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Clinical pathology > Theme 2- week 2 part 2 > Flashcards

Theme 2- week 2 part 2 Flashcards

1
Q

What is an isograft?

A

Isograft (genetically identical)- transplant between genetically identical individuals- between identical twins

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2
Q

What is an allograft?

A

Allograft (non-identical same species transplant)

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3
Q

What is an xenograft?

A

Transplant from different species

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4
Q

What is MHC?

A

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

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5
Q

What is the cell responsible for rejection? How was it found out?

A

Lymphoctyes

What caused rejection of transplants- have a green mouse with a green strain skin transplant- no rejection.

Took green piece of skin and put it on an orange mouse, skin rejected in 10 days- first set rejection.

Repeated this and rejected second time round within 6 days- second set

If took lymphocytes in orange strain into another orange strain mouse then put the skin graft on you would have the accelerated rejection in 6 days.

This shows the memory of the process was transferred by lymphocytes. This is the cell responsible for rejection.

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6
Q

What is HLA?

A

The human leukocyte antigen (HLA) system (the major histocompatibility complex [MHC] in humans) is an important part of the immune system and is controlled by genes located on chromosome 6. It encodes cell surface molecules specialized to present antigenic peptides to the T-cell receptor (TCR) on T cells.

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7
Q

What do class 2 HLA have that class 1 don’t?

A

HLA antigens have two types- class 2- alpha chain and beta chain and peptide that runs down the groove- heterodimer- expressed mainly on APC’s

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8
Q

What cells have class 1? What does it have?

A

Class 1- on all cells that are nucleated- not expressed on RBC- important as anyone that had a blood transplant would develop sensitisation.

Has a heavy chain and B2m that stabilises the molecule, with a groove with a peptide in it

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9
Q

What do class 1 antigens pick up peptides from?

A

Class 1 antigens pick up peptides from cytosolic proteins e.g. viruses

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10
Q

What do class 2 pick up from?

A

Class 2- pick up external ingested proteins (endocytic proteins) and intravesicular pathogens

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11
Q

What chromosome is MHC found?

A

MHC found on Ch6 short arm.

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12
Q

What are the regions of class 1 and 2 in a gene?

A

Class 1- generated by HLA-B, C and A

Class 2 have DR which have an alpha chain and beta chain. Have DQ, DM and DP.

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13
Q

Are HLA molecules polymorphic?

A

HLA Molecules are highly polymorphic

Polymorphism involves one of two or more variants of a particular DNA sequence.

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14
Q

What does HLA molecules being polymorphic allow them to bind to?

A

Allows them to bind them to different peptides.

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15
Q

What is the difference between MHC and HLA?

A

MHC is the gene, proteins in humans are called the HLA.

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16
Q

What is the difference between positive and negative selection of T cell receptors?

A
  • From birth, all lymphocytes are educated against antigens in your thymus through positive or negative selection and therefore that recognises MHC. Positive selection = recognition; negative selection = no recognition
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17
Q

What is MHC restriction?

A

MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

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18
Q

Can HLA be protective of certain types of infections?

A

HLA types can be protective of certain types of infectious disease

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19
Q

How does HLA variation allow autoimmune disease?

A

HLA variation may permit presentation of self-peptides and generate autoimmune disease

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20
Q

How does APC migration cause rejection?

A

Kidneys implanted in iliac fossa, when take clamps off, the APC and leukocytes will leave kidney and go to the lymphs in the groin- APCs will be recognised in the lymphs by the recipients lymphocytes and will be seen as foreign.

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21
Q

Difference between autologous and allogenic?

A

Autologous: Auto means self. The stem cells in autologous transplants come from the same person who will get the transplant, so the patient is their own donor.

Allogeneic: Allo means other. The stem cells in allogeneic transplants are from a person other than the patient, either a matched related or unrelated donor.

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22
Q

If foreign cell in body from transplant what happens?

