16. Immunodeficiency diseases Flashcards Preview

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Flashcards in 16. Immunodeficiency diseases Deck (26)
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1

How do you identify immunodeficiency?

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

2

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

3

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

4

Primary immunodeficiency

Immune defect is intrinsic to the immune system itself

Rare

Often genetic, but not always

Over 100 characterised PIDS

Mostly are fairly ‘new’ diseases

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

5

Immunological classification of immunodeficiency

Innate: Variety of manifestations – depends on problem

Adaptive:

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

    predominantly viral, fungal and mycobacterial infections

6

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

7

Combined immunodeficiencies

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

8

Immune dysregulation

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

9

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)

10

What can cause low antibodies (antibody defiency)?

Physiological

  • Transient hypogammaglobulinemia of infancy

Secondary

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

Primary

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

11

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

 

12

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

13

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

14

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

 

15

Treating antibody deficiency

Early recognition before lung damage occurs

Aggressive treatment of intercurrent infections

Replace immunoglobulin (passive immunity)

Long-term suppressive anti-microbials

16

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

17

Conditions seen in cellular immunodeficiency, particularly advanced HIV

18

Severe combined immunodeficiency

Rare, life-threatening primary immunodeficiency

Absent T cells

B cells may be present, but are non-functional

19

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)

20

Molecular causes of SCID

Variety of molecular causes, only three considered this year:

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

21

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

22

Jak3 deficiency

Autosomal recessive SCID

JAK-3 is downstream of common gamma chain

Deficiency prevents signalling

Immunologically identical to gamma chain deficiency

23

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

 

24

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

25

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

26

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)