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Bugs and Drugs > Primary Immunodeficiency and Transplantation > Flashcards

Primary Immunodeficiency and Transplantation Flashcards

1
Q

What is the average incidence of IgA deficiency?

A

1/500 to 1/700

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2
Q

What are the six main hallmarks of a primary immunodeficiency?

A
  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
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3
Q

Primary antibody deficiencies are caused by what?

A

Defects in the genes for B cell differentiation or Ig genes

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4
Q

What are the key clinical finding a an Ab deficiency?

A
  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
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5
Q

What three things mediate immune response to pyogenic bacteria?

A
  1. Ab
  2. Neutrophils
  3. complement
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6
Q

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

A

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

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7
Q

What is the cause of X-linked Agammaglobulinemia?

A

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

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8
Q

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

A

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

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9
Q

What are clinical manifestations of XLA?

A
  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

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10
Q

What vaccine should NOT be given if XLA is suspected?

A

Polio vaccine because they will get paralytic poliomyelitis

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11
Q

What is the cause of Hyper-IgM syndrome?

What problems does this create?

A

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
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12
Q

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

A

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

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13
Q

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

A
  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
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14
Q

What causes IgA deficiency?

What will serum levels be?

A

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

Serum:
Low IgA
normal IgM
normal OR low IgG

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15
Q

What are the clinical manifestations of IgA deficiency?

A
  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
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16
Q

What is the most common primary antibody deficiency?

A

CVID- common variable immunodeficiency

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17
Q

When are most cases of CVID diagnosed?

Who does it primarily affect?

A

Affects males and females of European descent and presents in adulthood

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18
Q

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

A

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

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19
Q

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

A

Hep B and C

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20
Q

Most patients with CVID have normal ______.

A

numbers of B cells

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21
Q

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

A

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

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22
Q

What are the 8 signs of a Tcell immunodeficiency?

A
  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
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23
Q

What is the defect in SCID?

A

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

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24
Q

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

A

Hemopoeitic Stem Cell transfusions

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25
Q

What are the 4 types of SCID?

A
  1. Reticular Dysgenesis
  2. Alymphocytosis
  3. Abscence of T lymphocytes
  4. Adenosine Deaminase Deficiency (ADA)
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26
Q

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

A

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

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27
Q

What is the cause of Alymphocytosis?

A

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

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28
Q

What is the cause of SCID with abscent T lymphocytes?

What are the three potential mutations?

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

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

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29
Q

What causes ADA deficiency?

A

Auto recessive that affects T, B, NK cells

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

30
Q

What are clinical manifestations of SCID?

A
  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
Q

What is DiGeorge syndrome?

A

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

32
Q

What are the 5 major defects with DiGeorge?

A
  1. No thymus
  2. Facial defects (micrognathia, low ears)
  3. cardio defects (truncus arteriosis)
  4. mental retardation
  5. feeding difficulty
33
Q

What is the cause of Wiscott-Aldrich syndrome?

A

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
Q

What are the four types of transplant?

A
  1. Autologous- from same person
  2. Syngeneic- from identical twin
  3. Allogeneic- from HLA related donor
  4. Xenogeneic- from different species
35
Q

What level of immunosuppression is needed for an autologous transplant?

A

None because it is self-to-self.

This is typical for cardiac bypass where vessels from leg are moved to heart

36
Q

What is the most common type of transplant?

A

Allogeneic

37
Q

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

A
  1. the level of HLA match between donor and recipient

2. the sensitization of the patient (do they have anti-HLA antibodies?)

38
Q

What is HLA?

What region of the chromosomes is it located on?

A

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
Q

What are the major HLA classes?

A

HLA I = HLA-A HLA-B HLA-C

HLA II =1 HLA-DR HLA-DQ HLA-DP

40
Q

What are clinical manifestations of SCID?

A
  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
Q

What is DiGeorge syndrome?

A

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

42
Q

What are the 5 major defects with DiGeorge?

A
  1. No thymus
  2. Facial defects (micrognathia, low ears)
  3. cardio defects (truncus arteriosis)
  4. mental retardation
  5. feeding difficulty
43
Q

What is the cause of Wiscott-Aldrich syndrome?

A

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
Q

What are the four types of transplant?

A
  1. Autologous- from same person
  2. Syngeneic- from identical twin
  3. Allogeneic- from HLA related donor
  4. Xenogeneic- from different species
45
Q

What level of immunosuppression is needed for an autologous transplant?

A

None because it is self-to-self.

This is typical for cardiac bypass where vessels from leg are moved to heart

46
Q

What is the most common type of transplant?

A

Allogeneic

47
Q

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

A
  1. the level of HLA match between donor and recipient

2. the sensitization of the patient (do they have anti-HLA antibodies?)

48
Q

What is HLA?

What region of the chromosomes is it located on?

A

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
Q

What are the major HLA classes?

A

HLA I = HLA-A HLA-B HLA-C

HLA II =1 HLA-DR HLA-DQ HLA-DP

50
Q

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

A
  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
Q

Which allorecognition (direct or indirect) occurs first?

A

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

52
Q

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

A

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

53
Q

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

A

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

54
Q

What is humeral rejection?

A

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
Q

What are the three main types of graft rejection?

A
  1. Hyperacute rejection
  2. Acute rejection
  3. Chronic rejection
56
Q

Describe the time scale add mechanism of hyperacute graft rejection.

How often does it occur?

A

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
Q

Describe acute rejection in terms of time scale and mechanism/

How often does this occur?

A

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
Q

Describe chronic rejection in terms of time scale and mechanism.

How often does it occur?

A

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
Q

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

A

Control acute rejection but are not effective at treating chronic infection

60
Q

What are three ways we can improve graft survival?

A
  1. HLA matching
  2. Testing for donor specific Ab (to prevent hyperacute)
  3. Immunosuppression
61
Q

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

A

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

62
Q

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

A

antigen specific

63
Q

What are the seven common immunosuppressive drugs?

A
  1. corticosteroid
  2. cytotoxic drugs
  3. antimetabolites
  4. calcineurin inhibitors
  5. Mycophenolate Mofetil
  6. Anti-IL2
  7. Antithymocyte globulin
64
Q

Why are corticosteroids used for immunosuppression?

A

They inhibit lymphocyte proliferation by down-regulating IL2

65
Q

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

A

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

66
Q

What are the two major antimetabolites used in immunosuppression?

A
  1. methotrexate- blocks folate acid synthesis

2. azathioprine- antagonizes purine synthesis (Cell mediated and humoral)

67
Q

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

A

Tacrolimus and cyclosporin blocks the NFAT pathway

68
Q

What is the function of mycophenolate mofetil?

A

It blocks lymphocyte production and guanine nucleotide synthesis

69
Q

What does antithymocyte globulin do?

A

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

70
Q

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

Which can be autologous? Which must be allogeneic?

A
  1. leukemia- either
  2. lymphoma- either
  3. immunodeficiency- must be allogeneic
71
Q

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

A

T and NK cells.

Humoral response is not seen in bone marrow transplant, however alloantibodies can prevent engraftment of HSC recipients

72
Q

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

A

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

Bugs and Drugs (21 decks)

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