A

This would be due to different HLA molecules. Strong immune reaction. Normal cell- when lymphocyte goes around the body will see everything as self- could see infectious disease protein or tumour. If foreign- different proteins and peptide grooves will be different forming a strong immune response.

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23
Q

What happens at the immunological synapse?

A
  • The recipients T cells is seeing a foreign APC from donor.
  • Need signal 1 by receptor and MHC. Need secondary signalling between APC and T cell
  • Two ways to recognise allogeneic APC cells- recognised by T cells/ CD4 or CD8- can be broken down by self APCs- called direct and indirect pathway- direct is the normal way antigens are presented.
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24
Q

Once cells in recipient have recognised the foreign antigen then start a response. What happens?

A

Effector functions of the immunological synapse – cause rejection

  • CD4 recognise cells are different from APC
  • CD4 cells cause effector pathways
  • 3 ways:
  • Interact with B cells in lymph to make antibodies
  • Cytotoxic CD8 cells to kill targets
  • Delayed relay reaction CD4 cells and will bind and cause influx of macrophages (DTH)
  • Transplant rejection = combination of antibody production, cytotoxic and DTH response
  • DTH = delayed hypersensitivity reaction
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25
What is HLA typing?
* A process in which blood or tissue samples are tested for human leukocyte antigens (HLAs) * HLAs are molecules found on the surface of most cells in the body * They make up a person’s tissue type, which varies from person to person * They play an important part in the body's immune response to foreign substances * HLA matching is done before a donor stem cell or organ transplant to find out if tissues match between the donor and the person receiving the transplant * Also called human leukocyte antigen matching * We inherit types from our parents. One form mother and one from father. * ¼ chance have the same haplotypes of your sibling
26
What is 1,1,1 mismatch in renal transplant? Recipient HLA A2, A8 B7, B44 DR 1, DR 4 • Donor HLA A2, **A3** B7, **B27**, DR1, **DR9**
* 1,1,1 mismatch- 1 mismatch at A, 1 at B and 1 at DR * Class 1 antigens in A and B are most important * Class 2 important gene is DR * Best it can be is 0,0,0- no mismatches
27
How does HLA typing work?
* Serological – cell based * Molecular = extraction of DNA, amplification and detection of sequence polymorphisms (i.e. tissue type) * Hybridisation to probes * Then sequenced * Means less rejection, better graft survival (e.g. on kidney waiting lists), establish relationships e.g. paternity/maternity * More mismatching = less graft survival
28
What is the renal transplant pathway?
29
Why do we antibody detection for renal transplant?
Prevents hyperacute rejection • General – against many HLA types • Specific – against donor -Pretransplant crossmatch -Living or cadaveric • Avoids aborted transplant
30
Where can you get antibodies that cause sensitising events?
Sensitising events- get antibodies from this -Previous transplant - Pregnancy - Blood transfusion
31
What is complement dependent cytoxicity test?
Detects complement fixing IgG /IgM HLA and non-HLAs which can lead to cell lysis
32
What are the advantages of complement dependent cytotoxicity?
Advantages - \>30yrs experience -Inexpensive
33
What are the disadvantages of complement dependent cytotoxicity?
* Limited sensitivity * • Subjective * • Non-complement fixing abs * • Viable reagent supply and quality control * • Non HLA antibody interference
34
What is flow cytometry?
Take donor serum and add it to cells. Add fluorescent dye. If Ab are adherent will be picked up.
35
What is luminex screening?
Do by beads with recombinant Class 1 and 2 antigens on them. Then add serum to see if Ab.
36
Types of Rejection
* Acute antibody mediated rejection * Acute cellular rejection * Chronic antibody mediated rejection
37
What is hyperacute rejection?
