):

Low concentrations of Abs coat target cells. Inflammatory cells as NK cells, monocytes, and
granulocytes then bind to the immunoglobulin Fc receptors and lyse, but do not phagocytize,
the target cells.

 Diseases of ADCC include:

• Transplantation rejection

• Immune reactions against neoplasms

• Immune reactions against parasites

ADCC Complement independent
cytotoxic HSR.

In the given

diagram,  a  macrophage  with  Fc
receptors  on  its  surface  is  able  to
recognize a target cell coated with
antibody  via  the  Fc  receptor
portion  of  the  attached  antibody.
The

macrophage

can

then

demolish the targeted cell by
elaboration of proteases.

This reaction is complement
independent (1)

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

. Anti-receptor antibodies:

IgG antibody is directed against receptors in target cells, either resulting in complement-
mediated destruction of the receptors, blocking or activation of receptors.

Diseases caused by this mechanism include:

  Myasthenia gravis: acetylcholine receptor antibody (blocking Ab).
  Graves’ disease (thyrotoxicosis): anti-TSH receptor antibody  ( Activating Ab)
  Pernicious anemia: anti-parietal cell antibody causing B12 deficiency

Complement activation in type II HSR:

• Activated C3 forms opsonin (C3b and C4b) recognized by phagocytes

• Formation of membrane attack complex (lytic enzymes)

• Formation of anaphylatoxins C3a and C5a.

Anti-receptor Antibodies

In  this  diagram,  antibody  is  directed
against acetylcholine receptors at the
motor end plate of a muscle, blocking
the  receptors  and  diminishing  the
muscular  response.  This  is  the
mechanism  for  muscle  weakness  in
myasthenia gravis (1).

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Type III HSR:

Immune Complex–Mediated (ICM HSR).

 Soluble circulatory antigens (not bound to any cell surface) causing immune complex

mediated injury. They are either exogenous or endogenous Ags.

 The reaction may occur 3 - 10 hours after exposure to the antigen.

Type III HSR can cause:

 Localized reactions as in:

 Hypersensitivity pneumonitis

 Post streptococcal glomerulonephritis

 Local vasculitis after vaccination ( Diphtheria and tetanus)

 Systemic reactions as in:

 Serum sickness

 Systemic lupus erythematosus

 Rheumatoid arthritis

Mechanism of Type III Hypersensitivity:

 Antigens bind to antibodies within circulation forming immune complexes.

 The formed immune complexes will be deposited any where in the body organs.

 Complement system will be activated and polymorph nuclear cells will be recruited

 The activated complement system leads to:

 Release of anaphylatoxins ( C3a and C5a)

 Production of C3b and C4b which are opsonizing and chemotactic factors

 MAC formation (membrane attack complex C5b-C9).

 The recruitment of the Polymorph nuclear cells resulting in inflammation and tissue

injury.

 Activation of platelets and Hagmen (Factor XII) leading to thrombosis of the micro

circulation and necrosis. FXII also can cause vasodilation through activation of kinins

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Diagram for mechanism of Type III HSR and role of Hagman factor (2)

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Local Reactions (

Arthus Reaction):

Inflammation caused by the deposition of immune complexes at a localized site.

Exogenous Ag may cause the Arthus reaction as in: Intrapulmonary Arthus-like
reactions in human which occurs due to inhaled antigen associated with farmer’s lung
and extrinsic allergic alveolitis.

Systemic form of Type III reaction (Serum Sickness): It may take place in these situations:

A. Introduction of:

1. Equine serum therapy, which is usually given as anti-toxin

2. Vaccines

3. Anti-lymphocyte globulins

4. Streptokinase

5. Hymenoptera venoms

6. Penicillin or other antibiotics.

B. After infections as bacterial infections, e.g. post-streptococcal glomerulonephritis or
after viral infections as Hepatitis B or post malarial infections.

C. It may occur after disseminated malignancies & autoimmune diseases

Clinical picture includes:

  Fever
  Lymphadenopathy
  Splenomegaly
  Arthritis
  Glomerulonephritis
  Endocarditis
  Vasculitis
  Urticarial rashes
  Abdominal pain
  Nausea and vomiting.

