VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells.

Haematopoietic stem cells (HSCs) home to the bone marrow via, in part, interactions with vascular cell adhesion molecule-1 (VCAM1)1-3. Once in the bone marrow, HSCs are vetted by perivascular phagocytes to ensure their self-integrity. Here we show that VCAM1 is also expressed on healthy HSCs and upregulated on leukaemic stem cells (LSCs), where it serves as a quality-control checkpoint for entry into bone marrow by providing 'don't-eat-me' stamping in the context of major histocompatibility complex class-I (MHC-I) presentation. Although haplotype-mismatched HSCs can engraft, Vcam1 deletion, in the setting of haplotype mismatch, leads to impaired haematopoietic recovery due to HSC clearance by mononuclear phagocytes. Mechanistically, VCAM1 'don't-eat-me' activity is regulated by ß2-microglobulin MHC presentation on HSCs and paired Ig-like receptor-B (PIR-B) on phagocytes. VCAM1 is also used by cancer cells to escape immune detection as its expression is upregulated in multiple cancers, including acute myeloid leukaemia (AML), where high expression associates with poor prognosis. In AML, VCAM1 promotes disease progression, whereas VCAM1 inhibition or deletion reduces leukaemia burden and extends survival. These results suggest that VCAM1 engagement regulates a critical immune-checkpoint gate in the bone marrow, and offers an alternative strategy to eliminate cancer cells via modulation of the innate immune tolerance.

A descriptive report of the variability in 3D hip and knee kinematics during a single limb squat in women who have patellofemoral pain and visually classified dynamic knee valgus.

Objective: To describe the variability in: (1) the contributions of 3D hip and knee kinematics to the dynamic knee valgus (DKV) movement pattern during a single limb squat in women with patellofemoral pain; and (2) the 3D strategies used to reduce DKV following an intervention.Methods: Secondary analysis of a feasibility study investigating a movement training intervention. In 23 participants, 2D knee frontal plane projection angles (FPPA) and 3D hip and knee frontal and transverse plane angles at peak knee flexion were calculated during a single limb squat at pre- and post-intervention, and the change in 2D and 3D angles computed. 3D angles at pre-intervention were summed for each participant to create cumulative bar graphs. Similar graphs were created for change in 3D angles. For visual comparison, graphs were ordered by increasing knee FPPA or change in knee FPPA.Results: The knee FPPA decreased from a mean of 7.2 degrees (SD: 7.1) to a mean of -8.9 degrees (SD: 8.9) following the intervention. A large portion of DKV, and change in DKV, was due to hip adduction and knee lateral rotation, yet participants with similar knee FPPA and change in knee FPPA displayed variation in all 3D components and change in 3D components.Conclusion: People who demonstrate similar observed movement patterns during a weight-bearing task may use different 3D strategies for execution.