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Fundamentals of P > Immunodeficiencies > Flashcards

Immunodeficiencies Flashcards

1
Q

Immunodeficiency

Classification: - describe

A

Primary (congenital): defect in immune system

Secondary (acquired): caused by another disease

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2
Q

Immunodeficiency

Clinical features: for recurrent/severe infections

A

recurrent infections (normal: <6-8 URI/year for the 1st 10 years; 6 otitis media and 2 gastroenteritis/year for the 1st 2-3 years)

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

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3
Q

Warning signs of PID

A

2 or more of the following:

8 or more new ear infections within 1 year
2 or more serious sinus infections within 1 year
2 or more months on antibiotics with little effect
2 or more pneumonias within 1 year
Failure of an infant to gain weight or grow normally
Recurrent, deep skin or organ abscesses
Persistent thrush (mouth/elsewhere on skin) after age 1
Need for intravenous antibiotics to clear infections
2 or more deep-seated infections
A family history of primary immunodeficiency

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4
Q

Primary Immunodeficiencies - cause and prevalence

A

Usually genetic

Infrequent but can be life-threatening

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5
Q

Primary Immunodeficiencies - describe their sub classification

A

sub-classification: primary component affected
e.g. B cells, T cells, combined (both B & T)
often T cell defects impair antibody production
defects in lymphocyte development or activation

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6
Q

Major B lymphocyte disorders: - list

A 
X-linked agammaglobulinaemia (Bruton’s disease)
 Common variable immunodeficiency (CVID)
 Selective IgA deficiency
 IgG2 subclass deficiency
 Specific Ig deficiency with normal Igs
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7
Q

X-linked Agammaglobulinaemia - define and describe effects

A 
Bruton’s disease
defect in btk gene (X chromosome)
 encodes Bruton’s tyrosine kinase
 block in B-cell development (stop at pre-B cells) 
 recurrent severe bacterial infections
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8
Q

Btk - function

A

Btk needed for pre-B cell receptor signalling

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9
Q

X-linked Agammaglobulinaemia - investigations

A
  • B cells absent / low; plasma cells absent
  • all Igs absent / very low
  • T cells and T cell-mediated responses normal
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10
Q

X-linked Agammaglobulinaemia - treatment

A

Treatment:

  • 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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11
Q

Predominant T cell disorders:

A

DiGeorge syndrome
Wiskott-Aldrich syndrome
Ataxia-telagiectasia

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12
Q

SCID - define

A

Combined immunodeficiencies:

Severe Combined ImmunoDeficiency (SCID)

  • involves both T and B
  • 50-60% X-linked; rest - autosomal recessive
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13
Q

SCID - Presentation:

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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14
Q

SCID - causes

A

common cytokine receptor γ-chain defect (signal transducing component of receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, IL-21); IL-7 needed for survival T cell precursors => defective T cell development => lack in B cell help (low Ab)
RAG-1/RAG-2 defect => no T and B cells
ADA (adenosine deaminase deficiency); => accumulation of deoxyadenosine & deoxy-ATP => toxic for rapidly dividing thymocytes

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15
Q

SCID - investigations

A

Lymphocyte subsets: T, B, NK (% and numbers) => low total lymphocyte count => SCID sign!
Pattern: very low/absent T; normal/absent B, sometimes also absent NK (γ-chain defect affecting IL-15 receptor)
Igs low
T cell function ↓ (proliferation, cytokines)

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16
Q

SCID - treatment

A

isolation => to prevent further infections
Do not give live vaccines !
Blood products from CMV-negative donors
IVIg replacement
Treat infections
Bone marrow/haematopoietic stem cell transplant
Gene therapy (for ADA and γ-chain genes)

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17
Q

SCID - outcome

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

18
Q

DiGeorge syndrome (thymic hypoplasia): - define and describe effects

A

22q11 deletion => failure development 3+4th pharyngeal pouches

complex array of developmental defects
dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
hypocalcaemia, cardiac abnormalities
variable immunodeficiency (absent/reduced thymus => affects T cell development)

19
Q

Wiskott-Aldrich syndrome (WAS): - define and describe effects

A

X-linked
defect in WASP (protein involved in actin polymerisation => defect in signalling)
thrombocytopaenia, eczema, infections
progressive immunodeficiency (T cell loss)
progressive ↓ T cells; ↓ T cell proliferation
Ab production (↓ IgM, IgG; high IgE, IgA)

