Author : Dr.

Saurav K Sarkar Designation : Lecturer

Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Hypersensitivity

Objective: The student should understand :

1. What is Hypersensitivity
2. Types of Hypersensitivity
3. immune mediators involved in Hypersensitivity
4. Characteristics of Hypersensitivity diseases
Hypersensitivity
The term hypersensitivity is used to describe immune responses which are
damaging rather than helpful to the host. Nearly 40 years ago Gell and Coombs
proposed a classification scheme which defined 4 types of hypersensitivity
reactions. The first 3 are mediated by antibody, the fourth by T cells.
TYPE DESCRIPTIVE INITIATION MECHANISM EXAMPLES

NAME TIME

Ag induces cross-linking of IgE bound to Systemic anaphylaxis, Local

IgE-mediated
I 2-30 mins mast cells with release of vasoactive anaphylaxis, Hay fever, Asthma,
hypersensitivity
mediators Eczema

Antibody-mediated Ab directed against cell-surface antigens Blood transfusion reactions,

II cytotoxic 5-8hrs mediates cell destruction via ADCC or Haemolytic disease of the newborn,
hypersensitivity complement Autoimmune Haemolytic anaemia

Ag-Ab complexes deposited at various

Immune-complex Arthus reaction (Localised); Systemic
sites induces mast cell degranulation via
III mediated 2-8hrs reactions disseminated rash, arthritis,
FcgammaRIII, PMN degranulation
hypersensitivity glomerulonephritis
damages tissue

cell-mediated Memory TH1 cells release cytokines that

IV 24-72hrs Contact dermatitis, Tubercular lesions
hypersensitivity recruit and activate macrophages

Type I Hypersensitivity
This will be familiar to most people and describes the rapid ('Immediate') allergic reaction. The symptoms
produced by exposure of a sensitised person to antigen depend upon the site of contact. Hayfever (allergic
rhinitis), eczema, asthma and urticaria all result from type I hypersensitivity. It is caused upon contact with
antigen against which the host has pre-existing IgE antibody. IgE is present in very low levels in serum in most
people (see on) - c.50ng (ie 5 × 108gm) per ml. Its' half life in serum is only 2-3 days but much of the IgE in the
body is bound to high affinity receptors (Fc epsilonRI), in the bound state the half-life is ~3 weeks. The high
affinity Fc epsilonRI receptors are found on mast cells and basophils. Each cell has a high density of these
receptors (40-250,000 per cell) so that a wide spectrum of antigen specificities is represented. The cells are
activated by the cross-linking of the Fc epsilonRI receptors via antigen binding to the bound IgE molecules.
Such cross-linking leads to rapid degranulation (60-300 secs) of the mast cells and the release of primary
inflammatory mediators stored in the granules. These mediators cause all the normal consequences of an
acute inflammatory reaction - increased vascular permeability, smooth muscle contraction, granulocyte
chaemotaxis and extravasation etc. Mast cell activation via Fc epsilonRI also leads to the production of two
other type of mediators. These secondary mediators, unlike the stored granule contents, must be
synthesised de novo and comprise arachadonic acid metabolites (prostaglandins and leukotrienes) and
proteins (cytokines and enzymes).

1
 Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Hypersensitivity

Mirroring the two types of mediators, one can see two components to the type I response.A very rapid early
response occurs when you are challenged with an antigen to which you are sensitised which is apparent within
a few minutes and maximal after about 20 minutes. If the challenge is cutaneous it produces the so-called
'wheal and flare' - raised patch surrounded by a pink effusion. The late response seen after some hours is
characterised by cellular infiltrate which gives a hard but barely
pigmented nodule in the case of skin.
That these responses are caused by distinct mediators can be shown
with inhibitory drugs. Arachadonic acid metabolism inhibitors, such as
indomethacin, block only the late response. Sodium cromoglycate
which blocks mast cell activation and degranulation blocks both early
and late responses.
Incidence and genetic susceptibility
Some 20-30% of the population exhibit type I hypersensitivity or
atopic allergy to common environmental substances. There is a
genetic component to atopic allergy such that if both your parents
exhibit this susceptibility you are more than 2 × more likely to do so
and if neither parent has manifest allergies you are less than half as
likely to when compared to
Molecule Effects
Primary mediators the population as a whole. Some
individuals have multiple and
Histamine Vascular permeability, sm contraction severe allergies, typically both
Serotonin vascular permeability, sm contraction hayfever and eczema; these
individuals are termed atopic and
ECF-A eosinophil chaemotaxis frequently have raised total serum
IgE levels (10 -100 × normal).
NCF-A neutrophil chaemotaxis
There is a correlation between
proteases mucus secretion, connective tissue degradation total [IgE] and atopy.
Secondary mediators Allergens
Leukotrienes vascular permeability, sm contraction Numerous ideas have been put
forward as to what property might
Prostaglandins vasodilation, sm contraction, platelet activation distinguish antigens which
Bradykinin vascular permeability, sm contraction stimulate a sufficient IgE response
to generate type I hypersensitivity
Cytokines numerous effects including activation of (allergens) from those antigens
vascular endothelium, eosinophil recruitment which rarely or never do so.
and activation However no common property
has yet been discerned. below is
a list of common allergens.

