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Primary Immunodeficiency (2) Flashcards

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1
Q

Name the components of the adaptive immune system.

A
  • T lymphocytes
    • CD4 T cells
    • CD8 T cells
  • B lymphocytes
    • B cells
    • Plasma cells
    • Antibodies
  • Soluble cytokines
    • Cytokines and chemokine
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2
Q

Define primary lymphoid organs

A

Organs involved in lymphocyte development

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3
Q

What are the primary lymphoid organs

A
  • Bone marrow
    • Both T and B lymphocytes are derived from haematopoetic stem cells
    • Site of B cell maturation
  • Thymus
    • Site of T cell maturation
    • Most active in the foetal and neonatal period, involutes after puberty
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4
Q

Describe the T lymphocyte development and the things that can go wrong.

A
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5
Q

Describe reticular dysgenesis

A
  • most severe form of severe combined immunodeficiency (SCID)
  • mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2)

Failure of production of:

  • Lymphocytes
  • Neutrophils
  • Monocyte/macrophages
  • Platelets

Fatal in very early life unless corrected with bone marrow transplantation

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6
Q

What are the causes of sever combined immunodeficiency?

A

• >20possible pathways identified

– Deficiency of cytokine receptors

– Deficiency of signalling molecules

– Metabolic defects

• Effect on different lymphocyte subsets (T, B, NK) depend on mutation

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7
Q

Describe X-linked SCID

A

– 45% of all severe combined immunodeficiency

– Mutation of common gamma chain on chromosome Xq13.1

Shared by cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21

Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells

– Phenotype

Very low or absent T cell numbers

Very low or absent NK cell numbers

Normal or increased B cell numbers but low Igs

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8
Q

Describe ADA deficiency.

A

– 16.5% of all severe combined immunodeficiency

– Adenosine Deaminase Deficiency
• Enzyme required for cell metabolism in lymphocytes

– Phenotype

Very low or absent T cell numbers

Very low or absent B cell numbers

Very low or absent NK cell numbers

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9
Q

What protects the SCID neonate in the first 3 months of life?

A

Still have maternal IgG circulating.

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10
Q

Describe the Clinical phenotype of severe combined immunodeficiency

A
  • Unwell by 3 months of age • Infections of all types
  • Failure to thrive
  • Persistent diarrhoea

• Unusual skin disease

– Colonisation of infant’s empty bone marrow bymaternal lymphocytes

– Graft versus host disease
• Family history of early infant death

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11
Q

Describe T-lymphocyte maturation.

A
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12
Q

What receptors to T cells express? What do they recognise?

A

They recognise peptides presented on HLA molecules.

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13
Q

Describe selection and central tolerance in the thymus.

A
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14
Q

How do T cells differentiate into CD8+ and CD4+ cells?

A
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15
Q

Describe CD8+ T cells.

A

Specialised cytotoxic cells

Recognise peptides derived from intracellular proteins in association with HLA class I

– HLA-A, HLA-B, HLA-C

Kill cells directly

– Perforin (pore forming) and granzymes

– Expression of Fas ligand

Secrete cytokines eg IFNg TNFa

Particularly important in defence against viral infections and tumours

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16
Q

Describe CD4+ T cells

A

– Recognise

  • peptides derived from extracellular proteins
  • presented on HLA Class II molecules (HLA-DR, HLA-DP HLA-DQ)

– Immunoregulatory functions via cell:cell interactions and expression of cytokines

  • Provide help for development of full B cell response
  • Provide help for development of some CD8+ T cell responses
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17
Q

Describe the CD4+ T cell subsets.

A
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18
Q

What is the first place after the marrow where T cell maturation/selection can be affected?

A

In the thymus.

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19
Q

Describe DiGeorge syndrome.

A
  • Di George Syndrome (22q 11.2 deletion syndrome) – a development defect of the pharyngeal pouch:
  • Features – CATCH 22:
    • C Cardiac abnormalities (ToF / Teratology of Fallot)
    • A Abnormal facies (high forehead, low-set and folded ears, micrognathia, broad nasal bridge)
    • T Thymic aplasia (± oesophageal atresia)
    • C Cleft palate
    • H Hypocalcaemia, hypoparathyroidism
    • 22 22q 11.2
  • Detected by FISH cytogenetic analysis
  • Not mentally retarded but higher schizophrenia as an adult
  • Phenotype:
    • Normal B cell number
    • Reduced T cell number  only a mild impairment of immunity that improves with age
      • Could present with PCP pneumonia and atypical viral infections
      • Need T-cells to control these
    • Genetics:
      • Deletion at 22q11.2 (TUPLE locus)
      • TBX1 responsible for some features
      • Initially a sporadic mutation  autosomal dominant inheritance
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20
Q

What can go wrong in the selection of CD4+ T cells?

