Primary Immunodeficiency and Transplantation Flashcards Preview

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Flashcards in Primary Immunodeficiency and Transplantation Deck (72):
1

What is the average incidence of IgA deficiency?

1/500 to 1/700

2

What are the six main hallmarks of a primary immunodeficiency?

1. Abnormal immune cell development
2. Abnormal cell-to-cell communication
3. Abnormal embryonic differentiation
4. Enzyme defects
5. Absence of cell surface adhesion molecules
6. Defective complement or Ig synthesis

3

Primary antibody deficiencies are caused by what?

Defects in the genes for B cell differentiation or Ig genes

4

What are the key clinical finding a an Ab deficiency?

1. recurrent infection by encapsulated bacteria
2. Gram- rods, staph, H influenza
3. Normal response to viruses but memory doesnt develop
4. Autoimmunity, lymphoid hypertrophy, allergy

5

What three things mediate immune response to pyogenic bacteria?

1. Ab
2. Neutrophils
3. complement

6

Why are patients with Ab deficiency still able to clear viral infection?

They still have a T cell response which is the prime factor for viral infection
They will not have long lasting immunity though so chicken pox, mumps, etc can reoccur in these patients

7

What is the cause of X-linked Agammaglobulinemia?

XLA is caused by a loss of function of BTK (bruton's tyrosine kinase) on the X chromosome.

This blocks B cell maturation at the pre-B cell stage. IgM forms the heavy chain, but then since cell signalling is lost, it cannot make a light chain

8

Who is more likely to get XLA, men or women? When will signs of disease show?

Men because it is x-linked and signs will show at about 6 months whene the passive transfer of the mother's Ab are gone

9

What are clinical manifestations of XLA?

1. recurrent respiratory infection, ear infections, sinus infection
2. Diarrhea bc of G. lamblia
3. Systemic infections
4. skin infections

CAN clear most viruses EXCEPT enteroviruses loke echo, coxsackie and polio

10

What vaccine should NOT be given if XLA is suspected?

Polio vaccine because they will get paralytic poliomyelitis

11

What is the cause of Hyper-IgM syndrome?
What problems does this create?

A defect in CD40/40L.
X linked = CD40L

1. CD40L on T cells following activation bind to CD40 on B cells to activate them and allow class switching
2. CD40L binds CD154 on macrophages to make IL12 which causes IFNg production

12

What pathogen would a person with HyperIgM have a tough time clearing? Why?

P. jiroveci because CD40 can't bind CD154 on macrophages to produce IL12 necessary for IFNg production

13

What would be the clinical findings of a person with hyper IgM?

1. elevated levels of IgM and low IgG IgA IgE
2. normal B and T cell count
3. respiratory infection, CMV, P. jiroveci, crypotocuccus
4. lymphoid hyperplasia

14

What causes IgA deficiency?

What will serum levels be?

The inability of B cells to differentiate into IgA secreting plasma cells

Serum:
Low IgA
normal IgM
normal OR low IgG

15

What are the clinical manifestations of IgA deficiency?

1. respiratory tract infection
2. diarrhea
3. occasional high IgE which can be directed against IgA (high risk in blood transfusions)
4. develop SLE
5. GI and lymphoid malignancy

16

What is the most common primary antibody deficiency?

CVID- common variable immunodeficiency

17

When are most cases of CVID diagnosed?
Who does it primarily affect?

Affects males and females of European descent and presents in adulthood

18

How do you differentiate someone with CVID from someone with Celiac's disease?

Put them on a gluten free diet.
Better = Celiacs
No change = CVID

19

What specific viruses can't be cleared by CVID patients?

Hep B and C

20

Most patients with CVID have normal ______.

numbers of B cells

21

Primary T cell immunodeficiencies result from ____________________ but they will often present as ____________.

They result from defective T cell differentiation or function but they will present as combined immunodeficiencies because T cells play a large role in activating macrophages and B cells

22

What are the 8 signs of a Tcell immunodeficiency?

1. Failure to Thrive
2. Infection by intracellular pathogens
3. Recurrent infection
4. Infection by opportunisitic pathogens
5. Diarrhea/malabsorption
6. Allergy
7. Autoimmunity
8. Lymphoma

23

What is the defect in SCID?

Caused by defect in T cell differentiation and may or may not involve B cell differentiation.

24

What is necessary for a SCID patient to survive past early childhood?