20
Q

Ataxia-Telangiectasia (AT): - define

A

autosomal recessive

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

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

21
Q

Ataxia-Telangiectasia (AT): - describe effects

A

progressive cerebellar ataxia (abnormal gait)
typical telangiectasia (ear lobes, conjunctivae)
immunodeficiency
increased incidence of tumours later in life
defects in production of switched Abs (IgA/G2)
T cell defects (less pronounced) <= thymic hypoplasia
upper & lower respiratory tract infections
autoimmune phenomena, cancer

22
Q

Phagocyte defects: - describe types and list examples

A 
quantitative (↓ number)
 qualitative
 Chronic granulomatous disease 
 Chediak-Higashi syndrome
 Leucocyte adhesion defects (LADs)
23
Q

Chronic granulomatous disease - define

A

Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components

as assembly of NADPH oxidase = superoxide anion in the activated phagocyte

24
Q

CGD - define

A

Phagocyte defects - CGD

formation of granulomas (wall off microbes)

25
Q

CGD - diagnosis

A

Diagnosis:

Tests that measure oxidative burst: 
NBT test (nitroblue tetrazolium reduction)
Flow cytometry assay dihydrorhodamine
26
Q

Chediak-Higashi syndrome - define

A

rare genetic disease
defect in LYST gene (regulates lysosome traffic)
neutrophils have defective phagocytosis
repetitive, severe infections

27
Q

Chediak-Higashi syndrome - explain the cause of recurrent infections

A

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

28
Q

Chediak-Higashi syndrome - diagnosis

A

decreased number neutrophils

neutrophils have giant granules

29
Q

LAD (leucocyte adhesion deficiency) - define

A

defect in β2-chain integrins (LFA-1, Mac-1)
defect in sialyl-Lewis X (selectin ligand)

delayed umbilical cord separation => diagnosis defect in β2-chain integrins (LFA-1, Mac-1)

30
Q

LAD (leucocyte adhesion deficiency) - presentation

A

Presentation:

=> skin infections, intestinal + perianal ulcers

31
Q

LAD (leucocyte adhesion deficiency) - investigations

A

↓ neutrophil chemotaxis

↓ integrins on phagocytes (flow cytometry)

32
Q

Complement deficiencies - effect and symptoms

A

can affect different complement factors severe/fatal pyogenic infections (C3 deficiency)
predisposition to infection with different pathogens
symptoms differ depending on C factor affected

33
Q

Complement deficiencies - describe examples

A 
recurrent infections (Neisseria) - deficiency terminal complex (MAC): C5, C6, C7, C8 &amp; C9
 severe/fatal pyogenic infections (C3 deficiency)
 SLE-like syndrome (C1q, C2, C4 deficiency)
 hereditary angioneurotic oedema: failure to inactivate complement (deficiency in C1 inhibitor); intermittent acute oedema skin/mucosa => vomiting, diarrhoea, airway obstruction
34
Q

Complement deficiencies - investigations

A

complement function: CH50 (haemolysis)

measure individual components

35
Q

PID: treatment principles - aims

A

Aims:

  • replace defective/absent component of IS
  • minimise/control infection
    prompt treatment of infection
    prevention of infection: isolation, antibiotic prophylaxis, vaccination (not live vaccines!)
    good nutrition
36
Q

PID: treatment principles - examples

A

Immunoglobulin replacement therapy
Bone marrow transplantation
Gene therapy

37
Q

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
38
Q

Secondary Immunodeficiency - list types of infections with examples for each

A

viral: HIV, CMV, EBV, measles, influenza
chronic bacterial: TB, leprosy
chronic parasitic: malaria, leishmaniasis
acute bacterial: septicaemia

39
Q

Secondary Immunodeficiency - list examples of malignancies

A

Myeloma
Lymphoma (Hodgkin’s, non-Hodgkin’s)
Leukaemia (acute or chronic)

40
Q

Secondary Immunodeficiency - explain the effect of extremes of age

A

Prematurity

  • infants < 6 months => maternal IgG
  • premature delivery: interrupts placental transfer of IgG => infant Ig deficient

Old age

  • decline in normal immune function

Fundamentals of P (62 decks)

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