Types of Hypersensitivity and Allergic Reactions: A Rhyme to Remember
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Example Case
A male patient presents with a pruritic rash for the past 2 days. He first noticed the rash on his right arm, and now he states it is spreading to his left arm. He has tried diphenhydramine with minimal improvement.
He states he is allergic to peanuts but does not specifically recall any recent ingestion. Although he shares with you that he was at a company picnic in the woods at a Metropark earlier in the week. He does not know if he accidentally ingested something then.
He also reports a history of myasthenia gravis and is unsure if the rash is related.
He denies any fevers, recent travel, recent medication changes, new soaps or detergents, other family members having the rash, sloughing of skin, mucosal lesions, arthralgia, chest pain, shortness of breath, or abdominal pain.
Hypersensitivity Reactions
Hypersensitivity reactions are undesirable overactive immune responses to a particular allergen or antigen.
There are 4 types of hypersensitivity reactions, and the underlying process that occurs to generate the immune response differs between them.
Learning and/or recalling the specifics of each type of reaction can be challenging at first.
However, I created an easy rhyme to help you remember the 4 types of hypersensitivity reactions and the underlying process that takes place for each.
Memorizing this will help you on future exams or for practical use.
The Army
Briefly I want to discuss the main players involved in generating a hypersensitivity reaction.
The primary goal of the immune system is to protect the body against infection, injury, disease, pathogens, and foreign antigens.
The immune system will detect anything suspicious or abnormal in the body and subsequently generate a response to attempt to repair the system back to baseline.
In order to accomplish the task, the immune system comprises cells that function to protect the body from infectious pathogens or foreign antigens.
The latter is the root cause to a hypersensitivity reaction as the immune system perceives a particular antigen as foreign and not belonging.
There are many types of cells involved in a hypersensitivity reaction, and the list below names the main ones.
Basophils = Release inflammatory mediators such as histamine and cytokines during an immune response
Mast Cells = Release inflammatory mediators such as histamine and cytokines during an immune response
Lymphocytes
B-Cells - Produce antibodies. Once a B cell encounters a foreign antigen it will then mature into a plasma cell to produce antibodies.
Cytotoxic T-Cells (CD8) = Destroy target cells, local tissue, and foreign antigens
Helper T-Cells (CD4) = Assist B cells to produce antibodies and cytotoxic T cells to destroy target cells and foreign antigens
Natural Killer Cells = Destroy target cells, local tissue, and foreign antigens
Macrophages = Engulf and destroy target cells and foreign antigens
Neutrophils = Release inflammatory mediators such as cytokines and destroy target cells, local tissue, and foreign antigens
Here is an easy way to organize all the cells to help you remember them:
The Recruiters = Release inflammatory mediators to recruit other cells to augment the immune response
Mast Cells
Basophils
The Destroyers = Destroy and kill target cells, local tissue, and foreign antigens
Natural Killer Cells
Cytotoxic T-Cells
Macrophages
Neutrophils (also a recruiter by releasing cytokines)
The Protectors = Produce antibodies
B-Cells
The Helpers = Help the other cells to function
Helper T-Cells
Below I created an easy way to remember the cellular functions using the cell names.
Cell Functions in Hypersensitivity Reactions
BasoPHIL= FILLed with histamine, cytokines, inflammatory mediators
MAST Cells = MASS release of histamine, cytokines, and inflammatory mediators
B-Cells = Build antiBodies
CytoTOXIC T-Cells = TOXIC destruction of cells and material
HELPer T-Cells = HELP other T-cells and B-cells
Natural KILLer Cells = Kill target cells
MACrophages = Massive Antigen Consumption, engulfs antigens and target cells
NeutroPHIL = Filled with cytokines, Foreign antigen destruction
Now that we understand the cells involved, let’s go through each of the 4 types of hypersensitivity reactions.
I created this rhyme to help you easily remember the underlying process that takes place during each reaction.
It will make more sense as they are discussed further. Remembering this rhyme will help you to recall the basics for tests, exams, boards, and for practical use.
Type I Hypersensitivity Reaction
“ONE antibody named IgE, causes mast cells to release histamine”
Type I is the reaction people commonly think of when referring to an allergic reaction.
The response occurs within minutes after an exposure to an allergen. This could be from ingestion of a food the individual is allergic to, introduction of an allergen through the skin such as bee venom from a sting, or inhalation of an allergen from environmental exposure.
Once the allergen has entered the body, an IgE antibody mediated response occurs causing mast cells and basophils to release histamine, cytokines, inflammatory mediators, as well as other contents that generate an allergic response.
Type I Hypersensitivity = allergen exposure => IgE mediated mast cell/basophil release of histamine, cytokines, and inflammatory mediators
There are 2 phases involved in a type I reaction: sensitization phase and reaction phase
Sensitization Phase
The sensitization phase occurs the first time an individual is exposed to the allergen they are allergic to.
This could be venom from a bee sting, food such as peanuts, or environmental exposures such as grass, pollen, or hay.
