Understanding type-1 hypersensitivity reaction

Introduction


The ability of our immune system to respond to, and attack potential harmful foreign agents is very important. Perhaps, even more important is the ability to recognize and attack potential harmful foreign substances while ignoring other foreign substances. Note that the emphasis here is ‘potential harmful foreign substances’ and not just any foreign substance. Thus, a healthy immune system must be able to distinguish harmful foreign substances from everything else.

The term hypersensitivity describes a pathologic/inappropriate immune response to a harmless antigen. The inducing antigen could be foreign or self. Autoimmune disease describes the inappropriate immune reaction to self-antigens.

However, the immune systems of some individuals respond inappropriately to harmless foreign substances, and even to self-proteins. Such inappropriate immune reactions constitute hypersensitivity reactions.

During normal immune responses, the damage on host tissues is minimal and relatively insignificant, whereas hypersensitive immune responses mounted against some foreign antigens may have serious and even fatal consequences on the host and may even result in death.

Classes of hypersensitivity


Based on the hypersensitivity mechanism, molecular mediators, and distinct cell types involved, we have four classes of hypersensitivity reactions called

  1. Type-1 hypersensitivity
  2. Type-2 hypersensitivity
  3. Type-3 hypersensitivity
  4. Type-4 hypersensitivity

Type-1 hypersensitivity


Type-1 hypersensitivity, also called IgE-mediated hypersensitivity is an inappropriate immune response to non-self antigens. Type-1 reactions occur within 2 to 30 minutes after contact with inciting foreign antigen, hence the name immediate hypersensitivity reaction.

Type-1 hypersensitivity

  • also called immediate hypersensitivity or allergy because it occurs immediately after contact with allergen
  • is mediated by immunoglobulin-E (IgE); non-allergic individuals produce significantly small amounts of IgE class of antibody
  • forms the pathologic basis of allergic reactions and allergic diseases
  • is triggered by allergens present in, the atmosphere, irritant food particles, and certain drugs
  • can manifest as a mild reaction such as urticaria, allergic rhinitis, hives, atopic dermatitis, etc or as severe life-threatening reactions such as acute severe asthma and anaphylaxis
  • may be local as well as systemic

Understanding allergy (type-1 hypersensitivity) and allergens


Allergy is an inflammatory immune reaction to a potential harmless foreign antigen. There are certain substances present in the atmosphere, the food we eat, and the drugs we take, that normally are unable to provoke a response by the immune system. However, some genetically susceptible individuals develop sensitivity when exposed to these harmless substances. These sensitivities manifest as inappropriate immune reactions, which constitute allergic reactions.

Nevertheless, note that not all immune intolerances and hypersensitivity reactions are forms of allergy. The only hypersensitivity reactions categorized as allergic reactions are type-1 hypersensitivity reactions.

Allergen: an allergen is a foreign antigen that triggers an allergic reaction. Even if the body fails to attack and destroy the antigens, they cause no harm to the body. However, if a person is sensitive to the foreign antigen, the person’s body mounts an inflammatory response aimed at getting rid of the foreign antigen.

Practically, allergen may be any foreign molecule: organic or inorganic, naturally occurring or synthetic. Common examples of allergens are foreign proteins found in pollen grains, dust particles, animal dander, irritant drugs such as penicillin, irritant food particles, fumes, etc. Generally, we encounter allergens through direct contact with the skin, by ingestion, inhalation, and injection.

Factors that predispose an individual to allergy


Actually, not all individuals that encounter a particular allergen develop an allergic reaction. Atopic individuals are individuals who are prone to IgE-mediated allergic reactions. Allergic reactions occur in individuals genetically susceptible. Such individuals produce more IgE antibodies than necessary. Normally, the amount of IgE produced by a non-allergic person is significantly low when compared to other antibody subtypes.

Obviously, genetic component is a strong determinant whether a person will develop allergy or not. Meaning that if parents have pollen allergy, chances are good that children will develop it too. Perhaps genetic factor plays a major role in determining whether an individual will develop allergy or not. However, other non-genetic factors may also contribute to the development of allergic diseases. Among the non-genetic factors are

  1. the presence of other diseases and general state of health
  2. the quantity of allergen the individual encounters
  3. nutritional status of the individual

Principal cells involved in IgE-mediated hypersensitivity reactions


Perhaps, mast cells in tissues and basophils in blood play the most significant role in the pathophysiology of tye-1 hypersensitivity reactions; nevertheless, B and T cells play essential roles in the generation of IgE antibodies, which mediate the type-1 reactions.

Mast cells are tissue immune cells that lurk in tissues where potential allergens might invade the host whereas basophils and eosinophils are circulating white blood cells that remain in bloodstream for most of their time.

