Before that, the allergen bind specifically to BCR on B cell. B cell present the peptide fragment on MHC class II to the TCR on naive CD4+ T cell. CD4 of CD4+ T cell bind to MHC class II and B7 of B cell bind to CD28 on the CD4+ T cell. B cell release cytokine that differentiate CD4+ T cell into follicular T helper cell (TFH).

The TCR and CD4 of TFH is still bound to MHC class II of B cell. The CD40L of T cell bind to CD40 of B cell. A cytokine is released to allow B cell to differentiate into plasma cell that release Immunoglobin G (IgG). This IgG is specific to the epitopes of the allergen. Here, the sensitization of antibody is completed.

These paragraphs are inspired by (Elsevier, 2019)

After the antigen- antibody complexes is formed and deposited on walls of blood vessels, the C1q bind to Fc receptor of IgG or IgM to initiate the classical pathway of complement system. C1q activate C1r, C1r then activate C1s which will cleave C4 into C4a and C4b. C1s also cleaves C2 into C2a and C2b. C2a bind onto C4b to become C4b2a that cleave C3 into C3a and C3b. C3b land on C4b2a to become C4b2a3b that cleave C5 into C5a and C5b.

C3a , C4a and C5a act as anaphylatoxins that increase the permeability of blood vessel wall. This result in swelling due to leakage of fluid from blood vessels. They are also chemotactic factor that attract neutrophil. The neutrophil degranulates and released lysosomal enzyme resulting in inflammation of blood vessels (vasculitis).

These paragraphs are inspired by (Elsevier, 2019)

Remarks : symptoms depend on type of tissue affected

Inspired by (Osmosis , 2024)

Osmosis . (2024). Type III hypersensitivity. Retrieved from Osmosis: https://www.osmosis.org/learn/Type_III_hypersensitivity

Hypersensitivity Type I (Also known as immediate Hypersensitivity)

Definition: Type 1 Hypersensitivity occurs as a result of exposure to an antigen/allergen which involves Immunoglobulin E (IgE) mediated release of antibodies against soluble antigen

It is also known as immediate sensitivity due to the rapid onset of symptoms following exposure to an allergen.(Reaction Time: Usually appears in a few minutes or within an hour after exposure to antigens) (Abbas, M., Moussa, M., & Akel, H. ,2023)

1.Sensitization

·        Exposure to allergen that are breathed or ingested is captured by phagocytes to induce the immune system to produce IgE antibodies specific to the allergen

·        When the allergens enter the body they are phagocytosed and processed by lysosome released enzymes into Allergen peptides which are brought to the lymph nodes and presented to Helper T cells(TH).

·        TH is now activated and differentiates into TH2 cells which will release interleukins (IL-4,5 and 3) to help B cells undergo class switching to produce IgE antibodies that are specific to the allergens from the standard IgM.

·        The need for IgE is due to the high affinity it has for the Fc receptor of mast cells and basophil cells.Thus,they become sensitized when these cells are coated with antibodies

·        The IgE Fc regions will bind to the Local mast cells on their Fc receptors and then enter the circulation to bind to Fc receptors on basophils and mast cells

2.Activation of Mast Cells and basophils(Subsequent exposure to allergen)

(Type 1 hypersensitivity: Immediate - Creative Med Doses. (2019))

After sensitization on the second exposure to the same allergen, the allergen binds to the fragment antigen-binding(Fab) on two or more bound IgEs on the mast cells which cause a cross-link and activates the mast cells to degranulate mediators(pro-inflammatory molecules),causing an allergic reaction

3.Release of Mediators( Megha, K., Joseph, X., Akhil, V., & Mohanan, P. (2021):

Activation of mast cells and mediators ,a signalling cascade event is triggered and a variety of mediators such as Histamine, Pro-inflammtory cytokines etc.

·        For example, Histamine binds to receptors on the blood vessel wall to cause vasodilation and Vascular permeability of the blood vessels.

