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Y3 immunology and haematology > 1y immunodeficiency > Flashcards

1y immunodeficiency Flashcards

1
Q

immune cell development

A

pluripotent stem cells differentiate into different types of immune cells (thymus/bone marrow) –> pre myeloid, lymphocyte committed stem cells, pre monocyte cells

pre myeloid - precursor for neutrophils

lymphocyte committed stem cells - precursors for T and B cells

pre monocyte cells - develop into monocytes and macrophages

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2
Q

what are the different types of T cells

A

effector and suppressor T cells

CD4 - Th1, Th2, Th17, regulatory T cells

regulatory CD8 cells

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3
Q

what are B cells responsible for

A

producing antibodies

once they start secreting antibodies they become plasma cells

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4
Q

what are the 2 types of immune responses

A

specific vs non specific

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5
Q

what defence is involved in specific immunity

A

antibody - plasma cells

cellular immunity - T cells and APCs

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6
Q

what defence is involved in non-specific immunity

A

complement

phagocytes

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7
Q

what usual organisms are isolated in antibody defence

A

pyogenic bacteria - staphylococci, streptococcus pnuemoniae, haemophilus influenzae

some viruses: enteroviruses - polio, ECHO

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8
Q

what usual organisms are isolated in cellular immunity defences

A

viruses - cytomegalovirus, herpes zoster, measles, papilloma

fungi - candida, aspergillus, pneumocystis

bacteria - myobacteria, listeria

protozoa - cryptosporidium

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9
Q

what usual organisms are isolated in complement defence

A

pyogenic bacteria

neisseria

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10
Q

what usual organisms are isolated in phagocyte defence

A

bacteria - staphylococci, gram -ve

fungi - aspergillus, candida

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11
Q

which is more specific: innate or adaptive immunity

A

adaptive

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12
Q

serum immunoglobulin levels through life (pre-natal to 10yrs)

A

for the 1st 6mths of life the main source of antibodies are the maternal antibodies that pass through the placenta

babies gradually start building their own antibodies with age

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13
Q

what does immunodeficiency mean

A

defects in any one or more components of the immune system

can lead to serious and often fatal disorders

collectively known as immunodeficiency diseases

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14
Q

why is the immune system important

A

integrity of the immune system is essential for defence against infectious organisms and their toxic products

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15
Q

classes of immunodeficiency diseases

A

1y or congenital

2y or acquired

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16
Q

what is the major consequence of immunodeficiency

other consequences

A

increased susceptibility to infection

also susceptible to certain types of cancer

certain immunodeficiencies are associated w/ an increased incidence of autoimmunity

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17
Q

what causes 1y immunodeficiency

A

genetic, congenital disorders - mainly caused by genetic aberrations

small number caused by autoimmunity

part of the immune system is missing/functioning abnormally

not 2y to other disease processes, toxins or drugs

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18
Q

what does 1y immunodeficiency predispose to

A

infections

tumours

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19
Q

where can the abnormality be in 1y immunodeficiency

A

components of the innate immune system

stages of lymphocyte development

responses of mature lymphocytes to antigenic stimulation

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20
Q

when to suspect immune deficiency

A

children - more than 3-4 infections each year or unusual infections or difficult to treat infections

adults - more frequent infections, more severe infection

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21
Q

defects in lymphocytes in 1y immunodeficiency

A

can happen at any level

the earlier the defect is in the process of development, the more severe the disease

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22
Q

what happens if there is a defect in TCR signalling

A

T cell receptor signalling

defect in antigen presentation, processing and recognitiion

defect in immune response

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23
Q

what does the increased susceptibility to infection in immunodeficiency depend on

A

the component of the immune system that is defective

indicates which infection the patient will be more susceptible to

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24
Q

what does the type of opportunistic infection present give us a clue to

A

degree and cause of immunodeficiency

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25
Q

what would repeated infection w/ encapsulated bacteria indicate

A

defective antibody production

mild immunodeficiency

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26
Q

what can antibody deficiency result in

A

IgG and IgA deficiency

can lead to recurrent resp infection

pneumococcus/haemophilus spp

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27
Q

what are infections w/ staphylococci/gram -ve bacteria/fungi associated w/

A

reduced number/function of phagocytes

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28
Q

what can complement defects predispose to

A

neisseria infection and encapsulated bacteria

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29
Q

what can defects in T cells or macrophages predispose to

A

infection w/ intracellular organisms - protozoa, viruses and intracellular bacteria

incl mycobacteria

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30
Q

T cell immunodeficiency and mycobacterial infection

  • severity of immunodeficiency
  • infection
A

severity of T cell immunodeficiency is reflected in patterns of mycobacterial infection

in mild T cell immunodeficiency it is able to invade the body outside the lungs

more severe immunodeficiency predisposes to widespread infection w/ mycobacteria of low virulence normally found in the environment