2
 Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Hypersensitivity

Systemic anaphylaxis: While we are probably all familiar with the consequences of a localised type I reaction
(anaphylaxis) which are unpleasant and annoying, the consequences of a generalised reaction are potentially
fatal. Ingestion of nuts or seafood, insect bites (venom), and drug injection may all cause life-threatening
reactions in highly sensitised individuals. Death in such cases is due to systemic release of vasoactive
mediators leading to general vasodilation and smooth muscle contraction resulting in sudden loss of blood
pressure, massive oedema and severe bronchiole constriction (systemic anaphylaxis).
Type II Hypersensitivity
The second class of damaging reactions is caused by specific antibody binding to
cells or tissue antigens. The antibodies are of the IgM or IgG classes and cause
cell destruction by Fc dependent mechanisms either directly or by recruiting
complement via the classical pathway. Except where the reaction is autoimmune,
the target cells are foreign to the host. In practise this means type II
hypersensitivity reactions are usually only seen in blood transfusion recipients and
patients with certain autoimmune diseases. The classic ABO incompatibility
reaction is a type II, with IgM antibodies causing complement lysis of erythrocytes.
Rhesus disease (or haemolytic disease of the newborn) is a special example since
the IgG antibodies which cause destruction of foetal red blood cells by antibody
dependent cellular cytotoxicity (ADCC) are passively acquired by the host via the
placenta. You will hear more about these in the next lecture.
Because of cross-matching transfusion reactions are now rare, nevertheless
sometimes IgG can exist for minor blood group antigens at a level sufficient to
cause destruction of the transfused cells but too low to detect in vitro.
Type III Hypersensitivity
Type III hypersensitivity is mediated by immune complexes essentially of IgG antibodies with soluble antigens.
Recent experimental work has overturned longstanding assumptions about the mechanism of this form of
reaction so you will find that almost all the textbooks are out of date. It is now thought that this form of
hypersensitivity has a lot in common with type I except that the antibody involved is IgG and therefore not
prebound to mast cells, so that only preformed complexes can bind to the low affinity FcgammaRIII.
The Arthus reaction
The Arthus reaction is the name given to a local type III hypersensitivity reaction. It is easy to demonstrate
experimentally by subcutaneous injection of any soluble antigen for which the host has a significant IgG titre.
Because the FcgammaRIII is a low affinity receptor and because the threshold for activation via this receptor is
considerably higher than for the IgE receptor the reaction is slow compared with a type I reaction, typically
maximal at 4-8hrs, and consequently more diffuse. The condition extrinsic allergic alveolitis occurs when
inhaled antigen complexes with specific IgG in the alveoli, triggering a type III reaction in the lung, for example
in 'pigeon fanciers lung' where the antigen is pigeon proteins inhaled via dried faeces. Complement is not
required for the Arthus reaction, but may modify the symptoms.
Generalised or systemic reactions
The presence of sufficient quantities of soluble antigen in circulation to produce a condition of antigen excess
leads to the formation of small antigen-antibody complexes which are soluble and poorly cleared. In the
normal animal these complexes fix complement but experiments in animals genetically deficient in C3 or C4
have shown that complement is not required for pathology to be observed following antibody-antigen complex
challenge. The major pathology is due to complex deposition which seems to be exacerbated by increased
vascular permeability caused by mast cell activation via FcgammaRIII as above. The deposited immune
complexes trigger neutrophils to discharge their granule contents with consequent damage to the surrounding
endothelium and basement membranes. The complexes may be deposited in a variety of sites such as skin,

3
 Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Hypersensitivity

kidney and joints. Common examples of generalised type III reactions are post-infection complications such as
arthritis and glomerulonephritis.
Type IV Hypersensitivity
This is the only class of hypersensitive reactions to be triggered by antigen-specific T cells. We would now call
these TH1 cells but they were originally termed TDTH after the alternative name for this reaction - delayed type
hypersensitivity. .
The classical mechanistic explanantion is illustrated above. Delayed type hypersensitivity results when an
antigen presenting cell, typically a tissue dendritic cell which has picked up antigen, processed it and displayed
appropriate peptide fragments bound to class II MHC is contacted by an antigen specific TH1 cell patrolling the
tissue. The resulting activation of the T cell produces cytokines such as chemokines for macrophages, other T
cells and, to a lesser extent, neutrophils as well as TNFbeta and IFNgamma. The consequences are a cellular
infiltrate in which mononuclear cells (T cells and macrophages) tend to predominate. It is usually maximal in
48-72 hours.

