Syndromes

Question 1

DiGeorge Syndrome

Answer 1

DiGeorge Syndrome is due to a mutation on the TBX1 gene on chromosome 22q11.2

Mutation leads to ⇣thymic development (among other things) → ⇣expression of AIRE and peripheral tissue antigens → ⇣apoptosis of self-reactive T cells (negative selection) and ⇣levels of Treg cells → autoimmune conditions later in life

Most pts have significantly ⇣, but functional T cells and normal B and NK cell counts

Tx: thymic transplantation or T cell/stem cell transplantation w/ prophylactic antibiotics

Question 2

Ommen Syndrome

Answer 2

Ommen Syndrome is an autosomal recessive SCID that is caused by missense mutations in the RAG1 and/or RAG2 genes, rather than their complete inactivation.

RAG1/2 missense mutations → ⇣generation of T cells → ⇣maturation of mTECs → ⇣expression of AIRE → ⇣apoptosis of self-reactive T cells & loss Treg cells → auto-reactive T cells in the gut & skin → red rash & ⇡inflammation in the gut → villous atrophy → ⇣intestinal absorptive capacity → chronic watery diarrhea & failure to thrive

It is also characterized by:

• low IgG, IgA, & IgM; virtual absence of B cells
• Desquamation
• Alopecia
• Lymphadenopathy
• Eosinophilia
• Hepatosplenomegaly
• Patients are highly susceptible to fungal, bacterial, and fungal infections
• Tx w/ bone marrow or cord blood HSC transplant

There is a fully intact innate immune system

Question 3

X-linked SCID

Answer 3

• Deficiency of cytokine signaling by the IL-7 receptor and the IL-15 receptor → loss of T cell and NK cell development (respectively)
  
  • Other causes:
    
    • IL-2 receptor gamma gene mutation
      
      • fails to produce common gamma chain subunit (component of IL-Rs)
    • Adenosine deaminase deficiency
      
      • ADA substrates build up → toxicity of immune cells
      • Routinely tested for in babies
    • RAG gene mutations
• More severe deficiency (when compared to X-linked agammaglobulinemia) because most B cell responses are dependent upon helper T cell activity
  
  • ∴ all lymphocytes lack the ability to undergo clonal expansion
    
    • Both Phytohemaglutinin (PHA = T cell proliferation) and Pokeweed mitogen (PWM = T & B cell proliferation) assays are negative.
• Symptoms: ⇡ in all types of infections (viral, bacterial, protozoal, fungal)
• Tx: bone marrow transplant

Question 4

X-linked agammaglobulinemia

Answer 4

• Mutation in BCR-associated tyrosine kinase → no maturation of B cells (no development of plasma cells) → agammaglobulinemia with functional T cells
• Symptoms: recurrent viral infections; “early infections” (otitis media); more common in males
• Labs:
  
  • 0-low CD19+ lymphocytes
  • low/absent IgM/IgG/IgA/IgE
  • Phytohemaglutinin (PHA = T cell proliferation) assay will be normal
  • Pokeweed mitogen (PWM = T & B cell proliferation) assay will be intermediate (since T cells are okay).
• Tx: Infusions of gamma globulin

Question 5

APECED (Autoimmune polyendocrinopathy)

Answer 5

Associated with mutations in AIRE

Develop a lot of autoimmune conditions because without AIRE, there are **self-reactive **T cells

Treat w/ bone marrow transplant and IVIG