XLP

Fig 1 highlights the differences in clinical presentation of XLP1 & XLP2

Fig 2 highlights the gene involved in XLP1. SH2D1A encodes a SLAM (Signaling Lymphocyte Activation Molecule) Associated Protein (SAP). SAP is a small SH2 containing Adaptor Protein which is expressed in T, NK cells & iNKT cells. SAP binds with very high affinity & Specificity to tyrosine based motifs located on the cytoplasmic domain of transmembrane proteins of SLAM family. SAP couples the SLAM family receptor to downstream molecules which may be activating or regulating signals.

multiple cellular defects have been documented, including altered CD8. T- and NK-cell cytotoxicity responses, CD4. T helper cell cytokine production and function, block of CD1d-restricted iNKT-cell development, defective antibody production associated with reduced numbers of switched memory B cells and defects in germinal center formation.

Fig 3 in XLP1 SAP deficiency affect both FYN dependent & FYN independent pathways. FYN dependent pathway affect Th2 Cytokine production, Natural Cytotoxicity & NKT cell development while FYN independent pathways affect T-B Conjugation, Germinal Center Formation and RICD (Reactivation induced cell death.

Fig 4 in XLP2 XIAP (X linked Inhibitor of Apoptosis) belong to family of inhibitors of apoptosis gene. It inhibits Caspases 3, 7 & 9.

XIAP is also involved in multiple signaling pathways, including copper metabolism, activation of the nuclear factor .B and the mitogen-activated protein kinases pathways and the transforming growth factor-.– receptor and bone morphogenetic protein–receptor signal transduction.

In XIAP-deficient patients, lymphocytes are characterized by an increased susceptibility to apoptosis in response to CD95 and tumor necrosis factor receptor–related apoptosis-inducing ligand receptor stimulation as well as enhanced activation-induced cell death (RICD). XIAP-deficient patients also display low but detectable numbers of iNKT cells in blood. some can have normal numbers of iNKT cells. NK cell–mediated cytotoxicity is apparently normal in XIAP-deficient

90% of XIAP deficiency present with HLH. Is XIAP deficiency an HLH causing disorder and whether it should be classified as HLH is being strongly considered.

Fig 5 ITK (Inducible T cell kinase) deficiency can also result in Lymphoproliferation. Mode of transmission is AR (Autosomal Recessive) Hence females are affected.