·        This is the result of inflammation of the skin causing it to be warm due to higher blood flow, Red(higher presence of blood) which are common symptoms of skin allergens due to allergic reactions.

1.Mast Cells and Basophils

·        Triggered by allergens to produce histamine and other inflammatory mediators

Causing itching,redness,swelling and edema

2.IgE Antibodies

·        Produced by class switched B cells

·        Specifically bind to allergens and adhere to basophils and mast cells surfaces

3.Antigen-Presenting Cells(APCs)

·        Dendritic Cells and etc

·        Help in activation and differentiation of Th2 cells (Which then help B cells undergo class switching)

4.Helper T cells(Th2 Cells)

·        Activated Th2 cells release cytokines, interleukins that stimulate B cells to undergo class switching to produce IgE antibodies

·        Cytokine also enhances the growth and activation of mast cells and basophils

5.Inflammatory mediators

·        E.g. Histamine released by mast cell degranulation and basophils

(iii) Symptoms (Abbas, M., Moussa, M., & Akel, H. ,2023):

Type I Hypersensitivities include

1.Atopic diseases, which is an exaggerated IgE mediated Immune responses

>Allergic:Asthma,rhinitis,conjunctivitis and dermatitis

 2.Allergic diseases, Which are immune responses to foreign allergens

>Anaphylaxis,urticaria,angioedema,food,and drug allergies

Common symptoms that are exhibited in this type of reaction involve vasoactive mediators that is caused by IgE bound mast cells and Basophils:

>Rash(Inflammation),Hives,erythema,pruritis,edema,flushing,bronchospasm,wheezing,rhinitis and gastrointestinal symptoms(abdominal cramping)

1.Edema

·        swelling caused by fluid retention that is commonly found to occur the feet, legs or ankles, however it can also occur in the hands, face or any other parts of the body as well.

·        Mast Cell activation and degranulation to produce histamine in response to an allergen in the dermis causes hyperpermeability of microvasculature allowing fluid to leak into surrounding tissues (Brainly(N.D))

2.Bronchoconstriction

Caused by the release of mediators such as histamine and affected tissues

·        Histamine causes bronchoconstriction directly by stimulating the H-1 receptor on the airway smooth muscle

·        Histamine causes bronchoconstriction indirectly by stimulating afferent vagal fibers in airways leading to the possibility of respiratory disease (Leff, A. (1982)

3.Inflammation

Caused by anaphylactic response mediated by IgE antibodies

·        The antibodies bind to mast cells and basophils, which are activated to undergo degranulation, producing granules which causes Vasodilation where more blood is able to flow through the blood vessels and Vascular permeability where fluids leaks out of the Blood vessels to the site of infection the resultant is the hallmarks of inflammation such as redness and Swelling. (Theoharides, T. C. et at al. (2012))

·        Presence of Skin bump and redness reactions are hallmarks of IgE mediated reactions

Khanal, S., & Khanal, S. (2024, February 28). Hypersensitivity type I: mechanism and clinical manifestation. Microbe Online. Available at https://microbeonline.com/hypersensitivity-type-i/ (Accessed 30 July 2024)

Abbas, M., Moussa, M., & Akel, H. (2023, July 17). Type I hypersensitivity reaction. StatPearls - NCBI Bookshelf. Available at Type I Hypersensitivity Reaction - StatPearls - NCBI Bookshelf (nih.gov) (Accessed 30 July 2024)

Megha, K., Joseph, X., Akhil, V., & Mohanan, P. (2021). Cascade of immune mechanism and consequences of inflammatory disorders. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373857/ (Accessed 30 July 2024)

Type 1 hypersensitivity: Immediate - Creative Med Doses. (2019, November 20). Creative Med Doses. Available at https://creativemeddoses.com/topics-list/type-1-hypersensitivity-immediate/ (Accessed 30 July 2024)

Pollard-Smith, T. (2017, November 24). The Greatest Debate of Them All - part 1: Ice - Open Health Clinic. Open Health Clinic. Available at https://openhealthclinic.com/the-greatest-debate-of-them-all-part-1-ice/ (Accessed 30 July 2024)

