Immunology Flashcards
1
Q
What are some key features of the Innate Immune system?
A
1st line of defence Fast acting Non-specific Present from birth No immunological memory
2
Q
What are some key features of the Adaptive immune system?
A
2nd line
Slow acting (occurring after a few days)
Highly specific
Immunological memory
3
Q
What are the physical and chemical barriers within the body?
A
Lysozyme in tears, saliva and sweat. Intact mucosal membranes Mucociliary escalator Intact skin with sebum to reduce pH. Acidic pH of stomach Rapid pH in duodenum and alkaline pH in jejunum and ileum. Normal flora in bowel, vagina and skin. Flushing of urinary tract.
4
Q
What are the cells involves in the innate system?
A
Mast cells NK cells Basophils Neutrophils Eosinophils Monocyte Macrophages Dendritic cells
5
Q
What is an antigen?
A
A molecule capable of inducing an immune response.
6
Q
What is an Antibody?
A
A glycoprotein produced by B lymphocytes that binds antigens with a high degree of specificity and affinity.
7
Q
What antigens do MHC I present?
A
Intracellular foreign antigens.
8
Q
What antigens do MHC II present?
A
Present extracellular antigens.
9
Q
Where are Major Histocompatibility complexes found?
A
MHC I - found on surface of all nucleated cells.
MHC II - found on professional antigen presenting cells e.g. dendritic cells, macrophages, B lymphocytes.
10
Q
How are antigens presented to T lymphocytes?
A
T lymphocytes migrate to lymph nodes where they encounter antigens presented by dendritic cells.
MHC II presents antigens to CD4+ helper T cells.
MHC I presents antigens to CD8+ cytotoxic T cells.
T cells recognise antigen if they have the correct T cell receptor (TCR).
11
Q
What are some features of dendritic cells?
A
MHC II present antigens.
Sentinel for the immunise system.
Excellent at activating adaptive immune system.
Internalises pathogen and processes it into peptides which it presents.
T cells which have not seen antigen before are activated.
12
Q
What are the cells involved in the adaptive immune system?
A
T lymphocytes
B lymphocytes
13
Q
Where do lymphocytes mature?
A
T cells - bone marrow then thymus.
B cells - bone marrow.
Both then migrate to secondary lymphoid organs to encounter antigens.
14
Q
What results in diverse set of antigen binding sites in lymphocytes?
A
V (D) J recombination which is a series of genetic changes to variant part of receptor.
15
Q
What are some characteristics of helper T 1 cells?
A
Release IFN-y Macrophage activation IgG production Defence against intracellular microbes Role in autoimmune diseases, tissue damage associate with chronic infection.
16
Q
What are some characteristics of helper T 2 cells?
A
Release IL-4, IL-5, IL-13. Mast cell and Eosinophil activation. IgE production - alternative macrophage activation. Defence against helminthic parasites. Role in allergic diseases.
17
Q
What are some characteristics of helper T 17 cells?
A
Release IL-17A, IL-17F, IL-22.
Neutrophilic, monocytic inflammation.
Defence against extracellular bacteria and fungi.
Role in autoimmune inflammatory diseases.
18
Q
What is the function of helper T cells?
A
Through release of cytokines they facilitate the activation and actions of other immune cells.
19
Q
What are cytokines?
A
Large heterogeneous soluble proteins that can act locally or at a distance.
Regulate and co-ordinate the cells of the innate and adaptive immunity.
Produced during normal haematopoiesis.
Produced in response to microbes, tissue damage or other antigens.
Produced by many cell type especially macrophages and T helper cells.
20
Q
How do T cells help B cells?
A
Some Th cells help B cells produce the correct antibody isotope so the antibody affinity improves.
21
Q
How do Cytotoxic T cells kill cells?
A
Induce apoptosis.
3 mechanisms:
-IFN-y and TNF-a release
-Cytotoxic granules (perforin and granzyme)
-Induce apoptosis via Fas and FasL interactions.
22
Q
What are some features of NK cells?
