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review Im > Immuno: Primary Immune Deficiencies 2 > Flashcards

Immuno: Primary Immune Deficiencies 2 Flashcards

1
Q

Name a defect in stem cells that causes SCID and name the gene that is mutated.

A

Reticular dysgenesis - adenylate kinase 2 (AK2)

NOTE: this is a mitochondrial energy metabolism enzyme

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2
Q

What is the most common type of SCID?

A

X-linked SCID

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3
Q

Which mutation is responsible for X-linked SCID?

A
  • Mutation in common gamma chain on Xq13.1
  • This is a component of many cytokine receptors leading to an inability to respond to cytokines,
  • Causing arrest in T and NK cell development and the production of immature B cells
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4
Q

Describe the typical cell counts you would expect to see in X-linked SCID.

A
  • Very low T cells
  • Very low NK cells
  • Normal or increased B cells
  • Low immunoglobulin
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5
Q

Describe the pathophysiology of ADA deficiency.

A
  • ADA - adenosine deaminase
  • This is an enzyme required by lymphocytes for cell metabolism
  • ADA deficiency leads to failure of maturation along any lineage
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6
Q

Describe the typical cell counts you would expect to see in ADA deficiency.

A
  • Very low T cells
  • Very low B cells
  • Very low NK cells
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7
Q

Describe the clinical phenotype of SCID.

A
  • Unwell by 3 months age (once protection by maternal IgG dissapates)
  • Infections of all types
  • Failure to thrive
  • Persistant diarrhoea
  • Unusual skin disease (colonisation of infant’s empty bone marrow by maternal lymphocytes can cause a graft-versus-host disease-like condition)
  • Family history of early death
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8
Q

What are the two mechanisms by which CD8+ T cells kill cells?

A

Perforin and granzyme

Fas ligand

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9
Q

Which cellular insults are CD8+ T cells particularly important in protecting against?

A
  • Viral infections
  • Tumour
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10
Q

Outline the immunoregulatory functions of CD4+ T cells.

A
  • Provide help to mount a full B cell response
  • Provide help for some CD8+ T cell responses
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11
Q

In which group of syndromes does the thymus gland fail to develop properly.

A
  • 22q11.2 deletion syndromes (e.g. Di George syndrome)
  • This is characterised by failure of development of the pharyngeal pouch
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12
Q

What are the main clinical features of 22q11.2 deletion syndromes?

A
  • Facial abnormalities (high forehead, low set ears, cleft palate, small mouth and jaw)
  • Underdeveloped parathyroid gland (resulting in hypocalcaemia)
  • Oesophageal atresia
  • Underdeveloped thymus
  • Complex congenital heart disease
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13
Q

What are the immunological consequences of an underdeveloped thymus gland?

A
  • Normal B cell count
  • Low T cell count
  • Homeostatic proliferation with age (T cell numbers increase with age)
  • Immune function is mildy impaired and tends to improve with age
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14
Q

What condition is caused by a deficiency of MHC Class II? Briefly outline its pathophysiology.

A
  • Bare lymphocyte syndrome (BLS) type 2
  • Deficiency of MHC Class II means that CD4+ T cells cannot be selected in the thymus leading to CD4+ T cell deficiency
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15
Q

Which defect leads to Bare lymphocyte syndrome?

A

Defects in the regulatory proteins involved in expression of class II genes:

  • Regulatory factor X
  • Class II transactivator
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16
Q

Describe the typical cell counts that you would expect to see in Bare Lymphocyte syndrome type 2.

A
  • Normal CD8+
  • Very low CD4+
  • Normal B cell count
  • Low IgG

NOTE: BLS Type 1 is a similar condition caused by failure of expression of HLA Class I

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17
Q

Outline the clinical phenotype of bare lymphocyte syndrome.

A
  • Unwell by 3 months of age
  • Infections of all types
  • Failure to thrive
  • Family history of early death
18
Q

What are the common clinical features of T lymphocyte deficiencies?

