MCB Lecture 60 & 61 Immune Related Injury Flashcards
Broadly, what is hypersensitivity?
Too much of an immune response, or an immune response directed at the wrong thing
Which are the types of hyper sensitivities that involve antibody?
1, 2 and 3
What are the 4 different types of hypersensitivity?
Type I: allergic reaction
Type II: antibodies forming against self
Type III: deposition of immune complexes
Type IV: persistence of antigen specific T cells
Describe the process of an allergic reaction
- Allergen diffuses across mucosa
- Th2 cells activated by the allergen
- Th2 stimulates B cells to undergo class switching
- IgG -> IgE
- Plasma cells produce and secrete IgE
- Mast cells bind IgE with FceR, and patrol for next allergen
- More allergen diffuses, and mast cells bind it
- Degranulation of mast cells
What are the features of allergens?
Small
Airborne
Soluble
Low dose
What are some common allergens?
Dust mites Cat dander Milk Peanuts Pollen Spores
Differentiate between the physiological and pathological reactions of type I hypersensitivity
Physiological: this response is directed against multicellular parasites in the gut
Pathological: response directed against non harmful things such as allergens
What are the two causes for susceptibility to Type I sensitivity?
Genetic
Environmental
When doing genome wide scans of individuals who have allergies, which genes are different?
FceR
Cytokines that activate Th2
ADAM-33: tissue remodelling
HLA
What is the connection between geographical location and allergy?
Developed countries have a high, and increasing rate of allergy
What are the hypotheses about environmental factors on allergy?
Hygiene hypothesis: lack of expose during childhood –> increased sensitivity
Counter regulation hypothesis:
Infection during childhood –> stimulation of Treg
Lack of exposure early on –> Treg less efficiently produced
Where does IgE bind?
Mast cells in tissues
Basophils in circulation
Where are mast cells located?
Tissues
Where are basophils located?
Circulation
List the steps when IgE binds to mast cells
- IgE binds and the mast cell patrols for any more of the mitogen in the tissue
- Antigen binds and cross links
3a. Preformed toxic granules are released
3b. Synthesis of lipid mediators, cytokines and chemokines - Released products activate the immune response
What are the two phases of the allergic reaction?
Acute phase and Late phase
When does the acute phase of the allergic reaction occur?
5-30 minutes
When does the late phase of the allergic reaction occur?
2 hours after, persisting for days
What are the mediators of the acute and late phases of the allergic reaction?
Acute: histamine
Late: leukotrienes, cytokines, chemokines
What are the features of the acute phase reaction?
Vasodilation: redness Vascular leakage: swelling Smooth muscle contraction Mucus production Local tissue damage
What are the features of the late phase reaction?
Bronchospasm
Leukocytosis
Epithelial damage
What are the four areas where the allergic reaction is felt?
Gastrointestinal tract
Airways
Blood vessels
Skin
Describe the airway specific features of the allergic reaction
Contraction of muscle in bronchioles
Cellular infiltrate
Increase in permeability of small vessels –> oedema
Breathing becomes difficult
Describe the gastrointestinal specific features of the allergic reaction
Expulsion (vomiting and diarrhoea) due to increased fluid secretion and peristalsis
Describe the skin specific features of the allergic reaction
Redness, itching, hives and puffiness due to vasodilation and increased vascular permeability
Describe the blood vessel specific features of the allergic reaction
Vasodilation and increased permeability –>
Oedema and increased lymph draining
What happens in the systemic allergic reaction?
Widespread mast cell degranulation
Anaphalactic shock due to widespread vasodilation
What are the symptoms of systemic mast cells degranulation?
Itching
Respiratory difficulty
Gastrointestinal expulsion
Describe broadly type II hypersensitivity
This is the binding of antibodies to self, causing damage
In type II hypersensitivity, what are the two mechanisms of cell injury?
a. Complement activation: phagocytosis or lysis of host cells
b. Inflammation: antibody and complement binding to cells, neutrophil activation
What are the steps of Type II ?
- Antibodies bind to host cells, tissue antigens
- Complement activation, inflammation
- Cell injury and Interruption of cell function
What is myasthenia gravis? What is it an example of?
This is an example of Type II
This is when there are antibodies for the Acetyl choline receptors in the motor end plates.
The receptors are removed (phagocytosed), and there is muscle weakness due to the lack of muscle innervation
What is Rhesus disease of the newborn? What is it an example of?
