HLA genetics, Transplantation and Autoimmune diseases Flashcards
1
Q
what does class III region of the HLA gene complex do
A
Codes for lots of genes including those encoding C2 & C4 complement components
2
Q
what does the class I region of the HLA gene complex do
A
codes for A, B, C locus
3
Q
What does the class II region of the HLA gene complex do
A
codes for DP, DQ, DR
4
Q
How do you define a haplotype
A
- the team of alleles encoded on a short section of one chromosome
5
Q
describe how the haplotype passes on to the child
A
- A single haplotype will have been inherited from one parent and will usually be passed on intact to offspring if the segment of chromosome is short enough
- the longer the segment of chromosome considered the more likely it is that crossovers will occur in the formation of the gametes and the haplotype passed onto the child will be a mixture of one parents two haplotypes
6
Q
What is linkage disequilibrium
A
- idea that two alleles that are close together stay together
7
Q
What are the two explanations of linkage
A
- founder effect
2. advantageous combination
8
Q
Describe how the founder effect works
A
- All started off in small populations
- initially there are a small members of the species
- if a little band went of then there are few members so there might be a few males and a few females
- the males can pass on the genes more quickly and populate with similar genes
9
Q
Describe how advantageous combination works
A
- there are advantageous combinations of alleles
10
Q
define autograft
A
- a graft of tissue given back to the same person e.g. skin in burn victims or bone marrow in stem cells
11
Q
define isograft
A
- graft between two identical siblings
12
Q
define allograft
A
- Graft between two numbers of the same species who are not identical and may be related
13
Q
define heterograft/xenograft
A
- Graft between two members of different species e.g. pigs heart to human, pig heart valves
14
Q
Kidney transplants are usually
A
allografts
15
Q
What can cause rejection of kidney transplants
A
- Antibodies - ABO blood groups, Class 1 HLA molecules
- T lymphocytes - interact with foreign HLA and peptide complexes
16
Q
What kind of rejection are there in kidney transplants
A
- Hyperacute rejection - rejection immediately within minutes, hours or up to about 4 days
- Acute rejection - rejection from 5 days to 3 months
- Chronic rejection - rejection from here afterwards
17
Q
What causes hyperacute rejection in kidney transplants
A
- Hyperacute rejection is antibody mediated with complement activation e.g. in xenografts it may be alternative complement pathway
18
Q
What causes acute rejection
A
- it may be antibody or more often T lymphocyte mediated
19
Q
What causes chronic rejection
A
- May be antibody or T lymphocyte mediated, muddled by the recurrence of the original disease or infection
20
Q
cadaveric kidneys do less well
A
than live donor kidneys
- live donor kidneys survive longer than kidneys from a dead person
21
Q
How do you avoid transplant rejection
A
- do not do the transplant if the recipient has antibodies against the donor HLA molecules
- match the donor and recipient for HLA alleles
- use anti-rejection therapy
- always use ABO compatible donors
- screen all patients on transplant waiting list for anti HLA antibodies
- perform a cross match between donor cells and recipient serum
22
Q
In what case do people make antibodies against foreign HLA
A
People do not make antibodies against foreign HLA unless they have been sensitised
- blood transfusion
- pregnancy
- previous graft
23
Q
How do you match donors for HLA alleles
A
- Try to match for A, B, and DR loci
- in the unrelated situation you are matching for the broad antigen groups - the first two digits of the alleles name
- in the related situation you will be matching for whole haplotypes
24
Q
What are the drugs that are taken in anti-rejection therapy
A
- Glucocorticosteroids such as prednisolone
- immunosupressives e.g. azathioprine and mycophenolate
- immunosuppressives such as ciclosporine and tacrolimus which interrupt the signalling within T lymphocytes
- monoclonal and polyclonal antibodies which deplete T lymphocytes
25
All of the anti rejection therapies can ..
