16. Immunodeficiency diseases Flashcards
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
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
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
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)?
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
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
- Naive B cell with surface IgM
- Meets antigen in lymphoid tissue
- Somatic hypermutation and class switch recombination
- 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:
- Stem cells harvested from HLA-matched donor
- Given to recipient by infusion
- Engraft in bone marrow
- 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)
