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Immunology > Immunodeficiencies > Flashcards

Immunodeficiencies Flashcards

1
Q

How is immunodeficiency classified?

A

Primary (congenital)
- defect in immune system

Secondary (acquired)
- caused by another disease

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2
Q

What are the clinical features of immunodeficiencies

A

Recurrent infections

  • <6-8 URI/year for 1st 10 yrs
  • 6 otitis media
  • 2 gastroenteritis/year for 1st 2-3 years

Severe infections, unusual pathogens (Aspergillus, Pneumocystis), unusual sites (liver abscess, osteomyelitis)

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3
Q

Outline the warning signs of Primary immunodeficiency

A
  • 8+ new ear infections within 1 year
  • 2+ serious sinus infections within 1 year
  • 2+ months on antibiotics w/ little effect
  • 2+ pneumonias in 1 year
  • Infant fails to gain weight / grow normally
  • Recurrent, deep skin or organ abscesses
  • Persistent thrush (mouth/elsewhere on skin) after age 1
  • Need for IV antibiotics to clear infections
  • 2+ deep-seated infections
  • Family history of primary immunodeficiency
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4
Q

What is the main cause of PID?

A

Usually genetic

- Infrequent but can be life-threatening

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5
Q

What are the major consequences of Primary immunodeficiency (PID)?

A

Adaptive immune system defects: T and B cell

Innate immune system lacks; phagocytes, complement

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6
Q

Describe the frequency of primary immunodeficiency of immune cells

A

50% antibody
30% T Cell

18% phagocytes
2% complement

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7
Q

How are defects in adaptive immunity classified?

A

Sub-classification: primary component affected e.g.

  • B cells
  • T cells
  • Combined (both B & T)
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8
Q

What cellular defects occuring adaptive immunity during primary immunodeficiency?

A

T cell defects impair antibody production

Defects in lymphocyte development or activation

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9
Q

Name the major B-lymphocyte immunodeficiency disorders

A
  • X-linked agammaglobulinemia (Bruton’s disease)
  • Common variable immunodeficiency (CVID)
  • Selective IgA deficiency
  • IgG2 subclass deficiency
  • Specific Ig deficiency with normal Igs
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10
Q

What is the first described immunodeficiency?

A

X-linked Agammaglobulinemia

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11
Q

What causes Bruton’s disease?

A

Defect in btk gene (X chromosome)

form of agammaglobulinemia

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12
Q

What is the role of the btk gene?

A

Encodes Bruton’s tyrosine kinase

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13
Q

What is the effect of btk gene defect?

A

Btk needed for pre-B cell receptor signalling

Blocks in B-cell development (stop at pre-B cells)

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14
Q

What is the consequence of Bruton’s disease?

A

Recurrent severe bacterial infections

  • 2nd half of first year (lung, ears, GI)
  • autoimmune diseases (35% of patients)
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15
Q

How do we investigate Brutons disease?

A
  • B cells absent / low;
  • Plasma cells absent
  • All Igs absent / very low
  • T cells + T cell-mediated responses normal
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16
Q

How is brutons disease treated?

A
  • IVIg: 200-600mg/kg/month at 2-3 wk intervals
  • or subcutaneous Ig weekly
  • prompt antibiotic therapy (URI /LRI)
  • Do not give live vaccines
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17
Q

What is SCID?

A

Severe Combined ImmunoDeficiency (SCID)

A form of Combined immunodeficiencies

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18
Q

Outline the predominant T cell disorders

A
  • DiGeorge syndrome
  • Wiskott-Aldrich syndrome
  • Ataxia-telangiectasia
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19
Q

Which lymphocyte disorder is SCID a form of?

A
  • involves both T and B

- 50-60% X-linked; rest - autosomal recessive

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20
Q

Describe the presentation of SCID

A
  • well at birth; problems > 1st month
  • diarrhoea; weight loss; persistent candidiasis
  • severe bacterial/viral infections
  • failure to clear vaccines
  • unusual infections (Pneumocystis, CMV)
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21
Q

What are the different causes of SCID?

A

Different causes; affect T & B cell development e.g.