Hemopoeitic Stem Cell transfusions

25

What are the 4 types of SCID?

1. Reticular Dysgenesis
2. Alymphocytosis
3. Abscence of T lymphocytes
4. Adenosine Deaminase Deficiency (ADA)

26

How does one acquire Reticular Dysgenesis SCID and what cells are affected?

It is autosomal recessive mutation and affects T, B, NK, leukocytes and platelets

27

What is the cause of Alymphocytosis?

Autosomal recessive mutation in RAG1/RAG2 so there cannot be VDJ rearrangement of T cell receptors and Ig genes

28

What is the cause of SCID with abscent T lymphocytes?
What are the three potential mutations?

X-linked that affects T and NK cells (common)
Auto recessive (less common)

Mutation is in JAK3, IL7R alpha chain or gamma c chain

29

What causes ADA deficiency?

Auto recessive that affects T, B, NK cells

Mutation in ADA enzyme that metabolizes purines
High levels of adenosine are toxic to lymphocytes

30

What are clinical manifestations of SCID?

1. Early onset of respiratory/GI infections
2. Oral candida
3. Diarrhea
4. growth impairment
5. LIVE VACCINE IS A THREAT
6. Graft vs Host bc of maternal lymphocytes

31

What is DiGeorge syndrome?

A T-cell deficiency with combined features due to improper development of the 3rd and 4th branchial arches

32

What are the 5 major defects with DiGeorge?

1. No thymus
2. Facial defects (micrognathia, low ears)
3. cardio defects (truncus arteriosis)
4. mental retardation
5. feeding difficulty

33

What is the cause of Wiscott-Aldrich syndrome?

X-linked disease caused by a mutation in the gene encoding WA syndrome protein
It is associated with age-related depletion in T cells in the periphery (born with right number and depletes as life goes on)

34

What are the four types of transplant?

1. Autologous- from same person
2. Syngeneic- from identical twin
3. Allogeneic- from HLA related donor
4. Xenogeneic- from different species

35

What level of immunosuppression is needed for an autologous transplant?

None because it is self-to-self.
This is typical for cardiac bypass where vessels from leg are moved to heart

36

What is the most common type of transplant?

Allogeneic

37

What determines the dose of immunosuppressant needed when doing an allogeneic transplant?

1. the level of HLA match between donor and recipient
2. the sensitization of the patient (do they have anti-HLA antibodies?)

38

What is HLA?
What region of the chromosomes is it located on?

Human leukocyte antigen and it is the most polymorphic gene found in humans.
It is the most potent alloantigen in transplantsI
It is on chromosome 6

39

What are the major HLA classes?

HLA I = HLA-A HLA-B HLA-C
HLA II =1 HLA-DR HLA-DQ HLA-DP

40

What are clinical manifestations of SCID?

1. Early onset of respiratory/GI infections
2. Oral candida
3. Diarrhea
4. growth impairment
5. LIVE VACCINE IS A THREAT
6. Graft vs Host bc of maternal lymphocytes

41

What is DiGeorge syndrome?

A T-cell deficiency with combined features due to improper development of the 3rd and 4th branchial arches

42

What are the 5 major defects with DiGeorge?

1. No thymus
2. Facial defects (micrognathia, low ears)
3. cardio defects (truncus arteriosis)
4. mental retardation
5. feeding difficulty

43

What is the cause of Wiscott-Aldrich syndrome?

X-linked disease caused by a mutation in the gene encoding WA syndrome protein
It is associated with age-related depletion in T cells in the periphery (born with right number and depletes as life goes on)

44

What are the four types of transplant?

1. Autologous- from same person
2. Syngeneic- from identical twin
3. Allogeneic- from HLA related donor
4. Xenogeneic- from different species

45

What level of immunosuppression is needed for an autologous transplant?

None because it is self-to-self.
This is typical for cardiac bypass where vessels from leg are moved to heart

46

What is the most common type of transplant?

Allogeneic

47

What determines the dose of immunosuppressant needed when doing an allogeneic transplant?

1. the level of HLA match between donor and recipient
2. the sensitization of the patient (do they have anti-HLA antibodies?)

48

What is HLA?
What region of the chromosomes is it located on?

Human leukocyte antigen and it is the most polymorphic gene found in humans.
It is the most potent alloantigen in transplantsI
It is on chromosome 6

49

What are the major HLA classes?

