Adaptive Immunity 2

How do antigens trigger B cells to produce antibodies

Antigens must be recognized and presented by B-cell antigen receptors (BCRs), triggering antibody production

Via thymus-independent or T-cell-dependent mechanisms.

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T-Independent antigens trigger a direct activation of B cells without the help of T helper cells. These antigens usually cause a weaker and short-lived immune response, mainly producing IgM antibodies

What are the two types of thymus-independent antigen responses? [IMPORTANT]

Antigens which are strong enough & capable of turning B cells on to make antibody by themselves

1) Critical Matrix: Large thymus-independent antigens form many cross-links with BCRs for a critical signalling mass

or

2) Non Specific Activation: Smaller antigens cross-link a subset of receptors which are portions of immunoglobulin (Igα or Igβ) (e.g., CD79) to activate B cells without T-cell help.

Where do T cells originate and mature

• T cells originate from bone marrow stem cells

• Mature in the thymus gland, developing into various types with specific adaptive immunity roles.

What are the roles of T cells in B-cell activation

Helper-T cell (also called TH cells, T4 cells or CD4+ cells) assist B cells when WEAKER THYMUS DEPENDANT antigens are insufficient to trigger B CELL DIFFERENTIATION, aiding SEPARATE antibody production.

The subset of T_H cells that triggers B cell is known as T_H2 cells but antigen must first be presented`

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1) B cell has to present antigen on the surface, this is done through endocytic process where the antigen will be taken into the cell into a lysosome

2) Then the antigen will (processed with &) bind to MHC class 2 molecule and be presented on the B cell surface

3) Once presented on the B cell surface, it awaits to come into contact with a T cell that will recognise it

Only certain clones of TH2 cell will recognise a certain antigen complex with MHC class 2 expressed on surface of B cell – high cell to cell specificity

The cell-to-cell specificity is important, otherwise will be activating antibody response all the time, thereby specificity is a control mechanism.

4) The antigen complex with MHC class 2 molecule will bind to the T cell receptor. Binding is stabilised with CD4 molecule.

CD4 molecule is very specific for this type of T cell

5) Once bound, it will activate a cascade within T helper cell to start producing cytokines, the cytokines produced are interleukins (IL 2/4/5)

6) These interleukins provide communication with B cell to turn on B cell to start synthesising the antibody

How do T-helper (Th2) cells assist B cells

1. T_H2 cells (CD4+) help B cells via endocytosis

2. Where B cell has to present antigen on the surface. The antigen will be taken into the cell into a lysosome.

3. Processing antigens in phagolysosomes

4. Presenting them with MHC class 2 molecule [MHC2] ON THE B CELL SURFACE

5. Other TH2 cells binds with antigen complex with MHC class 2 expressed on surface of B cell, stabilized by CD4, releasing cytokines (e.g., interleukins 2, 4, 5) to stimulate antibody production.

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Usually to measure if there is an infection happening/ how immunocompetent one is, the ratios between CD4 and CD8 will be measured in blood tests as a good indication.

Why is T-cell induction important for vaccination

• T-Dependent Antigens: Many vaccines rely on helper T cells (TH2/CD4+) to fully activate B cells.

• Some vaccine antigens (e.g., purified proteins) are poorly recognized by B cells ALONE.

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1. Without T-cell help, B cells may fail to produce high-affinity antibodies or memory cells. T-cell involvement AMPLIFIES the response.

2. T-cell help ensures the formation of memory B cells (for rapid antibody production upon re-exposure).

3. Memory T cells (CD4+) persist to accelerate future responses.

4. Cytotoxic T Cells (CD8+) kill infected cells. This is critical for intracellular pathogens (e.g., viruses).

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T-cell induction of B cells producing plasma cells to produce antibodies enhances vaccination success by ensuring a robust response to weaker antigens.

How does innate immunity boost T-cell production

1. Macrophages phagocytose pathogens

2. PRESENTING antigens on MHC2 using debris

3. Release interleukin-1 to stimulate T-cell division

4. Amplifying the adaptive response.

What is the role of macrophages in innate and adaptive immunity?

• Macrophages engulf pathogens, present antigens on MHC2, and signal T cells with interleukin-1

• Bridging innate and adaptive immunity for antibody production.

Why is the induction of cell-mediated immunity key to vaccination

Induction via innate (macrophages) and adaptive (T-helper cells) arms ENHANCES antibody production, critical for vaccination success against diverse pathogens.

