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Respiratory: Immunology > Primary immunodeficiency 2 > Flashcards

Primary immunodeficiency 2 Flashcards

1
Q

What are features of the acquired (adaptive) immune system?

A
  • Responsive to an unlimited number of molecules
  • Specificity - able to discriminate between very small differences in molecular structure
  • Memory - able to recall previous encounter with an antigen and respond more effectively than on the first occasion
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2
Q

What organs/tissues are involved in the adaptive immune response?

A

Thymus - maturation of T cells
Bone marrow - production of T cells and B cells
Lymph nodes (secondary lymphoid tissues) - sites of activation of T cells and B cells

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3
Q

Where is the thymus located?

A

Above the heart

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4
Q

Describe the life cycle of a T lymphocyte (4)

A
  • Produced by haematopoetic stem cells in bone marrow
  • Immature cells travel to thymus
  • In thymus, undergo selection - only 10% cells survive
  • Mature T lymphocytes enter circulation
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5
Q

What percentage of T cells mature?

A

Only around 10% of cells that enter the thymus will exit as mature T cells

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6
Q

What are the functions of T lymphocytes?

A
  • Defence against intracellular pathogens and viruses

* Immunoregulation (T helper)

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7
Q

What are the classifications of T lymphocytes?

A

CD4 and CD8

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8
Q

What is the function of TH1 cells?

A

Secrete IFNy that links TH1 cells to macrophages

macrophages then secrete IL-12 which allows for further activation of CD4

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9
Q

What are the functions of CD4+ T lymphocytes? (3)

A

Immunoregulatory functions

  • Provide costimulatory signals - necessary for activation of CD8+ T lymphocytes and naive B cells
  • Produce cytokines
  • Regulate lymphocytes and phagocytes
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10
Q

How do CD4+ T lymphocytes recognise peptides?

A

Recognise peptides presented on MHC Class II molecules

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11
Q

What are the functions of CD8+ T cells? (3)

A
  • Kill cells directly via production of pore-forming molecules (e.g. perforin) triggering apoptosis of the target
  • Secrete cytokines e.g. IFNγ
  • Particularly important in defence against viral infections and tumours
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12
Q

What are CD8+ T cells?

A

Specialised cytotoxic cells

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13
Q

How do CD8+ T lymphocytes recognise peptides?

A

Recognise peptides in association with MHC class I molecules

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14
Q

Where are B lymphocytes produced and where do they mature?

A
  • From haemopoetic stem cells in bone marrow

* Mature B lymphocytes found mainly in bone marrow, lymphoid tissue, spleen

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15
Q

What is the function of B lymphocytes? (2)

A
  • Antibody production

* Antigen presentation

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16
Q

Describe the process of the activation of B lymphocytes (6)

A
  • Encounters antigen occur in lymph node
  • Appropriate signals provided by T cells, stimulated B cells rapidly proliferate
  • Germinal Centre reaction: help from effector TFH cells
  • Generate B cells that express receptors of greater affinity than the original
  • Generate B cells that express antibodies with different Ig heavy chain constant regions
  • Further differentiation (long-lived memory cells and plasma cells which produce antibodies)
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17
Q

What are functions of antibodies? (4)

A
  • IgM and IgD antigen receptors
  • Opsonisation – IgG
  • Neutralisation – IgA and IgG
  • Mast cell activation - IgE
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18
Q

How can the adaptive immune system go wrong? (5)

A
  • Production of immune cells - reticular dysgenesis, severe combined immunodeficiency (SCID)
  • Impaired thymus function - DiGeorge syndrome
  • Disorders of T cell effector function (failure of signalling, cytokine production)
  • Failure of normal apoptosis (autoimmune lymphoproliferative syndromes)
  • Failure of HLA expression (no MHC) - Bare lymphocyte syndromes
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19
Q

What is reticular dysgenesis? (4)

A

Failure of production of:

  • Neutrophils
  • Lymphocytes
  • Monocyte/macrophages
  • Platelets
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20
Q

What is the treatment for reticular dysgenesis?

A

Fatal unless corrected with bone marrow transplantation

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21
Q

What is severe combined immunodeficiency?

A

Failure of production of lymphocytes

22
Q

What are the clinical features of SCID? (6)

A
  • Unwell by 3 months of age
  • Persistent diarrhoea
  • Failure to thrive
  • Infections of all types
  • Unusual skin disease
  • Family history of early infant death
23
Q

What types of infections do sufferers of SCID contract? (3)

A

Infections of all types

  • Common infections – more severe than usual
  • Unusual & opportunistic infections
  • Vaccine associated diseases – live attenuated vaccines (immune system not able to cope)
24
Q

What is the period of the between 3 and 6 months of age where maternal IgG levels drop before complete neonatal production of IgG?

A

Transient hypogammaglobulinaemia of infancy

25
Q

How does mother supply infant with antibody protection? (2)

A
  • Active transport of maternal IgG across placenta
  • Secretory IgA in colostrum
    & breast milk
26
Q

What are different causes of SCID with regards to T lymphocytes? (4)

A
  • Deficiency of cytokine receptors (req for development and maturation of T cells)
  • Deficiency of signalling molecules (block T cell development)
  • Metabolic defects (affects metabolism of T cell, affects development)
  • Defective receptor rearrangements (cannot create functional antigen binding site)
27
Q

What is the commonest form of SCID?

