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Hypersensitivity, Overview of the 4 Types, Animation.

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Type I hypersensitivity (IgE-mediated hypersensitivity) - causes, symptoms, pathology

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Type II hypersensitivity (cytotoxic hypersensitivity) - causes, symptoms, & pathology

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Type III hypersensitivity (immune complex mediated) - causes, symptoms & pathology

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Reaction Time: 24-72 hours, sometimes 3 to 4 weeks after exposure to an antigen.

It is T cell mediated and no antibodies are involved.

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Type IV Hypersensitivity (Described Concisely)

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Source: Khanal, S., & Khanal, S. (2024, June 13). Hypersensitivity type IV: mechanism and clinical manifestation. Microbe Online. https://microbeonline.com/hypersensitivity-type-iv/ 

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The initiator of the hypersensitive reaction is when an antigen-presenting cell comes into contact with an antigen [1].

Some examples of antigens are listed below [1].

Intracellular bacteria: Mycobacteria um tuberculosis, M. leprae, Listeria monocytogenes, Brucella abortus

Intracellular fungi: Pneumocystis carinii, Candida albican, Histoplasma capsulatum, Cryptococcus neoformans

Intracellular parasites Leishmania sp.

Intracellular viruses: Herpes simplex virus, Variola (smallpox), Measles virus

Contact antigens: Picrylchloride, hair dyes, nickel salts, poison ivy, and poison oak

References:

1. Khanal, S., & Khanal, S. (2024b, June 13). Hypersensitivity type IV: mechanism and clinical manifestation. Microbe Online. https://microbeonline.com/hypersensitivity-type-iv/

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APC: Macrophages, Dendritic Cells, B cells

Cytokines: Interferon gamma, Interleukins, tumor necrosis factor-alpha, and beta

T cells: CD4 helper T cells and CD8 cytotoxic T cells

Phagocytic Cells: Macrophages, neutrophils, monocytes

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Type III hypersensitivity reaction is initiated when there is an antigen-antibody interaction, which consists of a allergen (antigen) with its specific antibody.

this interaction forms aggregates called immune complexes.

usually soluble and can circulate around the body and deposited into other parts of the body.

this will trigger a classical complement pathway that will result in inflammation and tissue damage.

Encyclopædia Britannica, inc. (n.d.-a). Encyclopædia Britannica. https://www.britannica.com/science/immune-system-disorder/Type-III-hypersensitivity

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Type 3 Hypersensitivity Made Easy -  Immunology

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main components involved: antibodies (IgM and IgG), antigens, neutrophils, macrophages, complement proteins

there is 3 parts in this process.

1. immune complex formation

when body is exposed to antigen, antibodies IgM or IgG will be produced within 4 to 10 days, and they will then bind with antigens to form insoluble immune complexes.

antigens can either be endogenous, that is found in the body's tissues. e.g red blood cells antigens

or it can be exogenous such as bacteria (E. coli O:157 H:7 antigen), fungi (Aspergillus. fumigatus antigen) or viruses (influenza antigen) that enters from external environment.

2. immune complex deposition

when these antigens bind with either IgG or IgM antibodies to form immune complexes, they will be deposited in various tissues around the body such as blood vessel walls.

this deposition will then attract neutrophils to the site in which the deposition is, then the classical complement pathway will be triggered.

3. inflammatory reaction

after the deposition, there will be a classical complement pathway activation.

the activation of the pathway is caused when the complement protein C1 binds to the immune complex.

this will eventually result in the release of complement protein C3a, C4a and C5a, which serves as anaphylatoxin to stimulate mast cells to produce histamines.

histamines will lead to the increase in vascular permeability, leading to more immune complex binding to the vessel walls.

complement proteins C3a and C5a serves as chemoattractants to attract neutrophils and macrophages to the site of deposition. (Jeffery,2012)

enzymes such as lysosomes and free radicals will then be secreted by neutrophils will result in damages to the tissues.

example: serum sickness

occurs when the body is exposed to a foreign serum protein

takes roughly 6-10 days for antibody development and antigen-antibody complex formation

host antibody binds to the foreign serum and forms immune complexes.

immune complexes were the deposited into the joints

this triggers the activation of the classical complement pathway

complement proteins C3a and C5a will be released and attract neutrophils and macrophages to the joint (site of deposit) (ncbi, 2023)

neutrophils will secrete lysosomes and free radicals that will damage the joints

this will result in arthritis, hence presented as a symptom.

