Chapter 14: Hypersensitivity Reaction Type IV, Cell Mediated Delayed Reaction
Type-IV DELAYED OR CELL MEDIATED HYPERSENSITIVITY REACTION (CMI)
In Type-IV Hypersensitivity there is no role of Ab and no role of complement.
This is mainly dependant on T-lymphocytes activity.
Type-IV reaction is characterized by cellular infiltrate, composed mainly of lymphocytes and macrophagic cells. This inflammatory infiltrate appears at least 24 hours after the challenge with the provoking stimulus. The macrophagic cells in this lesion frequently fuse to form giant cells and epitheloid cells.
This reaction is mostly due to organisms that grow in the cell and resists killing e.g. T. bacilli, viruses and fungus.
This reaction may take place by the Single Ag challenge.
The delayed reaction may be divided into the following four categories and Reaction appearing within 72 hours.
- Jone- Mote phenomenon: – This reaction appears within 24 hours. Peak 1-6 days. There is swelling of the skin. Microscopic examination shows predominantly the presence of basophils.
- Contact hypersensitivity reaction: – This reaction appears after contact with Ag and peak reaction is at 48-72 hours.
Clinically the picture is like eczema. Ag which can give this reaction e.g. Nickle, Chromate, Rubber industry and poison IVY.
Microscopically there are lymphocytes infiltrate with the presence of macrophagic cells accompanied by edema. Microvesicles may be seen in the epidermis.
- Tuberculin hypersensitivity: – This reaction was first described by Robert Koch where Purified protein derivatives (PPD) were injected subcutaneously. The reaction peak appears after 48 to 72 hours. This reaction gives the status of previous sensitization. There is local induration at the site of injection.
Microscopically there are lymphocytes and macrophagic cells infiltrate.
- Granulomatous type:- This is a more serious condition. Its peak level is seen after at least 14 days. Skin shows induration and even sometimes ulceration. This may be due to tuberculosis or chemical like talc.
Microscopically there is the presence of typically epitheloid cells, lymphocytes and multinucleated giant cells giving rise to typical granuloma look.
Robert Koch’s Phenomenon
Robert Kock in 1890 injected Tubercle bacilli to Rabbit. The rabbit developed signs and symptoms after 2 – 3 weeks as follows:-
- Enlargement of lymph nodes.
- Enlargement of the liver.
- Local ulcer.
- Healing took 4 – 6 weeks.
When later on this immunized Rabbit was exposed to tuberculous bacilli. He showed only induration after 24 hours and peak reaction was between 48 to 72 hours.
Mantoux Test or Tuberculin Test (TT)
This test is based on the Robert Koch’s phenomenon. It gives an idea of immunization or status of immunization and the possibility of active tuberculous disease.
Tuberculin (PPD) is injected intradermally. The reaction appears after 4 to 8 hours and the peak is 48 to 72 hours.
Initially, there is erythema and neutrophil infiltration. This is followed by mononuclear cells (lymphocytes and macrophage) infiltrate causing induration at the site of injection.
Induration 5-10 mm is positive means that the person has previous exposure to tuberculous bacilli or has a history of immunization.
- Negative means = There is no history of previous exposure to tuberculosis.
- False-positive = There may be a false-positive reaction in patients on cortisone therapy.
Mechanism of CMI
The mechanism can be explained in two ways:
A. This was described by Dumond who gave the name to different lymphokines produced by the activated CD4+ T-lymphocytes (Inflammatory cells-Th1).
Activated CD4+ cell produces lymphokines, named as follow:
- Macrophage chemotactic factor (MCF)
- Macrophage inhibition factor (MIF).
- Macrophage activating factor (MAF).
- Specific macrophage activating factor (SMAF).
- Neutrophil chemotactic factor. This attracts polys, monocytes, eosinophils, and lymphocytes.
- IL-2 also called T-cell growth factor.
- Skin reactive factor.
- Interferon- γ . This activates macrophagic cells and it is antiviral.
- Lymphotoxin (TNF- b) It can lyes the tumor cells.
- TNF-α- it affects the endothelial cells.
- TF (Transfer Factor), this will transfer the memory of the exposed Ag.
B. Antigens after processing by APC when presented along with MHC-II molecule stimulates CD4+ (Th0) which in turn transforms to Th1, which gives CMI and Th2, which stimulate B-L. Another possibility is that if APC presents Ag along with MHC-I, then CD8+ cells are stimulated. These events can be shown in the following diagram:
TNF-α and Lymphotoxin
- Increase secretion of prostacyclin which leads to vasodilatation.