A
  • Viral infections (e.g. CMV)
  • Fungal infections (e.g. PCP)
  • Some bacterial infections (e.g. TB, salmonella)
  • Early malignancy

NOTE: disorders of T cell effector function include defects in cytokine production, cytokine receptors and T-B cell communication

19
Q

List some investigations that may be used for suspected T cell deficiencies.

A
  • Total white cell count and differentials
  • Lymphocyte subsets
  • Immunoglobulins
  • Functional tests of T cell activation and proliferation
  • HIV test
20
Q

How are lymphocyte counts different in children compared to adults?

A

Higher in children compared to adults

21
Q

Describe the typical levels of CD4, CD8, B cells, IgM and IgG that you would expect to see in the following diseases:

  1. SCID
  2. Di George
  3. BLS Type 2
A
  1. SCID
    • CD4 low
    • CD8 low
    • B cells normal/low
    • IgM normal/low
    • IgG low
  2. Di George
    • CD4 low
    • CD8 low
    • B cells normal
    • IgM normal
    • IgG normal/low
  3. BLS Type 2
    • CD4 low
    • CD8 normal
    • B cells normal
    • IgM normal
    • IgG low
22
Q

Outline some management approaches for immunodeficiency involving T cells.

A
  • Aggressive prophylaxis/treatment of infection
  • Haematopoietic stem cell transplantation
  • Enzyme replacement therapy (e.g. PEG-ADA for ADA deficiency)
  • Gene therapy
  • Thymic transplantation (in Di George syndrome)
23
Q

Describe the stereotypical presentation in the following lymphocyte deficiencies.

  1. X-linked SCID
  2. IFN-gamma receptor deficiency
  3. 22q11.2 deletion syndrome
  4. Bare lymphocyte syndrome type 2
A
  1. X-linked SCID: severe recurrent infections from 3 months of age, CD4 and CD8 are absent, B cells present, Ig low, normal facial features and echocardiogram
  2. IFN-gamma receptor deficiency: young adult with chronic infection with Mycobacterium marinum
  3. 22q11.2 deletion syndrome: recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
  4. Bare lymphocyte syndrome type 2: 6-month old baby with two recent serious bacterial infections. T cell present but only CD8. IgM present but IgG is low.
24
Q

What determines the class of immunoglobulin?

A

Heavy chain

25
Q

What determines the effector function of immunoglobulin?

A

Constant region of the heavy chain

26
Q

Briefly outline the functions of antibodies.

A
  • Identification of pathogens and toxins (particularly against extracellular pathogens)
  • Interacts with other components of the immune response (e.g. complement, phagocytes, NK cells)
  • Important in defence against bacteria
27
Q

Outline the pathophysiology of Bruton’s X-linked hypogammaglobulinaemia.

A
  • Prevents the maturation of B cells at that point at which they emerge from the bone marrow
  • Caused by an abnormal B cell tyrosine kinase (BTK) gene
  • This results in the absence of mature B cells and, hence, an absence of antibodies
28
Q

Outline the clinical phenotype of Bruton’s X-linked hypogammaglobulinaemia.

A
  • Boys present in the first few years of life
  • Recurrent bacterial infections (e.g. otitis media, pneumonia)
  • Viral, fungal and parasitic infections
  • Failure to thrive
29
Q

Outline the pathophysiology of X-linked hyper IgM syndrome.

A
  • Blocks the maturation of IgM B cells through germinal centres into B cells that produce other classes of immunoglobulin (i.e. prevents germinal centre reactions)
  • Caused by a mutation in the CD40 ligand gene
  • This is technically a T cell problem, however, it means that CD4+ T helper cells cannot provide help to B cells so they cannot undergo germinal centre reactions

NOTE: CD40 ligand is encoded on Xq26

30
Q

Describe the typical biochemical results you would expect to see in X-linked hyper IgM syndrome.

A
  • Normal B cells
  • Normal T cells
  • No germinal centre reactions
  • High IgM
  • Absent IgG, IgA and IgE (failure of isotype switching)
31
Q

Outline the clinical phenotype of X-linked hyper IgM syndrome.

