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Immunology (aimen n) - use these > 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
  • Severe infections, unusual pathogens (Aspergillus, Pneumocystis), unusual sites (liver abscess, osteomyelitis). - An immunocompetent patient is not infected by these pathogens
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3
Q

Outline the warning signs of Primary immunodeficiency

A
  • Recurrent infections, esp. frequent thrush/fungal infections(= unusual)
  • Require ↑ antibiotics
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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 does Primary immunodeficiency (PID) usually cause?

A

Innate immune system lacks; Phagocytes, Complement

Adaptive immune system defects: T-cells, B cells.

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6
Q

How are defects in adaptive immunity classified?

A

Sub-classification: primary component affected e.g.

  • B cells
  • T cells
  • Combined (both B & T) = SCID
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7
Q

What cellular defects occur in adaptive immunity during primary immunodeficiency?

A

T cell defects impair antibody production

Defects in lymphocyte development or activation

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8
Q

Counterintuitively, a patient with an immunodeficiency could simultaneously present with ……..

A

Autoimmunity

Immunodeficient = lacking an element of immunity
+
Autoimmunity = Damage body’s own tissues bc the immune defect also affects elements of the immune system that regulate other immune cells

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9
Q

Defects in earlier stem cells affect ……

Defects at a later stage lead to a more …………. pathology

A

-the entire immune system - e.g. defects in HSCs/common lymphoid progenitor/common myeloid progenitor
= affects many immune cells

-restricted - e.g. mature T-cells/mature B-cells/plasma cells - e.g. 1 particular T-cell/B-cell

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10
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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11
Q

What is the first described immunodeficiency?

A

X-linked Agammaglobulinemia

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12
Q

What causes Bruton’s disease (agammaglobulinemia) ?

A

Defect in BTK gene (X chromosome)

BTK gene encodes Bruton’s tyrosine kinase

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13
Q

What is the role of the btk gene?

A

Encodes Bruton’s tyrosine kinase

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14
Q

What is the effect of BTK gene defect?

A

BTK needed for pre-B cell receptor signalling

BTK defect blocks B-cell development (stop at pre-B cells)

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15
Q

What is the consequence of Bruton’s disease?

A
  • Recurrent severe bacterial infections

- Autoimmune diseases

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16
Q

What inheritance pattern does agammaglobulinaemia follow?

A

Agammaglobulinaemia = X-linked

Carrier mother + unaffected father = affected male offspring

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17
Q

What happens to B-cell at Pro-B stage?

A

Pro-B cell rearranges its Ig(BCR)

At Pre-B stage, B-cell now presents a pre-BCR on its surface

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18
Q

Pre-B cell requires …… downstream in order to continue development

A

BTK signal

Missing in agammaglobulinaemia = no subsequent B-cell development = patients lack B-cell + Ab production

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19
Q

How do we diagnose Brutons disease (agammaglobulinaemia)?

A
  • B cells absent / low; Plasma cells absent
  • All Igs absent / v. low
  • T cells + T cell-mediated responses normal

agammaglobulinaemia = B-cell restricted immunodeficiency

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20
Q

How is brutons disease (agammaglobulinaemia) treated?

A
  • IV Ig/Subcutaneous Ig
  • Prompt antibiotic therapy (URI /LRI)
  • Do not give live vaccines bc cannot clear the pathogen
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21
Q

What is SCID?

A

Severe Combined ImmunoDeficiency (SCID)

A form of Combined immunodeficiencies

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22
Q

Outline the predominant T cell disorders

A
  • DiGeorge syndrome
  • Wiskott-Aldrich syndrome
  • Ataxia-telangiectasia
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23
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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24
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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25
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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26
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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27
Q

What is the effect of RAG enzyme defects?

A

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

RAG enzymes are involved in TCR + BCR rearrangement

RAG defect = no T-cells/B-cells

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28
Q

RAG enzymes are involved in ………

A

TCR + BCR rearrangement

RAG defect = no T-cells/B-cells

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29
Q

What is the effect of ADA deficiency?

A

ADA deficiency = deoxyadenosine & deoxy-ATP accumulate = toxic for rapidly dividing thymocytes

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30
Q

How is SCID investigated?

A

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

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

  • Igs low
  • T cell function ↓ (proliferation, cytokines)
31
Q

How is SCID treated?

A
  • Isolation
  • Do not give live vaccines !
  • Blood products from CMV -ve donors
  • IV Ig replacement
  • Treat infections
  • Bone marrow/HSC Transplant - replenish BM with precursors w/o the mutation
  • Gene therapy (for ADA and γ-chain genes)
32
Q

Describe SCID prognosis and survival is dependent on ………….

A

Dependent on promptness of diagnosis

33
Q

What is DiGeorge syndrome?

A

Complex array of developmental defects

Affects thymus - thymic hypoplasia

chr22q11 deletion

Cardiac issues

34
Q

What are the physical signs of DiGeorge syndrome?

A

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

35
Q

What are the clinical symptoms of DiGeorge syndrome?