- Increase expression of E- selectin.
- Chemotactic factor.
All the above (1, 2, 3) functions ultimately lead to extravasation of lymphocytes and monocytes at the site.
Summary: The Mechanism of Type IV CMI can be summarized as Follows.
Mainly type IV CMI is by activation of CD4+ Th1 cell, which gives rise to granuloma formation by the release of lymphokines.
T-L (CD8+Tc) Cytotoxicity
Tc cells cause lysis on cell contact and there is no killing of bystander cells. Because lytic molecules are released only at the site of TCR contact.
Figure 113 – T-cell Cytotoxicity
Tc-cell Cytotoxicity is important in:
- Graft rejection
- Viral infection
- Tumor immunity
Mechanism of killing:
There is a killing of the target without phagocytosis.
This may take place by means of:-
- Perforin, granzyme dependant killing which drills holes in the cell membrane in the presence of calcium (just like C9).
- Proteolytic enzyme production: (lymphotoxin) activates an enzyme in the target cells to cleave DNA in the Nucleus. There is the presence of clumps of nuclear DNA. this looks to be a consequence of the process of programmed cell death or apoptosis.
Causes of Type IV
- Bacterial causes are Mycobacterium tuberculosis, Brucellosis, Leprosy, and Syphilis.
- Viral causes are Smallpox, Measles, Herpes simplex.
- Fungal cause is Candidiasis, Histoplasmosis, and Coccidioidomycosis.
- The protozoal cause is Leishmaniasis.
- Chemical causes are hair dyes, nickel salt, chromium, potassium dichromate, silicosis, and berylliosis.
- Drugs causes are penicillin and neomycin.
What is the Difference between Necrosis of Type-III Immune Complex Disease and Type-IV CMI?
Type-III necrosis is dependant on complement and neutrophils while type IV is dependant upon T-lymphocytes and macrophages.
- A corticosteroid may be given.
- Antibodies like anti-lymphocytes and anti-thymocytes may be tried.
- Cytotoxic drugs like azathioprine, cyclosporin, and cyclophosphamide may also be used.
- Treatment of specific disease like tuberculosis, need anti-tuberculous therapy.
|Type-I, anaphylactic, immediate and atopy||Type-II cytotoxic||Type-III immune- complex disease||Type-IV delayed-type, cell-mediated immunity|
|Depends||IgE||IgG, IgM||IgG. IgM, IgA||T-lymphocytes|
|Passive transfer with||IgE, cytotropic Ab||Ab||Ab||T-L|
|Antigen||Heterologous||Autologous||Auto or heterologous||Auto or heterologous|
|Complement||No||Yes or No||Yes||No|
|Cells involved in the initiation||Mast cells basophil||None||None||APC, T-L, macrophages|
|Target tissue||Vascular endothelium, bronchi, smooth muscle,||Blood or tissue cells||vascular and epithelial cells||Modified self infected cells|
|Mechanism||Ag + IgE mast cells basophils and chemical mediators||Ig + tissue Ag = C-activation = lysis , opsonization, and ADCC||Ag + Ab =C-activation,Mast cells and Neutrophil activation||CD4+ activated =mediators, CD8+= cytotoxic|
|Inflammatory cells attracted||Eosinophils and neutrophils||Neutrophils||neutrophil||monocytes and macrophage|
|Primary results||Increase vascular permeability, increase transudation erythema, edema, wheal, bronchospasm||cell lysis, phagocytosis, inflammation, and decreased C||vasculitis, necrosis, thrombi, vasoconstriction, decreased C||Erythema, induration, granuloma formation|
|Treatment||Avoidance, antihistamine, steroids||Immunosuppressant, steroids||Immunosuppressant, steroids||Anti-inflammatory, steroids|
|Example||Drugs, hay fever, bees, food, vaccines||Glomerulonephritis, SLE, HD of newborn, blood transfusion reaction, autoimmunity||Arthus reaction, serum sickness, chronic GN, SLE, Rheumatoid arthritis, vasculitis||Contact dermatitis, tuberculosis fungal and viral infection, Graft, rejection|
|General beneficial effects||IgE secretions, resistance to the parasite, the expulsion of inhaled pathogens by wheezing, and GI secretions||Anti-bacteria, and antiviral||Acute inflammation, neutrophil activation||Immunity to T.B, virus, and fungus|
Table XXI – Comparison of Hypersensitivity Reactions