Session 1 Flashcards
Goodpasture’s syndrome
Systemic lupus erythematosus
Myasthenia gravis
Rheumatoid arthritis
Graves‘ disease
Haemolytic anaemia
The term hypersensitivity describes? (HE SAID THIS WILL COME UP IN THE EXAM)
the antigen-specific immune responses that are either inappropriate or excessive and result in harm to host
excessive e.g. Type 1 allergies
mechanisms -> those used to fight infections
hypersensitivity reaction driven by innate -> septic shock
hypersensitivity driven by adaptive (what we will discuss today)
What are the triggers for hypersensitivity reactions?
• Hypersensitivity to exogenous antigens
- Non infectious substances (innocuous) e.g. allergens
- Infectious microbes e.g. infective endocarditis
- Drugs (Penicillin)
• Hypersensitivity to intrinsic antigens (autoimmunity lecture - more difficult to treat)
- Infectious microbes (mimicry) (when you are infected mount a immune reaction to foreign antigens and self antigens/cells)
- Self antigens (auto-immunity) (no known cause yet !!!! In exam)
Types of hypersensitivity reactions
What is the different between them all
- Type I or immediate (Allergy)
- Environmental non infectious antigens
- Type II or antiBody mediated
- Type III or immune Complexes mediated
• Type IV or cell mediated (Delayed)
(Environmental infectious agents and self antigens)
Type 1,2,3 are antibody
Type 1 is IgE
Tpe 2 cell antigen
Type 2 & 3 and IgM and IgG
Type 2 cell antigen bound vs type 3 soluble antigen
Common feature of hypersensitivity reactions
• Sensitization phase
First encounter with the antigen. Activation of APCs and memory effector cells. A previously exposed individual to the antigen is said to be “sensitized.”
• Effector phase
Pathologic reaction upon re-exposure to the same antigen and activation of the memory
cells of the adaptive immunity.
Can’t have a hypersensitivity reaction in the first encounter -> you will have antigen specific antibody & antigen specific T cells.
Type II hypersensitivity
Give the most 4 important facts and examples if they have any
- Usually develops within 5-12 hr
- Involves IgG or IgM antibodies
- Targets cell bound antigens
Exogenous: Blood group antigens, Rhesus D antigens
Endogenous : self antigens
• Induces different outcomes:
Tissue/cell damage
Physiological change
Type II hypersensitivity : mechanisms
Individual already sensitised because it has the antibody
Antibody will bind to trigger
Will activate the complement pathway
Activate cell lysis membrane attack complex
Recruit neutrophils - release toxins
Innate cell called NKC bind to the antibody by the FC receptor and release toxins/ radicals on the target cells
Type II hypersensitivity : importance of complement pathways
An example of disease caused by type II hypersensitivity (IgM)
Haemolytic transfusion reaction
- Life-threatening condition
- Shock, kidney failure, circulatory collapse, and death
Immune mechanism
- Incompatibility in the ABO group or rhesus D antigens
- Donor RBC destroyed by recipient’s immune system
- RBC lysis induced by type II hypersensitivity involving by the naturally occurring antibodies (IgM)
If you are blood type A natural autoantibody against b antigen is IgM
An example of disease caused by type II hypersensitivity (IgG)
Mother does not have Rhesus factor
Rh+ antigens from the fetus gets transported to the mother from the blood i.e. in birth -> mother becomes sensitised (antigen on the cell membrane and this is antibody mediated thus is type 2) -> mother becomes pregnant again now in the effector phase ->EFFECTOR PHASE re exposure mother now has memory cells (can produce antigen) -> complement activation & Ab dependent cytotoxicity -> rhesus haemolytic disease of newborn -> maternal IgG can get to the baby via the placenta (only IgG can cross the placenta) within 72 hrs of delivery must give RHOGAM IgG against Rhesus factor -> bind to fecal RBC and prevent them from lysis and prevent the fecal RBC from sensitising the mother
Type II hypersensitivity : mechanisms
Type II hypersensitivity : therapeutic approaches know for exam
E.g. prednisolone but stone side effect profile
Humour always or spleen macrophages problem wont make distinction if antibody is bound to a microbe or a self cells.g. RBC or platelet with destroy everything - e.g. autoimmune haemolytic anaemia
