Hypersensitivity: Type 1 – Causes

00:01 Right, now having given you a little overview of those four different types, let’s now look in a bit more detail at each one. So Type I hypersensitivity - IgE-mediated mast cell degranulation.

00:15 You’ve already seen this picture.

00:17 So these Type I hypersensitivity reactions, IgE-mediated mast cell degranulation.

00:22 That’s what we usually think of as allergic types of responses, allergy.

00:27 And this type of response often referred to as atopy, an inappropriate production of IgE antibodies is caused by a multitude of different factors.

00:38 Genetics is important, but other factors also are important.

00:43 Regarding the genes, there is not a single dominant allergy gene; it’s rather that several genes contribute to the development of the allergic process.

00:54 Amongst them, the gene encoding the FcεR1, the gene encoding the cytokine interleukin-4 which is very important in causing B-cells to class switch to IgE production, CD14, HLA-DR, there are a number of different genes.

01:11 So it’s really the combination of genes that’s important, not any one single specific gene.

01:17 And of course the environment is also very important, it’s not a purely genetic situation we have here.

01:23 And early microbial exposure, and early allergen exposure perhaps in the uterus seem to play an important role.

01:31 Immune responsiveness overall is abnormal, with a decreased production of gamma interferon, and perhaps overall a more Th2 type of environment with those Th2 cells that secrete cytokines such as interleukin-4 and interleukin-5 and interleukin-6. They’re the more dominant population.

01:53 And remember, all of these responses are normal responses.

01:56 So a Type I hypersensitivity reaction is based upon something that is a normal protective immune response.

02:01 For example against a parasitic worm infection.

02:04 If you have a parasitic worm infection in your gut for example, you’d be very grateful to having this sort of response because it would help expel the worms from the gut.

02:15 However in a substantial minority of individuals, IgE-mediated mast cell degranulation occurs in response to what should be a harmless environmental antigen.

02:25 And afterall, grass pollen is not going to cause you any harm, but in a significant number of people, there’s a response to this that actually leads to pathology.

02:34 Maybe you yourself suffer from allergies.

02:36 You’ll certainly know people that do, because it’s a very common affliction of people to suffer from these allergic reactions.

02:45 In Type I hypersensitivity, there’s an immediate IgE response, but this resolves within around about an hour.

02:55 However it is frequently followed by what is referred to as the late phase reaction.

03:01 This occurs around about 4-12 hours later.

03:03 And it involves CD4+ helper T-cells, monocytes and eosinophils becoming activated.

03:14 So there are a number of different types of atopic allergy, that is allergy caused by excessive production of IgE.

03:22 Rhinoconjunctivitis which you may know as hay fever, affects around about 20-35% of individuals.

03:30 Asthma affects around about 10-20% of individuals, atopic eczema again around about 20% of individuals, urticaria similar kinds of numbers, food allergy maybe around about 3-5% of individuals develop food allergy, and insect venom hypersensitivity in about one in a hundred people.

03:57 We use the term anaphylaxis to describe a severe systemic hypersensitivity to allergen in an injection, a sting or by epithelial exposure, for example in the gut mucosa.

04:13 It involves a rapid vasodilation which leads to a substantial drop in blood pressure.

04:21 There is constriction of the airways, edema and anaphylactic shock can result that is often fatal.

04:32 However, immediate administration of epinephrine can reverse the bronchoconstriction and vasodilation and rescue the patient.

04:45 Let’s have a look at some of the mediators that mast cells produce that contribute towards the inflammatory process.

04:53 We can divide these mediators into two groups.

04:56 Ones that have already been made by the mast cell and are stored within granules within the mast cell.

05:03 And then newly synthesized mediators that are made from arachidonic acid.

05:10 Histamine is the classical mast cell inflammatory mediator.

05:14 It causes smooth muscle contraction and an increase in vascular permeability.

05:20 Heparin is produced and stored in granules, and this is an anticoagulant.

05:26 And eosinophil chemotactic factor is a third example of a pre-made mediator stored in the granules, and this as its name suggests mediates eosinophil chemotaxis.

05:39 So all these substances are ready to go, and the second the mast cell degranulates, they can mediate their effects.

05:46 Regarding the newly synthesized mediators, prostaglandin D2, prostaglandin E2 and prostaglandin F2α can mediate smooth muscle contraction and increase vascular permeability just like histamine.

06:01 Leukotriene B4 is a chemotactic factor for neutrophils.

06:08 And leukotriene C4, D4 and E4 cause smooth muscle contraction and vascular permeability again just like the prostaglandins and the histamine.

06:19 Let’s look at how the leukotrienes and prostaglandins are synthesized.

06:25 They are both produced from phospholipids, by the use of phospholipase A2 to generate arachidonic acid.

06:34 Then either via the lipoxygenase pathway which produces leukotrienes or via the cyclooxygenase pathway involving COX1 and COX2 which produces prostaglandins, these mediators are generated within the mast cell.

06:56 This is a list of allergens.

06:59 You’ll be very familiar with many of these I am sure.

07:02 So they include things like pollens, things associated with animals like animal dander, house dust mites and so forth, molds, various chemicals, and a number of food allergens.