increase susceptibility to infection
26
in bone marrow transplant what cell are you worried about in rejection
- antibody mediated rejection does not matter
- all problems are T lymphocyte mediated
- there is no need for serum screening of recipients or for cross matching
27
what rejection can you have in bone marrow transplant
- There is host versus graft rejection
| - graft versus host rejection
28
In bone marrow transplant in graft versus host what happens
- Donor T lymphocytes react against host HLA and peptide complexes
29
What is the worse reaction in graft versus host rejection in bone marrow transplant
- severe skin rash
- multi organ involvement and failure
- death
30
What kind of matching do you want in bone marrow transplant
Matching is very important
- in identical twins and 2 haplotype match are acceptable
- identical twins will not require anti-rejection therapy but there is more chance of recurrence of leukaemia if leukaemia is why the transplant is being done
- in unrelated donors detailed matching of the alleles is desirable
- need a bit of rejection to prevent recurrence of leukaemia
31
How do you prevent host versus graft and graft versus host
- In autografts there are not any graft versus host and host versus graft = this is because you can use the patients purified stem cells with the malignant cells removed
- in allografts- the T lymphocytes can be depleted from the donated marrow or purified stem cells can be used
- anti-rejection therapy is used but can be stopped
32
define hypersensitivity
- Damage to the body by its own immune system
33
What is type I hypersensitivity
- IgE mediated release of histamine from mast cells/basophils
- includes hayfever, asthma, anaphylactic shock
34
What does atopy mean
- Some people genetically predispose to making IgE to common environmental antigens - atopy
35
What is type II hypersensitivity
- IgG and IgM mediated destruction by complement and/or phagocytosis
- each antibody mediated haemolytic anaemia, thrombocytopenia, myasthenisa gravis, goodpastures, pemphigus and pemphigoid
- almost always autoimmune, occasionally allergic
36
What is type III hypersensitivity
- immune complexes causing pathology either where they are formed (e.g. extrinsic allergic alveolitis) or when deposited from circulation (vasculitis, glomerulonephritis, arthritis) may be autoimmune allergic or antimicrobial activity
37
What is type IV hypersensitivity
- Mediated by activated T-lymphocytes
- broadly two patterns: with granulomas involving CD4 T lymphocytes and macrophages and without granulomas probably involving CD8 T lymphocytes
examples
- tuberculosis (granulomatous)
- hepatitis B (non-granulomatous)
- allergy e.g. nickle sensitivity, coeliac or autoimmune: possible sarcoid (granulomatous) and all the organ specific endocrine autoimmune diseases (non- granulomatous)
38
describe type V hypersensitivity
- mediated by antibodies which stimulate rather than destroy their target
Examples
- Graves
39
Describe how tolerance induction happens for B lymphocytes
- In the bone marrow = B lymphocytes - there is clonal deletion in the bone marrow if naive B cell has antibody engaged by antigen - negative selection
- in the periphery = there is a second chance when mature B lymphocytes engages antigen in the periphery and requires T cell help, if there is no help the B lymphocyte will die
40
How does an auto-reactive B lymphocyte get T cell help
- there is a potential for auto-reactive B lymphocyte to get T cell help if it encounters material with self like and non self determinants
41
How does tolerance fo T lymphocyte induction work
- In thymus T lymphocytes that recognise self HLA+ self peptide too enthusiastically are deleted - negative selection
- in the periphery - mature naive T lymphocytes are presented with peptide on self HLA in periphery by dendritic cell, if the dendritic cell is not activated by signals of damage etc it will not express co-stimulatory molecules, the T lymphocyte activation will fail and the T lymphocyte will die
42
What is meant by an autoimmune disease
- there may or may not be inflammation within the tissues and there may or may not be autoantibodies
- if autoantibodies are present they may be involved in the causation of the disease or they may be apparently a result of the disease sometimes useful for diagnosis
- the inflammation should not be caused by continuing infection in the affected tissue or this will be called an infectious disease, however the infection may be involved in triggering the autoimmune process
43
How can you test for autoantibodies
- using indirect immunofluorscent tests, ELISA, Coombes test
44
Name the haematology autoimmune disease
- haemolytic anaemia
- autoimmune thrombocytopenia, and neutropenia