A

If you don’t express class II, cannot select CD4+ cells

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21
Q

Describe Bare lymphocyte syndrome (type 2)

A
  • Absent expression of MHC Class II molecules (BLS type 1 exists when MHC class 1 fails to express)
  • Defect in a regulatory protein involved in Class II gene expression
    • Regulatory factor X
    • Class II transactivator
    • Phenotype:
      • T-cells = low CD4 cells; normal CD8 cells
      • B-cells = normal; BUT low IgG or IgA antibody (due to lack of CD4+ T cell help)
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22
Q

Describe 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 infant death
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23
Q

What can go wrong in T cell activation and effector function?

A

Disorders of T cell effector function

  • Cytokine production – IFN
  • Cytokine receptors – IL12 receptor • Cytotoxicity
  • T-B cell communication
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24
Q

Summarise all the failures in T cells.

A
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25
Describe the Clinical features of T lymphocyte deficiencies
T cell deficiency – Viral infections • Cytomegalovirus – Fungal infection • Pneumocystis, Cryptosporidium – Some bacterial infections – esp intracellular organisms • Mycobacteria tuberculosis, Salmonella – Early malignancy
26
What are the Investigation of T cell deficiencies
* Total white cell count and differential * Remember that lymphocyte counts are normally much higher in children than in adults * Lymphocytesubsets * Quantify CD8 T cells, CD4 T cells as well as B cells and NK cells Immunoglobulins • IfCD4Tcelldeficient Functional tests of T cell activation and proliferation * Useful if signalling or activation defects are suspected * HIV test
27
What is this looking at
Each dot represents a cell In left: 59.62% CD4+ and 28.46% CD8+
28
Fill out.
Di George- may be subtle effect on IgG BLS - lack IgG - no isotype switch
29
How do you manage immunodeficiency involving T cells?
Aggressive prophylaxis/treatment of infection Haematopoieiticstemcelltransplantation – To replace abnormal populations in SCID – To replace abnormal cells - class II deficient APCs in BLS Enzymereplacementtherapy – PEG-ADA for ADA SCID Genetherapy – Stem cells treated ex-vivo with viral vectors containing missing components. Transduced cells have survival advantage in vivo. Thymictransplantation – To promote T cell differentiation in Di George syndrome – Cultured donor thymic tissue transplanted to quadriceps muscle
30
MENTI Severe recurrent infections from 3 months,CD4 and CD8 T cells absent, B cell present, Igs low. Normal facial features and cardiac echocardiogram * Bare lymphocyte syndrome type II * X-linked SCID * 22q 11.2 deletion syndrome * IFN gamma receptor deficiency
X-linked SCID
31
Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG * Bare lymphocyte syndrome type II * X-linked SCID * 22q 11.2 deletion syndrome * IFN gamma receptor deficiency
22q 11.2 deletion syndrome
32
Young adult with chronic infection with Mycobacterium marinum * Bare lymphocyte syndrome type II * X-linked SCID * 22q 11.2 deletion syndrome * IFN gamma receptor deficiency
IFN gamma receptor deficiency
33
6 month baby with two recent serious bacterial infections. T cells present – but only CD8+ population. B cells present. IgM present but IgG low * Bare lymphocyte syndrome type II * X-linked SCID * 22q 11.2 deletion syndrome * IFN gamma receptor deficiency
34
Describe B lymphocyte maturation
35
Describe B-cell central tolerance
36
What happens when there is an antigen encounter with a B cell? (T cell independent)
37
What happens when there is an antigen encounter with a B cell? (T-cell dependent)
38
Describe immunoglobulins.
• Soluble proteins made up of two heavy and two light chains – Heavy chain determines the antibody class * IgM,IgG,IgA,IgE,IgD, * subclasses of IgG and IgA also occur. – Antigen is recognised by the antigen binding regions (Fab) of both heavy and light chains – Effector function is determined by the constant region of the heavy chain (Fc)
39
Describe antibody function.
– Identification of pathogens and toxins (Fab mediated) – Interact with other components of immune response to remove pathogens (Fc mediated) * Complement * Phagocytes * Natural killer cells – Particularly important in defence against bacteria of all kinds
40
What goes wrong in the differentiation from Pre B cells to B cells.
![]() Bruton’s X-linked hypogammaglobulinaemia
41
Describe Bruton’s X-linked hypogammaglobulinaemia
• Abnormal B cell tyrosine kinase (BTK) gene Pre B cells cannot develop to mature B cells * AbsenceofmatureBcells * No circulating Ig after ~ 3 months
42
What is the Clinical phenotype of X linked agammaglobulinaemia?
Boys present in first few years of life Recurrent bacterial infections – Otitis media, sinusitis, pneumonia, osteomyelitis, septic arthritis, gastroenteritis Viral, fungal, parasitic infections – Enterovirus, Pneumocystis, Failure to thrive
43
