Wk 3 TBL Primary Immunodeficiencies Flashcards
What are 3 categories of adaptive IS immunodeficiencies?
- SCID
- B cell/antibody deficiencies
- T cell deficiencies
What are 2 types of SCID?
- X-linked
- autosomal
What are 3 B cell/Ab deficiencies?
- X-linked agammaglobulinemia
- Hyper-IgM syndrome
- Combined variable immunodeficiency (CVID)
What is an example of a T cell deficiency?
DiGeorge Syndrome
What is SCID?
simultaneous loss of B and T cell fxn
- can be absence of B cells, or B cells that can’t make Abs, absence of T cells, T cells that can’t make cytokines
- results in defects in early lymphocyte development
What are signs/ characteristics of SCID?
- susceptibility starts at birth
- unexpected severity, frequency
- opportunistic infections
- failure to thrive
- fatal if untreated
- stem cell transplant
- corrective gene therapy
What is special about IL-2, related to immunodef?
Activatd T cells express high affinity IL-2R w/ beta, alpha and gamma components on intracellular domain
-when bound to IL-2 -> clonal expansion
-not expressed on thymocytes except IL-2R-gamma, which is called the common gamma chain and is a shared component of multiple cytokine receptors (IL-2R, IL-4R, IL-7R, IL-15R, IL-21R)
-when binds IL-7 -> lyphoid commitment -> survival, proliferation, and differentiation
What happens in X-linked SCID?
Loss of IL-2R gamma -> impaired IL-7 signaling
-absence of T and NK cells
-B cell may be present or increased but can’t make Ig
What is the fxn of IL-2?
=common gamma chain
=shared component of multiple cytokine receptors
-critical for lymphoid survival, proliferation and differentiation
What is X-linked SCID?
=absence of IL-2gamma receptor
What is autosomal recessive SCID?
-can be induced by loss of or defects in adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) (scavenger molecules that clean up toxic metabolites and prevent them from killing lymphoid progenitors)
-> loss of B cells, T cells, NK cells
-progressive
OR
loss of Rag recombinase gene (AKA Omenn’s syndrome) - induces recombination of VDJ regions during lymphocyte development
-w/o it, no antigen receptor rearrangement
-> apoptosis during B or T cell development
-NK cell remain present
What are PNP and ADA?
=purine nucleoside phosphorylase
=adenosine deaminase
Both clear toxic metabolites from cells
-w/o them -> autosomal recessive SCID
What is Omenn’s syndrome?
mutations in RAG (recombination-activating gene) -> autosomal recessive SCID
What are 4 key features of antibody deficiencies?
- onset of disease susceptibility starts ~4-6 months after birth
- recurrent bacterial infections w/ unexpected frequency, severity, and complications
- common features: sinusitis, otitis, bronchitis, pneumonia
- can be susceptible to diseases even with vaccination
X-linked agammaglobulinemia
AKA Bruton’s Tyrosine deficiency
Btk gene on X-chromosome
-normal pre-B cell populations in BM, but unable to mature
X-linked agammaglobulinemia
AKA Bruton’s Tyrosine Kinase deficiency
- w/o Btk, there is no survival signal -> apoptosis of all developing B cells -> no Ig
- recurrent infections: sinusitis, otitis media, pneumonia
- chronic enteroviral meningoencephalitis
What is the fxn of Bruton’s tyrosine kinase?
Intracellular molecule that is induced in B cells after heavy chain of Ab is expressed on the surface (a successful heavy chain rearrangement, positive selection of developing B cell)
-mediates signal that promotes cell survival
What happens if the B cell heavy chain fails rearrangement?
apoptosis of developing B cell
-occurs in absence of successful heavy chain rearrangement b/c no Btk-mediated survival signal
What is Hyper-IgM syndrome?
X-linked antibody deficiency
-results from lack of CD40L on Th cells so cannot provide costimulatory signal to B cells ->
-> poor AID acticity -> defective affinity maturation and isotype switching
-> poor GC formation
-> high titers of IgM, low of others
-poor vaccine response
-neutropenia
-increased susceptibility to severe bacterial infection and opportunistic infections
-autosomal recessive versions too: deficiencies in CD40, AID
-give immunoglobulin therapy
What is a key illness associated w/ X-linked hyper IgM?
Pneumocystis jirovecii pneumonia
What is CVID?
=combined variable immunodeficiency
-can have later onset (2nd-3rd decade)
-10% result from defects in TACI
-variable defects in Ab production (can be decrease in one to absence of all isotypes)
-recurrent and chronic infections
What is TACI?
a receptor for B cell activation factor (BAFF)
-defective in 10% of CVID cases
What is IgA deficiency?
most common immunodeficiency
-80-90% asymptomatic
-recurrent infections, giardiasis
-may progress to CVID
-linked to increased risk of autoimmune disease
DiGeorge Syndrome
-22q11.2 chromosomal deletion
-partial or complete failure (aplasia) of thymic development
-partial -> some T cell defects, complete -> absence of T cells (~1% cases)
-hypoparathyroidism and hypocalcemia
congenital heart defects
-heterogeneous facial deformities, cleft palate, rounded jaw
-severe viral, fungal, mycobacterial infections
