Genetic Immunodeficiency Disorders Flashcards
When should you consider a PI?
severe- infection that requires hospitalization or IV antibiotics for infections
persistent- infection won’t completely clear up or clears very slowly
unusual- infection caused by uncommon organism or has an uncommon presentation (eg. flesh eating helicobactor)
recurrent- infection keeps coming back
runs in the family- others in the family have had a similar susceptibility to infection
How do PIs normally manifest in general?
atopy autoimmunity infection malignancy granulomatosis lymphoproliferation
What are the categories of immunodeficiency disorders?
antibody defects
combined/cellular defects
phagocyte immune defects
compliment defects
Name the discussed antibody production defects.
X-linked agammaglobulinemia (XLA)
Common Variable Immunodeficiency (CVID)
X-Linked Hyper IgM syndrome
Selective IgA deficiency
How do antibody production defects typically present?
sinopulmonary infections (recurrent sinusitis, otitis media, chest XR documented pneumonia, haemophilus, mycoplasma, pneumococcus)
GI infections/recurrent diarrhea (giardia)
meningitis/sepsis (enterovirus meningoencephalitis in XLA)
Describe XLA.
X-linked agammaglobulinemia
XLR inheritance (almost exclusively males) but de novo is possible
mutation in BTK genes result in no Bruton’s tyrosine kinase which blocks B-cell development –> near absence of B-cells and no antibody production
Describe CVID.
common variable immunodeficiency
most common symptomatic PI
umbrella term describing phenotype of reduced serum level of all kinds of Ig (G, M, and A) with decreased or absent specific antibody production
half only have infections but other half have infection and autoimmune/inflammatory complications (responsible for early death in patients)
many genes contribute (not all are B-cell related)
Describe X-Linked Hyper IgM syndrome.
problem with antibody class switching leading to low IgG, IgA, and IgE with normal to high IgM
more unusual infections compared to CVID or XLA
increased risk of lymphoma
AR forms possible
A1CDA or CD40LG genes associated
Describe Selective IgA deficiency.
common (1 in 500 caucasions)
most have no symptoms
some susceptibilities for respiratory or GI manifestations
increased risk for autoimmunity (RA, Lupis, etc.)
cause is unknown
How are antibody deficiencies treated?
Ig replacement
antibiotic prophylaxis
inflammatory complications/autoimmunity require careful use of immune suppression/modulation
future targeted therapy for known genetic defects (eg. Abetacept for CTLA4)
List the cellular/combined defects discussed.
Severe Combined Immunodeficiency Disease
Wiskott-Aldrich syndrome
What is SCID?
defects in 1+ cell line resulting in cytokine signaling, T-cell receptor signaling, VDJ recombination, or purine metabolism
most common is XL gammaC
many fatal first 2 years of life if not treated
early interventions key (avoid live vaccines, avoid breast feeding due to CMV risk, may need to admit to hospital)
treat with BMT early, ERT for ADA SCIDS, 3rd gen gene therapy
What is TREC detection?
NBS that looks for t-cell receptor excision circle which will be present in properly developed immune systems
requires follow-up with immunology for positive screen to confirm with lymphocyte screening
if one or more lymphocytes are low, genetics is important for treatment decisions
What is Wiskott-Aldrich syndrome?
presents with bacterial, viral, and fungal disease
eczema
small platelets (bruise easily)
XL (males only)
treat with prophylactic antibiotics, Ig replacement (if indicated), rituximab for autoimmune cytopenia
HCT is curative
Name the phagocyte immune defects discussed.
Chronic Granulomatous disease
Chediak-Higashi