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31
Q

what is mycobacterium tuberculosis

A

virulent organism

causes lung infection in immunocompetent people

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32
Q

what is reactivation of latent herpes infection linked to

A

T cell immunodeficiency

recurrent attacks of coldsores (HSV) or shingles (HZV) may suggest mild immunodeficiency

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33
Q

what is recurrent candida infection suggestive of

A

defects in the Th17 pathway

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34
Q

examples of viral induced tumours

what are they characteristic of

A

herpes virus induced tumours - Kaposi sarcome (HHV8)
non-Hodgkin lymphoma - EBV

T cell dysfunction

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35
Q

3 causes of 1y immunodeficiency

A

mutations
polymorphisms
polygenic disorders

36
Q

what is a mutation

A

permanent alteration in the DNA sequence that makes up a gene - the sequence differs from what is found in most people

mutations affecting the immune system are rare, can affect any part of the immune system and cause severe disease

37
Q

what are polymorphisms

A

involves one of two or more variants of a particular DNA sequence - aka alleles of the same gene occurring at a single locus in at least 1% of the pop

most common polymorphism involves variation at a single base pair

can also be much larger in size and involve long stretches of DNA

38
Q

polymorphisms in the immune system

A

common traits that affect any part of the immune system and cause a moderate increased risk for infection

not usually as severe as diseases associated w/ mutations

39
Q

what are polygenic disorders

A

disorders caused by the combined action of more than one gene

40
Q

polygenic disorders of the immune system

A

relatively common disorders of the immune system and affect mainly antibodies

some of these polygenic conditions may be caused by autoimmunity

41
Q

what condition do many mutations result in

A

severe combined immunodeficiency (SCID)

42
Q

what is SCID

A

group of disorders that affect both T and B cells

43
Q

prognosis of SCID

A

infants die within the first few mths of life unless treatment is given

44
Q

genetics of SCID

A

some are autosomally inherited and there may be a hx of consanguinity

other types are X linked and there may be a hx of early deaths in maternal uncles

45
Q

treatment for SCID

A

stem cell transplant can be a cure - has to be done quickly

if performed very soon after birth 90% survive

if delayed for a few mths - 50% survive

many countries screen for SCID in newborns

46
Q

what can polymorphisms result in

A

human leukocyte antigen (HLA) alleles are polymorphic and affect the outcome of infections

polymorphisms in mannan-binding lectin (MBL) and complement affect the risk for infections

47
Q

impact of non-functioning HLA alleles

A

individuals w/ HLA alleles that are unable to bind viral peptides have a worse outcome

48
Q

what is MBL

A

collagen-like protein that binds sugars in bacterial cell walls and activates the classic complement pathway

49
Q

examples of polygenic disorders

A

common variable immunodeficiency (CVID)

IgA deficiency

specific antibody deficiency

  • relatively common polygenic disorders that affect antibody production
50
Q

how common is CVID

A

most common 1y immunodeficiency requiring treatment

occurs in ~1/20 000 young people

M+F

51
Q

immune features of CVID

A

low levels of total IgG

IgA, IgM levels and B/T cell numbers are variable

52
Q

clinical features of CVID

A

recurrent resp tract infections

gut, skin and nervous system infections

autoimmunity is common

many pts have hx of other affected family members or of consanguinity - autosomal recessive inheritance

53
Q

what happens to pts w/ specific antibody deficiency

A

recurrent infections w/ pneumococcus/haemophilus spp despite normal total IgG

don’t respond to polysaccharide agents and have poor titres of antibodies to pneumococcal antigens even after vaccination

54
Q

example of 1y immunodeficiency caused by autoimmunity - polygenic

A

pts w/ autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) frequently experience severe recurrent candida infection
- defect in central tolerance and experience many types of autoimmunity

55
Q

what differences in immune system do pts w/ APECED have

A

some pts w/ APECED produce antibodies against IL-17 –> impaired responses to candidiasis

other individuals who have no genetic defects produce antibodies against IFN-gamma
- recurrent problems w/ mycobacterial infection