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Type IV hypersensitivity reaction (Cell-mediated HSR,
Delayed type HSR):

It is mediated by antigen-specific effector T cells.

 The term “delayed” refers to the cellular response that generally becomes apparent 48–

72 h after antigen exposure

Examples of type IV HSR:

 Tuberculin and leishmanin tests.

 Cellular responses to intracellular pathogens such as mycobacteria, fungi, and

intracellular parasites.

 Graft rejection and graft versus host reactions.

 Granulomatous inflammation as occurs in Crohn’s disease and sarcoidosis.

 Tumor immunity

 Some autoimmune reactions

 Contact allergy and allergic contact dermatitis: A well-known example of allergic contact

dermatitis is the reaction provoked by the lipid-soluble chemicals as urushiol oil , and
Ivy poison .

Intracellular microorganisms and contact Ags. associated with DTHSR:

  Bacterial  infections
  Mycobacterium tuberculosis
  Mycobacterium leprae
  Listeria monocytogen
  Brucella abortu

  Fungal infections
  Candida albicans
  Pneumocyctis carinii
  Histoplasma capsulatum
  Cryptococcus neoformans

  Viral infections
  Herpes simplex virus
  Small pox
  Measles

  Parasitic infections
  Leishmania SPP
  Toxoplasma gondii

   Contact Ags
  Hair dyes
  Nickle SALTS
  Poison Ivy
  Poison oak

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Mechanism of Type IV HSR:

Sensitization stage:

A. Memory Th1 cells against DTH antigens are generated by dendritic cells during the

sensitization stage.

B. These Th1 cells can activate macrophages and trigger inflammatory response.

Effector stage:
Secondary contacts yield what is called DTH.

  Th1 memory cells are activated and produce cytokines as :
•  IFN –gamma and TNF, which cause tissue damage and inflammation.
•  IL-2 activates T-cells and CTL.
•  Chemokines act for macrophages recruitment.
•  IL-3, GM-CSF increase the monocyte/macrophage.
  Inflamed area becomes red and fluid filled.
  Due to tissue damage there is activation of clotting cascades and tissue repair
  Continued exposure to antigen can cause chronic inflammation and result in granuloma

formation

Mechanism of Type IV HSR (5)

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Abbreviations and their meaning:

  MCAF : Monocyte chemotactic and  activating factor
  CTLs : cytotoxic T-lymphocytes
  TH1 : T-helper 1
  GM-CSF: granulocyte macrophage colony stimulating factor
  MIF : Macrophage migration inhibitory factor
  MHC : Major histocompatibility complex
  APCs antigen presenting cells

Contact dermatitis

 The response to poison oak is a classic type IV HSR.
 Small molecules act as haptens and complex with skin proteins to be taken up by APCs

and presented to Th1 cells to get sensitization.

 During secondary exposure Th1 memory cells become activated to cause DTH.

Contact dermatitis (5, 6)

College of Medicine University of Mosul /Department of: Microbiology
Subject: Microbiology-Immunology Stage: 3

2021-2022

Lecturer: Dr. Ahmed Alharbi Date: 22/12/2021 No. 2

Pag

Time required by number of DTH examples to appear
Delayed Reaction

Maximal reaction time

Contact dermatitis 48-72 hours
Tuberculin test

48-72 hours

Granuloma formation at least 14 days

Patch test:

  Any individual suspected of having allergic contact dermatitis may need patch test.
  Patches with specific allergens will be applied on skin for 2-3 days.
  Patch testing helps identify which substances may be causing a delayed-type allergic

reaction in a patient, and may identify allergens not identified by blood testing or skin
prick testing.

 It is intended to produce a local allergic reaction on a small area of the patient's back,

where the diluted chemicals are planted. The chemicals included in the patch test kit are
the offenders in approximately 85–90 percent of contact allergic eczema, and include
chemicals, food, drink, preservatives----- etc.

Patch test (7)