Background/Purpose: To study the mechanism that leads to bone inflammation in a 4-year old patient of mixed Puerto Rican and African-American background who presented with sterile osteomyelitis (Majeed syndrome), that is caused by two novel compound heterozygous LPIN2 mutations.

Methods: Targeted genetic analysis for known autoinflammatory genes was performed that revealed Majeed syndrome and functional studies (stimulation assays and immune-histochemistry) on patient’s monocytes, monocyte-derived M1 (MDM1) and M2 (MDM2) macrophages (culture with GM-CSF or M-CSF respectively for 5 days) from the Majeed patient, patients with NOMID (n=3) and DIRA (n=4), and healthy controls (n=4) were conducted to assess IL-1 production and the production of other inflammatory cytokines and chemokines.

Results: The patient has a novel splice site mutation on one allele of LPIN2, that leads to a loss of exon 10 and 11, and a novel 16.0 Kb deletion on the other allele deleting exons 7-18 including a conserved residue that confers phosphatase activity. Treatment with IL-1 blocking treatment led to complete clinical remission. Functional studies from monocytes and MDM1 macrophages show increased LSP+ATP induced IL-1 production and increased upregulation of gasdermin D with increased cell death in MDM1s from the Majeed pt. similar to NOMID patients but higher than controls. In contrast, the Majeed pt’s MDM2 produced lower amounts of IL-10 than MDM2 from HC, NOMID and DIRA patients. However, unstimulated Majeed pt’s MDM2 spontaneously produced high levels of IL-8 and CCL2/MCP1 and LPS and ATP stimulated MDM2 macrophages from the Majeed pt. produced significantly higher levels of IL-6, TNF, IL-8 and other chemokines compared to MDM2s from healthy controls and NOMID patients. MDM2 from DIRA patients were more inflammatory than NOMID and HC but less than the Majeed pt’s MDM2s. Studies evaluating the effect of the LPIN2 mutations on osteoclast function are ongoing.

Conclusion: We report two novel loss-of-function mutations in LPIN2, in an American pt. of mixed racial background. The increase in caspase-1 activity and gasdermin D levels in the Majeed pt. are consistent with increased inflammasome activation in monocytes and MDM1s. However, the differentiation of Majeed monocytes into inflammatory MDM2 macrophages that express high levels of TNF, IL-6, IL-8 and chemokines known to activate osteoclasts distinguish the Majeed syndrome pt. from pts with GOF mutations in NLRP3 (causing cryopyrinopthies) and suggest a possible mechanism of sterile osteomyelitis by causing an inflammatory local bone environment that may prevent bone healing.

Acknowledgements: This work was supported by the NIH IRP of NIAID

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/majeed-syndrome-causing-lpin2-mutations-may-prevent-bone-healing-by-rendering-m2-macrophage-proinflammatory/