The allergen enters the body through ingestion, direct contact, inhalation, or puncture.
The B cells detect the allergen as a foreign substance that does not belong, and they subsequently produce IgE antibodies against that particular allergen.
The IgE antibodies bind to mast cells and basophils that are filled with histamine, cytokines, and inflammatory mediators to be used in the inflammatory and immune response.
B cells recognize the allergen as foreign. The B cells subsequently make IgE antibodies against that allergen. The IgE antibodies bind to mast cells and basophils.
Reaction Phase
The second time an individual is exposed to that specific allergen, the previously produced IgE antibodies anchored to the mast cells and basophils will bind to the allergen.
This cross-linking will cause mast cell and basophil degranulation, or release of their contents including histamine, cytokines, and inflammatory mediators.
Histamine causes a number of physiological changes in the body including vasodilation and increased vascular permeability leading to hypotension and edema.
Histamine also increases mucous secretion, airway edema, bronchospasm, and bronchial smooth muscle tone which can all lead to respiratory distress, especially seen with anaphylaxis.
Smooth muscle spasms can occur in the GI tract leading to abdominal cramping, nausea, vomiting, and diarrhea.
Skin findings such as flushing and urticaria occur from vasodilation, increased vascular permeability, and inflammation.
Cytokine release leads to communication and recruitment of other immune and inflammatory mediated cells to further augment the hypersensitivity response.
Examples
As alluded to above, a type 1 hypersensitivity reaction is the standard allergic reaction that people commonly think of.
The severity can range from a minor local reaction or a systemic response involving multiple organ systems as seen with anaphylaxis.
In addition to food allergies and anaphylaxis, other examples of type 1 hypersensitivity include allergic rhinitis, allergic conjunctivitis, some types of medication reactions, and asthma.
Now back to the rhyme:
“ONE antibody named IgE, causes mast cells to release histamine” Type I reactions involve IgE antibodies against a particular antigen/allergen that will cause mast cell release of histamine, cytokines, and inflammatory mediators.
Type II Hypersensitivity Reaction
“TWO autoantibodies attacking me, named IgM and IgG”
Unlike type I hypersensitivity in which the immune system produces antibodies in response to a foreign allergen/antigen, type II reactions produce autoantibodies against the host.
The immune system inappropriately perceives the host or “self” as a foreign antigen that does not belong, and it subsequently produces autoantibodies against itself/those host antigens.
IgM and IgG autoantibodies bind to antigens on host cells, receptors, and extracellular tissues leading to destruction and/or dysfunction.
Antibodies that attack the host are called autoantibodies, and they inappropriately perceive host antigens as foreign and therefore not belonging.
For example if the immune system mistakes host red blood cells as being foreign, it will make IgM and IgG autoantibodies against its own red blood cells leading to destruction. This is the basic pathophysiology for autoimmune hemolytic anemia.
Once IgM or IgG autoantibodies bind to a host antigen, an immune response will generate leading to dysfunction or destruction of that host target. The destruction occurs through antibody dependent cell-mediated cytotoxicity or activation of the complement system.
Type II Hypersensitivity = IgM and IgG autoantibodies => destruction and dysfunction of host antigens.
IgM and IgG autoantibodies inappropriately perceive host antigens (blue triangle) on the host target (red circle) as foreign rather than self, and subsequently bind to it.
Binding of IgM and IgG autoantibodies to the host target will activate the complement system leading to destruction or dysfunction of the target
Binding of IgM and IgG autoantibodies to the host target will activate natural killer cells (NK) to destroy the target. This process is called antibody dependent cellular cytotoxicity.
Examples
As briefly discussed above, autoimmune hemolytic anemia is a type II hypersensitivity reaction in which autoantibodies attack host red blood cells.
Autoantibodies can also recognize extracellular substances as foreign. This is the case with Goodpasture syndrome in which autoantibodies attack the basement membrane of the lungs and kidneys leading to hemoptysis, shortness of breath, chest pain, hematuria, and extremity edema.
Reactions from ABO incompatibility is another type II reaction in which preformed antibodies attack red blood cells.
Autoantibodies may also target antigens on host receptors.
This can lead to receptor overstimulation (Graves’ disease) or receptor blockage/destruction (myasthenia gravis).
Hyperthyroidism occurs in Graves’ disease as a result of autoimmune antibodies chronically stimulating TSH receptors leading to excessive release of thyroid hormone.
Alternatively, autoantibodies in myasthenia gravis block and destroy nicotinic cholinergic receptors at the neuromuscular junction leading to muscle weakness and fatigue.
Now back to the rhyme:
“TWO autoantibodies attacking me, named IgM and IgG”. Type II reactions involve IgM and IgG autoantibodies that attack host antigens.
Type III Hypersensitivity Reaction
“THREEs complex get the hint, as it involves the complement”
Type III hypersensitivity occurs when IgG antibodies bind directly to the antigen forming an antigen-antibody immune complex.
