16. Immunodeficiency diseases Flashcards Preview

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Flashcards in 16. Immunodeficiency diseases Deck (26)
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How do you identify immunodeficiency?

Get infections that are: opportunistic unusual unusually severe protracted or not responding to standard therapy frequent


Definition of immunodeficiency?

no definitive definition diagnosis is largely descriptive Infections more likely to be significant if........ -Infections are verified rather than simply reported -Organisms can be identified -End-organ damage has occurred


Secondary immunodeficency

Immune defect is secondary to another disease process

Very common

Extremes of age

Malignancies (esp myeloma, lymphoma)

Metabolic eg diabetes

Drugs eg chemotherapy, steroids

Infection eg HIV


Primary immunodeficiency

Immune defect is intrinsic to the immune system itself


Often genetic, but not always

Over 100 characterised PIDS

Mostly are fairly ‘new’ diseases

  • Fatal in pre-antibiotic era
  • Characterisation required developments in technology


Immunological classification of immunodeficiency

Innate: Variety of manifestations – depends on problem


  • B cells: Antibody-deficiency (or humoral immunodeficiency) predominantly bacterial infections of the respiratory tract
  • T cells:  Cellular immunodeficiency;

    predominantly viral, fungal and mycobacterial infections


How do CD4 T cell defects affect B cells?

•CD4 T cell defects affect B cells, as T cell help is need for B cell maturation

•This is particularly marked in infants; less marked in adults, who have already matured their B cells


Combined immunodeficiencies

•Immunodeficiency syndromes affecting both antibody production and T cells are called combined immunodeficiencies


Immune dysregulation

In addition to infections, many immunodeficiency syndromes manifest with immune dysregulation: uncontrolled inflammation, autoimmune diseases


Predominantly antibody defiency

  • Low IgG; other isotypes may be affected
  • Recurrent pyogenic URTIs and LRTIs
  • Sometimes gut infections too
  • Infections get better with anti-microbials, but response may be sub-optimal and long courses required
  • If untreated, leads to irreversible lung damage (bronchiectasis)


What can cause low antibodies (antibody defiency)?


  • Transient hypogammaglobulinemia of infancy


  • IgG loss:
    • Renal: nephrotic syndrome
    • Skin: extensive burns
  • Impaired production:
    • Immunosuppressive drugs


  • X-Linked agammaglobulinemia
  • X-Linked hyper-IgM syndrome
  • Many others that are beyond scope


Maturity of antibody production and transient hypogammaglobulinaemia of infancy

Transient hypogammaglobulinaemia of infancy: period of antibody deficiency at around 6 months, baby used up mum's IgG but hasn't made its own yet

this is a physiological state but can be correlated with increased infections

Infants with antibody deficiency usually present after 3-6 months; up until this time they are protected by maternal IgG antibody



XLA - a prototype antibody deficiency syndrome

Signalling via Bruton’s tyrosine kinase (btk) required for signal transduction at pro-B stage

If Btk absent, this results in maturation arrest:

  • no heavy chain rearrangement, no B cells leave marrow, no immunoglobulin production

•Disease is called X-linked agammaglobulinaemia (XLA); also known as Bruton’s disease, Btk deficiency or Bruton’s XLA


X-linked hyper IgM syndrome (CD40L deficiency)

Failure of B cell maturation from primary to secondary

Low IgG & IgA, raised (or normal) IgM

Recurrent bacterial infections

Presents age 3-6 months

The immunological lesion actually resides on the T cell

  • CD40 ligand (also known as CD154)
  • Interaction with CD40 on B cells required for affinity maturation


Normal CD40L involvement in IgG antibody production

  1. Naive B cell with surface IgM
  2. Meets antigen in lymphoid tissue
  3. Somatic hypermutation and class switch recombination
  4. High affinity IgG antibodies produced

This needs helper T cells, with CD40L on T cell to CD40 on B cell



Treating antibody deficiency

Early recognition before lung damage occurs

Aggressive treatment of intercurrent infections

Replace immunoglobulin (passive immunity)

Long-term suppressive anti-microbials


Cellular immunodeficiency

used to mean CD4 T cell deficiency

When congenital, antibodies will also be affected (combined immunodeficiency)

Manifests particularly with:

  • Opportunistic infection
  • Viral infection
  • Fungal infection
  • Mycobacterial infection

Classic secondary cause is HIV infection


Conditions seen in cellular immunodeficiency, particularly advanced HIV


Severe combined immunodeficiency

Rare, life-threatening primary immunodeficiency

Absent T cells

B cells may be present, but are non-functional


How does SCID present?

All basically present in a similar fashion

  • Usually soon after birth
  • Rash (graft versus host - maternal lymphocyte engraftment)
  • Failure to thrive
  • Chronic diarrhoea
  • Infections, especially opportunistic
    • Bacterial
    • Mycobacterial (esp BCG)
    • Viral (esp CMV, EBV)
    • Fungal (PCP, oral thrush)


Molecular causes of SCID

Variety of molecular causes, only three considered this year:

  • Common gamma chain deficiency
  • JAK3 deficiency
  • RAG1/2 deficiency


Common gamma chain deficiency

  • X-linked SCID
  • Common gamma chain forms part of membrane receptor for several cytokines, some are required for T cell maturation
  • Absent T cells
  • B cells present but non-functional


Jak3 deficiency

Autosomal recessive SCID

JAK-3 is downstream of common gamma chain

Deficiency prevents signalling

Immunologically identical to gamma chain deficiency


RAG 1 & 2 deficiency

  • An autosomal recessive form of SCID
  • RAG 1/2 required for somatic recombination events between V(D)J gene segments
  • No RAG1/2 means no T and B cell receptors



SCID therapy

Stem cell transplant:

  1. Stem cells harvested from HLA-matched donor
  2. Given to recipient by infusion
  3. Engraft in bone marrow
  4. Reconstitution of T and B cells

Also gene therapy: first condition to be successfully treated by gene therapy


DiGeorge Syndrome: another combined immunodefieicny syndrome

Failure migration 3th/ 4th branchial arches

Full phenotype:

  • Absent parathyroids (low calcium, tetany)
  • Cleft palate
  • Congenital heart defects
  • Thymic aplasia (low T cell numbers, immunodeficiency)

Most patients have microdeletions chromosome 22

Variable presentation

  • Huge spectrum of immunodeficiency from mild-SCID-like
  • Autoimmunity is also common
  • Patients with 22q11 microdeletions may have none of the above, all of the above and anything inbetween


Terminal complement deficiency

Deficiency of terminal complement components C5-C9

Leads to specific susceptibility to Neisseria species (meningitis and gonorrhoea)

Otherwise immunologically robust

Diagnose by functional complement assays (speak to your immunology laboratory)