This is when the mother is Rhesus negative and the baby is Rhesus positive.
When the baby’s blood crosses into the mother, she forms antibodies to the antigen on the RBC.
The mother launches an adaptive immune response agains the RBCs of the baby
The baby dies
This is an example of Type II hpersensitivity
What is rheumatic heart disease?
What is it an example of?
Rheumatic heart disease is an example of molecular mimicry, Type II
- Streptococcus infection, leaving behind antigen
- Host makes antibodies for this bacterially derived antigen
- Antigen is similar to that found in myocytes in the heart
- Host antigen directed against the heart valves, myocardium and pericardium
How can Rhesus disease of the newborn be treated?
Anti-D gamma globin given to mother
This destroys the RBCs of the baby before the mother can launch an immune response against them
Briefly describe type III hypersensitivity
This is the inappropriate formation and deposition of immune complexes
What are immune complexes?
These are antigen + antibody complexes
Describe the normal formation of immune complexes
Normally:
- Antibody and C3b binds to the antigen forming a large complex in circulation
- RBC binds the complex by CR to C3b
- Circulates to liver and spleen
- Phagocytes bind the complex by CR and FcR
- Phagocytosis and clearance of the immune complex
When do immune complexes cause disease?
When they are not properly cleared and are deposited in the vasculature or in the organs
What can cause an excess of antigen?
- Persistent infection
- Autoimmunity: thing can’t be gotten rid of
- Constant exposure
What can cause deposition of immune complexes?
a. If the complexes are too small
b. in adequately cleared
How can Type III cause systemic disease?
The complexes are in the circulation and can be deposited in any organ to which the blood circulates
What are lesions of Type III?
Give examples
These are accumulation of immune complexes in organs
Glomerulonephritis
Arthritis
Vasculitis
What is an example of Type III systemic disease?
Systemic lupus Erythematosis
What is vasculitis?
What causes it?
Vasculitis is inflammation of the vasculature
It is caused by immune complex deposition in the vasculature in Type III
What causes System Lupus Erythromatosis?
Caused by failure to maintain tolerance
What is the manifestation of systemic lupus erythromatosis?
Widespread deposition of immune complexes in the organs of the body
Describe the mechanism of Systemic lupus erythromatosis
- Immune response (antibodies) directed against self antigen, such as neuleoproteins
- Lots of antibody in blood
- Immune complexes form on the blood
- Immune complexes deposited in the basement membrane of organs
Which antigens elicit a type III hypersensitivity such as lupus?
Nucleoproteins
Cytoplasmic proteins
Phospholipid complexes
Surface antigens of blood vessels
What are the ways that an individual can become susceptible to type III?
- Inherited
2. Environmental
What is the clinical classification of lupus?
4 or more of a range of symptoms:
Rashes, ulcers, arthritis etc.
What is an example of localised type III hypersensitivity?
Acute post infection Glomerulonephritis
Describe the mechanism of disease for Acute Post-infection glomerulonephritis
- After a streptococcal infection, there is lots of strep antigen
- Immune complexes form in the blood of this strep antigen
- Immune complexes are deposited in the glomeruli
What is the purpose of the Arthus reaction?
To test to see if an individual has been sensitised to an antigen
Describe the steps in the Arthus reaction
Individual may or may not be sensitised to the antigen
- Antigen injected intradermally
- Local immune complexes form is vascular walls –> vasculitis
- Oedema, ulceration, haemorrhage
Broadly describe type IV hypersensitivity
This is the prolonged activation of the adaptive immune response
What are the two types of type IV hypersensitivity?
- Delayed type hypersensitivity
2. Direct cell cytotoxicity
Describe what happens in Delayed type hypersensitivity
There is no resolution of the normal interaction of CD4+ and macrophages
What are the two types of intracellular antigens that lead to type IV hypersensitivity?
- Intracellular pathogens
Mycobacterium tuberculosis, Schistosoma spp., Leishmania spp. - Intracellular acting chemicals
Hair dye, poison ivy
What is the point of the tuberculin reaction?
To determine if an individual is sensitised to the tubercule bacillus antigens
Describe the steps in the tuberculin reaction and the morphology of the positive response
- Inject individual with tuberculin (bacterial peptides)
2. If individual is sensitised –> T cell mediated inflammatory response appears
What is a granulomatus pus lesion, and what is it an example of?
It is an example of DTH in type IV
It is a lesion formed when T cells are replaced by macrophages
What causes a granulomatous lesion?