  • Cytokine receptor defects
  • RAG defects
  • Adenosine Deaminase Deficiency
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22
Q

How do cytokine receptor defects effect T and B cell development?

A

Common cytokine receptor γ-chain defect
(signal transducing component of receptors for IL-2, 4, 7, 9, 11, 15, 21)

IL-7 needed for survival T cell precursors => defective T cell development => lack in B cell help (low Ab)

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23
Q

What is the effect of RAG enzyme defects?

A

RAG-1/RAG-2 defect => no T and B cells

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24
Q

What is the effect of adenosine deaminase deficiency?

A

Accumulation of deoxyadenosine & deoxy-ATP => toxic for rapidly dividing thymocytes

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25
Q

How is SCID investigated?

A

Lymphocyte subsets
- T, B, NK (% and numbers)
=> low total lymphocyte count

Pattern:
- T very low/absent
- B normal/absent
sometimes NK also absent (γ-chain defect affecting IL-15 receptor)

  • Igs low
  • T cell function ↓ (proliferation, cytokines)
26
Q

How is SCID treated?

A
  • Isolation
  • Do not give live vaccines !
  • Blood products from CMV -ve donors
  • IVIg replacement
  • Treat infections
  • Bone marrow/ HSCT
  • Gene therapy (for ADA and γ-chain genes)
27
Q

Describe SCID prognosis and survival

A

Dependent on promptness of diagnosis

Survival >80%
- early diagnosis
- good donor match
no infections pre-transplant

Survival <40%

  • late diagnosis
  • chronic infections
  • poorly matched donors

Regular monitoring post BMT => engraftment

28
Q

What is DiGeorge syndrome?

A

Complex array of developmental defects

29
Q

What are the physical signs of DiGeorge syndrome?

A

Dysmorphic face: cleft palate, low-set ears, fish-shaped mouth

30
Q

What are the clinical symptoms of DiGeorge syndrome?

A

Hypocalcaemia, cardiac abnormalities

Variable immunodeficiency (absent/reduced thymus => affects T cell development)

31
Q

What is Wiskott-Aldrich SYndrome (WAS)?

A

X-linked

Defect in WASP (protein involved in actin polymerisation => defect in signalling)

32
Q

What are the clinical signs of Wiskott-aldrich syndrome?

A

Thrombocytopaenia, eczema, infections

33
Q

Describe the progression of wiskott aldrich syndrome?

A

Progressive immunodeficiency (T cell loss)

Progressive ↓ T cells; ↓ T cell proliferation

Ab production (↓ IgM, IgG; high IgE, IgA)

34
Q

What is ataxia telangiectasia?

A

Autosomal recessive

Defect in cell cycle checkpoint gene (ATM) => sensor of DNA damage => activates p53 => apoptosis of cells with damaged DNA

35
Q

What is the role of the ATM gene?

A

ATM gene stabilises DNA double strand break complexes during V(D)J recombination => defect in generation of lymphocyte antigen receptors & lymphocyte development

36
Q

What are the consequences of ataxia telangiectasia?

A

Progressive cerebellar ataxia (abnormal gait)

Typical telangiectasia (ear lobes, conjunctivae)

Immunodeficiency
Increased incidence of tumours later in life

37
Q

What are the causes of ataxia telangiectasia?

A
  • Combined immunodeficiency (B & T)
  • Defects in production of switched Abs (IgA/G2)
  • T cell defects (less pronounced) => thymic hypoplasia
  • Upper & lower respiratory tract infections
  • Autoimmune phenomena, cancer
38
Q

What are the 2 types of innate immunity defects?

A
  • Phagocyte defects

- Complement defects

39
Q

What are the types of phagocyte defects?

A

Quantitative (↓ number)

Qualitative

  • Chronic granulomatous disease
  • Chediak-Higashi syndrome
  • Leukocyte adhesion defects (LADs)
40
Q

What is chronic granulomatous disease?

A

Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components
- Formation of granulomas (wall off microbes)

41
Q

How is chronic granulomatous disease?

A

Diagnosis: Tests that measure oxidative burst:

  • NBT test (nitroblue tetrazolium reduction)
  • Flow cytometry assay dihydrorhodamine
42
Q

Outline how an NBT reduction test is carried out?