Macrophages and neutrophils can clear immune complexes through phagocytosis. However, when the number of immune complexes begin to accumulate it can overwhelm the innate immune system.
Immune complexes then begin to deposit in blood vessels, in the glomeruli of the kidneys, and in joints. This causes a local inflammatory response.
Furthermore, immune complexes are really good at activating and interacting with the complement system, especially when they are deposited rather than free floating.
Complement system activation enhances the immune system response by recruiting other inflammatory cells to the area (such as mast cells, neutrophils, and macrophages).
This causes tissue and cellular inflammation and destruction leading to symptoms of vasculitis, glomeurolonephritis, and arthritis.
Type III Hypersensitivity = IgG antigen-antibody immune complex deposition => complement activation => inflammatory response
IgG antibodies bind directly to the antigen to form immune complexes. Accumulation of immune complexes leads to antigen-antibody deposition in joints, kidneys, and blood vessels. Immune complexes activate the complement system which further augments the inflammatory immune response by recruiting neutrophils (PMN), mast cells, and macrophages (MP). Arthritis, glomerulonephritis, and vasculitis occur as a result.
Examples
Examples of type III hypersensitivity include lupus, rheumatoid arthritis, serum sickness, post-streptococcal glomerulonephritis, and reactive arthritis. They are all immune complex mediated and lead to various symptoms of vasculitis, glomerulonephritis, and arthritis depending on where the immune complexes deposit.
Now back to the rhyme:
“THREEs complex get the hint, as it involves the complement”. Type III reactions involve antigen-antibody immune complex formation that activates and interacts with complement to generate an inflammatory response.
Type IV Hypersensitivity Reaction
“FOUR T cells like to raid, but the response is more delayed”
Unlike the other types of hypersensitivity, a type IV reaction does not involve antibodies and is T cell mediated. This type of reaction is much more delayed than the others.
First, the antigen is detected by antigen presenting cells (APCs) such as macrophages. The antigen then binds to the MCH class II receptor on the APC. The APC is now ready to present the foreign antigen to helper T cells.
Type IV Hypersensitivity = antigen presenting cells => T cells => delayed response
Type IV reactions occur in 2 phases: sensitization phase and effector phase
Sensitization Phase
Sensitization occurs the first time the helper T cell is presented with the foreign antigen by the APC.
The helper T cell will then form into a memory T cell for that specific antigen. The next time the memory T cell interacts with that same antigen, it will cause an inflammatory response.
The foreign antigen (in this case poison ivy/red circles) is presented to helper T cells (Th) by the antigen presenting cell (APC). The helper T cell then becomes a memory T cell (Th1) for that specific antigen.
The next time the memory T cell is presented with that same antigen, it will produce an inflammatory response.
Effector Phase
As the antigen persists in the body and/or the next time an individual is exposed to that same antigen, the sensitized memory helper T cells will again be presented with that same antigen by APCs.
This time, however, the memory helper T cells will remember that antigen from before and will generate an inflammatory response.
The memory helper T cells will release inflammatory mediators and cytokines.
Cytotoxic T cells will arrive and cause tissue and cellular destruction.
Other macrophages will arrive to become additional antigen presenting cells as well as destroy local tissue.
Lastly, other helper T cells will arrive and they too will become sensitized memory cells to further facilitate the immune response.
Memory helper T cells (Th1) are again presented with the same poison ivy antigen by antigen presenting cells (APCs).
This time the memory helper T cells remember the antigen and release cytokines to recruit cytotoxic T cells (Tc), other macrophages (MP), and other helper T cells that will become additional memory T cells (Th1).
This generates an inflammatory immune response.
Examples
Common examples of type IV hypersensitivity reactions include TB skin testing and poison ivy.
A trick to remember that poison ivy is a type IV reaction is alter the spelling of poison ivy to poison IV to represent the Roman numeral IV.
Now back to the rhyme:
“FOUR T cells like to raid, but the response is more delayed”. Helper T cells (also known as CD4 cells, representing the 4 in this rhyme as well as it being a type IV reaction) induce an inflammatory response that is delayed. The helper T cells first recognize antigens on antigen presenting cells leading to sensitization and transformation of the helper T cells into memory helper T cells. An inflammatory response is generated the next time that presensitized memory helper T cell interacts with the same antigen. This 2 step process makes the reaction delayed.
Conclusion
I hope that helps to explain the 4 different types of hypersensitivity reactions.
Type I occurs when allergens (antigens) bind to IgE antibodies anchored to mast cells and basophils thereby causing degranulation of histamine and cytokines.
Type II inflammatory response occurs when IgM and IgG autoantibodies wrongfully perceiving host cells, receptors, and antigens as foreign.
Type III inflammatory response occurs when antibody-antigen immune complexes form and deposit into blood vessels, kidneys, and joints leading to complement activation.
Type IV immune response occurs when memory helper T cells interact with antigen presenting cells to produce a reaction.
The rhyme below can help you remember the underlying process that takes for each type of reaction.
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Below is a summary table I put together if this helps you retain information easier.