A
Respond by activating receptors to ligands n infected cells or to antibody tagged cells or directly to bacteria via TLR2.
They produce IFN-g which will help stimulate macrophages, Th1 cells and CD8+ cytotoxic cells.
Especially important if T cell response is not optimal.
23
Q
How do NK cells kill invaders or damaged cells?
A
Inhibitory receptors on NK cell bind to MHC I molecules. If abnormal then NK cell is activated. Release perforin which bores a hole in membrane of invading cell. Granzyme then enters and triggers Caspase pathway resulting in apoptosis.
24
Q
What is the product of B cell activation?
A
Antibody secretion.
25
What are the different portions of Antibodies?
Fab portion binds specifically to particular antigen.
Fc portion interacts with different cells of the immune system.
Changes in heavy chains change the antibody isotope
26
What are the different functions of immunoglobulin (antibody) isotopes?
IgM pentamer (big) - best at activating complement.
IgG monomer - can cross placenta. Secondary response.
IgA dimer - Contained in secretions.
IgE monomer - Parasitic infections and allergy.
27
When are the different antibody isotopes produced?
IgM produced as foetus
IgG not til birth
IgA 1-2 months after birth.
28
What are the effector functions of antibodies?
Neutralisation of microbes and toxins
Opsonisation and phagocytosis of microbes.
Antibody-dependent cellular cytotoxicity.
Lysis of microbes
Phagocytosis of microbes opsonised with complement fragments.
Inflammation
Complement activation
29
What is opsonisation?
Tagging of a microbe so that it is phagocytksed more easily and efficiently.
Antibodies, plasma proteins and complement fragments can be opsonins.
30
What is the timeline of antibody mediated immunity?
Foreign antigen encountered then lag phase occurs while activated B cells are differentiating into plasma cells. No antibodies are produced during lag phase. Once plasma cells are formed a low volume of IgM is released to neutralised initial infection. Memory B cells are also produced.
If same antigen is encountered again then accelerated response occurs - B cells quickly proliferate to create plasma cells and cause a high release of IgG and low amount of IgM.
31
What are the 3 methods of activating the complement cascade?
Classical - immune complexes.
Lectin - binding microbial polysaccharides like mannose to circulating lectins like mannose binding lectin.
Alternative - direct binding of complement proteins to a pathogen.
32
What do all 3 methods of complement cascade activation then lead to?
Formation of C3 Convertase.
This then divides complement into large fragment called C3b and small fragment C3a.
C3b acts as an opsonin and precursor for C5 converts.
C3a is pro inflammatory.
33
What are the affects of complement?
Chemotaxis of phagocytes into sites of inflammation.
Opsonisation
Lysis of micro-organisms
Maintain solubility of Ag/Ab complexes.
34
What are the features of a tuberculosis granuloma?
Multinucleate giant cell
Cuff of lymphocytes surrounding granuloma.
Central area of necrosis.
35
What drives granuloma formation?
IL-2 and IFN-y form positive feedback loop.
| TNF also contributes
36
What is a granuloma?
Site of chronic inflammation where macrophages may mature into giant or epithelioid cells.
Lymphocytes are also present and support macrophages by secreting IFN-y.
37
What type of immunity is used to tackle pyogenic bacteria and some enteroviruses?
Antibody specific immunity.
38
What type of immunity is used to tackle viruses, fungi, bacteria and protozoa?
Cellular immunity - B and T cells.
39
What type of immunity is used to tackle pyogenic bacteria and neisseria?
Complement system
40
What type of immunity is used to tackle bacteria and fungi?
Phagocytes
41
What is immunodeficiency?
Defects in 1 or more components of the immune system that often result in serious/fatal disorders.
42
How are immunodeficiency disorders classified?
Primary - congenital
| Secondary - acquired
43
What is the major consequence of immunodeficiency?
Increased susceptibility to infection.
Also susceptible to certain types of cancer.
Can be associated with increased incidence of autoimmunity.
44
What are some features of Primary Immunodeficiency?
Part of immune system is either missing or functioning abnormally.