A

X-linked SCID

45% of all severe combined immunodeficiency

28
Q

What is x-linked SCID? What does it result in? (3)

A

Mutation of a component of the IL-2 receptor

  • Failure of T cell and NK cell development
  • Production of immature B cells
  • Shrinkage of the thymus
29
Q

What would a blood count of a SCID individual show? (3)

A
  • Very low or absent T cells (because IL2 is so important for T cell development)
  • Normal or increased B cells (not really affected)
  • Poorly developed lymphoid tissue and thymus
30
Q

What is IL-2?

A

T cell growth factor (activated CD4+ T cells secrete IL-2 to activate other CD4 and CD8 cells)

31
Q

What is prophylactic treatment for SCID? (5)

Definitive treatment? (2)

A

Prophylactic treatment

  • Prophylactic antibiotics
  • Prophylactic antifungals
  • No live attenuated vaccines
  • Aggressive treatment of existing infections
  • Antibody replacement - Intravenous immunoglobulin

Definitive treatment

  • Stem cell transplant from HLA identical sibling if possible
  • Gene therapy
32
Q

Explain process of gene therapy for SCID

A

Stem cells treated ex vivo to express missing component

33
Q

What is DiGeorge syndrome?

A

Complex developmental disorder caused by chromosomal deletion at 22q11 - affected gene is usually TBX1

34
Q

What is TBX1 gene responsible for?

A

Embryonic development of pharyngeal pouch

35
Q

What are clinical features of DiGeorge syndrome? (8)

A
  • Developmental defect of 3rd/4th pharyngeal pouch
  • Low set ears, abnormally folded ears, high forehead, cleft palate, small mouth and jaw
  • Hypocalcaemia
  • Oesophageal atresia
  • T cell lymphopenia
  • Complex congenital heart disease
  • Psychiatric disorders (OCD, schizophrenia)
  • Developmental delay
36
Q

What kind of infections are caused by DiGeorge Syndrome? (3)

A
  • Recurrent viral infections
  • Recurrent bacterial infections
  • Frequent fungal infections

(Why? Answers will be on medblogs)

37
Q

What will laboratory investigations of DiGeorge syndrome find? (5)

A
  • Absent or decreased number of T cells (defective T cell activation response)
  • Normal or increased B cells
  • Low IgG, IgA, IgE
  • Poor antibody responses to specific pathogens
  • Normal NK cells numbers
38
Q

How is DiGeorge syndrome managed? (4) Why may treatment become less aggressive when older?

A
  • Correct metabolic/cardiac abnormalities
  • Prophylactic antibiotics
  • Early and aggessive treatment of infection
  • Immunoglobulin replacement
  • T cell function improves with age
39
Q

What are disorders of T cell effector function? (3)

A

Incldude disorders in…

  • Cytokine production
  • Cytotoxicity
  • T-B cell communication
40
Q

What can cause disorders of T cell effector function?

A

Infection with mycobacteria

affects IL-12: IFNy network

41
Q

What can infection with mycobacteria result in?

A

Affects IL-12: IFNy network
Normally…
* Infected macrophages stimulated to produce IL-12
* IL-12 induces T cells to secrete IFNγ
* Then IFNγ feeds back to macrophages and neutrophils
* Stimulates production of TNF
* Activates NADPH oxidase

42
Q

What deficiencies can cause disorders of T cell effector function? (4)

A 
Deficiencies in:
* IL-12
* IL-12 receptor
* IFNγ 
* IFNγ receptor
(result in increases susceptibility to infection)
43
Q

What types of infection can cause disorders of T cell effector function? (4)

A
  • Tuberculosis
  • Atypical mycobacteria
  • BCG infection after immunisation
  • Deep fungal infections e.g. aspergillus
44
Q

What are clinical features of T cell deficiencies? (4)

A
  • Recurrent infections (viral, fungal, bacterial, intracellular pathogens e.g. mycobacteria)
  • Opportunistic infections
  • Malignancies at young age
  • Autoimmune disease
45
Q

What are first line investigations of T cell deficiencies? (3) Second line? (4)

A

First line investigations

  • Total white cell count
  • Quantitation of lymphocyte subpopulations
  • Serum immunoglobulins (marker of functional T cells)

Second line investigations

  • Functional tests of T cell activation and proliferation
  • Additional tests of lymphocyte lineage
  • A HIV test is ESSENTIAL
46
Q

What are B cell maturation defects? (5)

A
  • Failure of lymphocyte precursors: Severe combined immune deficiency
    *Failure of B cell maturation: Bruton’s X-linked hypogammaglobulinaemia
  • Failure of production of IgG antibodies:
    Common variable immune deficiency, selective antibody deficiency
  • Failure of TFH cell costimulation
  • Failure of IgA production: selective IgA deficiency
47
Q

What are common variable immune deficiencies?

A

Heterogenous group of disorders - disease mechanism unknown

48
Q

What are clinical features of common variable immune deficiency?

A
  • Recurrent bacterial infections - often with severe end-organ damage (e.g. bronchiectasis, persistent sinusitis, recurrent gastrointestinal infection)
  • Autoimmune disease
  • Granulomatous disease
49
Q

What are clinical features of B cell deficiencies?

A
  • Recurrent infections (primarily bacterial infections, often very common organisms)
  • Opportunistic infections
  • Antibody-mediated autoimmune disease
50
Q

What do investigations of B cell deficiencies involve?

A

First line investigations

  • Total white cell count and differential
  • Serum/urine immunoglobulins

Second line investigations

  • Quantitation of B and T lymphocytes
  • Specific antibody responses to known pathogens
51
Q

How are B cell deficiencies managed?

A
  • Aggressive treatment of infection
  • Immunoglobulin replacement
  • Stem cell transplantation in some situations
52
Q

find annotated version of investigation of primary antibody deficiencies

A

…

Respiratory: Immunology (4 decks)

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