16. immunodeficiency diseases Flashcards
what is meant by immunodeficiency?
no definitive definition infections are: opportunistic, unusual, unusually severe, protracted or not responding to standard therapy and frequent
secondary immunodeficiency
immune defect is secondary to another disease process
very common
causes of secondary immunodeficiency
extremes of age malignancies (esp myeloma, lymphoma) metabolic, eg diabetes drugs, eg chemotherapy, steroids infection, eg HIV
primary immuonodeficiency syndrome (PID)
immune defect is intrinsic to immune system itself
rare, often genetic
over 100 characterised
most are fairly ‘new’ - fatal pre-antibiotics
antibody deficiency
B cells affected
humoral immunodeficiency
predominately bacterial infections of respiratory tract
cellular immunodeficiency
T cells affected
predominately viral, fungal and mycobacterial infections
combined immunodeficiency
immunodeficiency syndromes affecting antibody production an dT cells
immune dysregulation
uncontrolled inflammation, autoimmune diseases
manifestation of many immunodeficiency syndromes (in addition of infection)
predominately antibody deficiency
low IgG - other isotopes may be affected
manifests with recurrent pyogenic infection of upper and lower respiratory tract
sometimes gut/skin infections too
infections rarely respond to antimicrobials - suboptimal/long course required
may lead to irreversible lung damage (bronchiectasis) is untreated
physiological cause of antibody deficiency
transient hypogammaglobulinaemia of infancy
secondary causes of antibody deficiency
IgG loss
- renal: nephrotic syndrome
- skin: extensive burns
impaired IgG production
- immunosuppressive drugs
primary causes of antibody deficiency
x-linked agammagloobulinaemia
x-linked hyper-IgM syndrome
+ many others
maturation of antibody production (infants)
normally a period of relative antibody deficiency
around 6 months
physiological state
= transient hypogammaglobulinaemia of infancy
infants with antibody deficiency usually present around 3-6 months (protected by maternal IgG until then)
XLA - X-linked agammaglobulinaemia
signalling via Bruton’s tyrosine kinase (btk) required for signal transduction at pro-B stage
maturation arrest occurs if no btk present
XLA - deficiency of btk
what happens in B cell maturation arrest?
no heavy chain rearrangements
no B cells leave marrow
no immunoglobulin production
X-linked hyper IgM syndrome
CD40L deficiency low IgG and IgA raised/normal IgM recurrent bacterial infections present age 3-6 months immunological lesion in T cell CD40L - no B cell cross linking, no affinity maturation
treating antibody deficiency
early recognition, before long damage occurs
aggressive treatment of intercurrent infections
replace immunoglobulin - passive immunisation
long term suppressive antimicrobials
cellular immunodeficiency
CD4 T cell deficiency
when congenital, antibodies also affected
classic secondary cause = HIV
cellular immunodeficiency manifestation
opportunistic infection
viral infection
fungal infection
mycobacterial infection
severe combined immunodeficiency (SCID)
rare, life threatening primary immunodeficiency
absent T cells
B cells may be present, but non-functional
SCID presentation
usually soon after birth
rash (GVH- maternal lymphocyte engraftment)
failure to thrive
chronic diarrhoea
infections - esp opportunistic
bacterial, mycobacterial (esp BCG), viral (CMV, EBV), fungal (PCP, oral thrush)
SCID molecular causes
common gamma chain deficiency
JAK-3 deficiency
RAG 1/2 deficiency
common gamma chain deficiency
X-linked SCID
common gamma chain forms part of membrane receptor for several cytokines (some 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 - also prevents signalling
immunologically identical to gamma chain deficiency
RAG 1/2 deficiency
autosomal recessive SCID
RAG 1/2 required for somatic recombination events between V(D)J segments
no T or B cell receptors
SCID therapy
stem cells harvested from HLA-matched donor given to recipient by infusion engraft in bone marrow reconstitution of T and B cells alternative = gene therapy
DiGeorge syndrome
failure of migration of 3rd/4th branchial arches
most patients have micro deletions on chromosome 22
can present with any isolated part of full phenotype
DiGeorge syndrome full phenotype
absent parathyroids (low calcium, tetany) cleft palate congenital heart defects thymic aplasia (low T cell numbers, immunodeficiency)
DiGeorge syndrome presentation
variable
huge spectrum fo immunodeficiency: from mild to SCID-like
autoimmunity is common
terminal complement deficiency
deficiency of terminal complement components (C5-C9)
susceptible to Neisseria species - esp meningitidis
otherwise immunologically orbust
diagnosis by functional complement assays