Mainly caused by mutations.
Can also be caused by autoimmunity.
45
How does primary immunodeficiency often present?
- Recurrent, unusual or difficult to treat infections.
| - Tumours
46
Where may an abnormality occur in a primary immunodeficiency/
Components of the innate immune system.
Stages of lymphocyte development.
Responses of mature lymphocytes to antigenic stimulation.
47
What are some examples of congenital disorders of innate immunity?
```
Chronic granulomatous disease.
Leukocyte adhesion deficiency type 1/2/3
Chediak-Higashi syndrome
NK cell deficiencies
Toll-like receptor signalling defects
Mendelian susceptibility to mycobacterial diseases.
```
48
What are some examples of Antibody deficiencies?
Agammaglobulinaemias:
X-linked
Autosomal recessive forms.
```
Hypogammaglobulinaemias/isotpe defects:
Selective IgA deficiency
Selective IgG2 deficiency
Common variable immunodeficiency
ICF syndrome
```
Hyper-IgM syndromes
Defective T cell signalling:
proximal TCR signalling defects
Wiskott-Aldrich syndrome
Hyper-IgE syndromes
Familial Hemophagocytic lymphohistiocytoses:
X-linked lymphoproliferative syndrome,
X-linked immunodeficiency magnesium defects (EBV infection, neoplasia syndrome)
Perforin deficiencies
Granule fusion
49
Why is knowing where the immunodeficiency occurs important?
Increased susceptibility to infection depends on the component of the immune system that is defective.
50
What is repeated infection with encapsulated bacteria a sign of?
Defective antibody production.
51
What does antibody deficiency lead to?
Recurrent respiratory infection by pneumococcus or haemophilus app.
52
What are infections with staphylococci, gram-negative bacteria and fungi associated with?
Reduced number or function of phagocytes.
53
What do some complement defects predispose?
Meningitis caused by neisseria meningitidis
54
What do defects in T cells or macrophages predispose?
Infection with intracellular organisms such as protozoa, viruses and intracellular bacteria including mycobacteria.
55
How does mild T cell immunodeficiency affect mycobacterium tuberculosis infection?
Organism can invade body out with the lungs and in severe cases predisposes widespread infection.
56
What is reactivation of latent herpesvirus infection linked to?
T-cell immunodeficiency
57
What is recurrent Candida infection suggestive of?
Defects in TH17 pathway
58
What are some condition that are characteristic of T-cell dysfunction?
Herpesvirus induced tumours e.g. Kaposi sarcoma
| Non Hodgkin lymphoma (EBV)
59
What are the causes of primary immunodeficiency?
Mutations
Polymorphisms
Polygenic disorders
60
What is a mutation?
Permanent alteration in DNA sequence that makes up a gene. Mutations in immune system are rare but can affect any part and cause severe disease.
61
What is a polymorphism?
One of two or more variants of a particular DNA sequence. Most commonly at a single base pair.
In immune system can cause a moderate increased risk for infection.
62
What are polygenic disorders?
Disorders caused by the combined action of more than one gene. Mainly affect antibodies.
May be caused by autoimmunity.
63
What is Severe combined immunodeficiency?
SCID
Group of disorders that affect both B and T cells.
Some are autosomal inherited whilst others are X-linked.
Stem cell transplant can cure SCID but needs to be done quickly.
64
What are some examples of SCID disorders?
```
Defective pre-TCR checkpoint
DiGeorge syndrome
FoxN1 deficiency
TCR alpha chain deficiency
Defective T cell thyme egress and defective T cell signalling.
Bare lymphocyte syndrome
MHC class 1 deficiency
Reticular dysgenesis
ADA deficiency
PNP deficiency
X-linked SCID
Defects in V (D) J recombination
```
65
What are some features of human leukocyte antigen polymorphisms?
Affect outcomes of infections
Unable to bind viral peptides have a worse outcome.
Results in a defective MHC and subsequently defective antigen presentation.
66
What is Mannen-bindng lectin?