How do Th1 cells amplify cytotoxic T cells

Th1 cells stimulate cytotoxic T-cell precursors to kill intracellular pathogens, such as virally infected cells, enhancing cell-mediated immunity.

How do cytotoxic T cells identify virally infected cells

"Cytotoxic T cells target cells with intact MHC1 presenting viral antigens, left on the surface via endocytic processing or membrane penetration."

What happens when cytotoxic T cells engage infected cells

Cytotoxic T cells bind to MHC1-antigen complexes

Causing degranulation and apoptosis of the infected cell to eliminate intracellular pathogens."

Why is cell-mediated immunity without antibodies important for vaccination

Cell-mediated immunity, driven by cytotoxic T cells, targets intracellular pathogens like VIRUSES without antibody involvement, key to vaccination success.

Describe T_H1 cells subset

TH1 cell, another subclass of TH cells, trigger (innate) cell mediated immunity. (Also known as inducer T-cell or delayed type hypersensitivity cells (TH/DTH cells)

1) STIMULATING MACROPHAGE

TH1 cell will recognise macrophage that is presenting an antigen with an MHC class 2 molecule, stimulating TH1 cell to release a variety of cytokines especially interferon γ (IFN-γ).

IFN-γ will specifically cause macrophages to ↑/ amplifies phagocytosis [ innate immunity turned on by adaptive immunity]

E.g. If particular bacterial cell has evolved to evade phagocytosis, one way to overcome is to ↑ capacity of phagocytosis cells and make process faster

2) Cooperate with Cytotoxic T-Cells (T8 or CD8+ cells or killer T-cells)

Cytotoxic T cells are very important when dealing with intracellular pathogens like viruses. [NK cells recognizes viral infected cells as some viruses withdraw the MHC class 1 molecule when invading the cell - they do not have a MHC class 1 molecule]

With cooperation of the TH1 cell, it stimulates T cell precursors to become cytotoxic T-cells.

Cytotoxic T-cells can recognize virally infected cells and kill virally infected cells.

When the cell is infected by a virus, this time the MHC class 1 molecule is still intact with the cell surface of the host cell (not withdrawn)

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This presentation of MHC class 1 molecule is advantageous:

a.Virus can be processed within the cell to be expressed on the surface with the MHC class 1 molecule

b.Virus from penetrating the cell, it may leave some of their cell membrane on the target/ host cell so some of the antigen may be left on the surface of virally infected cell and the presence of MHC class 1 molecule will complex with the antigen

Virus/ antigen complexed with MHC class 1 molecule being presented on virally infected cell are targets for cytotoxic T-cells

Cytotoxic T-cells have granules with perforins and granzymes inside, it degranulate (releasing its contents into the virally infected cell) leading to cell death by apoptosis

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Immunity against virally infected cells

Innate immunity from virally infected cells themselves, the virally infected cells let the neighboring environment know they are infected by releasing IFN-α & β so the IFN will prevent viral replication (blocked) in uninfected cells

Innate immunity also has NK cells which will recognize virally infected cells that are not recognize virally infected cells that aren’t expressing MHC class 1 molecule

Expression of viral antigen on MHC class 1 molecule in infected cells are targets for cytotoxic/ killer T-cells.

Presentation of viral antigen with MHC class 2 molecule can also occur, which would be targets for TH2 cells thereby B cell response and macrophage activation

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1. TH1 Cells Activate Macrophages

Mechanism:

• TH1 cells recognize antigen-MHC II complexes on macrophages → secrete IFN-γ.

• IFN-γ enhances macrophage functions:

  • ↑ Phagocytosis.

  • ↑ Reactive oxygen species (ROS) and nitric oxide (NO) production.

  • ↑ Antigen presentation (feedback loop).

Example:

• In tuberculosis, M. tuberculosis resists phagocytosis. TH1-derived IFN-γ forces macrophages to destroy the bacteria.

Why It Matters:

• Bridges adaptive immunity (TH1) with innate immunity (macrophages).

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2. TH1 Cells Help Cytotoxic T Cells (CD8+)

Mechanism:

• TH1 cells secrete IL-2, stimulating CD8+ T cell proliferation/differentiation.

• CD8+ T cells kill virally infected cells via:

  • Perforin (pores in cell membrane).

  • Granzymes (induce apoptosis).

Viral Evasion vs. Immune Response:

Scenario	Immune Response
Virus downregulates MHC I	NK cells kill infected cells (innate).
Virus leaves MHC I intact	CD8+ T cells recognize viral peptide-MHC I and kill the cell.

