Immunology Flashcards
What does central tolerance consist of?
Positive Selection and Negative Selection
What is Positive Selection?
Positive Selection is the selection of immature lymphocytes that expresses T cell receptors that binds moderately to MHC complexes on thymic cells.
They would receive “survival” signal, which allows them to continue their development.
What happens to those immature lymphocytes which does not bind or bind minimally to MHC complexes?
They would undergo “death by neglect”
What is Negative Selection?
Negative Selection is the selection of immature lymphocytes that expresses T cell receptors that binds too strongly to MHC complexes on thymic cells.
Because of this, they have a high likelihood of becoming self-reactive and attack own’s cells. They thus undergo apoptosis.
Why is thymic tolerance important for the proper function of the immune system?
Thymic tolerance of T cells (central tolerance) is important so as to eradicate immature lymphocytes that has a potential to become self-reactive and attack its own cells. Hence, it is important to prevent autoimmunity.
What are the 3 signals that naive T cells require to be activated?
- T cell receptors binding peptide-MHC molecule
- Co-stimulation
- Cytokines
What is co-stimulation?
Co-stimulation is the second signal expressed from APC to T cells to activate an immune response.
Co-stimulatory molecules on T cells will bind to Co-stimulatory molecules on APC
Gives an example of co-stimulation.
CD28 on T cell receptors bind to B7.1 (CD80) and B7.2 (CD86) on dendritic cells.
This triggers the production of IL-2, which promotes the proliferation and differentiation of T helper cells (particular Th1)
Describe how the requirement for costimulation during activation of naïve T cells promote self-tolerance in the absence / presence of infection.
In the presence of an infection, pathogens expresses pattern recognition receptors (e.g. pathogen-associated molecular patterns, PAMPs). This triggers the maturation of APC like dendritic cells, allowing more costimulation.
Briefly describe the 3 mechanisms of peripheral tolerance.
- Ignorance - when T cells receptors bind to peptide-MHC are too weak to cause an activation of mature T cells in the periphery.
- Anergy - when T cells are functionally inactivated following an encounter with the antigen, but does not undergo apoptosis, or cell death. Instead, it remains in a prolonged state of unresponsiveness due to the lack of co-stimulation.
- regulation - when T cells bind too strongly to self-antigen but not strong enough to attack it, are re-directed to regulatory function via the induction of transcription factor, FOXP3.
List the 4 types of hypersensitivity reactions.
Mnemonics: ACID
A — allergy/atopic/anaphylactic (IgE antibody mediated reaction / immediate hypersensitivity) (type I)
C — cytotoxic (antibody-mediated reaction / cytotoxic hypersensitivity) (type II)
I — immune complexes (type III)
D — delayed (type IV)
Type I to Type III hypersensitivity are all antibody-mediated.
However, Type IV hypersensitivity is T-cell mediated.
Describe the mechanism of Type I hypersensitivity reaction.
Type I Hypersensitivity is an immediate, IgE-antibody mediated reaction.
Genetic predisposition -> 2nd exposure to an allergen -> preformed IgE (sensitisation during the 1st exposure) will coats mast cells and basophils -> antigen (allergen) will bind to 2 IgE antibodies (known as crosslinking), resulting in the degranulation of the cells. This releases histamines and other mediators (e.g. prostaglandins, leukotrienes, and tryptase).
Name the 3 tests that can be done to check for allergy.
- Skin prick test
- Scratch test
- Intradermal test
Addition: Blood test to check for elevated tryptase (which is relatively specific for mast cell degranulation)
What can be given to a patient with allergy?
2nd gen H1 receptor blockers (antihistamines) (e.g. cetirizine, fexofenadine)
Glucorticoids to suppress the immune reaction
Give some examples of Type I Hypersensitivity reactions.
Mnemonics: 3As to be First
- Anaphylaxis
- Allergic (e.g. drugs, food)
- Atopic allergy (e.g. allergic rhinitis, asthma, eczema)
Describe the mechanism of action of Type II Hypersensitivity Reaction.
Type II hypersensitivity is a cytotoxic, antibody-mediated reaction. It is often limited to a particular tissue type. This is because antibody are specific to the tissues (antigens).
Activation of complement system: IgG and IgM bind to tissue-specific antigens, which activates the complement cascade, and result in phagocytosis and lysis of cells
Opsonisation, and phagocytosis of cells with C3b
ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity): NK cells bind to the Fc region of antibody-antigen complex -> release perforins, granzymes, and granulysin -> apoptic cell death
Antibody-mediated cellular dysfunction (only non-cytotoxic mechanism)
Give some examples of Type II Hypersensitivity reaction.
Type II hypersensitivity have a few different mechanisms, and thus can be classified under
Destruction of cells
Inflammatory
Impaired cellular function
Some examples include:
Destruction of cells:
Autoimmune haemolytic anemia
Acute haemolytic transfusion reaction
Inflammatory
Goodpasture syndrome
Rheumatic Fever
Cellular dysfunction Graves (TSH receptors autoantibodies that acts like TSH, and promotes the thyroid gland to produce more thyroid hormones) Myasthenia gravis (autoantibodies against postsynaptic acetylcholine receptors)
Describe the mechanisms of Type III Hypersensitivity
Type III hypersensitivity is a immune complex, antibody-mediated reaction.
Antigens bind to IgG antibodies, forming a antigen-antibody complex. This immune complex then deposit in tissues (esp. blood vessels) and results in the initiation / activation of the complement cascade, which triggers the neutrophils to release lysosomal enzymes (e.g. perforins, granzymes). This leads to lysis and cell death.
List a few examples of Type III Hypersensitivity reaction.
Rheumatoid arthritis Arthus reaction (vaccination against tetanus and diphtheria) Serum sickness Systemic Lupus Erythematosus (SLE) Lupus nephritis
Describe the mechanism of Type IV Hypersensitivity.
Type IV Hypersensitivity is a delayed, cell-mediated reaction.
The nickel penetrates the skin of Mr L. → Langerhans cells (APC) takes up the antigen and migrates to the lymph nodes. This results in the formation of sensitised T lymphocytes.
The repeated contact with the antigen results in presensitised T cells response.
CD4+ T cells → recognise antigen on APC → release inflammatory lymphokines cytokines (IFN-y and TNF-a) → activates the macrophages → phagocytosis of target cells
CD8+ T cells → recognise antigen on somatic cells → cell-mediated cytotoxicity → direct cell destruction
Why is Type IV Hypersensitivity delayed?
Because T-cell mediated (delayed) reaction requires a pre-sensitised T cells and takes 2-3 days to be activated.
Give some examples of type IV hypersensitivity.
Contact dermatitis (e.g. metal stuff like nickel; poison ivy; rubber gloves)
GVHD (Graft-vs-Host Disease)
Mantoux tuberculin skin test
What is HLA?
Human Leukocyte Antigen (HLA) is a gene cluster found on chromosome 6 that encodes for major histocompatibility complex (MHC) molecules.
What is MHC?
Major Histocompatibility Complex (MHC) are peptides found on the surface of all cells that display antigenic peptides as a normal physiological function, so that they can be recognised by T cells as either self- or non-self antigens.