Collagen like protein that binds sugars in bacterial cell walls and activates the classic complement pathway.
Polymorphisms in this affect the risk of infections.
67
What is Common Variable imunnodeficiency (CVID)?
Affects antibody production
Have low levels of IgG.
Causes recurrent respiratory tract infections.
Gut, skin and nervous system infections may also occur.
Autoimmunity is common in CVID.
68
What are some features of Autoimmune Polyendocrinopathy candidiasis ectodermal dysplasia (APECED)?
Frequently experience recurrent severe candida infection.
Defect in central tolerance and experience many types of autoimmunity.
Some produce antibodies against interleukin 17 which results in impaired responses to Candida.
Other produce antibodies to interferon gamma and experience recurrent mycobacterial infection.
69
How does Severe combined Immunodeficiency present?
Children have defective T and B cells and therefore develop infections in 1t few weeks of life.
Unusual or recurrent infections
Diarrhoea
Unusual rashes
Fam Hx of neonatal death or consanguinity.
Total lymphocyte count less than 1x10^9/L
70
How does antibody deficiency present?
Presents later in life.
Babies born with maternal Ig transferred across placenta.
Chronic or recurrent bacterial respiratory infection.
Need to exclude secondary immunodeficiency.
71
What is the treatment for primary immunodeficiency?
Prevent infection - prophylactic antibiotics, immunoglobulin replacement therapy.
Stem cell transplantation.
Gene therapy
72
What are hypersensitivity reactions?
Excessive immune responses to antigens, causing damage.
73
What are the different types of antigens that can cause a hypersensitivity reaction?
Infectious agents
Environmental substances
Self-antigens
74
How does the type of antibody triggered by dust effect the outcome of the hypersensitivity reaction?
If IgE is dominant the manifests as allergy symptoms such as asthma or rhinitis.
If IgG dominant than may trigger hypersensitivity such as farmers lung.
75
What are happens?
Small molecules irritants that bind to proteins and elicit an immune response.
76
What are the key features of type I hypersensitivity?
Degranulation of mast cells and eosinophils.
Effects within minutes
Known as allergy.
Mast cells function in the presence of IgE.
77
What is atopy?
Atopy = allergy
78
What are some atopic traits?
```
Anaphylaxis
Angioedema
Urticaria
Rhinitis
Dermatitis
Asthma
eczema
```
79
What is the atopic march?
The natural progression of allergic diseases that begin in early life. Usually get better as you get older except for rhinitis.
80
What are allergens?
Antigens that trigger allergic reactions.
81
What are the different types of peanut allergy?
Allergy to protein Ara h2, very stable protein so causes severe systemic reactions.
Allergy to Ara h8 is not as stable so less severe however does have cross reactions with other foods e.g. hazelnuts.
82
What is the allergen in the penicillin allergy?
Beta- lactam.
83
What stimulates the production of IgE?
B cells produce it when stimulated by IL-4 which is secreted by TH2 cells.
84
What are the features of degranulating cells?
Mast cells reside in many tissues whereas eosinophils migrate towards area of reaction when needed.
Mast cell initiate allergic symptoms after allergen and IgE interaction.
Mast cells have receptors of IgE and FceRI a special high affinity IgE receptor.
Days later antigens cross link IgE and mast cell degranulates and synthesised mediators of inflammation.
85
What is the role of filaggrin?
Expressed by keratinocytes and is involved in maintaining epithelial barriers and moisturising surfaces and controlling pH.
Polymorphisms in the gene encoding is an established cause of allergy.
86
What causes the vasodilation, increased vascular permeability and drop in BP during anaphylaxis?
Mast cells produced prostaglandins and leukotrienes through the cyclooxyrgenase and lipoxygenase pathways causing the vasodilation and increased vascular permeability.
Fluid shifts from vascular space to extra-vascular space then causes decreased vascular tone and subsequently drop in BP.
Histamine release fro mast cells in skin also contributes to this fluid shift and swelling.
87
How does the allergic rhinitis reaction occur?