- aplastic anaemia
45
Name the endocrine autoimmune disease
- type 1 diabetes
- hashimoto's, graves, priamry myxodema
- primary hypoparathyrodism
- addisons disease
- primary gonadal failure
46
Name the skin autoimmune disease
- vitilliogo
- pemphigus and pemphigoid
- psoriasis
- some eczema
47
Name the rheumatology autoimmune disease
- rheumatoid arthritis
- ankylosing spondylitis and reactive arthritis
- systemic lupus erythematosus
- sjogren's syndrome
- progressive systemic sclerosis
48
Name the cardiovascular autoimmune diseases
- vasculitis like polyarteritis nodosa
- wegeners syndrome
- buerger's disease
- behcet's disease
- some cardiomyopathies
- carditis of rheumatic fever with aschoff nodules
49
Name neurological autoimmune diseases
- multiple sclerosis
- guillian-Barre syndrome
- myasthenia gravis
- eaton-lambert syndrome
50
Name respiratory autoimmune diseases
- Fibrosing alveolitis
| - sarcoid
51
Name gastro-intestinal autoimmune diseases
- pernicious anaemia
- coeliac disease
- Crohn's disease and ulcerative colitis
- chronic autoimmune hepatitis, primary biliary cirrhosis, cholangitis
52
describe the different roles of autoantibodies
- may be little or no inflammation but autoantibodies contribute to the pathology of the disease by blocking or stimulating
- may be inflammation with no apparent infection in inflamed tissue and definite autoantibodies that definitely contribute to the pathology of the disease
- there may be inflammation with no apparent infection in the inflamed tissue and autoantibodies - the autoantibodies seem to be the result of the disease
- there may be inflammation with no apparent infection in the inflamed tissue and no autoantibodies
53
What thing can cause autoimmune disease
- Genetics
54
What diseases are associated with HLAB27
- ankylosing spondylitis
- reactive arthritis
- colitic arthritis
- psoriatic arthritis
55
What disease are associated with Cw6
- psoriasis
56
What genetics are associated with coeliac disease and type 1 diabetes
- coeliac disease = DQ2 & DQ8
| - Type 1 diabetes = DQ8 & DQ2
57
What genetics are associated with multiple sclerosis
DQ6
58
what genetics are associated with rheumatoid arthritis
DR4
59
How do HLA alleles predispose to autoimmune diseases
1. Selection of peptides to present to T lymphocytes in thymic selection and initiation of immune response
2. Linkage disequilibrium with allele of nearby gene
60
what infections can pre-dispose to autoimmune disease
- Syphilis can lead to paroxysmal cold haemoglobinuria = this is an autoimmune haemolytic anaemia (happens in the cold)
- mycoplasma can lead to autoimmune haemolytic anaemia
- chlamydia and yersinia infections can lead to reactive arthritis
- some viral infections can lead to guillain- Barre syndrome
61
What neoplasms can pre-dispose to autoimmune disease
- Carcinoma of the lung = this can lead to eaton-lambert syndrome
- thymoma can lead to myasthenia gravis
- lyphomas can lead to autoimmune haemolytic anaemia, autoimmune thrombocytopenias, and pemphigus
- various neoplasms can cause dermatomyositits
62
What poisons can lead to autoimmune disease
- cheap oil can lead to Spanish cooking oil poison
63
How can trauma lead to autoimmune disease
- trauma to one eye can lead to sympathetic ophthalmia
64
Describe the possible role of infections in autoimmune disease
1. inflamed tissue might actually be infected but no one has discovered the infections - these diseases would not be autoimmune
2. there might be an infection elsewhere in the body again, covert, disseminating, microbial proteins into the circulation and being deposited in the tissues where they provoke inflammation - not autoimmune
3. they might break self-tolerance and cause autoimmune disease
4. infection might be irrelevant in most autoimmune diseases
65
describe what happens in graves disease
- autoantibody against TSH receptor that stimulates thyroid into hypertrophy (goitre) and increased secretion of T3 and T4; hyperthyroidism
- causes inflammation of extrinsic eye muscles (diplopia) and growth of tissue behind eyes (proptosis)
- associated with DR3
66
Describe what happens in myasthenia gravis
- autoantibody to acetylcholine receptor causes muscle weakness
- weakness, diplopia, respiratory paralysis, maybe death if untreated
- association with thymoma or thymic hyperplasia
- associated with DR3
67
describe what happens in eaton-lambert syndrome
- Autoantibody to presynaptic calcium channels in neuromuscular junction
- causes weakness (myasthenia)
- associated with carcinoma of the lung (especially small cell)
68
What happens in auto-immune haemolytic anaemia
- autoantibodies to red cells causing destruction by complement system and phagocytes
- some antibodies act in the warm and some in the cold
