Abstract：
:Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.
journal_name
Bloodjournal_title
Bloodauthors
Miller PG,Sperling AS,Gibson CJ,Viswanathan K,Castellano C,McConkey M,Ceremsak J,Taylor MS,Birndt S,Perner F,Arnason J,Agrawal M,Schram AM,Nikiforow S,Pihan G,Hasserjian RP,Aster JC,La Rosée P,Morgan EA,Berliner N,doi
10.1182/blood.2020008206subject
Has Abstractpub_date
2020-12-24 00:00:00pages
3051-3055issue
26eissn
0006-4971issn
1528-0020pii
463846journal_volume
136pub_type
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