Inhaled allergens stimulate mast cells in nasal mucosa.
Vasodilation and oedema follows and causes nasal stuffiness and sneezing.
Leukotrienes increases mucus secretion which causes discharge.
88
How does the allergic reaction occur in asthma?
Increase mucus secretion by leukotrienes contributes to airflow obstruction.
Leukotrienes also cause smooth muscle contraction in lungs again reducing airflow.
several hours after initial response the airflow may deteriorate again reflecting the migration of leukocytes into the bronchi in response to chemokine. May last several hours.
89
What is the treatment for type I hypersensitivity reactions?
beta-2-adrenergic agonists e.g. salbutamol to mimic sympathetic nervous system and work to mainly prevent bronchial smooth muscle contraction.
Epinephrine - stimulates both alpha and beta adrenergic receptors to decrease vascular permeability and increase BP.
Antihistamines - block specific histamine receptors and have important role in allergies that affect the nose, skin, and mucus membranes.
Specific receptor antagonists to block effects of leukotrienes e.g. montelukast.
Corticosteroids - prevent immediate hypersensitivity, the late phase and chronic allergic inflammation.
90
What are some examples of mine mediated haemolysis?
Autoimmune haemolytic anaemia could be induced by infections/drugs. Usually part of a systematic autoimmune disease e.g. SLE. Autoantibodies produced by malignant B cells.
Type II autoimmune hypersensitivity against solid tissue - good pasture syndrome.
Alloimmune haemolysis involving the rhesus antigen.
Penicillin acts a happen when it binds to red cells and induces antibody production against itself.
91
How does type II hypersensitivity work?
Antibodies opsonise cells and may activate complement, generating complement products that further opsonise cells.
These cells are then phagocytosed.
Antibodies can also recruit leukocytes by binding to Fc receptors or activating complement and thereby releasing by-products that are chemotactic for leukocytes.
Antibodies specific for cell surface hormone receptors interfere with normal physiology. For example in Grave's disease autoantibodies stimulate the activity of TSH receptors even in the absence of TSH.
92
What are some examples of Type II hypersensitivity diseases?
```
Autoimmune haemolytic anaemia
Pemphigus vulgaris
Vasculitis caused by ANCA
Good pasture syndrome
Acute rheumatic fever
Myasthenia gravis
Grave's disease (hyperthyroidism)
Pernicious anaemia
```
93
What are the key features of Type III hypersensitivity?
Immune complex disease - complexes of antigens and antibodies form and cause damage where they are produced or move through circulation and cause damage elsewhere.
IgG involvement.
Takes time for complexes to form and cause damage.
94
What is meant by polyvalent antigens?
They can attach to more than one molecule.
95
How are complexes cleared during a type III hypersensitivity reaction?
Complement breaks down large complexes and complement receptor 1 transfers complexes to phagocytes.
96
How does immune complex disease occur?
Failure of clearance of complexes. This activates the innate immune system.
97
What are some examples of human immune complex mediated diseases?
Systemic lupus erythematosus.
Polyarteritis nodosa
Poststreptococcal glomerulonephritis.
Serum sickness
98
What are the key features of type IV hypersensitivity?
Slowest form - 2-3days to develop.
Mediated by T cells
Delayed hypersensitivity =
99
How does a type IV hypersensitivity reaction occur?
Macrophages initiate the reaction when they recognise danger signals and initiate inflammatory response.
Dendritic cells loaded with antigen migrate to lymph nodes and present them to T cells.
Specific T cell clones proliferate in response and migrate to site of infection.
Tumour necrosis factor secreted by T cells and macrophages stimulates most of the damage caused.
Macrophages stimulate T cell through release of IL-12.
100
What antigens drive rheumatoid arthritis?
Citrullinated proteins.
Citrullination is the conversion of amino acid arginine to the amino acid citrulline. auto reactive T and B cells recognise citrullinated protein and antibodies are produced against it. referred to as Anti-cyclic citrullinated peptide antibodies (CPP).
101
What is the pathophysiology of rheumatoid arthritis?
