16. Immunodeficiency diseases

Question 1

How do you identify immunodeficiency?

Answer 1

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

Question 2

Definition of immunodeficiency?

Answer 2

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

Question 3

Secondary immunodeficency

Answer 3

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

Question 4

Primary immunodeficiency

Answer 4

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

Question 5

Immunological classification of immunodeficiency

Answer 5

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

Question 6

How do CD4 T cell defects affect B cells?

Answer 6

• 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

Question 7

Combined immunodeficiencies

Answer 7

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

Question 8

Immune dysregulation

Answer 8

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

Question 9

Predominantly antibody defiency

Answer 9

• 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)

Question 10

What can cause low antibodies (antibody defiency)?

Answer 10

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

Question 11

Maturity of antibody production and transient hypogammaglobulinaemia of infancy

Answer 11

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

Question 12

XLA - a prototype antibody deficiency syndrome

Answer 12

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

Question 13

X-linked hyper IgM syndrome (CD40L deficiency)

Answer 13

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

Question 14

Normal CD40L involvement in IgG antibody production

Answer 14

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

Question 15

Treating antibody deficiency

Answer 15

Early recognition before lung damage occurs

Aggressive treatment of intercurrent infections

Replace immunoglobulin (passive immunity)

Long-term suppressive anti-microbials

Question 16

Cellular immunodeficiency

Answer 16

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

Question 17

Conditions seen in cellular immunodeficiency, particularly advanced HIV

Answer 17

Question 18

Severe combined immunodeficiency

Answer 18

Rare, life-threatening primary immunodeficiency

Absent T cells

B cells may be present, but are non-functional

Question 19

How does SCID present?

Answer 19

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)

Question 20

Molecular causes of SCID

Answer 20

Variety of molecular causes, only three considered this year:

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

Question 21

Common gamma chain deficiency

Answer 21

• 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

Question 22

Jak3 deficiency

Answer 22

Autosomal recessive SCID

JAK-3 is downstream of common gamma chain

Deficiency prevents signalling

Immunologically identical to gamma chain deficiency

Question 23

RAG 1 & 2 deficiency

Answer 23

• 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

Question 24

SCID therapy

Answer 24

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

Question 25

DiGeorge Syndrome: another combined immunodefieicny syndrome

Answer 25

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

Question 26

Terminal complement deficiency

Answer 26

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)