The problem which this explanation faces is the rarity of antigen-specific T cells. Despite the fact that "memory
T cells", unlike naive T cells, do circulate through tissues, there is some doubt that a single T cell could initiate
the event. The answer to this conundrum may lie in the recent observations that at least some Type IV
reactions absolutely require the presence of 'natural' IgM antibody for initiation. Due to the nature and kinetics
of the reaction it is still believed that activation of memory TH1 cells is primarily responsible for propagating the
reponse, but initiation may
require IgM and probably
also complement. One
theory is that limited IgM-
antigen complexes in local
capilliaries may lead to a
limiting, localised
complement activation
within the vessel activating
the vascular endothelium
and thus recruiting
inflammatory cells including
memory T cells.

The classical example of delayed type hypersensitivity is in tuberculosis but this will be covered in the Lent
term. A more familiar example is contact hypersensitivity which results from exposure of certain individuals to
metal salts and small reactive chemicals. It is important to note that in such cases the antigen must be a
complex of the hapten and a self peptide and T cells specific for Ni++ and reactive chemicals eg
dinitrofluorobenzene have been isolated.
Chronic Inflammation- Immune aspects
Chronic inflammation is a process that takes place when an immune stimulus persists for a prolonged period
of time, beyond that in which the immune system would normally have eliminated the antigen. There are three
general types of situation in which this may occur
• an infection in which the host immune response fails to eradicate the organism
• environmental antigen in which there is persistent or frequent exposure
• autoimmunity

4
 Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Hypersensitivity

A good example of the first case is Mycobacterial infection. This will be considered next term. We will consider
a single example of the latter two situations and, since you have already discussed the inflammatory and
histological aspects of chronic inflammation, we will restrict our consideration to the immunological aspects.
Asthma
Asthma is essentially a disease in which the primary
physiological manifestation is reversible airflow limitation.
Although clinical asthma is subdivided into extrinsic (ie where
there is a recognised external trigger) and intrinsic (where the
trigger is either non-antigenic or not recognised) forms, it is
believed that in all cases the initial development of the
condition involves type I hypersensitivity to an inhaled
antigen. Nevertheless most individuals with such
hypersensitivity do not go on to develop the chronic
inflammatory condition which we term asthma, whose
definition includes long-term changes such as connective
tissue deposition and hypertrophy of the bronchial smooth
muscles in addition to inflammatory and immunological
criteria.
In cases of extrinsic asthma, the patient is believed to be chronically or periodically exposed to the antigenic
stimulus at very low level, which may not always trigger an clear response. This exposure leads to a
hyperreactivity of the bronchioles to inflammatory mediators. If you measure the reduction in airway function
after experimental intrabronchial challenge with an inflammatory mediator (eg histamine), asthmatics show a
characteristically high sensitivity which is related to the severity of their disease.
What is the cause of this hyperreactivity? One clue is that the effect is reversible, so that asthmatics who are
rigorously isolated from triggering stimuli gradually lose hyperreactivity over a period of months. This loss
correlates with changes in the cell populations found in the lungs. Asthmatics have an increase in mast cell
density and a very significant increase in both eosinophils and T cells. The abnormal cell accumulations are
believed to be antigen-driven by stimulation of the TH2 cells found in the lungs of asthmatics. Cytokines
produced by TH2 cells can stimulate eosinophil production, recruitment and activation. In addition a poorly
characterised factor has been observed to 'prime' mast cells so as to reduce their threshold for activation.
Rheumatoid arthritis
Although we are extremely ignorant about the causes of this autoimmune disease, and for example the roles
played by ' rheumatoid factor ' (IgM anti-IgG antibody) and antibody glycosylation, it is a chronic inflammatory
disease which there is
an immune response
dominated by TH1 cells,
akin to type IV
hypersensitive reactions.
We know that the
inflammation can be
temporarily eliminated
(almost) either by
causing destruction of
most of the T cells (by
eliciting a type II reaction
after infusion of a
suitable monoclonal

5
 Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Hypersensitivity

antibody) or by a short course of treatment with anti-TNFalpha monoclonal antibody. This amelioration lasts for
a few months.
The implications of this are that the continuous stimulation of T cells is required to maintain the inflammatory
process and that TNFalpha plays a key role in that process. The currently accepted view is that whatever
initiates the disease, once joint damage is established it is a self-perpetuating process in which auto-antigens
released as a result of the damage stimulate T cells which recruit and activate macrophages which lead in turn
to further damage, the maintenance of inflammation - via vascular endothelial activation - and the perpetuation
of the proliferation and cytokine secretion of local TH1 cells. Presumptively the key cytokines are TNFalpha and
IL-12 released by macrophages and IFNgamma from T cells.