What happens when B cells can't undergo a germinal centre reaction?
B cell maturation defect Hyper IgM syndrome (X-linked recessive)
44
What is the genetic mutation in Hyper IgM syndrome?
Mutation in CD40 ligand gene T cell CD28 (CD40L, CD154) – Member of TNF Receptor family – Encoded on Xq26 – Involved in T-B cell communication – Expressed by activated T cells – NOT on B cells
45
Describe Hyper IgM syndrome
Normal number circulating B cells Normal number of T cells but activated cells do not express CD40 ligand No germinal centre development within lymph nodes and spleen Failureofisotypeswitching ElevatedserumIgM Undetectable IgA, IgE, IgG
46
Describe the Clinical phenotype of hyper IgM syndrome
Boys present in first few years of life Recurrentinfections-bacterial Subtle abnormality in T cell function predisposes to Pneumocystis jiroveci infection, autoimmune disease and malignancy Failuretothrive
47
Describe Common variable immune deficiency
* Low IgG, IgA and IgE * Recurrent bacterial infections * Heterogenous group of disorders – Many different genetic defects – many unidentified – Failure of full differentiation/function of B lymphocytes • Defined by – Marked reduction in IgG, with low IgA or IgM – Poor/absent response to immunisation – Absence of other defined immunodeficiency
48
Describe the clinical features in Common variable immune deficiency
* Pneumonia, persistent sinusitis, gastroenteritis * Often with severe end-organ damage – Pulmonary disease • Interstitial lung disease • Granulomatous interstitial lung disease (also LN, spleen) • Obstructive airways disease – Gastrointestinal disease • Inflammatory bowel like disease * Sprue like illness * Bacterial overgrowth – Autoimmune disease • Autoimmune haemolytic anaemia or thrombocytopenia * Rheumatoid arthritis * Pernicious anaemia * Thyroiditis * Vitiligo – Malignancy • Non-Hodgkin lymphoma
49
Describe Selective IgA deficiency.
Prevalence = 1:600 2/3rd individuals asymptomatic 1/3rd have recurrent respiratory tract infections Genetic component, but cause as yet unknown
50
Summarise the B cell maturation defects.
51
Clinical features of B lymphocyte deficiencies
• Antibody deficiency (or CD4 T cell deficiency) – Bacterial infections • Staphylococcus, Streptococcus – Toxins • Tetanus, Diptheria – Some viral infections • Enterovirus
52
What are the Investigation of B cell deficiencies?
* Total white cell count and differential * Remember that lymphocyte counts are normally much higher in children than in adults * Lymphocytesubsets * Quantify B cells as well as CD4 T cells, CD8 T cells and NK cells * Serumimmunoglobulinsandproteinelectrophoresis• Production of IgG is surrogate marker for CD4 T cell helper function * Functional tests of B cell function Specific antibody responses to known pathogens/immunisations - measure IgG antibodies against tetanus, Haemophilus influenzae B and S. pneumoniae Ifspecificantibodylevelsarelow,immunisewiththeappropriatekilled vaccine and repeat antibody measurement 6–8 weeks later
53
Describe this.
Protein electrophoresis.
54
Fill out.
55
What is the mx of immunodeficiency involving B cells?
Aggressive prophylaxis / treatment of infection Immunoglobulin replacement if required – Derived from pooled plasma from thousands of donors – Contains IgG antibodies to a wide variety of common organisms – Aim of maintaining trough IgG levels within the normal range – Treatment is life-long • Immunisation – For selective IgA deficiency – Not otherwise effective because of defect in IgG antibody production
56
1 year old boy. Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent * IgA deficiency * Common variable immunodeficiency * Bruton’s X linked hypogammaglobulinaemia * X linked hyper IgM syndrome due to CD40ligand mutation
Bruton’s X linked hypogammaglobulinaemia
57
Recurrent bacterial infections in a child, episode of pneumocystis pneumonia, high IgM, absent IgA and IgG * IgA deficiency * Common variable immunodeficiency * Bruton’s X linked hypogammaglobulinaemia * X linked hyper IgM syndrome due to CD40ligand mutation
X linked hyper IgM syndrome due to CD40ligand mutation
58
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE * IgA deficiency * Common variable immunodeficiency * Bruton’s X linked hypogammaglobulinaemia * X linked hyper IgM syndrome due to CD40ligand mutation
Common variable immunodeficiency
59
Recurrent respiratory tract infections, absent IgA, normal IgM and IgG * IgA deficiency * Common variable immunodeficiency * Bruton’s X linked hypogammaglobulinaemia * X linked hyper IgM syndrome due to CD40ligand mutation
IgA deficiency
60
Summarise the Types of Primary Immunodeficiency.
61
Laboratory Tests for Primary Immunodeficiency
White cells Full blood count Lymphocyte subsets Special tests for white cell migration/function - Adhesion molecules – eg CD18 - Test for oxidative killing – DHR test Immunoglobulins IgM, IgG, IgA Specific Igs and response to vaccination Complement Complement function - CH50 and AP50 Individual complement components

Immunology (10 decks)

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