User:Kinkreet/Immunology/Hypersensitivity cont.

On the first allergen exposure, dendritic cells will activate TH2 cells by binding to their MHC class II/antigen/TCR. TH2 will release IL-4 and IL-13 which activates B cells to release IgE, as well as IL-5 to encourage the degranulation of eosinophils and mast cells to induce an allergic reaction.

On the second allergen exposure, the IgE produced by B cells in the first exposure will quickly bind to the antigen and activate mast cells and basophils, which induces an acute response (acute because it is activated quickly, and dies down quickly, but of course, the chronic response may remain)

The cytokines environment (milieu) determines which TH cell type TH0 cells differentiate into. IL-4 and IL-13 drives B cells to produce IgE, which is skewed towards producing an allergic response. On the other hand, when IFNγ is in the environment, it induces B cell to produce IgG instead of IgE. IgG is the main antibody involved in the immune response, and is skewed towards a non-allergic immune response, because it does not cause the degranulation of mast cells or basophils.

Which response?
Before describing environmental factors which affects which effect takes place, Allergens are those which are good at activating the TH2 response. They are efficient at doing this because most are low molecular weight, highly soluble and stable proteins, able to pass through tissues and make it to the mucosa. They are also enzymatically active, which means only a low dose is required. It is also because of this low dose which makes the body recognize it as an antigen. When humans are stimulated with different doses of house dust mite allergens, a low dose gave high concentrations of IL-4 and low concentrations of IFNγ in the peripheral blood, signifying a TH2 response; when in high dose, the concentration of IL-4 is low and the concentration of IFNγ increases, signifying a TH1 response.

TH2 response
When an antigen presenting cell presents antigen to a TH0 cell, in a IL-4, IL-5 and IL-3 milieu, will differentiate into TH2 cell. The TH2 cell will then present that antigen to the B cell by displaying it on its own MHC class II molecules. In addition, it will present CD40L, which binds to CD40 on the B cell to provide the costimulatory response. The BCR binding and costimulatory signal only acts to activate the B cell, only when IL-4 binds to the IL-4R on the B cell will make the B cell switch to producing IgE. The IgE binds with high affinity to FcRε1 receptors and when the antigen binds to the bound-IgE, it causes IgE to cross link, and this it will signal for the degranulation of the mast cell. This signal is amplified because the mast cell provides further co-stimulatory and cytokine signals for the B cell to class switch to IgE. Basophils also expresses FcRε1 and can thus amplify the B cell response.

The release of granules can have different effects in different tissues. In the gastrointestinal tract, it can increase fluid secretion, peristalsis (the symmetrical contraction and relaxation of muscles which causes food to move down the tract); it decreases the diameter of the airways and increase mucous secretion, leading to congestion and blocking of the airways and swelling; it increases blood flow and blood vessel permeability, allowing more fluid to flow into tissues and lymphatic system, and stimulating effector responses.

The mast cell granules contain histamines, more cytokines, leukotrienes and prostaglandins. Histamine increases vascular permeability and cause smooth muscle contraction; IL-4 and IL-13 have already been mentioned to promote differentiation of TH0 cells to TH2 cells; TNF-α promotes tissue inflammation. Leukotrienes (such as C4, D4, E4) are fatty acid signal molecules which primarily signal for smooth muscle contraction, but also to increase vascular permeability and stimulate mucous secretion. Prostaglandins are chemoattractants for T cells, eosinophils and basophils, recruiting more cells to produce a bigger response. Basophils contains granules which contain mainly histamine and IL-4 and IL-13.

Eosinophils contains similar granule contents as mast cells, but also have toxic proteins and free radicals which kill off the micro-organism or parasite. Eosinophil is also special in that it can cause tissue remodelling - eosinophil peroxidase causes histamine to be released from mast cells; eosinophil collagenase causes remodelling of connective tissues; matrix metalloproteinase-9 causes matrix protein degradation. IL-3, IL-5 and GM-CSF encourage the bone marrow to produce more eosinophils. TGF encourages epithelial proliferation and myofibroblast formation. IL-8 attracts neutrophils.

Allergic Asthma
Allergic asthma is a TH2 response also termed extrinsic asthma, because it is driven by environmental factors such as pollen, HDM, plants and some foods. Asthma is characterised by episodes of wheezy breathing, narrowing of the airways and rapid changes in airway obstruction.

Normally, the inhaled antigen binds to IgE on mast cells and cross links them, leading to the release of bronchocontrictor mediators such as leukotrienes and prostaglandin D4 (PGD2), leading to smooth muscle contraction and restriction of the airways.

The antigen also binds to epithelial cells, which when activated releases stem-cell factor (SCF), which maintains the mucosal mast cells at the airway surface.

Both the mast cells and epithelial cells produce thymic stromal lymphopoietin (TSLP), which when exposed to dendritic cells, will cause the dendritic cell to produce CCL17 and CCL22, and these chemokines attract T<sub?H 2 cells to the site. As mentioned already, TH2 cells will amplify the signal for class switching to IgE, or production and proliferation of eosinophils (IL-5), basophil and mast cells (IL-9). Lastly epithelial cells release CCL11, which attracts eosinophils.

Normally, this process is regulated using Treg cells, patients with asthma have a defect in Treg which means their body produce an over-active response. Hypersensitivity are all classified based on the timeliness of the response, an acute response occurs within seconds of allergen exposure. The acute response is mainly caused by mast cell degranulation. Chronic asthma is where cytokines and eosinophilic products are constantly produced, this causes a chronic inflammation of the airways. As mentioned before, eosinophils can cause tissue remodelling using its enzymes, and this causes a permanent narrowing of the airways and can further damage tissues.

Hygiene Hypothesis
The hygiene hypothesis is the theory which explains why cases of allergies and asthma are increasing in developed countries. It is thought that genetics are modified with age, and so early exposure to pathogens will lead to a pro-inflammatory response, and not allergic response. To explain this hypothesis, people have proposed the immune regulation theory, which states that unhygienic environments boost regulatory circuits and increases the production of IL-10, a.k.a. the human cytokine synthesis inhibitory factor (CSIF), thus reducing the response to those pathogens which are presented to it early in life.

Treating Allergies
The symptom and the cause must be treated in parallel.

Symptoms
You can reduce the effect of the effector pathway by blocking the receptors associated with it, such as anti-histamines, which blocks the histamine receptor; or it can block the synthesis of specific mediators, such as lipoxygenase inhibitors; or you can prevent mast cell degranulation.

Cause
Allergen-specific immunotherapy (SIT) aims to desensitize patients by injecting increasing doses (high doses) of the allergen over a time period of years, so that the IgE production over time for this allergen would be decreased, and the T cell will not be as sensitive to the allergen. Instead, the TH1 cells would produce IFNγ instead, which encourage B cells to produce IgG, which does not lead mast cells, eosinophils nor basophils to degranulate. Furthermore, it promotes Treg1 to produce IL-10 and TGFβ, inhibiting cytokine production and proliferation, respectively, and thus down regulate T cell responses.