Rixe, N. (2023, August 28). Serum sickness. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK538312/

Usman, N. (2023, May 22). Type III hypersensitivity reaction. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK559122/

Mousa, H. M., Saban, D. R., Foster, C. S., Coma, M. C., & Streilein, J. W. (1970, January 1). Allergy and immune-mediated tissue injury. SpringerLink. https://link.springer.com/10.1007/978-3-319-90495-5_333-1

VP;, K. (n.d.). Aspergillus antigens: Which are important?. Medical mycology. https://pubmed.ncbi.nlm.nih.gov/16110811/

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Type III Hypersensitivity - Immune complex disease

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common symptoms:

fever

rash/ itch --> caused by histamine

arthritis --> inflammation in the joints

swelling in areas like eyes

Usman, N. (2023, May 22). Type III hypersensitivity reaction. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK559122/

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some treatments include:

1. use of antihistamine

histamines will be secreted by mast cells due to the trigger by anaphylatoxins

this will lead to allergic symptoms like sneezing, swelling etc

using antihistamine drugs will help relieve the discomfort of the allergic reactions

2. steroid

one example of steroid treatment include corticosteroids, that helps treat rheumatoid arthritis and lupus as it reduces inflammation as it decreases the number of inflammatory cells via apoptosis, and this will eventually reduce tissue damage.

the drugs mentioned can be used for most types of type III hypersensitivity reaction, as well as the example mentioned, serum sickness.

professional, C. C. medical. (n.d.). What is serum sickness?. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/serum-sickness

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Common Allergens for these diseases related to Type 1 hypersensitivity:

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For Systemic anaphylaxis:

Certain medications such as penicillin

Insect bites such as venom from fire ants

Food Allergies such as peanuts, nuts, fish and shellfish

Citation :

Mayo Foundation for Medical Education and Research. (n.d.). Anaphylaxis. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/anaphylaxis/symptoms-causes/syc-20351468

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For acute urticaria:

Food Allergies

Bee or wasp stings

Allergy testing, such as skin prick test

Citation:

Acute urticaria: Causes, features, and treatment - dermnet. DermNet®. (2024, May 23). https://dermnetnz.org/topics/acute-urticaria

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For seasonal rhinoconjunctivities:

Indoor Allergens, such as dust mites

Outdoor Allergens, such as pollens from trees

Citation :

de Groot, H., Brand, P. L. P., Fokkens, W. F., & Berger, M. Y. (2007, November 10). Allergic rhinoconjunctivitis in children. BMJ (Clinical research ed.). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072026/#:~:text=The%20most%20important%20allergens%20involved,do%20not%20cause%20allergic%20rhinoconjunctivitis.

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For Asthma:

Pet dander, such as pet fur, pee or saliva

Pollen, from trees or weeds

Molds

Dust mites

Citation:

professional, C. C. medical. (n.d.). What is allergic asthma?. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/21461-allergic-asthma

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Components of the Immune System Involved 

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Components of the Immune System Involved 

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Symptoms of Type 1 hypersensitivity:

Rash, inflamed and bumpy red skin

Flushing, warmth sensation

Hives, raised red bumps / splotches on the skin

Itching sensation

Edema, swelling of the tissues when blood vessels leak fluid

Wheezing, high pitched whistling sound when breathing

rhinitis, nasal congestion, runny nose

stomach cramps

Citations :

MediLexicon International. (n.d.). What are the different types of hypersensitivity reactions?. Medical News Today. https://www.medicalnewstoday.com/articles/hypersensitivity-reactions#type-1

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Epinephrine

--> Increases Vasodilation and peripheral vascular resistance

= decreases airway/mucosal edema

Bronchodilators

-->Relaxes and smooth the muscles in the airways

= improve overall airflow in the lungs

Antihistamines

--> Prevents histamine from binding to the antigen receptors

= reducing many symptoms of allergies

Glucocorticoids

--> Suppresses Inflammation due to anti-inflammatory effect

= increased production of inflammatory mediators

Citations :

Abbas, M. (2023, July 17). Type I hypersensitivity reaction. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK560561/

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Immunotherapy

exposing the patient to small doses of allergens

--> this helps patients build up tolerance to eliminate symptoms

Lifestyle Adjustments:

For Food allergies, have dietary restrictions on food that are harmful for the body

For environmental allergens, have frequent habits to elimate pet dander / use purifiers in houses

Citation for Allergen Immunotherapy

Immunotherapy for allergies. Allergy & Asthma Network. (2024, May 16). https://allergyasthmanetwork.org/health-a-z/immunotherapy/

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When encountered with an allergen,

--> IgE binds to their surface via the Fc recptors, triggering mast cells, releasing inflammatory mediators

--> leads to allergic symptoms, contributing to the symptoms experienced by the patient

Mast cells also release cytokines and chemokines:

--> Recruits and activate other cells, amplifying inflammatory response

--> Amplifying overall reactions to the allergens

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After receiving signals from IgE antibodies when antigen binds to the antibodies via Fc receptors, regarding the presence of antigens

--> it releases cytokines and chemokines

The cytokines and chemokines recruit and activate other immune cells

--> contributing to the factor of inflammation as immune cells are activated and recruited to the site of infection

Hence it serves as a amplification of immune response

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Type II: Cytotoxic Reaction (Shermichael)

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Type II: Cytotoxic Reaction (Shermichael)

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Initiator of reaction

Cell surface antigens

Such as those found on RBC (ABO blood group antigens)

Tissue Antigens

Drug-induced antigens on cells

Components of immune system involved:

IgG and IgM

Activation of classical complement pathway

NK cells, Neutrophils, Eosinophils and macrophages

Symptoms:

