12 - Immune dysfunction and hypersensitivity Flashcards
1
Q
What is hypersensitivity?
A
- Any immune response against a foreign antigen that is exaggerated beyond the norm
2
Q
What is Type I Hypersensitivity?
A
- Localised or systemic reactions that result from the release of inflammatory molecules (such as histamine) in response to an antigen
- Type I is immediate and characterised by the production of IgE antibodies against foreign present in the environment
- IgE is distinct from other immunoglobulins because it has:
a) An extra constant region domain
b) A different structure to the hinge region
c) The primary binding sites are different leading to very high affinity - Two stages of response
a) Sensitisation (Priming)
b) Degranulation (Memory) - Allergies result when allergens bind to IgE molecules that are already bound to mast cells, basophils, and eosinophils
a) This causes the sensitised cells to degranulate and release histamine, kinins, proteases, leukotrienes, and prostaglandins - This can result in hay fever, asthma, urticaria, various other allergies, or in severe cases where the inflammatory mediators exceed the body’s coping mechanism = acute anaphylaxis
- Type I is diagnosed by skin testing and can be prevented by avoidance of allergens and immunotherapy
a) Some type I hypersensitivities are treated with antihistamines
3
Q
What is Type II Hypersensitivity?
A
- This occurs when cells are destroyed by an immune response
a) Mediated by antibodies binding to specific cells
b) Reactions are caused by IgG, IgA, or IgM antibodies against cell surface and extracellular matrix antigens
c) Reactions may target tissues
4
Q
What is Type III Hypersensitivity?
A
- Caused by immune complexes that are formed when antibodies meet antigens
a) Immune complexes can be formed by persistent infection, inhalation of antigenic material, autoimmune disease, or cryoglobulins - Type III hypersensitivities may be localised or may affect a number of body systems simultaneously
- Normally, immune complexes are removed from the body via phagocytosis, however, in type III hypersensitivity reactions, immune complexes escape phagocytosis and circulate in the bloodstream until they become trapped in organs, joints, and tissues
a) This can cause significant tissue damage
5
Q
What is Type IV Hypersensitivity?
A
- Delayed-type hypersensitivity reflects the presence of antigen-specific T-cell mediated inflammation
- There are four subgroups of type IV hypersensitivity
a) Type IVa secrete large amounts of interferon-gamma and lead to macrophage activation
b) Type IVb reactions develop after T-helper type 2 cell activation of eosinophils via cytokines IL-4 and IL-5
c) Type IVc reactions involve CD8+T cells acting as effector cells themselves to produce cytokines and drive cytotoxic activity
d) Type IVd reactions involve T-cell activation of neutrophils, causing sterile neutrophilic inflammation of the skin - Type IV hypersensitivity takes 24-72 hours to reach maximal intensity
6
Q
What is immune therapy?
A
- Administration of molecules or cells that suppress, activate, enhance, attenuate, or terminate immune responses, either at the molecular or cellular level, to prevent disease pathogenesis before it occurs, to alleviate ongoing disease symptoms, or to cure established disease pathology
7
Q
What are the five categories of immunotherapy and what are they used for?
A
- Passive immunisation - infection
- Allergen desensitisation - allergic disease
- Immunomodulators - cancer, transplantation, autoimmune/inflammatory disease
- Vaccines and antibodies - cancer, infection
- Cell-based therapy - cancer
8
Q
What is passive immunisation?
A
- Problem
a) An individual’s immune system is not responding to infection - Reasons for problem:
a) Immune-related disorder
b) Acute infection
c) Infection during chemotherapy or immuno-suppressive therapy - Treatment:
a) Immunoglobulin preparations are used to provide passive immunisation by direct administration of antibodies (e.g. intravenous injection) to a non-immune person to provide immediate protection against infection or disease
b) Two sources of immunoglobulin preparations are normal human immunoglobulin and specific immunoglobulin using pooled plasma - How long does it last?
a) Can last up to 4 months, depending on how quickly the antibodies degrade once administered
9
Q
What is allergen-specific immunotherapy?
A
- Problem
a) An individual’s immune system responds too strongly to certain molecules in the environment
b) Severe symptoms include allergic rhinitis, allergic asthma, and anaphylaxis - Treatment:
a) Determine which allergens are causing allergic response, then administer increasing amounts of the specific allergen to which the patient is known to be allergic
b) The mechanism is not definitively known, but successful allergen desensitisation includes change in IgE response to IgG response - Clinical considerations:
a) Need to accurately identify the correct allergen to be used for immunotherapy
b) The optimal duration of the maintenance therapy is uncertain, but recommended treatment duration is 3-5 years
c) Immunotherapy is generally most effective when given subcutaneously with an increasing dose of the specific allergen at each subsequent treatment visit
d) The patient should be under observation for at least 30 minutes following injection
10
Q
What are immunomodulators?
A
- A molecule that stimulates or inhibits immune cell responses, generally in a non specific manner
11
Q
What are cell-based therapies?
A
- To increase number of activated T cells that target tumour cells, tumour-infiltrating lymphocytes (TILs) that recognise tumour cells are isolated and expanded
12
Q
How are transplants rejected?
A
- Cytotoxic T cells recognise that MHC on transplant cell is different and swiftly remove it from the body
- Usually takes 10-14 days for rejection to occur, however memory to antigen means that 2nd exposure will be rejected quicker (in 3-7 days)
13
Q
What are the types of transplant rejection?
A
- Host versus Graft
- Graft versus Host
a) Mainly in bone marrow transplants
b) Donor immunocompetent T cells recognise recipient incompetent tissue
c) Destroys skin, liver, GIT
d) To prevent this conditioning is neccessary (graft must contain immunocompetent cells, host possesses alloantigen lacking in donor MHC, host incapable of mounting immunologic reaction) - Hyperacute
a) Occurs in minutes to hours
b) Type III hypersensitivity
c) Associated with humoral arm of immune system - B lymphocytes
d) Pre-formed graft specific cytotoxic antibodies already exist in body
e) Results in graft loss - Acute
a) Occurs in days to months
b) Type IV hypersensitivity
c) It is cell mediated
d) Graft’s HLA is seen as foreign which evokes graft specific cytotoxic antibodies produced
e) Rarely results in graft loss because it can be controlled since it takes longer to occur - Chronic
a) Low level and takes months to years to manifest clinically (fibrosis, arteriopathy, loss of function, eventual graft loss)
b) Begins at time of rejection
c) Involves both immune and non immune mechanisms - Primary Graft Failure
a) Not due to immune system
b) Primary cause is due to time taken to perform transplantation
c) In liver transplants - time between liver being removed and new liver being established means that no filtering of blood is happening - toxins and bacteria start to build up and new liver simply can’t cope with the demands of the new body due to this build up and so liver is rejected
14
Q
What are some treatments to stop rejection of transplant?
A
- Immunomodulators
a) Methotrexate
b) Thalidomide
c) Cyclosporine, FK 506, Rapamune
d) IL-2 blocking Ab
15
Q
What is the general approach to successful organ transplantation therapy?
A
- Careful patient preparation and matching
- Use of combinational therapy for immunosuppression
- Increase immunosuppression required to gain engraftment and/or treat established graft rejection
- Decrease immunosuppression to maintain long term graft survival