Example:

• In HIV, CD8+ T cells target infected CD4+ cells.

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3. TH1 vs. TH2: Opposing Roles

Feature	TH1 Response	TH2 Response
Trigger	Intracellular pathogens (viruses, TB)	Parasites/allergens
Key Cytokine	IFN-γ, IL-2	IL-4, IL-5, IL-13
Effector Cells	Macrophages, CD8+ T cells	B cells (antibody production)
Hypersensitivity	Type IV (delayed)	Type I (allergic)

Clinical Implication:

• Leprosy:

  • Tuberculoid leprosy (TH1-dominated) → localized lesions.

  • Lepromatous leprosy (TH2-dominated) → disseminated infection.

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Key Takeaways

1. TH1 cells drive cell-mediated immunity via:

   • Macrophage activation (IFN-γ).

   • CD8+ T cell help (IL-2).

2. Viruses evade immunity by:

   • Downregulating MHC I (NK cell target).

   • Hiding in cells (CD8+ T cell target).

3. TH1/TH2 balance determines infection outcome (e.g., chronic vs. cleared).

Therapeutic Applications:

• Vaccines (e.g., COVID-19 mRNA vaccines) aim to stimulate TH1 + CD8+ responses.

• Autoimmunity: Excessive TH1 activity → tissue damage (e.g., Crohn’s disease).

What are the core principles of adaptive immunity

"Adaptive immunity involves recognition, specificity, and memory of non-self antigens, mediated by B cells and T cells."

What are the key cellular components of adaptive immunity

1. B cells (antibody producers)

2. Th2 T cells (B-cell helpers)

3. Th1 T cells (cytotoxic amplifiers),

4. Effector T cells (killer T cells)

5. Receptors (MHC1/MHC2) and cytokines.

Why are Th2 cells critical in adaptive immunity

"Th2 cells coordinate the immune response by aiding B cells in antibody production, linking humoral and cell-mediated immunity."

What is T cell expansion?

Using antigen presentation by innate immune system to amplify adaptive immune system:

SIGNAL 1:

a) Stimulate the TH2 cells to divide and this is done through macrophages (from innate immunity)

b) The interaction between an antigen presented on the surface of a macrophage in conjunction with an MHC class 2 molecule (antigen is stabilized on the surface with MHC class 2 molecule).

To note: T cells has specificity, is not a fit for all antigen so will only recognize specific antigen

SIGNAL 2:

a) Macrophage releases interleukin-1 (IL-1)

b) IL-1 is the signal molecule that stimulates the TH2 cell to then divide and ↑ in numbers

What are Hypersensitivity Reactions?

Hypersensitivity Reactions: Types I–IV (Gell and Coombs Classification)

Hypersensitivity reactions are exaggerated immune responses to harmless antigens (allergens) or self-antigens, leading to tissue damage. They are classified into four types (I–IV) based on immune mechanisms and clinical presentation.

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1. Type I (Immediate/IgE-Mediated) Hypersensitivity

• First exposure: Allergen → B cells produce IgE (with TH2 help). IgE binds to mast cells/basophils (sensitization).

• Second exposure: Allergen cross-links IgE on mast cells → degranulation → release of:

  • Histamine, leukotrienes, prostaglandins → vasodilation, smooth muscle contraction, inflammation.

- Antihistamines (e.g., diphenhydramine)
- Epinephrine (anaphylaxis)

2. Type II (Antibody-Mediated Cytotoxic) Hypersensitivity

• IgG/IgM binds to cell-surface antigens → activates:

  • Complement → MAC lysis (e.g., transfusion reactions).

  • Fc receptor-mediated phagocytosis (e.g., autoimmune hemolytic anemia).

  • Antibody-dependent cellular cytotoxicity (ADCC) (e.g., Graves’ disease).

• Autoimmune diseases:

  • Graves’ disease (anti-TSHR antibodies → hyperthyroidism).

  • Myasthenia gravis (anti-AChR antibodies → muscle weakness).

- Immunosuppressants (e.g., prednisone)
- Plasmapheresis (remove antibodies)

3. Type III (Immune Complex-Mediated) Hypersensitivity

• Excess antigen-antibody (IgG/IgM) complexes deposit in tissues → complement activation → neutrophil recruitment → inflammation.

