Hypersensitivity

Author : Dr. Saurav K Sarkar Discipline : B. Tech (Biotech)

Designation : Lecturer Semester : VI

Module : BT 501 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

NAME

TIME

MECHANISM

EXAMPLES

I

IgE-mediated hypersensitivity

Ag induces cross-linking of IgE bound to Systemic anaphylaxis, Local 2-30 mins mast cells with release of vasoactive anaphylaxis, Hay fever, Asthma, mediators Eczema

II

Antibody-mediated cytotoxic hypersensitivity

5-8hrs

Ab directed against cell-surface antigens Blood transfusion reactions, mediates cell destruction via ADCC or Haemolytic disease of the newborn, complement Autoimmune Haemolytic anaemia

III

Immune-complex mediated hypersensitivity

2-8hrs

Ag-Ab complexes deposited at various Arthus reaction (Localised); Systemic sites induces mast cell degranulation via reactions disseminated rash, arthritis, FcgammaRIII, PMN degranulation glomerulonephritis damages tissue

IV

cell-mediated hypersensitivity

24-72hrs

Memory TH1 cells release cytokines that Contact dermatitis, Tubercular lesions 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).

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Author : Dr. Saurav K Sarkar Discipline : B. Tech (Biotech)

Module : BT 501 Topic : Hypersensitivity

Designation : Lecturer Semester : VI

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

Histamine

Vascular permeability, sm contraction

Serotonin

vascular permeability, sm contraction

ECF-A

eosinophil chaemotaxis

NCF-A

neutrophil chaemotaxis

proteases

mucus secretion, connective tissue degradation

Allergens

Secondary mediators Leukotrienes

the population as a whole. Some individuals have multiple and severe allergies, typically both hayfever and eczema; these individuals are termed atopic and frequently have raised total serum IgE levels (10 -100 × normal). There is a correlation between total [IgE] and atopy.

vascular permeability, sm contraction

Prostaglandins vasodilation, sm contraction, platelet activation Bradykinin

vascular permeability, sm contraction

Cytokines

numerous effects including activation of vascular endothelium, eosinophil recruitment and activation

a list of common allergens.

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Numerous ideas have been put forward as to what property might distinguish antigens which stimulate a sufficient IgE response to generate type I hypersensitivity (allergens) from those antigens which rarely or never do so. However no common property has yet been discerned. below is

Author : Dr. Saurav K Sarkar Discipline : B. Tech (Biotech)

Module : BT 501 Topic : Hypersensitivity

Designation : Lecturer Semester : VI

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 Discipline : B. Tech (Biotech)

Module : BT 501 Topic : Hypersensitivity

Designation : Lecturer Semester : VI

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 IgMantigen 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 Discipline : B. Tech (Biotech)

Module : BT 501 Topic : Hypersensitivity

Designation : Lecturer Semester : VI

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 Discipline : B. Tech (Biotech)

Module : BT 501 Topic : Hypersensitivity

Designation : Lecturer Semester : VI

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.

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