HLA I = HLA-A HLA-B HLA-C
HLA II =1 HLA-DR HLA-DQ HLA-DP

50

What are the two types of immune recognition of allografts? How does each occur?

1. Direct recognition where the graft recipients T cells recognize foreign MHC displayed on foreign APC and the CD8 cells kill the graft and CD4 cells cause inflammation
2. Indirect allorecognition- when the recipient T cell recognizes recipient APC presenting foreign (donor) peptide. CD4 cells will drive inflammation and B cells will produce alloantibodies

51

Which allorecognition (direct or indirect) occurs first?

Direct occurs first because it is donor peptide presented on donor APC. After some time, all the donor APC will be killed

52

What is the role of CD8 in T cell mediated rejection of the graft?

It kills cells present in the allograft causing tissue and endothelial death which can lead to thrombosis and ischemia

53

What is the role of CD4 in T cell mediated rejection of a graft?

It will produce cytokines and cause inflammation which resembles delayed type hypersensitivity in the graft and vessels resulting in ischemia and graft destruction

54

What is humeral rejection?

When T cells help activate B cells which will generate Ab against the graft. Ab binding to the graft will cause vascular injury, thrombosis and ischemic damage via complement mechanisms

55

What are the three main types of graft rejection?

1. Hyperacute rejection
2. Acute rejection
3. Chronic rejection

56

Describe the time scale add mechanism of hyperacute graft rejection.

How often does it occur?

Hyperacute rejection occurs within minutes to hours of the transplantation and is due to the presence of pre-formed anti-HLA antibodies that bind to endothelium and promote clotting.

This rarely occurs because people are screened for preformed donor Ab

57

Describe acute rejection in terms of time scale and mechanism/

How often does this occur?

It occurs days to months after transplantation and can be cell or Ab mediated.

It occurs when patients stop taking immunosuppressant drugs because they "feel better"

58

Describe chronic rejection in terms of time scale and mechanism.

How often does it occur?

It occurs months to years after the transplant and occurs for most grafts.

It is the most common cause of long term kidney failure

59

Immunosuppressive drugs can control __________ rejection well, but they are not effective for ______.

Control acute rejection but are not effective at treating chronic infection

60

What are three ways we can improve graft survival?

1. HLA matching
2. Testing for donor specific Ab (to prevent hyperacute)
3. Immunosuppression

61

Routine screenings of are done in post-transplant recipients to check for the development of _______.

donor specific HLA AB to help diagnose potential Ab-mediated rejection

62

Currently used immunosuppressive drugs are NOT _________ therefore they can place the recipient at higher risk of infection

antigen specific

63

What are the seven common immunosuppressive drugs?

1. corticosteroid
2. cytotoxic drugs
3. antimetabolites
4. calcineurin inhibitors
5. Mycophenolate Mofetil
6. Anti-IL2
7. Antithymocyte globulin

64

Why are corticosteroids used for immunosuppression?

They inhibit lymphocyte proliferation by down-regulating IL2

65

What is a major cytotoxic drug that can allow for immunosuppression and what is the mechanism?

Cyclophosphamide alkylates and damages cells by crosslinking DNA to inhibit T cell and B cell immunity and inflammation

66

What are the two major antimetabolites used in immunosuppression?

1. methotrexate- blocks folate acid synthesis
2. azathioprine- antagonizes purine synthesis (Cell mediated and humoral)

67

What is the major calcineurin inhibitor that allows for immunosuppression? What is the mechanism?

Tacrolimus and cyclosporin blocks the NFAT pathway

68

What is the function of mycophenolate mofetil?

It blocks lymphocyte production and guanine nucleotide synthesis

69

What does antithymocyte globulin do?

it induces immunosuppression by making Ab against thymocytes so less T cells are in circulation

70

What are the three conditions that would require hematopoietic stem cell transplantation?

Which can be autologous? Which must be allogeneic?

1. leukemia- either
2. lymphoma- either
3. immunodeficiency- must be allogeneic

71

What cells are involved in the rejection of allogeneic HSC transplants?

T and NK cells.
Humoral response is not seen in bone marrow transplant, however alloantibodies can prevent engraftment of HSC recipients

72

What is GVHD?
What are the clinical presentations?
What is the benefit?

Donor T cells recognize the recipients tissue as foreign and mount an immune response.

It causes rashes, destruction of gut epithelium, bile duct and jaundice.

The benefit of GVHD is that donor T cells can provide a Graft-Vs-LEukemia effect reducing the risk of recurrence