L16 Immunodeficiency diseases Flashcards
When are infections more likely to be significant
- Infections are verified rather than simply reported
- Organisms can be identified
- End-organ damage has occurred
General classification of immunodeficiency
- Secondary immunodeficiency
- Primary immunodeficiency syndrome (PID)
Features of secondary immunodeficiency
- Immune defect is secondary to another disease process
- Very common
- Extremes of age
- Malignancies (esp myeloma, lymphoma)
- Metabolic eg diabetes
- Drugs eg chemotherapy, steroids
- Infections eg HIV
Features of primary immunodeficiency syndrome (PID)
- 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
Human immune system –> 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)
Effect of CD4 T cell defects on B cells
- CD4 T cell defects affect B cells, as T cell help is needed for B cell maturation
- This is particularly marked in infants; less marked in adults, who have already matured their B cells
- Immunodeficiency syndromes affecting both antibody production and T cells are called combined immunodeficiencies
- In addition to infections, many immunodeficiency syndromes manifest with immune dysregulation: uncontrolled inflammation, autoimmune diseases
What is immunodeficiency predominantly caused by
- Predominantly antibody deficiency
- Low IgG; other isotypes may be affected, but low IgA/M with normal IgG is rarely significant
- Manifests with recurrent pyogenic infections of the upper and lower respiratory tract
- Sometimes gut infections in addition
- Infections typically respond to anti-microbials, but response may be sub-optimal and long courses required
- If untreated, leads to irreversible lung damage(bronchiectasis)
Physiological cause of antibody deficiency
Physiological:
- Transient hypogammaglobulinemia of infancy
Secondary cause of antibody deficiency
IgG loss:
- Renal (nephrotic syndrome)
- Skin (extensive burns)
Impaired production:
- Immunosuppressive drugs
Primary causes of antibody deficiency
- X-linked agammaglobulinemia
- X-linked hyper-IgM syndrome
- (Common variable immunodeficiency)
- Many others that are beyond scope
Maturation of antibody production
- In healthy infants, there is normally a period of relative antibody deficiency around 6 months known as ‘transient hypogammaglobulinemia of infancy; 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 - prototype antibody deficiency syndrome
- Signalling via bruton’s tyrosine kinase (btk) required for signal transduction at pro-B stage
- Maturation arrest occurs if absent: 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 and IgA, raised(or normal) IgM
- Recurrent bacterial infections
- The immunological lesion actually resides on the T cell (CD40 ligand, interaction with CD40 on B cells required for affinity maturation)
When does X-linked hyper IgM syndrome present usually
- Presents age 3-6 months
Production of high affinity IgG antibodies - X-linked hyper-IgM syndrome
Naive B cell, surface IgM –> meets antigen in lymphoid tissue –> somatic hypermutation and class-switch recombination –> high affinity IgG antibodies
Treating antibody deficiency
- Early recognition before lung damage occurs
- Aggressive treatment of intercurrent infections
- Replace immunoglobulin
- Long-term suppressive anti-microbials
Cellular immunodeficiency
Poor terminology; used to mean CD4 T cell deficiency
- When congenital, antibodies will also be affected (combined immunodeficiency)
What does cellular immunodeficiency manifest particularly with
- Opportunistic infection
- Viral infection
- Fungal infection
- Mycobacterial infection
What is a classic secondary cause of cellular immunodeficiency
- HIV infection
Severe combined immunodeficiency
- Rare, life-threatening primary immunodeficiency
- Absent T cells
- B cells may be present, but are non-functional
How does severe combined immunodeficiency 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
- 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 of which are required for T cell maturation
- Absent T cells
- B cells present but non-functional
JAK-3 deficiency
- Autosomal recessive SCID
- JAK-3 is downstream of common gamma chain; deficiency likewise prevents signalling
- Immunologically identical to gamma chain deficiency
RAG 1 and 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
What is DiGeorge syndrome caused by
- Failure migration 3rd/4th branchial arches
DiGeorge syndrome - full phenotype
- Absent parathyroids (low calcium, tetany)
- Cleft palate
- Congenital heart defects
- Thymic aplasia (low T cell numbers, immunodeficiency)
Where do most patients with DiGeorge syndrome have microdeletions
- Chromosome 22
DiGeorge syndrome - 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 suseptibility to neisseria species
- Otherwise immunologically robust
- Diagnose by functional complement assays