Formation of mast cells begins in the bone marrow; however, mast cells precursors (immature mast cells) leave bone marrow and circulate in blood vessels. They circulate in bloodstream to peripheral tissues (specifically highly vascularized tissues). In the tissues, they differentiate into mature mast cells. Mature mast cells do not circulate in blood vessels anymore.

Mast cells are present in virtually all connective tissues of the body, but their highest concentrations are present in tissues that act as host-environment interfaces where potential allergen might invade the host. Examples of such locations are skin, mucus membranes of airways and GI tract. You will most likely find the highest populations of mast cells in above-mentioned tissues.

Although eosinophils and basophils normally circulate in bloodstream, they migrate from blood to tissues at site of inflammation and allergic reactions. Perhaps, mast cells play the most significant role in earliest events that constitute the pathogenesis of allergic reactions.

First contact with allergen results in GENERATION OF IgE and SENSITIZATION


Upon first contact with allergen, antigen-presenting cells internalize the and consequently display processed fragments of the on MHC-II proteins. After displaying the processed antigen, APCs migrate to nearby lymph nodes where they encounter and activate naïve/resting Th cells bearing receptors for the displayed antigens.

Activated helper T cells in turn secrete cytokines that stimulate B cells to transform into plasma cells that produce allergen-specific antibodies.

Naïve/resting Th cells (denoted Th0) have the potential to differentiate into either Th1 or Th2 cells. This is because naïve Th cells release both Th1 and Th2 cytokines.

Atopic individuals have a higher TH2/TH1 cell ratio

Based on the cytokines T (H) helper cells produce, we categorize TH cells into two sub-populations cells. These are TH1 and TH2 subtypes.

TH1 produce a mix of cytokines that promote the cellular immune responses (e.g. type–IV hypersensitivity reactions) whereas TH2 cells produce cytokines that act on B cells to promote the generation of antigen-specific antibodies (humoral response). Thus, TH2 cells are key players in the pathogenesis of type-1 reactions. Individuals predisposed to allergic reactions produce a cytokine microenvironment that promote a higher than normal TH2/TH1 cell ratio.

During allergic sensitization, IL-4 released mainly by mast cells and Th2 cells stimulate Th0 cells to differentiate into Th2 cells. IL-4 particularly stimulates the differentiation of Th0 cells into Th2 cells, while suppressing the induction of Th1 cells. Acting on activated B cells, IL-4 stimulates their proliferation and differentiation and induces class switch from IgM to IgE subtype.

In addition to IL-4, Th2 cells secrete IL-13, which also stimulates plasma cells, making antibodies against the allergen to switch to IgE production. Thus, in genetically susceptible individuals, inappropriate Th2 response creates a cytokine microenvironment that promotes the generation of antigen/allergen-specific IgE antibodies.

sensitization prior to degranulation

Secreted allergen specific-immunoglobulin E antibodies bind to their high affinity receptors on surfaces of mast cells and basophils priming these cells for degranulation during a subsequent contact with the inducing antigen.

Activated B cells (plasma cells) then secrete great amounts of antigen-specific IgE antibodies into surrounding tissues and blood. Secreted IgE binds to high-affinity receptors expressed on the surfaces of tissue mast cells, in various tissues and basophils in blood. This ends the sensitization phase and primes the individual for degranulation during subsequent contact with the inducing allergen. However, the symptoms of allergy do not manifest upon sensitization.

Sensitization occurs, in genetically proned individuals, upon their first contact with the allergen.

Re-exposure to allergen triggers MASSIVE DEGRANULATION by mast cells and basophils


Half-life of IgE in plasma is about 2 days; actually, IgE does not survive in plasma for more than 3 days. However, surface IgE bound to mast cells are more stable and can remain viable for many weeks.

Non-allergic individuals produce significantly low amounts of IgE antibodies, whereas allergic individuals produce significantly larger amounts of IgE.

Following sensitization, IgE-bound mast cells await a second encounter with the same allergen.

This diagram shows IgE-mediated mast cell degranulation. Besides, mast cells can degranulate by IgE-independent mechanisms. IgE-independent mast cell degranulation is seen in anaphylactoid reactions.

This diagram shows IgE-mediated mast cell degranulation. Besides, mast cells can degranulate by IgE-independent mechanisms. IgE-independent mast cell degranulation is seen in anaphylactoid reactions.

Upon a second encounter with the same allergen, the allergens bind to antigen-specific IgE molecules already fixed on mast cells. A single allergen binds to two adjacent IgE molecules on mast cell membrane. This cross-linking or bridging of adjacent mast cells-fixed IgE causes the mast cell-fixed IgE antibodies to cluster and aggregate. The aggregation of mast cell-bound IgE receptors generates signals on the cell membrane of mast cells.

Transduced membrane signals leads to the generation of intracellular signals in sensitized mast cells and basophils. These intracellular signals trigger

  1.     The release of preformed (primary) mediators by mast cells and basophils, and
  2.     The formation and generation of secondary chemical mediators by these cells
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