Synovium becomes infiltrated by T cells (Th1 and 17) and macrophages.
TNF and IL-17 attract and activate neutrophils that cause damage to the synovium.
Osteoclasts are activated and destroy bone at the joint margins, creating erosions.
Persistent IL-6 secretion triggers acute-phase response.
Association with HLA-DR4
102
What is the pathophysiology of Multiple Sclerosis?
Acute attacks occur during which inflammatory lesions of Th1 and Th17 cells and macrophages develop in affected nervous tissue.
The lesions cause reversible, relapsing disability typical of early MS. Myelin loss impairs the ability of neurones to conduct impulses resulting in neurologic symptoms.
Chronic disability occurs later from axonal loss.
103
What are some examples of diseases mediated by type Iv hypersensitivity reactions?
```
MS
RA
Type 1 diabetes mellitus
Inflammatory Bowel Disease
Psoriasis
```
104
What is the treatment of delayed hypersensitivity?
Prevention through avoiding antigens
Anti-inflammatory drugs - NSAIDs, Corticosteroids, Drugs that's block TNF and IL-6, antibodies against B cells.
Immunosuppressive drugs.
105
What is immunological tolerance?
Unresponsiveness to an antigen that is induced by previous exposure to that antigen.
106
What are tolerogens?
Antigens that induce tolerance.
107
What. happens to T and B cells that are bearing self reactive molecules?
They are eliminated or down regulated by several different mechanisms.
108
What is central tolerance?
The process of eliminating B and T lymphocytes that have a high affinity for self antigens.
This process of negative selection occurs in the Thymus and the Bone Marrow.
109
What is peripheral tolerance?
Mature lymphocytes that recognise self-antigens in peripheral tissues become incapable of activation or die by apoptosis.
110
What are some different mechanisms of peripheral tolerance?
Anergy - functional unresponsiveness.
Antigen recognition with co-stimulation.
Treg suppression
Deletion
Some self-antigens are sequestered from the immune system by anatomic barriers.
111
How can peripheral tolerance be overcome?
Inappropriate access of self-antigens.
Inappropriate or increased local expression of co-stimulatory molecules.
Alteration in the way in which self-antigens are presented.
112
When is overcoming peripheral tolerance more likely to happen?
During inflammation or tissue damage.
There is increased activity of proteolytic enzymes which cause intra and extracellular proteins to be broken-down.
This leads to high levels of peptides being presented to responsive T cells.
Structures of self-peptides may be altered by free radicals, ionising radiation and viruses so they bypass established tolerance.
113
What is autoimmunity?
Adaptive immune responses to self-antigens.
114
What are autoantibodies?
Antibodies directed at normal cellular components referred to as autoantigens.
115
When does autoimmune disease occur?
When auto-reactive T and B cells cause tissue damage through hypersensitivity reactions II, III, or IV.
116
What are some characteristics of natural antibodies?
- Produced by B1 cells.
- Bind with low affinity to antigens on variety of bacteria. This activates complement system to clear them.
- Cross react with inherited A and B antigens on RBCs. Make IgM anti-A and anti-B antibodies unless they inherited either A or B antigens.
- Bind to normal cellular constituents such as nuclear proteins or DNA.
117
What are some genetic factors that may cause breakdown of T cell tolerance?
```
Clusters within families
Alleles of MHC
Common polymorphisms
AIRE gene mutated and central tolerance can't take place.
B27, DR2, DR3, DR4 defects.
```
118
What are some environmental factors that may cause breakdown of T cell tolerance?
Infections - molecular mimicry, upregulation of co-stimulation, antigen breakdown and presentations changes.
Drugs - molecular mimicry, genetic variation in drug metabolism.
UV radiation - skin inflammation trigger, modification of self-antigen.
119
What is molecular mimicry?
Structural similarity between self-proteins and microbial antigens that may trigger an autoimmune response.
120
What is the epidemiology of autoimmune disease?
3% of population have an autoimmune disease.
Clustering in families
Almost all types of autoimmune disease are more common in women except ankylosing spondylitis.