Will only occur when blood from recipient has preformed Ab. Preformed antibodies * Xenograft rejection -Anti-Galα1-3Gal * ABO incompatible transplantation -ABO antibodies • HLA incompatible transplantation- Anti-HLA
38
Why perform the pretransplant crossmatch
Avoid hyperacute rejection
39
What is acute cellular rejection? How does it occur? When does it occur after transplant?
* T cell dependent * Animal models * T cell immunosuppression * Directed against foreign HLA molecules * Effect of HLA mismatch * Typically 7- 10 days after transplant Lymphocytes where rejection starts- CD4 and CD8 cells- target where the HLA molecules are on the kidney cells of the donor
40
What are post-transplant anti-HLA Abs? What is the treatment?
Biomarker of poor outcome Anti-HLA antibodies is associated with increased acute and chronic rejection and decreased graft survival in kidney, heart, lung, liver, and corneal transplants No known treatment • Intensification of immunosuppression
41
What are innate defences?
* Skin (barrier, sebum, normal flora) – e.g. burns * Mucous membranes (tears, urine flow, phagocytes) * Lungs (goblet cells, muco-ciliary escalator. Cystic fibrosis) * Interferons, complement, lysozyme, acute phase proteins * Normal commensal flora in gut – antibiotic treatment alters flora e.g. C. difficile, Candida spp. * (Extremes of age, pregnancy, malnutrition)
42
What is an example of a second line defences?
Neutrophils (NE)- adaptive- very important after initial breach of innate defences
43
What are qualitative defects for neutrophils?
Qualitative defects (e.g. lose ability to kill or chemotaxis)
44
What are quantative defects with neutrophils?
Quantitative defects (less present)
45
What are examples of qualitative neutrophil defects?
* Qualitative – Chemotaxis – rare, congenital, e.g. ina**dequate signalling** * Qualitative –Killing power - **inherited**, e.g. Chronic Granulomatous Disease- NADPH into neutrophil doesn’t work. At risk of Staph. aureus infections
46
What are quantative defects for neutrophils?
* Quantitative defects * eg - cancer treatment, bone marrow malignancy, aplastic anaemia - drugs * “Neutropenic”
47
What is the treatment for neutropenic patients?
Treatment – broad spectrum e.g. Antipseudomonal penicillin +/- gentamicin, 2nd line treatment e.g. a carbapenem
48
What are bacterial infections for neutropenic patients?
Bacterial infections – e.g E. coli- cause ulcers and mucositis inside the gut so gut bacteria cross the bowel into the bloodstream causing bacteraemia, S. aureus Often normal flora. e.g. Coag neg staph
49
What are fungal infections for neutropenic patients?
Fungal infections – Candida spp.- cause thrush , Aspergillus spp- can breathe it in and go into alveoli causing pneumonitis
50
What are congenital T cell deficiencies?
Congenital – rare – T helper dysfunction +/-hypogammaglobulinaemia
51
How can you get acquired T cell deficiencies?
Acquired – drugs e.g. ciclosporin after transplantation (decreases graft versus host disease and rejection), steroids Acquired – viruses e.g. HIV
52
What are bacterial T cell deficencies?
BACTERIAL – Listeria monocytogenes- brie, patte, Mycobacteria
53
What are viral T cell deficencies?
VIRAL – transplants - HSV, CMV, VZV. Serological testing, prophylaxis and treatment with e.g. aciclovir and ganciclovir
54
What are fungal T cell deficencies?
FUNGAL – e.g. Candida spp., Cryptococcus spp., Pneumocystis spp.
55
T cell deficiencies – Protozoan and Parasitic infections- how do you acquire?
* Cryptosporidium parvum - oocysts shed by cattle/humans. Faecal oral route. Most patients recover after prolonged illness of up to 3 wks. May take much longer in T-cell deficients. Symptomatic treatment only (in most cases) * Toxoplasma gondii Comes from cats or cats’ litter, pregnancy women with cats need to be very careful once in contact Wash hands thoroughly
56
Hypogammaglobulinaemia definition
Hypogammaglobulinemia is a problem with the immune system in which not enough gamma globulins are produced in the blood
57
How do you get Hypogammaglobulinemia?