A

Hypocalcaemia, cardiac abnormalities

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

36
Q

What is Wiskott-Aldrich SYndrome (WAS)?

A

X-linked

Defect in WASP (protein involved in actin polymerisation => T-cells incorrectly model actin cytoskeleton = incorrect signalling)

37
Q

What are the clinical signs of Wiskott-aldrich syndrome?

A

Thrombocytopaenia, eczema, recurrent infections

38
Q

Describe the progression of Wiskott Aldrich syndrome?

A

Progressive immunodeficiency (T cell loss)

Progressive ↓ T cells; ↓ T cell proliferation

Ab production (↓ IgM + IgG; ↑ IgE + IgA)

39
Q

Innate immunity defects involve which progenitor of haematopoiesis?

A

common myeloid progenitor (differentiates into macrophages + neutrophils)

40
Q

What are the 2 types of innate immunity defects?

A
  • Phagocyte defects

- Complement defects

41
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

42
Q

What are the types of phagocyte defects?

A

Quantitative (↓ number)

Qualitative

  • Chronic granulomatous disease
  • Chediak-Higashi syndrome
  • Leukocyte adhesion defects (LADs)
43
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)

chronic granulomatous disease = phagocytosis defect. no destruction of pathogen by phagolysosome = pathogen resides in phagolysosome

patients form granulomas = immune attempt to surround the infection, areas full of macrophages unable to clear the pathogen = keep it there

44
Q

How is chronic granulomatous disease diagnosed?

A

Diagnosis: Tests that measure oxidative burst:

  • NBT test (nitroblue tetrazolium reduction)
  • Flow cytometry assay dihydrorhodamine
45
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
46
Q

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

A

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

Takes ~30 mins

47
Q

What is Chediak-Higashi Syndrome?

A
  • rare genetic disease
  • defect in LYST gene (regulates lysosome traffic)
  • neutrophils have defective phagocytosis - no phagosome-lysosome fusion = large granules
  • repetitive, severe infections
48
Q

What is the role of the LYST gene?

A

Regulates lysosome traffic

49
Q

What causes recurrent infections in chediak-higashi syndrome?

A

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

50
Q

How is Cjhediak-Higashi Syndrome diagnosed?

A
  • Necreased number neutrophils

- Neutrophils have giant granules

51
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)

52
Q

Describe the presentation of leukocyte adhesion deficiency

A

Skin infections, intestinal + perianal ulcers

53
Q

How is leukocyte adhesion deficiency investigated?

A

↓ neutrophil chemotaxis

↓ integrins(adhesion molecules) on phagocytes (flow cytometry)

54
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

55
Q

What are the symptoms of complement deficiencies?

A

Symptoms differ depending on C factor affected

56
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)

57
Q

What is Hereditary angioneurotic oedema?

A

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

58
Q

How are complement deficiencies investigated?

A
  • measure individual components

- complement function: CH50 (haemolysis)

59
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
60
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
61
Q

Outline common secondary immunodeficiency infections

A

Viral:

  • HIV, CMV, EBV,
  • Measles
  • Influenza

Chronic bacterial:

  • TB
  • Leprosy

Chronic parasitic:

  • Malaria
  • Leishmaniasis

Acute bacterial
- Septicaemia

62
Q

What malignancies cause immunodeficiency?

A
  • Myeloma
  • Lymphoma (Hodgkin’s, non-Hodgkin’s)
  • Leukaemia (acute or chronic)
63
Q

What are the age extremities causing immunodeficiency?

A

prematurity

old age

64
Q

How does prematurity cause immune vulnerability?

A
  • infants < 6 months => maternal IgG

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

65
Q

How does old age affect the immune system?

A

Decline in normal immune function

66
Q

T-cell defects often impair …….

A

B-cell function/Ab production = Combined immunodeficiency

T-helper cells aid B-cells - TH2 cells, TFH cells

67
Q

Selective IgA deficiency

IgA =

A

IgA = mucosal Ig - respiratory tract, urogenital tract, GI tract

-low serum + secretory IgA

68
Q

PID Treatment - Stem Cell Gene Therapy

A
  • Extract BM cells from patient
  • Separate immune cell progenitors
  • Insert normal gene via virus vector
  • Reinsert stem cells into patient
69
Q

HIV infection depletes ……

A

CD4+ T-cells

70
Q

Blood cancer metastases deplete …..

A

leukocytes

71
Q

HIV is a …..virus that infects ……… cells, causing their ………..

A
  • retro
  • CD4+ T
  • depletion

When APCs(dendritic cells) bind to T-cell, transfers HIV particles to T-cells

72
Q

Which infections are commonly associated w AIDS?

A
  • Parasites - Toxoplasma
  • Intracellular bacteria - Mycobacterium TB
  • Fungi
  • Viruses
73
Q

What does HAART do?

A

Highly Active Anti-Retroviral Therapy

Stops HIV progressing to AIDS

Immunology (aimen n) - use these (14 decks)

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