OpenStax. (2019, December 1). 15.1 hypersensitivities. Pressbooks. Available at https://open.oregonstate.education/microbiology/chapter/19-1hypersensitivities/ (Accessed 30 July 2024)

Leff, A. (1982). Pathogenesis of asthma. CHEST Journal, 81(2), 224–229. Available at https://pubmed.ncbi.nlm.nih.gov/6276107/#:~:text=Histamine%20may%20act%20directly%20to%20cause%20bronchoconstriction%20by,by%20stimulation%20of%20afferent%20vagal%20fibers%20in%20airways. (Accessed 30 July 2024)

Brainly(N.D)In a hypersensitivity reaction,what produces edema?.Available at https://brainly.com/question/37875258 (Accessed 30 July 2024)

Theoharides, T. C., Alysandratos, K., Angelidou, A., Delivanis, D., Sismanopoulos, N., Zhang, B., Asadi, S., Vasiadi, M., Weng, Z., Miniati, A., & Kalogeromitros, D. (2012). Mast cells and inflammation. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1822(1), 21–33. Available at https://pubmed.ncbi.nlm.nih.gov/21185371/ (Accessed 30 July 2024)

-->Antibody binds directly to antigen of cell membrane to activate the complement response

-->complement proteins are circulating protein that when activated lead to an inflammatory response against a particular target

-->AB mediated response against Ag on the surface of cell membrane

Examples of antigens: Penicillin, hydrochlorothiazide, quinine, rhesus antigens on the surface of red blood cells

In reference, to what we have learnt from lesson 4,

Both Ig G and Ig M can activate the compliment system which causes:

1. Increase in inflammatory mediators

2. Opsonization-->Phagocytosis

3. Membrane Attack Complex (MAC)

4. Natural Killer (NK) cells (ADCC) (IgG)

-Complement proteins (innate) for activation of classical pathway of complement proteins

-Antibodies Ig G and Ig M (adaptive) from B cells for antibody-mediated cellular dysfunction

Cellular components involved:

-NK cells (innate) during ADCC

-Phagocytes such as neutrophils and macrophages (innate) during opsonization

-Mast cells and basophils (innate) during inflammatory responses

Classical Pathway of Type II Hypersensitivity:

1. Antibody(Ab) binds to antigen via its Fragment Antigen Binding (Fab) region

2. Globular head of C1q recognizes the Fc region of the Ab (Ig G/Ig M)

3. C1q activates C1r which is the inactive serine protease that then activates the C1s to active form

4. C1s then cleaves C4 into C4a and C4b and C2 into C2a and C2b. C4b lands on the antigen presenting cell and C2a lands on the C4b forming C3 convertase.

5. C3 convertase cleaves C3 into C3a and C3b. C3b then sits on the C3 convertase forming C5 convertase ( C4b2a3b).

6. C5 convertase cleaves C5 into C5a and C5b

7. C5b recruits C6 and C7. C7 binds to the surface of the antigen presenting cell. C8 is inserted into the membrane

8. C8 recruits about 10 to 16 pieces of C9 and forms Membrane Attack Complex (MAC) -->causing the lysis of the cell

Opsonization occurs:

-->C3b can land on the cell membrane (APC) to act as an opsonin which will allow the phagocytes to recognize the APC more easily for opsonization. Thus, increasing the rate of phagocytosis.

Increase in Inflammatory mediators:

-->C3a,C4a,C5a are anaphylatoxins that can bind to the receptors of the mast cell

-->increases permeability of the wall of blood vessels

-->vasodilation

-->Neutrophils leaves blood vessels via extravasation

-->increase inflammation causing infection

Antibody dependent Cellular Toxicity (ADCC) is activated by Ig G:

1. Natural Killer(NK) cells detect the antigen-antibody complexes via the Fragment crystallizable (Fc) region of the Ab and becomes activated

2. NK cells then release perforins to punch holes on the host cell and granzymes to trigger apoptosis.

-Fatigue

-Weakness

-Joint pain

-Skin rashes

Hemolytic anemia: Fatigue, weakness, pale skin, jaundice -->caused by low oxygen carrying and may lead to heart failure

Goodpasture syndrome: Hemoptysis (coughing up blood), kidney problems

Myasthenia gravis: Muscle weakness and fatigue

Increase in bilirubin formation due to hemolysis causes jaundice and may lead to kernicterus.