56
Q

autosomal recessive SCID

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

T and B cells

recombinase (RAG) mutations

all pathogens

57
Q

Wiskott-Aldrich syndrome

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

T and B cells

actin cytoskeleton

all pathogens

58
Q

X-linked SCID

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

T and NK cells reduced, B cells not functional

cytokine receptor common gamma chain

all pathogens

59
Q

DiGeorge syndrome

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

T cells

absent thymus

intracellular pathogens

60
Q

anti-IL-17

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

autoantibodies

T cells

TH17 responses

candida

61
Q

anti -IFN gamma

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

autoantibodies

T cells

Th1 responses

mycobacteria

62
Q

hyper IgM syndrome

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

B cells

mutations in CD154

pneumococcus and haemophilus

63
Q

X-linked antibody deficiency

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

B cells

mutations in BTK

pneumococcus and haemophilus

64
Q

CVID

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

polygenic

B cells

unknown defect

pneumococcus and haemophilus

65
Q

IgA deficiency

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

polygenic

B cells

unknown defect

pneumococcus and haemophilus

66
Q

specific antibody deficiency

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

polygenic

B cells

unknown defect

pneumococcus and haemophilus

67
Q

TAP defects

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

antigen presentation

impaired antigen processing

all pathogens

68
Q

HLA

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

polymorphisms

antigen presentation

viruses

69
Q

complement deficiency

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

complement

membrane attack complex

bacteria - esp Neisseria

70
Q

MBL

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

polymorphisms

complement cascade

many pathogens

71
Q

chronic granulomatous disease

  • genetics
  • cell/pathway
  • defect
  • main type of infection
A

monogenic

phagocytes

oxidative burst

staphylococci and invasive fungi

72
Q

diagnosis - clinical presentation of SCID

A

children - defective T cells and B cells, develop infections in the first few wks of life

unusual/recurrent infection

diarrhoea

unusual rashes

73
Q

diagnosis - SCID hx

A

FHx neonatal death

FHx consanguinity

74
Q

diagnosis - SCID lymphocyte count

A

very low total lymphocyte count - <1x10^9/L

lymphocyte numbers should be measured by flow cytometry

75
Q

diagnosis - clinical presentation of antibody deficiency

A

presents later in life

some forms e.g. CVID don’t present until adulthood

chronic/recurrent bacterial resp infection

76
Q

diagnosis - antibody levels in antibody deficiency

A

measure IgG, IgA, IgM

w/ low levels of immunoglobulins, causes of 2y immunodeficiency should be excluded

if total Igs are normal, measure specific antibodies against haemophilus and pneumococcus

if these tests are all normal, it is important to check no problems are apparent w/ complement/neutrophil function

77
Q

aim of treatment of 1y immunodeficiency

A

prevent infection

78
Q

treatment of 1y immunodeficiency

A

mild immunodeficiency - prophylactic abx may be adequate

more severe antibody deficiency - immunoglobulin replacement therapy

79
Q

what is immunoglobulin therapy

A

antibodies against a wide range of pathogens

Ig pooled from thousands of normal donors

Ig replacement can be given IV or SC

plasma screened for HIV, hep B and C antibodies

80
Q

treatment of SCID

A

if confirmed - definitive treatment

until definitive treatment, avoid serious infection

stem cell transplant for SCID and most T cell deficencies

81
Q

steps to avoid serious infection in SCID

A

avoid live vaccines - MMR, polio

prophylaxis against opportunist infections e.g. pneumocystis jiroveci

82
Q

stem cell transplants

A

most successful if done within wks of birth before the infant has developed any infection
- if this is possible, 90% success rate and curative

when SCT isn’t an option - attempt gene therapy

83
Q

gene therapy for 1y immunodeficiency

A

uses recombinant technology to correct the genetic defect in the pts own stem cells which can then reconstitute the immune system

used in pts w/ SCID for whom no suitable stem cell donor was available

84
Q

what criteria must be met for gene therapy to be successful

A
  1. genetic mutation for each pt must be identified and there must be evidence that correcting the mutation will improve the condition
  2. transfected gene must confer a proliferation/survival advantage
  3. gene therapy mustn’t cause malignancy
85
Q

gene therapy in X linked SCID

A

Y3 immunology and haematology (20 decks)

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