121
What are the features of non-organs specific autoimmune diseases?
Affect multiple organs
Associated with responses against widely distributed self-molecules e.g. intracellular molecules involved in transcription and translation.
122
What are the features of organ specific autoimmune diseases?
Restricted to one organ
| Endocrine glands
123
What are some examples of self-antigens and the diseases they result in?
* TSH receptor - hypo/hyperthyroidism
* Insulin receptor - Hyper/hypogylcaemia
* Acetylcholine receptor - myasthenia gravis
* Epidermal cell adhesion molecules - Blistering skin diseases
* Factor VIII - acquired haemophilia
* Beta-2 glycoprotein I and other anticoagulant proteins - Antiphospholipid syndrome.
* RBCs - haemolytic anaemia
* Platelets - Thrombocytopneic purpura.
* Double stranded DNA, Histones - SLE
124
What is rejection in terms of transplantation?
Damage done by the immune system to a transplanted organ.
125
What is an autologous transplant?
Tissue returning to the same individual after a period outside the body, usually in a frozen state.
126
What is Syngeneic transplant?
Transplant between identical twins (isograft). Usually no problem with rejection.
127
What is Allogeneic transplant?
Transplant between genetically nonidentical members of the same species. Always a risk of rejection.
128
What is cadaveric transplant?
Organs from a dead donor.
129
What is xenogeneic transplant?
Transplant between different species and carries the highest risk of rejection.
130
What criterion must be met before undergoing solid organ transplant?
Good evidence that the damage is irreversible.
Alternative treatments are not applicable.
The disease must not recur.
131
How is the risk of rejection minimised?
Donor and recipient are ABO compatible.
Donor must not have anti-donor HLA antibodies .
Donor is selected with as close to possible HLA match.
Patient must take immunosuppressive treatment.
132
What is hyper acute rejection?
Rejection within hours of transplantation.
Preformed antibodies bindning to either ABO or HLA class I antigens on the graft.
Antibody binding triggers type II hypersensitivity reaction and graft is destroyed by vascular thrombosis.
Now rare due to ABO and HLA matching.
133
What is acute rejection?
Type IV hypersensitivity reaction that takes place within days or weeks of transplantation.
Donor dendritic cells stimulate allogeneic response in a local lymph node and T cells proliferate.
HLA incompatibility is main cause.
134
What is chronic rejection?
Rejection that takes place months or years after transplant.
Allogeneic reaction mediated by T cells can result in repeated acute rejection.
Recurrence of pre-existing autoimmune disease may also cause it.
135
What is the immunopathology of graft rejection?
Afferent phase - donor MHC molecules on dendritic cells are recognised by the recipient's CD4+ Cells.
Effector phase - CD4+T cells recruit effector cells responsible for the tissue damage e.g. macrophages, B cells, CD8+ Cells, NK cells.
136
What is autologous stem cell transplant?
Marrow is removed, frozen and then reinserted into patient after they have had chemo.
137
What is allogenic stem cell transplant?
Very risky procedure where marrow from a donor is used.
Only carried out in haemolytic malignancy, notable myeloid cell production reduction and in primary immunodeficiencies such as SCID.
138
What are some sources of stem cells?
Bone marrow
Peripheral blood - harvested after treating donor with colony-stimulating factors.
Umbilical cord blood - immature lymphocytes are less likely to cause GVHD.
139
What is conditioning?
Process of destroying the recipient's stem cells and allowing the engraftment of donor cells.
140
What is Graft versus Host Disease (GVHD)?
Donor T cells respond to allogeneic recipient antigens.
70% mortality if severe.
Acute involves skin, gut, liver and lungs widespread.
Chronic effects skin and liver.
141
How do corticosteroids provide immunosuppression?
Low doses act on antigen presenting cells treating early stages of graft rejection.
High doses work directly on T cells and are used in episodes of rejection.
142
How do T-cell signalling blockage drugs work?
Cyclosporine and Tacrolimus.
| Interacting with proteins in the intracellular T-cell signalling cascade.