Fever, Fatigue, chills

Hemolytic anemia (fatigue, shortness of breath, jaundice, dark urine due to destruction of RBC)

Hyperacute transplant rejection (rapid graft loss, pain, swelling, inflammation at site of transplant/graft)

Possible Treatments:

Immunosuppressive therapy

Monoclonal Antibodies (such as rituximab which targets B cells can be used in some conditions)

Intravenous immunoglobulin (to modulate the immune response)

Avoidance (avoid known triggers)

Libretexts. (2022, December 24). 12.4C: Type II (Cytotoxic) reactions. Biology LibreTexts. https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.04%3A_Immunity_Disorders-_Hypersensitivity/12.4C%3A_Type_II_(Cytotoxic)_Reactions

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a) Initial Exposure and Sensitization phase

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a) Initial Exposure and Sensitization phase

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a) 1st encounter with the antigen

1. Antigen enters the body and the APC engulfs the pathogen via phagocytosis, enclosing the pathogen in a phagosome. The phagosome fuses with the lysosome, forming a phagolysosome.

2. Antigen Processing and Presentation.

The antigen is processed by digesting the antigen into smaller antigenic peptides, by hydrolytic enzymes in the lysosome.

MHC receptors are synthesised by ribosomes on the rough endoplasmic reticulum, and modified in the Golgi apparatus.

A transport vesicle from the Golgi apparatus containing the MHC receptor fuses with the phagolysosome. The antigenic peptides will then bind to the MHC receptor, forming a antigenic peptide:MHC complex.

The vesicle containing the antigenic peptide:MHC complex is transported to the cell surface membrane. It then fuses with the cell surface membrane, embedding the antigenic peptide:MHC complex in the cell surface membrane. The antigenic peptide can now be presented to naïve T cells to activate these cells.

3. T cell activation.

During antigen presentation, antigen-presenting cells (APCs) present the antigenic peptide to mature naïve T cells. Naïve T cells with specific T cell receptors (TCRs) will recognise and bind to the antigenic peptide:MHC complex on APCs.

 Activation of naïve T cells require the following signals:

– Signal 1: Binding of antigenic peptide:MHC complex with TCR

– Signal 2: Binding of co-stimulatory molecules

– Signal 3: Secretion of cytokines by APC

4. Clonal Expansion and memory T cell formation.

The naïve T cell will be activated to proliferate, producing large numbers of genetically identical daughter cells, via clonal selection and expansion. These cells then undergo differentiation to form effector T cells:

– Helper T cells (TH), which contain CD4 co-receptors

– Cytotoxic T cells (TC), which contain CD8 co-receptors

– Memory T cells (either TH or TC cells)

References:

1. Gaudino, S. J., & Kumar, P. (2019). Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis. Frontiers in immunology, 10, 360. https://doi.org/10.3389/fimmu.2019.00360

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Source: Khanal, S., & Khanal, S. (2024, June 13). Hypersensitivity type IV: mechanism and clinical manifestation. Microbe Online. https://microbeonline.com/hypersensitivity-type-iv/ 

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1. Re-exposure

On the second exposure of an individual to the same antigen, sensitized Th1 cells secrete chemokines and cytokines such as interferon gamma [1]

2. Macrophage Activation

Macrophages have a higher phagocytotic activity due to the activation by the cytokines. [3]

3. Recruitment of Inflammatory Cells

Chemokines recruit inflammatory cells to the site, such as more macrophages. [4]

4. Formation of Granuloma.

Large numbers of immune cells result in the formation of a granuloma.

References:

1. MacLeod, M. K., Clambey, E. T., Kappler, J. W., & Marrack, P. (2009). CD4 memory T cells: what are they and what can they do?. Seminars in immunology, 21(2), 53–61. https://doi.org/10.1016/j.smim.2009.02.006

2. Khanal, S., & Khanal, S. (2024c, June 13). Hypersensitivity type IV: mechanism and clinical manifestation. Microbe Online. https://microbeonline.com/hypersensitivity-type-iv/

3. Arango Duque, G., & Descoteaux, A. (2014). Macrophage cytokines: involvement in immunity and infectious diseases. Frontiers in immunology, 5, 491. https://doi.org/10.3389/fimmu.2014.00491

4. Sokol, C. L., & Luster, A. D. (2015). The chemokine system in innate immunity. Cold Spring Harbor perspectives in biology, 7(5), a016303. https://doi.org/10.1101/cshperspect.a016303

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Contact Hypersensitivity --> Contact Dermatitis

Treated with Topical Steriods and Oral corticosteroids

Mantoux Tuberculin Skin test --> results in induration of the skin.

Treatment for Tuberculosis.

Granulomus type --> Sarcoidosis, granuloma

Treated with Anti-TNF antibodies.

Resources:

1. Marwa K, Kondamudi NP. Type IV Hypersensitivity Reaction. [Updated 2023 Aug 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562228/

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Sarcoidosis

Granuloma

Rashes (Contact dermatitis)