A
  1. Control neutrophils + Patient neutrophils
  2. Incubate in nitroblue tetrazolium
  3. Activate using microbe / cytokines
  4. Checks production of active oxygen species
  5. If oxygen species produced; cells cleave active dye
    = blue
  6. Deficient patients have no colour as they are defective
43
Q

How is a dihydrorhodamine assay used to diagnose chronic granulomatous disease?

A

Dihydrorhodamine assay used in similar manner

Cells producing active oxygen species will cleave the dye making the cells fluoresce, if deficient no fluorescence will occur

Takes ~30 mins

44
Q

What is Chediak-Higashi Syndrome?

A
  • rare genetic disease
  • defect in LYST gene
  • neutrophils have defective phagocytosis
  • repetitive, severe infections
45
Q

What is the role of the LYST gene?

A

Regulates lysosome traffic

46
Q

What causes recurrent infections in chediak-higashi syndrome?

A

Defect phagosome-lysosome fusion => defective killing of phagocytosed microbes => recurrent infections

47
Q

How is Cjhediak-Higashi Syndrome diagnosed?

A
  • Necreased number neutrophils

- Neutrophils have giant granules

48
Q

What defects cause LAD (Leukocyte Adhesion Deficiency)?

A
  • Defect in β2-chain integrins (LFA-1, Mac-1)

- Defect in sialyl-Lewis X (selectin ligand)

49
Q

Describe the presentation of leukocyte adhesion deficiency

A

Skin infections, intestinal + perianal ulcers

50
Q

How is leukocyte adhesion deficiency investigated?

A

↓ neutrophil chemotaxis

↓ integrins on phagocytes (flow cytometry)

51
Q

What is the effect of complement deficiencies?

A

Can affect different complement factors severe/fatal pyogenic infections (C3 deficiency)

Predisposition to infection with different pathogens

52
Q

What are the symptoms of complement deficiencies?

A

Symptoms differ depending on C factor affected

53
Q

What recurrent infections occur in complement deficiencies?

A

Recurrent infections (Neisseria) - deficiency terminal complex (MAC): C5, C6, C7, C8 & C9

Severe/fatal pyogenic infections (C3 deficiency)

SLE-like syndrome (C1q, C2, C4 deficiency)

54
Q

What is Hereditary angioneurotic oedema?

A

Failure to inactivate complement (deficiency in C1 inhibitor); intermittent acute oedema skin/mucosa => vomiting, diarrhoea, airway obstruction

55
Q

How are complement deficiencies investigated?

A
  • measure individual components

- complement function: CH50 (haemolysis)

56
Q

What are the aims of primary immunodeficiency treatments?

A
  • Ig replacement therapy
  • Bone marrow transplantation
  • Gene therapy
  • Prompt infection treatment
  • Prevention of infection: isolation, antibiotic prophylaxis, vaccination
    (not live vaccines!)
  • Good nutrition
57
Q

What are the secondary immunodeficiency causes?

A 
Infections: viral, bacterial
Malignancy 
Extremes of age
Nutrition (anorexia, iron deficiencies)
Chronic renal disease
Splenectomy
Trauma/surgery, burns, smoking, alcohol
Immunosuppressive drugs
58
Q

Outline common secondary immunodeficiency infections

A

Viral:

  • HIV, CMV, EBV,
  • Measles
  • Influenza

Chronic bacterial:

  • TB
  • Leprosy

Chronic parasitic:

  • Malaria
  • Leishmaniasis

Acute bacterial
- Septicaemia

59
Q

What malignancies cause immunodeficiency?

A
  • Myeloma
  • Lymphoma (Hodgkin’s, non-Hodgkin’s)
  • Leukaemia (acute or chronic)
60
Q

What are the age extremities causing immunodeficiency?

A

prematurity

old age

61
Q

How does prematurity cause immune vulnerability?

A
  • infants < 6 months => maternal IgG

- premature delivery: interrupts placental transfer of IgG => infant Ig deficient

62
Q

How does old age affect the immune system?

A

Decline in normal immune function

Immunology (14 decks)

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