A
  • Boys present in the first few years of life
  • Recurrent infections (mainly bacterial)
  • Subtle abnormality in T cell function (predisposes to PCP, autoimmunity and malignancy)
  • Failure to thrive
32
Q

What is common variable immunodeficiency and what are the main features?

A

A group of disorders caused by some form of failure of differentiation of B lymphocytes.

Defined by:

  • Marked reduction in IgG, IgA and IgE
  • Poor/absent response to immunisation
  • Absence of other defined immunodeficiency
33
Q

Outline the clinical phenotype of common variable immunodeficiency.

A
  • May present in adults or children
  • Recurrent bacterial infection (often severe)
  • Pulmonary disease (e.g. interstitial lung disease)
  • GI disease (e.g. IBD-like disease)
  • Autoimmune disease (e.g. AIHA)
  • Malignancy (e.g. NHL)
34
Q

What is the prevalence of selective IgA deficiency?

A

1 in 600

35
Q

What are the clinical features of antibody deficiency?

A
  • Bacterial infections (e.g. Staphylococcus)
  • Toxins (e.g tetanus)
  • Some viral infections (e.g. enterovirus)
36
Q

List some investigations that may be used for suspected B cell deficiencies.

A
  • Total white cell count and differential
  • Lymphocyte subsets
  • Serum immunoglobulins and protein electrophoresis
  • Functional tests of B cell function (e.g. measure IgG antibody against a specific pathogen (e.g. S. pneumoniae, if this is low, vaccinate using a killed vaccine and check levels again in 6-8 weeks)

NOTE: IgG prodution is a surrogate marker for CD4+ T helper cell function

37
Q

Which peak repesents immunoglobulin in protein electrophoresis?

A

Gamma peak

NOTE: albumin produces a large peak

38
Q

Outline the typical levels of CD4, CD8, B cell, IgM, IgG and IgA you would expect to see in:

  1. SCID
  2. Bruton’s X-linked Hypogammaglobulinaemia
  3. X-linked Hyper IgM syndrome
  4. Selective IgA deficiency
  5. Combined variable immunodeficiency
A
  1. SCID
    • CD4 low
    • CD8 low
    • B cell low
    • IgM low
    • IgG low
    • IgA low
  2. Bruton’s X-linked Hypogammaglobulinaemia
    • CD4 normal
    • CD8 normal
    • B cell low
    • IgM low
    • IgG low
    • IgA low
  3. X-linked Hyper IgM syndrome
    • CD4 normal
    • CD8 normal
    • B cell normal
    • IgM high
    • IgG low
    • IgA low
  4. Selective IgA deficiency
    • CD4 normal
    • CD8 normal
    • B cell normal
    • IgM normal
    • IgG normal
    • IgA low
  5. Combined variable immunodeficiency
    • CD4 normal
    • CD8 normal
    • B cell normal
    • IgM normal
    • IgG low
    • IgA low
39
Q

Outline the management approaches to immunodeficiency involving B cells.

A
  • Aggresive prophylaxis/treatment of infection
  • Immunoglobulin replacement
  • Immunisation (only if the patient is able to produce antibodies)
40
Q

Describe a stereotypical presentation of the following diseases:

  1. Common variable immunodeficiency
  2. X-linked hyper IgM syndrome
  3. Bruton’s X-linked hypogammaglobulinaemia
  4. IgA deficiency
A
  1. Common variable immunodeficiency: adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
  2. X-linked hyper IgM syndrome: recurrent bacterial infections as a child, episode of PCP, high IgM, absent IgA and IgG
  3. Bruton’s X-linked hypogammaglobulinaemia: 1-year old boy. Recurrent bacterial infections, CD4 and CD8 cells present, B cells absent, absent IgG, IgA and IgM
  4. IgA deficiency: recurrent respiratory tract infections, absent IgA, normal IgM and IgG

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