1. Jeffery, Actor. K (2023) Chapter 8 : Immune hypersensitivities. Available at https://www.sciencedirect.com/science/article/abs/pii/B9780443153075000111 (Assessed on 31 July 2024)

2. James. W, Nelson. L (2013) Type II Hypersensitivities reactions. Available at https://www.sciencedirect.com/topics/medicine-and-dentistry/type-ii-hypersensitivity (Assessed on 31 July 2024)

3. Hasudungan, Armando. (2019 December 4). Hypersensitivity Type II (Cytotoxic reaction) - causes, pathophysiology, complement system [YouTube] Available at https://www.youtube.com/watch?v=Em0Wi07dj4E (Assessed on 31 July 2024)

sensitisation phase: Antigen-presenting cells (APCs) such as macrophages and dendritic cells encounter the allergen, processes it by engulfing it to release peptide fragments, and present it on their surface via Major Histocompatibility Complex (MHC) class II molecules. The peptide fragments on the MHC class II complex of the APC is recognized by the T-cell receptor (TCR) on naïve CD4+ T helper cells, and the CD4 co-receptor on the T helper cell binds to the B7 molecules on the APC. This interaction triggers the APC to release cytokines, such as interleukin-12 (IL-12), which stimulate the proliferation and differentiation of the naïve CD4+ T cells into effector T helper 1 (effector Th1) cells.

In the effector phase, subsequent exposure to the same antigen induces a delayed-type hypersensitivity response. Effector CD4+ T helper cells secrete cytokines like interleukin-2 (IL-2) and interferon-gamma (IFN-γ), which promote the release of additional effector Th1 cytokines, further mediating the immune response by activating macrophages and other inflammatory cells. Activated macrophages release pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6), increasing endothelial permeability and allowing more immune cells to enter the affected area. Macrophages also secrete lysosomal enzymes, complement components, and reactive oxygen species which will affect surrounding cells, leading to tissue damage. Additionally, activated CD8+ T cells directly destroy target cells presenting the peptide fragment of the allergen via MHC class I molecules by releasing perforin and gramzymes to the target infected cell carrying the peptide fragment. In dealing with certain intracellular pathogens, macrophages may transform into multinucleated giant cells to better contain the pathogens.

When Th1 cells migrate to the injection site, where the bacterium Mycobacterium tuberculosis has been injected into the skin, an inflammatory response is triggered, resulting in induration (hard and thickened skin).

Hemolytic Disease of the newborn.

-->Mother is Rh –ve while father is Rh +ve and the first child is also Rh +ve.

-->During the delivery of the first child, some Rh + fetal blood cells may have entered the Rh-ve mother’s bloodstream, sensitizing her immune system. Thus, the mother’s immune system will produce Rh antibodies against the Rh D antigen. -->During second pregnancy the Rh antibodies can diffuse through the placenta and attack the Rh-positive red blood cells of the fetus causing anemia which are lysis of red blood cells in the second baby.

When an Rh- mother is pregnant with a Rh+ child. The mother's own immune cells recognises the rhesus factor on the fetus' red blood cells as foreign and thus triggers an immune response to destroy the fetus' red blood cells. Taking in anti-RH antibodies during labour and delivery of the child prevents rhesus negative sensitization, which could've led to hemolytic disease of the newborn.

Hypersensitivity therapy can also help to reduce the effects of type IV hypersensitivity through exposure of limited amounts of triggering substance, gradually allowing the body to stop recognising it as a threat and not provoke an immune response.