Hypersensitivity and Autoimmunity

Question 1

What is the underlining cause of autoimmunity and the difference to hypersensitivity?

Answer 1

Autoimmunity: Failure of the immune system to recognise own molecules as self –> loss of tolerance

• Enables immune response against its own cells and tissue, causing damage and disease
• Major factors contributing to development of autoantibodies are genetic susceptibility and environmental factors such as infections by pathogens
• Mechanisms that cause autoantibodies:
  > Failure to delete auto-reactive lymphocyte in primary lymphoid tissues

> Molecular mimicry by invading microbes

Autoimmune diseases usually have a hypersensitivity reaction as part of their pathogenesis e.g. Type 1 diabetes mellitus involes a type IV hypersensitivity reaction

+ Hypersensitivity component of an autoimmune disease describes the mechanism by which cellular damage happens, DOES NOT DESCRIBE DISEASE AS WHOLE

Question 2

Describes the characteristic mechanisms of each of the four types of hypersensitivites, giving examples for each (define hypersensitivity)

Answer 2

Hypersensitivity: Over activated normal response of the immune system

Hypersensitivity type I: Immediate reactions mediated by IgE and mast cells (allergies)
> Systemic anaphylaxis can be fatal –> result of the activation of basophils in blood by IgE

Hypersensitivity type II: Mediated through IgG + complement and causes the direct destruction of cells and tissues (Three types)

> Complement activated reactions (Host antibodies react with cell membrane ptoeins –> leads to complement cascade and lysis/ or phagocytosis)

• Mixing of dfferent blood groups results in lysis of foreign cells

> ADCC (antibodies bind to cell surface protein i.e. autoantigen, Fc receptor of immune cell bind to antibodies, lysis of target cells occur through cytoplasmic granules (perforin and ggranzymes)

-Examples: Abs produced against foetal red blood cell (Rhesus antigens)

>Antibody-mediated cell dysfunction

Hypersensitivity type III: Mediated by IgG and IgM forming complexes between soluble antigen and antibody

> Complexes lead to systemic disease or disease in organs (RA)

Hypersensitivity type IV: Callled delayed-type hypersenstivity (takes 24 hrs to several days to develop) –> mediated by immune cells

> contact dermatitis, tuberculin, DM

Question 3

What does allergen and atopy mean?

Answer 3

Allergen: Antigens that trigger IgE poduction and activation (Usually proteins)

Atopy: Refer to allergic reactions

• Often a genetic tendency to develop allergies (asthma, rhinitis)
• Allergic reactions occur in skin (atopic dermatitis), nose, eyes and lungs (asthma)

Question 4

What are the three phases of the Hypersensisitivity type 1 cellular mechanism?

Answer 4

1) Sensitization phase- allergen-specific IgE is produced by plasma cells in genetically predisposed individuals and then bind to Fc receptors on mast cells and basophils

2) Activation phase- re-exposure to allergen triggers mast cells/basophils and respond by release of their pro-inflmmatory cytokines from granules

3) Effector phase- complex repsonse occurs as a result of histamine and active agents released by mast cells and basophils

Question 5

What is the process of mast cell degranulation and what are the treatment options?

Answer 5

1. Allergen in contact (e.g. skin, mucous membrane)
2. Allergen binding to IgE –> triggers reaction
3. Fc receptor on mast cell trigger: increase in cAMP levels –> influx of Ca2+
4. Fusion of granules to membrane and relase of pro-inflammatory mediators (histamine, heparin, cytokines)
5. Pre-formed vesicles
6. Newly formed mediators
7. Release of mediators

Treatments:

1) Environmental: avoidance of allergen

2) Prevent symptoms: antihistamines, epinephrine

> degranulation is prevented if cAMP levels remain high

3) Hypo or desensitisation: Inject with increasing doses of alleren over time (trigger IgG antibody speficic to the allergen so it binds to allergen and removes allergen before it an reach and react with IgE on mast cells )

> Bee stings (allergens that enter the blood)

4) Anti IgE humanised antibody: Anti IgE monoclonal antibodies bind IgE in serum, dont allow IgE bind to FcR of mast cells or basophils therefore no degranulation .

> Treatment for asthma