143
How do monoclonal antibodies against IL-2 receptor work?
Block IL-2 receptor directly.
Very potent so only used to treat episodes of acute graft rejection.
Basiliximab and Daclizumab
144
How does Rapamycin work?
Interacts with signalling events downstream in IL-2 receptor pathway.
Easier to take than monoclonal antibodies so used to prevent graft rejection.
145
How do anti-proliferatives work?
Inhibit DNA production which prevents lymphocyte proliferation.
Not specific for T cells so can cause bone marrow failure.
Azathioprine, Mycophenolate motefil, Methotrexate.
146
What are some side effects of cyclosporine?
```
Viral, bacterial and fungal infections
Increased risk of certain cancers.
Nephrotoxic properties
Diabetes
Hypertension
Largely due to inhibiting calcineurin.
```
147
What are some side effects of rapamycin?
```
Raised lipid and cholesterol levels.
Hypertension
Anaemia
Diarrhoea
Rash
Acne
Thrombocytopenia
Decreased platelets and haemoglobin.
```
148
How do Xenotransplanted organs cause rejection?
Galactose-alpha1,3-galactose is a sugar present on cells of most non-primate species. We have antibodies to fight against it following exposure in gut bacteria.
Activate complement ad trigger hyper acute rejection.
Complement inhibitors from other species do not inhibit human complement.
149
What immunoglobulins are need for post exposure prophylaxis?
Human Normal immunoglobulin (HNIG) needed for hepatitis A, measles, Polio and rubella.
Specific immunoglobulins are required for Hepatitis B, rabies, tetanus and varicella-zoster virus.
150
What is intravenous immunoglobulin (IVIg)?
Plasma derived IgG that I key for primary and secondary immunodeficiency disorder replacement therapy. Also used in autoimmune disorders.
1-3g/kg high dose given
Pooled from several thousand donors.
151
What are some examples of conditions where IVIg is the treatment?
```
Primary immunodeficiency
Wiskott Aldrich syndrome
IgG subclass deficiencies with recurrent infections
Idiopathic thrombocytopenia purpura.
Kawasaki disease
Multiple myeloma
Children with HIV
Guillain-Barre syndrome
Allogenic bone marrow transplantation
```
152
What are the different types of immunotherapy?
Direct - antibodies target antigen on tumour and destroy it by recruiting immune cells or by delivering a toxin/radioisotope to it.
Indirect - immune system os activated so it can deal with tumour.
153
What are some examples of direct immunotherapies?
Monoclonal antibodies
Chimeric antigen receptors (CARs)
Bi-specific antibodies
154
What are some examples of Indirect immunotherapies?
```
Tumour vaccines
Dendritic cell vaccines
Adoptive cell transfer
Cytokine therapies
Checkpoint inhibitor therapies
Stimulatory antibodies.
```
155
What is a polyclonal response?
Immunisation with an antigen will typically lead to a poly clonal response where many different B cell clones will generate antibodies specific for the antigen.
156
What is the basic process of monoclonal antibodies?
Immunisation
Fusion and immortalisation of B cells
Isolation and screening
Expansion of desired hybridoma.
157
What are some features of Rituximab?
1st line treatment for Non-Hodgkins lymphoma.
Specific for the CD20 molecule on the cell surface of small sub pop of B cells.
Crossover mAB.
found to have benefits in SLE and RA.
158
What are some features of anti-TNF therapy?
Treatment for RA, Ankylosing spondylitis, Crohn's disease and UC.
Chimeric antibody that blocks the functions of tumour necrosis factor alpha.
159
What are some features of Herceptin?
Trastuzumab.
Treatment for human growth epidermal growth factor receptor 2 (HER2) positive breast cancer.
The antibody binds HER2 on cancer cells and marks them out for destruction by the immune system.
160
What are some features of Skyrizi (Risanlizumab)?
Interleukin-23 inhibitor that selectively blocks it by binding to its p19 subunit.
Used in treatment for psoriasis, Crohn's and UC.
