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Genetic defects in the cytotoxic machinery of natural killer and\n                    <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>\n                    8\n                    <jats:sup>+<\/jats:sup>\n                    T cells underlie primary\n                    <jats:styled-content style=\"fixed-case\">HLH<\/jats:styled-content>\n                    , with residual cytotoxicity determining disease severity. Improved sequencing techniques have expanded the range of causal mutations and have redefined many cases of secondary\n                    <jats:styled-content style=\"fixed-case\">HLH<\/jats:styled-content>\n                    as primary\n                    <jats:styled-content style=\"fixed-case\">HLH<\/jats:styled-content>\n                    and vice versa, blurring the distinction between both subtypes. These insights allow\n                    <jats:styled-content style=\"fixed-case\">HLH<\/jats:styled-content>\n                    to be conceptualized as a threshold disease, in which interplay between various genetic and environmental factors causes progressive inflammation into a critical point, beyond which uncontrolled activation of immune cells and excessive cytokine production give rise to the cardinal symptoms of\n                    <jats:styled-content style=\"fixed-case\">HLH<\/jats:styled-content>\n                    . Various pathogenic pathways may thus converge to a common end stage of fulminant\n                    <jats:styled-content style=\"fixed-case\">HLH<\/jats:styled-content>\n                    .\n                  <\/jats:p>","DOI":"10.1111\/bjh.14147","type":"journal-article","created":{"date-parts":[[2016,6,5]],"date-time":"2016-06-05T23:06:41Z","timestamp":1465168001000},"page":"203-217","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":177,"title":["Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities"],"prefix":"10.1111","volume":"174","author":[{"given":"Ellen","family":"Brisse","sequence":"first","affiliation":[{"name":"Laboratory of Immunobiology Rega Institute KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine H.","family":"Wouters","sequence":"additional","affiliation":[{"name":"Laboratory of Paediatric Immunology KU Leuven University Hospital Gasthuisberg Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Matthys","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology Rega Institute KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,6,5]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"1414","article-title":"Haemophagocytic syndrome in rheumatic patients. 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