• Systemic Lupus Erythematosus (SLE) → glomerulonephritis, arthritis.
  - Corticosteroids
  - Immunosuppressants (e.g., cyclophosphamide for severe SLE)

4. Type IV (Delayed-Type/Cell-Mediated) Hypersensitivity

• Sensitized TH1/CD8+ T cells recognize antigen → release IFN-γ, TNF-α → macrophage activation → granuloma formation/tissue damage.

• Delayed onset (24–72 hrs).

• Autoimmune diseases (Type 1 diabetes, MS).

- Topical corticosteroids (e.g., hydrocortisone)
- Systemic immunosuppressants (e.g., methotrexate for chronic cases)
- Avoidance of trigger (e.g., gluten in celiac disease)

How is histamine synthesized and inactivated

"Histamine is synthesized from L-histidine by histidine decarboxylase and inactivated by histamine N-methyl transferase, followed by diamine oxidase."

Where is histamine found in the body

"Histamine is present in most tissues, including the CNS, with the highest concentrations in the lungs, skin, and GI tract."

How is histamine stored and released

"Histamine is produced and stored in mast cells and basophils as histamine-heparin complex granules, released upon cell activation."

What are the main actions of histamine

Histamine causes:

• Smooth muscle contraction (bronchoconstriction in lungs, GI tract contractions)

• Vasodilation (lowers BP, increases vascular permeability causing oedema)

• Gastric acid secretion.

What triggers an allergic reaction involving histamine

"An allergen binds to IgE antibodies on mast cells, activating them to degranulate and release histamine, prostaglandin-D2 (bronchoconstriction), and leukotrienes (oedema)."

How do histamines contribute to allergic symptoms

"Histamines activate H1 receptors, causing vasodilation (redness, BP drop), increased vascular permeability (swelling), smooth muscle contraction (bronchoconstriction, GI cramping), and nerve sensitization (itching)."

What are the symptoms of an allergic response caused by histamine

"Symptoms include redness (vasodilation), swelling (increased permeability), hyperventilation (bronchoconstriction), GI issues (cramping, nausea, vomiting, diarrhea), and itching (nerve sensitization)."

How do CNS-penetrating H1 antihistamines affect the body

"CNS-penetrating drugs (e.g., promethazine, chlorpheniramine) block H1 receptors involved in wakefulness, causing sedation due to histaminergic neuron inhibition."

What distinguishes peripheral-only H1 antihistamines

"Peripheral-only drugs (e.g., cetirizine, loratadine) are non-sedating, allowing higher doses without CNS effects."

What are the side effects of antihistamines

"Side effects include dry secretions, confusion (antimuscarinic effects), skin hypersensitivity (rashes), heart palpitations, and sedation (not directly from histamine)."

What are H1 antihistamines used for

"H1 antihistamines treat allergies, short-term insomnia, and motion sickness (anti-emetic properties in older drugs like cyclizine)."

What precautions are needed with sedating antihistamines

"Sedating antihistamines are cautioned in urinary retention, angle-closure glaucoma, severe hepatic disease, epilepsy, porphyria (non-sedating are safe), and pregnancy."

What triggers H2 receptor activation

"H2 receptor activation, leading to gastric acid secretion, is triggered by histamine, gastrin, and M3 muscarinic receptors on parietal cells in the stomach epithelium."

How do H2 receptors function

"H2 receptors are G-protein-coupled receptors following a Gs pathway, stimulating the cAMP system to increase gastric acid production and secretion."

What are H2 receptor antagonists used for

"H2 receptor antagonists (e.g., famotidine, cimetidine) treat peptic/duodenal ulcers and acid reflux (GERD), often prescribed with proton pump inhibitors like omeprazole."

What are the side effects of H2 receptor antagonists

"Side effects are uncommon but include diarrhea, dizziness, headaches, and muscle pains; cimetidine inhibits liver P450 and acts as an androgen receptor antagonist at high doses."

Where are H3 receptors located and what do they do

"H3 receptors, histamine autoreceptors in the CNS, inhibit histamine release when activated; antagonists increase release, agonists decrease it."

How do H3 receptors affect neurotransmitters

"H3 receptor activation modulates CNS neurotransmitter release, including noradrenaline, monoamines, acetylcholine, and neuropeptides."

What are H4 receptors and their discovery

"H4 receptors, recently discovered with a structure similar to H3, are histamine receptors found on immune cells like mast cells, macrophages, and granulocytes."

What happens when H4 receptors are activated

"H4 receptor activation causes itching; the only known agonist is the anti-psychotic clozapine."

What is the suspected role of H4 receptors

"H4 receptors are believed to play a role in the immune system and inflammation, though their full function remains unknown."