69
What are the causes of auto-immune haemolytic anaemia
- idiopathic
- infectious (syphilis, mycoplasma, EBV, and other viral infections)
- neoplasms (especially CLL, lymphoma)
- other autoimmune diseases (SLE, RA, PSS, UC)
- Drugs (penicillin, alpha methyl dopa, these may be more allergic than autoimmune)
70
What can cause autoimmune thrombocytopenia
- idiopathic
- SLE
- CLL, lymphoma
- drugs - including antibiotics such as cotrimoxazole
71
What happens in autoimmune pemphigus
- Skin disease with autoantibodies to desmosomes
- bullae form within epidermis forming sores on the skin and also mouth ulcers
- death can occur from fluid loss and infection
- various subdivisions including paraneoplastic form secondary to lymphoma which involves oesophagus and bronchioles
72
What happens in pemphigoid
- Skin disease with autoantibodies to hemisdesmosomes
- stable bullae that are less likely to break down than in pemphigus
- various subdivisions can affect mucous membranes
73
What happens in goodpastures syndrome
- autoantibodies to type IV collagen in basement membrane causing glomerulonephritis (haematuria, renal failure, and alveolitis, haemoptysis, respiratory failure)
74
What are the symptoms of lupus
- fever
- malaise
- lymphadenopathy
- arthralgia
- arthritis
- vasculitis
- serositis - pleural effusions
- fibrosing alveolitis
- glomerulonephritis
- photosensitive skin rash
75
What happens in systemic lupus erythematosus
- various autoantibodies causing type II and type III hypersensitivity
- anti red cell, anti platelet, anti cardiolipin, and anti clotting factors
- circulating immune complexes (type III hypersensitivity) causes much of the pathology
76
How do you test for systemic lupus erythematosus
- Anti nuclear antibody tests (ANA indirect immunoflurescence,
- anti DNA antibodies
- a variety of extractable nuclear antigen tests (ENA)
77
What happens in type 1 diabetes
- infiltration of islets with lymphocytes including CD8 T lymphocytes - insulitis
- specifically kills beta cells
- there are auto-antibodies - anti-islet cell antibodies, anti-insulin antibodies, but not in all patients and probably a byproduct of the damage, though anti-insulin antibodies may cause insulin resistance
- can get autoantibodies against replacement insulin giving insulin resistance
- autoantibodies not routinely used in diagnosis
78
Describe how hashimoto's thyroiditis works
- Florid lymphocytic infiltration of the thyroid
- goitre and reduction in thyroid function (hypothyroidism; mysoedema)
- many B lymphocytes and autoantibodies including anti-thyroid peroxidase (TPO) and anti-thyroglobulin but most damage probably done by T lymphocytes
- Anti-TPO is the usual test together with thyroid function tests
79
What is pernicious anaemia
- Autoimmune gastritis
- lymphocytic infiltrate in lamina propria
- autoantibodies against parietal cells (parietal cell antibody, useful diagnostic test) also anti - intrinsic factor antibodies in gastric juice
- prevents secretion of intrinsic factor so there is no absorption of B12
- also achlorhydria and predisposition to stomach malignancy
80
Describe how coeliac disease works
- Allergy to gluten (gliadin) but autoantibodies occur in: anti transglutaminase (an IgA antibody) and anti-endomysial
- also anti gliadin antibodies
- increased intraepithelial lymphocytes, lymphocytic infiltration in lamina propria, shortening of vili, deepening of crypts
- malabsorption with steatorrhoea, dermatitis herpetiformis, prediposes to bwoel malignancy especially MALT lymphoma
81
what genetics is coeliac disease associated with
Associated with DQ2 and DQ8
82
What does the histology of coeliac disease look like
- increased intraepithelial lymphocytes
- lymphocytic infiltration in lamina propria
- shortening of vili
- deepening of crypts
- malabsorption with steatorrhoea
- dermatitis herpetiformis,
83
Describe chronic autoimmune hepatitis
- affects young women
- untreated, ends in liver failure
Autoantibodies
- ANA positive, anti-sooth muscle antibodies
- Anti-liver/kidney microsome
- antibodies to soluble liver antigen
84
Describe primary biliary cirrhosis
- immune attack against biliary tree
- culminates in cirrhosis and liver failure if untreated
- anti-mitochondrial antibodies are the diagnostic test
- ANA may also be positive
85
What antibodies are positive with primary sclerosing cholangitis
- associated with UC
| - often ANCA positive
86
What rheumatoid arthritis antibodies are involved
- rheumatoid factor positive
- autoantibody against antibodies
- also associated with DR4
87
describe ankylosing spondylitis
- inflammation at enthesis where capsule and ligaments are attached to the joint
- also iritis and aortitis
- no autoantibodies - strongly associated with HLAB27
