L16. Immunodeficiency diseases (Theme 1) Flashcards
define immunodeficient diseases
diseases that are opportunistic, unusual, Unusually severe,
protracted or not responding to standard therapy
, frequent
what is secondary immunodefiency
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
what is primary immunodefiency
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
what is the immunological classification of immunodefiency
human immune system- innate,adaptive-B cells and Tcells
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
side notes
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
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 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)
what are the causes of antibody deficiency
Physiological-
Transient hypogammaglobulinemia of infancy (see next slide)
Secondary- IgG loss: --Renal: nephrotic syndrome --Skin: extensive burns --Impaired production: Immunosuppressive drugs-target B cells
Primary
- X-Linked agammaglobulinemia
- X-Linked hyper-IgM syndrome
- (Common variable immunodeficiency – module 302)
- Many others that are beyond scope
describe the 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
what is XLA
a 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
study slide 13
what is 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
mechanism for X-Linked Hyper-IgM syndrome
production of high affinity IgG antibodies- after somatic hypermutation an class switch recombination
how do you treat antibody deficiency
Early recognition before lung damage occurs
Aggressive treatment of intercurrent infections
Replace immunoglobulin
Long-term suppressive anti-microbials
how is Cellular immunodeficiency caused
Poor terminology; 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
describe severe combined immunodeficiency
Rare, life-threatening primary immunodeficiency
Absent T cells
B cells may be present, but are non-functional
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)
what are the causes of severe combined immunodeficiency -SCID
Variety of molecular causes, only three considered this year:
- Common gamma chain deficiency
- JAK3 deficiency
- RAG1/2 deficiency
