Fig. 1

Proteins screened in relation to pathways involved in pathogenesis of primary haemophagocytic lymphohistiocytosis (HLH). Cytotoxic T lymphocytes and natural killer cells contain specialized secretory lysosomes - cytotoxic granules, which upon contact with a target-cell degranulate. These granules contain perforin, a membrane-disrupting protein that facilitates the delivery of granzymes (proteases) that initiate apoptotic death in target-cells. If perforin is deficient, it is suggestive of a diagnosis of Familial HLH type 2. To check the degranulation process, we can artificially activate NK and CTL cells in the laboratory and measure using flow cytometry, a cell surface protein, CD107a (Granule Release Assay (GRA). If abnormal, it is an indirect marker of a host of proteins which may be involved in the degranulation process - for example in trafficking, docking, priming for exocytosis, or membrane fusion. An abnormal GRA may be suggestive of a diagnosis of familial HLH 3–5 or Griscelli, Chediak-Higashi or Hermansky-Pudlak. In boys there are two X-Linked conditions, which result in protein deficiencies which can be screened for; SLAM – Associated Protein (SAP) which is important in the killing of EBV infected cells – if deficient – suggestive of X linked Lymphoproliferative Disease ((XLP) type 1, and X Linked Inhibitor of Apoptosis Protein (XIAP) which if deficient – suggestive of XLP type 2. XLP X linked lymphoproliferative disease type 1, XLP2 X linked lymphoproliferative disease type 2, FHLH familial haemophagocytic lymphohistiocytosis, CTL cytotoxic T lymphocyte, NK natural killer