Prolonged DTH, persistent microbes
What is the structure of a granuloma?
Macrophages in the centre
Giant cells: fused macrophages
Lymphocytes around the outside
Fibroblasts around the outside
What is tuberculosis and example of?
Type IV DTH
Describe the steps of tuberculosis
- Mycobacterium is breathed in
- Enters and takes up residence in alveolar macrophages, resists killing
- APC presents tuberculis antigen on MHC II
- T cells are activated
- Granulomas form because the bacteria can’t be cleared
What are the three possible outcomes of tuberculosis?
Which is the most common?
- Self limiting: most common
No symptoms, asymptomatic
Granuloma and fibrous scarring forms, possibly with bacteria inside - Primary progressive
Immune system cannot contain the infection
Granuloma grows, and there is compromised respiratory function - Secondary progressive
Proliferation of dormant organisms from an old granuloma to compromise respiratory function
What is miliary TB?
This is the dissemination of the infection leading to loss of function and death
Describe the Direct cell cytotoxicity type of Type IV hypersensitivity
This is when CD8+ kills host cells after toxin have altered the host antigens so they are now recognised as foreign
What is an example of Direct cell cytotoxicity type IV?
Poison ivy
Describe what poison ivy does
- Pentadecacatechol from poison ivy is lipid soluble and crosses cell membrane
- Inside the cell, it alters the host proteins
- The altered host proteins are presented and recognised as different
- Immune response launched, CD8+ kill host cells
Give an example of complex hypersensitivity
Sometimes more than one of the hypersensitivities occurs
Eg. hypersensitivity pneumonitis
This is caused by exposure to mould on hay or bark, or feathers. (Occupational)
Type III and Type IV hypersensitivity results
What are the two mechanisms for autoimmunity?
Genetic
Environmental
In inherited autoimmunity, which genes are affected?
HLA: diseases linked to different haplotypes
AIRE: autoimmune regulator (presents body antigen in the thymus to prime T cells)
How can tissue change lead to auto immunity ? (4)
- Injury now presents cryptic antigens
- Inflammation
- molecular mimicry
- drugs and toxins altering the antigen
Describe why autoimmunity does not always lead to disease. What seems to be required for disease?
In ageing, there are many autoreactive antibodies, by they rarely cause disease.
Viral infection cause transient auto antigen but is rapidly cleared
We need some sort of triggering event
Differentiate between organ specific and systemic autoimmune disease
Organ specific:
Eg. Thyroid, ovaries, neurological (MS)
Systemic:
Many organs affected
Eg. SLE, rheumatoid arthritis
What are the different types of transplant?
Autograft
Isograft
Allograft
Xenograft
What is usually the cause of graft rejection?
HLA mis matching
What are the two mechanisms of recognition of allografts?
Direct and indirect
Describe direct rejection of allografts
- Donor APCs from the graft present the donor antigen to lymphocytes in the lymphoid tissue
- Antibodies and immune response against the graft
How does the host kill the organ that has been transplanted once it has been recognised as foreign?
Compare direct and indirect
Direct: killing by attacking the vasculature and parenchma of the graft (ischemia and thrombosis ), via CD8+ cytotoxicity, CD4+ T lymphocytes activating phagocytosis
Indirect: CD4+ t lymphocytes activate phagocytosis. B lymphocytes produce antibodies that bind antigens on vascular surface
What are the four different types of rejection of grafts?
Give a time scale for each
- Hyper acute rejection: minutes to hours
- Acute cellular: days to weeks, months to years
- Acute vascular: days to weeks, months to years
- Chronic: months to years
Describe hyper acute rejection of grafts
This is when the recipient already has antibodies to the tissue of the graft.
How may an individual already have antibodies to a graft?
Previous donation
Multiparous women
Previous blood donation
Describe acute cellular graft rejection
CD8+ kill the parenchyma and endothelium
What is the appearance of the tuberculin reaction?
Inflammation : Oedema due to increased permeability Erythema Induration: many cells Fibrin deposition
What is acute vascular graft rejection?
Antibodies destroy the vasculature to the graft
Describe chronic graft rejection
This is T cell mediated cytokine secretion, leading to parenchymal fibrosis
What a the two ways that we can improve graft survival?
HLA matching
Immunosuppression
What is parenchyma?
Parenchyma is the functional parts of an organ, in contrast to the stroma which is the connective tissue which is just supportive
What are the features of kidney transplant?