Immunodeficiency and now for autoimmune disease MOA unknown -> one thought
Is something is missing you restore it or if something is excessive you reduce it
Type II hypersensitivity : Plasmapheresis therapy
explain what it is and what it is used for
Myasthenia gravis
Goodpasture’s syndrome
Grave’s disease
Plasma is discarded and patient is given substitution fluid -> removal of autoantibody
Short term relief and allows healing of damaged tissue
Give 4 facts about Type III hypersensitivity
- Usually develops within 3-8hr
- Involves immune complexes between IgG or IgM and antigens
- Targets soluble antigens
- Foreign (Infection)
- Endogenous (self antigens)
• Tissue damage caused by immune complex deposition
Type III hypersensitivity : key factors affecting IC pathogenesis
- People with low affinity antibodies more likely to produce immune complexes
-Immune complexes can activate complement
C3b can bind to this complement
RBC have C3b receptor and can bind to the complement and take it to the kupffer cells in the liver to be destroyed
Patient deficient in C2 & C4 have deficiency of C3b (c3 convertse). cannot remove complexes that well
T3 hypersensitivity reaction
Pressure, filtration, which favour immune complex deposition
Type III hypersensitivity : Immune mechanisms
Easily cleared large by complement C3b bind to RBC and taken to liver and destroyed
Small can be phagocytosed by macrophages, monocytes
Intermediate ones deposit, when the deposit they activate compliment C3b binds to tissue opsonisation of tissue C£a chmoattraction of neutrophils
When neutrophils come binds to the tissue -> degranulation
Examples of diseases caused by type III hypersensitivity
Rheumatoid arthritis (self antigen)
Glomerulonephritis (infectious)
Systemic lupus erythematosus
Rheumatoid arthritis (self antigen)
Glomerulonephritis (infectious)
state what the antigen is in both of them and features of each and prognosis for RA
Fc portion of IgG in the host (this is acting like an antigen)
The antibody against this is IgM
Systemic lupus erythematosus
state the antigen and who and what it effects
- Antigen = Ds-DNA
- Most prevalent immune complexes disease
- Ratio female:male (9:1)
- 40-60% patients with cardiac, respiratory, renal, joint & neurological features
- Repeated miscarriage
- Every patient is unique!!!!!!
Type IV hypersensitivity
State when it develops
What it involves
The different subtypes
- Usually develops within 24-72hr
- Involves lymphocytes & macrophages
Different subtypes
• Contact hypersensitivity (48-72 hr)
- Epidermal reaction (eczematous rash)
• Tuberculin hypersensitivity (48-72hr)
- Dermal reaction (induration and swelling)
• Granulomatous hypersensitivity (21-48 days)
- Persistence of the antigens (tissue damage)
- Wall off the infected cells
Low molecular weight antigen, that needs to bind to a host protein to illicit an immune response - Mostly in the epidermis only when they bind to host protein when they drive the hypersensitivity reaction
T cell have come in contact with TB Positive TST positive for both IRN positive for latent
Most severe form will induce tissue damage usually an antigen which persists inside the body
Microbe persists inside the body way to seal of the cells but will be tissue destruction
TB, sarcoidosis, Chrons microscopic
Chronic granulomatous disease In this genetic condition phagocytes are unable to generate the free radical superoxide. Bacteria are phagocytised but the phagocytes cannot kill them as they can’t generate an oxygen burst. This results in many chronic infections in the first year of life. Numerous granulomas (these will be described in the next session on chronic inflammation) and abscesses affecting the skin, lymph nodes, and sometimes the lung, liver and bones occur, however they are ineffective at eliminating the infectious agents.
Sarcoidosis
Depends on the organ involved[2]
Lungs: wheezing, cough, shortness of breath, chest pain
Type IV hypersensitivity : mechanisms of tissue destruction
Diseases caused by type IV hypersensitivity to exogenous antigens
Granulomatous hypersensitivity:
• Tuberculosis • Leprosy (tuberculoid) • Schistosomiasis • Sarcoidosis
Contact hypersensitivity:
• Nickel • Poison ivy • Organic chemicals
Type IV hypersensitivity :
Give two examples of where it is used as a determination of the sensitization status
- What is this image showing?
