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T-B+NK- SCID (JAK3 and γc)

Definition

SCID with absent T and NK cells due to defects in either γc or JAK3

Clinical background

T-B+NK- SCID present with opportunistic infections, recurrent infections and failure to thrive (1). The X linked SCID X1 is the most common cause of SCID. JAK3 SCID is autosomal recessive and much rarer (1). Most patients present in infancy; although several patients with hypomorhic mutations and reversions have been described who have presented later.

Immunologic background

gc and JAK3 are the shared component of the gc cytokine signal transduction pathways. Upon binding of cytokine, gc dimerises or trimerises with cytokine specific receptors. The aggregation of these receptor components, enables JAK3 and JAK1 to phosphorylate each other enabling them to then phosphosphorylate STAT molecules (Signal transducer and activator of transcription). Upon phosphorylation, STATs dimerise, translocte to the nucleus and activate gene transcription. gc cytokine signal transduction pathways include IL-2, IL-4, IL-7, IL-9, IL-15, IL-21. The immunophenotype observed (T-B+NK-) occurs because IL-7 cytokine signalling is required for T cell development and IL-15 cytokine signalling is required for NK cell development, but not B cell development (see below).

Animal models

gc SCID deficient mice show significant differences from human XSCID patients (2). Like humans they lack NK cells; however they have limited numbers of T cells and, unlike the human situation, they have decreased numbers of B cells, due to IL7 dependent early B cell differentiation in mice. JAK3 deficient mice are similar to gc deficient mice in that they have some T cells, lack NK cells and have greatly reduced B cell numbers. (3-5). The differences between the murine models and human suggests some species specific function of these genes or of the cytokines signalling through gc dependent receptors.

References

 

 

   1.   Ochs, H., Smith, C. I, E. and Puck, J. M. Primary Immunodeficiency: A molecular and Genetic Approach Oxford Univeristy Press 2007.

2. Cao X, Shois EW, Hu-Li J, et al Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. 1995 Immunity 2: 223-238

   3.   Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ. defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. 1995 Science 270: 797-797.

4. Noska T, van Deursen JM, Tripp RA et al. Defective lymphoid development in mice lacking Jak3. Science 1995 270: 800-802.

   5.   .Park SY, Saijo K, Osawa M et al. Developmental defects of lymphoid cells in Jak3 kinase deficient mice. 1995 Immunity 3:771-782.

 

Last update: 2009-12-07 11:25:10
Immunologic phenotypes (T-B+NK- SCID (JAK3 and γc))

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