* Antibody problems!! * Congenital – e.g. X-linked agammaglobulinaemia (rare) * Acquired – multiple myeloma, burns * Usually encapsulated bacteria e.g. S. pneumoniae * Parasitic - e.g. Giardia lamblia * Treatment – Immunoglobulin
58
Complement deficiency- how do you acquire?
Encapsulated bacteria. Need complement to help kill organisms. e.g. C5-8 then Neisseria meningitidis is important – Frequent, serious S. pneumoniae infections as poor quality opsonisation
59
What is the function of the spleen?
Spleen - source of complement and antibody producing B-cells, removes opsonised bacteria from blood.
60
Causes of splenectomy?
Causes - traumatic, surgical or functional e.g. sickle cell anaemia
61
What causes problems after splenectomy?
S. pneumoniae, Haemophilus influenzae type B, N. meningitidis, malaria
62
Treatment after reaction from splenectomy?
High mortality- as spleen helps recover from diseases like S. pneumoniae have an infection quickly, vaccination, prophylactic penicillin, education – seek help if unwell
63
What are biologics and what are their function?
Antibodies or other peptides given to patients Inhibit inflammatory cytokine signals e.g. tumour necrosis factor or TNF, inhibiting T-cell activation, or depleting B-cells. E.g. used in severe rheumatoid arthritis
64
What are the risks of using biologics?
Risks- tuberculosis, herpes zoster, Legionella pneumophila, and Listeria monocytogenes
65
Reasons for organ transplant and stem cells?
Solid organ transplants - Liver in paracetamol overdose Stem cells in haematological malignancy.
66
What treatment is given after organ transplant?
Anti-rejection treatment suppresses cell mediated immunity to stop effects of cytotoxic and natural killer cells. Degree of immunosuppression varies on how closely the donor and recipient are matched and organ involved.
67
Example of a diary of infections in transplantation
1. The initial disease e.g. HBV 2. Surgery and hospital admission e.g. S. aureus wound infection 3. Organ receipt e.g. Toxoplasmosis, CMV 4. Opportunistic infection during initial immunosuppression (initial 3/12, e.g. CMV, Aspergillus) 5. Later opportunistic infection (after 3/12, e.g. Zoster, Listeria)
68
Management of infection in these patients – general principles
* Treat the known infection – empirical, need specimens from likely site of infection to guide therapy * E.g. remove catheters if causing infection * Reverse defect if possible/stop immunosuppression * Prevention most important *
69
Investigation of infections
* History & exam * Urgent diagnosis & treatment * Blood cultures * Respiratory samples - common problem…. * Other samples as systems suggest e.g. urine, serology samples - antibody/antigen * Radiology
70
Management of infection in these patients – general principles PREVENTION how is it done?
* Hand washing /aseptic technique / protective isolation / HEPA air filtration- filtered air with pressure going in one way * Vaccines (avoid live in T-cell deficient) * Prophylactic antimicrobials and passive immunoglobulin * Special diet to prevent them from getting something from the food
71
19 yo student, bruising, fever Diagnosed with acute myeloid leukaemia (AML). Chemotherapy started First 2 courses uneventful Few days into final course chemo, febrile neutropenic. Blood cultures E. coli. Given piperacillin/tazobactam. Where could the focus be?
? Give them broad spectrum antibiotics as they are febrile neutropenic. E.coli from UTI, hospital acquired pneumonia or from gut Responds
72
One week later blood cultures have yeast – Candida albicans Where could the focus be? What would we do next?
* From line infection- need to start antifungal therapy and take the line out * Liposomal amphotericin B (antifungal), followed by fluconazole treatment. Neutrophils returning at this point
73
Needs stem cell transplant after he relapses 6/52 post transplantation short of breath, diffuse shadows CXR – Pneumocystis jirovecii on broncho-alveolar lavage. Septrin treatment Discharged 6/12 later readmitted with a lobar pneumonia, BCs - Streptococcus pneumoniae. Treated with iv benzylpenicillin. Home Well up until now

Clinical pathology (8 decks)

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