- Diseases caused by Type IV hypersensitivity to endogenous antigens?
- Type IV hypersensitivity :Granulomatous hypersensitivity
- • Autoimmune disease
- Pancreatic Islet cells: Insulin-dependent diabetes mellitus
- Thyroid gland: Hashimoto’s thyroiditis
- Involvement of CD8+ T cells & antibodies
- IgG: rheumatoid arthritis (IgG)
Hashimoto’s disease (IV) versus Graves’ disease (II) MOA
Type III and IV hypersensitivity : Therapy
Anti-inflammatory drugs
- Non-steroidals
- Corticosteroids (oral prednisolone)
- Second drugs as steroid-sparing agents (<10 mg oral steroid)
- Azathioprine (anti-proliferative immunosuppressant - antimetabolite)
- Mycophenolate mofetil
- Cyclophosphamide (anti-proliferative immunosupressants - alkylation agent )
Monoclonal antibodies
• B Cells and T cells
• Cytokine network
• APCs
Systemic manifestations of allergic reaction: anaphylaxis
What is type 1 hypersensitivity?
Not a disease is a mechanism
Type I hypersensitivity : Examples of allergens
Perennial- lasting long
Type I hypersensitivity : mechanisms
Should drive the TH1 response not allergic resuts in IgG4 not a problem
TH2 response -> b -cells produce IgE
IgE binds on surface of mast cell
Does not differentiate between harmless or not harmless Just works when IgE bound
Skin
Lung asthma
Why do people have allergies?
- ENVIRONMENT
Large family everyone gets sick
Rural home different animals and bacteria
Intestinal micro flora diversity in micro flora eat a variety of food
Low antibiotic usage
- GENES
1 of your parents 13%
both 17%
genetic susceptibility = atopy
- alter normal flora diversity -> DYSBIOSIS
Give examples that result in loss of microbiota diversity/dysbiosis
C - SECTION x8 likelihood of developing an allergy
Mast cell progenitor made in bone and matures in bone
STEM CELL FACTOR important for survival
where are their strategic locations?
Strategic location
• Most mucosal and epithelial
tissues = gastrointestinal
tract, skin, respiratory
epithelium • In connective tissue
surrounding blood cells
Skin manifestation of allergic reactions and cause? LO
Urticaria -> mast cell activation within the epidermis
Mediators = Histamine and leukotrienes/cytokines
If prolonged and chronic exposure = atopic dermatitis and eczema
raised erythema
Faces manifestations of allergic reactions? Cause? Mediators? Location of mast cells/effects which regions?
Angioedema
Caused by mast cell activation in the deep dermis.
Mediators = Histamine and bradykinin
lip, eyes, tongue and upper respiratory airways
What is anaphylaxis
Systemic manifestations of allergic reaction: anaphylaxis -> life threatening
Signs of anaphylaxis
- Give examples of other allergic diseases
Food allergies, asthma
Type I hypersensitivity : therapy
explain what the first one is and how it works
Allergen desensitization or immunotherapy
“It involves the administration of increasing doses of allergen extracts over a period of years, given to patients by injection or drops/tablets under the tongue (sublingual)”
90% effective in patients with bee and wasp venom anaphylaxis
Potential mechanisms:
- CD4+CD25 Regulatory T cells
- Shift from TH2 to TH1
- Inhibitory anti-inflammatory cytokines
- Allergen specific blocking IgG
Conclusion
- Type I hypersensitivity reactions are involved in a number of disorders
- A ? are considered as important factors for the development of allergic diseases
- The immunological mechanisms involve a ?
- ? of antigen-specific IgE on mast cells represents the main trigger of the clinical manifestations of the allergic disorders
- Oral immunotherapy and anti-IgE represent both promising therapies for the treatment of anaphylaxis
reduced infectious burden coupled to changes in the microbial dysbiosis (environment)
TH2 response and the production of IgE against innocuous antigens
Crosslinking