Dialysis in the interim
A family member can donate one of theirs
What are the features of heart, lung and liver transplant?
Urgent, no interim solution
Anatomy compatibility must be considered
What is immunodeficiency?
What are the two types?
Immunodeficiency is too little immune response
Primary (genetically predisposed)
Acquired
Describe primary immunodeficiency
The individual has a genetic predisposition to be immuno deficient.
This could be mutations in any part of T cell of B cells
How can mutations in T cell function affect B cell?
Because T cells activate B cells, the genes for B cell might be fine, but they won’t function correctly if the T cells have a mutation
What is secondary immunodeficiency? Eg. ?
This is when an individual acquires a disease that makes them immunodeficient
AIDS
Describe the cause and pathogenesis of AIDS
- Individual becomes infected with HIV
- HIV takes up residence in any cell expressing CD4, so mainly CD4+, but also macrophages and dendritic cells
- These immune cells die by a number of mechanisms
- Profound immuno suppression
What are the ways that CD4+ dies due to HIV ?
- Microbe kills CD4+ directly (death upon entry, lysis after replication, induces apoptosis)
- Bystander CD4+ induced into apoptosis
- CD4+ presents viral peptide and is killed by CD8+
Killing of CD4+ in HIV infection leads to …
Profound immunodeficiency
What are the phases of HIV infection?
What is the time scale?
Acute phase; several weeks
Asymptomatic, chronic phase; ten years
Symptomatic phase
AIDS, crisis phase
Describe the T cell concentration over the course of the phases of HIV infection
Acute phase: rapid drop in T cell concentration
Seroconversion: T cell numbers recover somewhat
T cells slowly drop over asymptomatic phase
T cells < 500 per micro litre: symptomatic phase
T cells < 200 per micro litre: AIDS
Describe what is seen in the crisis phase
Individual develops:
a. Opportunistic infections
b. secondary neoplasms
c. Neurological disorders; macrophages enter brain
How does AIDS cause secondary neoplasms?
CD4+ normally aid in the killing of rapidly proliferating cells, to avoid neoplasm formation
Also, viruses that cause genetic mutation (leading to neoplasm) that would normally be killed, aren’t
How does AIDS affect neurological function?
Macrophages get into the brain and interrupt function and can cause tumours
What is seroconversion?
This is when the body launches an immune response against the HIV and clears the viraemia
The T cell count recovers
State the two mechanisms of tissue injury in type II hypersensitivity
- Complement activation
2. Inflammation
Describe how comment activation causes damage in type II hypersensitivity
- Antibodies bind to cellular or tissue agents
- Complement system is activated
3a. Chemotaxis
3b. Opsonisation –> if too big for phagocytosis, Antibody dependent Cell mediated cytotoxicity
3c. Lysis
What is Antibody dependent Cell mediated cytotoxicity
This occurs in type II hypersensitivity
- Antibodies attach to the host’s cells
- Opsonisation of the host cell
- Host cell too big to be phagocytosed
- Cell damaged by this antibody mediated cytotoxicity
Describe how inflammation can cause tissue damage in type II hypersensitivity
- Antibodies bind to host cells
- Complement cascade is triggered
- Chemotaxis –> inflammation
- Neutrophils are recruited
- Neutrophils release ROS and toxic enzymes
Why is SLE said to have a ‘protean’ clinical manifestation?
The manifestations appear and disappear to varying levels of severity.
Describe how inflammation can cause autoimmunity
Anergic autoreactive bystanders are activated
Describe how tissue injury (infection) can cause autoimmunity
- Cryptic epitopes are now exposed
- Tissue antigens are altered by infection
Describe how molecular mimicry can cause autoimmunity
For example, Streptococcal infection.
We now have antibodies for the infection, but they are also reactive against antigen on myocytes.
Describe how drugs and toxins can cause autoimmunity
These alter the structure of our own antigens, so that when they are presented by our MHC I they are recognised as foreign
Describe the contents of the granule that mast cells release upon cross linking of the IgE with allergens
Histamine
Proteases
Cemokines
What three groups of things do mast cells release when they cross link allergens with the IgE?
- Granule
- Membrane phospholipids
- Cytokines
What cytokines do mast cells release?
What is the function of these cytokines?
- TNF and chemokines
Recruitment of leukocytes
2. IL-4, IL-5: stimulation of Th2 More class switching
- IL-13: mucous production
