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FRI0613 H-ferritin and pro-inflammatory cytokines are increased in the bone marrow of adult patients affected by macrophage activation syndrome
  1. P Ruscitti1,
  2. P Cipriani1,
  3. F Ciccia2,
  4. P Di Benedetto1,
  5. AR Lizzi3,
  6. V Liakouli1,
  7. O Berardicurti1,
  8. F Carubbi1,
  9. G Guggino2,
  10. G D'Andrea3,
  11. G Triolo2,
  12. R Giacomelli1
  1. 1Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
  2. 2Division of Rheumatology, Department of Internal Medicine, University of Palermo, Palermo
  3. 3Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, Italy

Abstract

Background During macrophage activation syndrome (MAS), an inflammatory life-threatening syndrome, extremely high levels of serum ferritin may be observed [1]. Ferritin is an intracellular iron storage protein comprising 24 subunits that may be divided in heavy (H) subunits and light (L) subunits, based on their molecular weight [2]. The H-/L-subunits ratio may change, depending on the specific tissue and the physiologic status of the cell. In the normal condition, ferritin enriched in L subunits (L-ferritin) has been found in the liver and in the spleen, whereas the ferritin enriched in H subunits (H-ferritin), may be mainly observed in the heart and kidneys [2].

Objectives We investigated the tissue expression of both H-and L-ferritin as well as the macrophage subsets expressing these molecules, in the inflammatory BM infiltrate of MAS patients. In addition, the co-expression of IL-1β, TNF, IFN-γ and H- or L ferritin, within the inflammatory cells, was assessed. Finally, we explored if the imbalance between H-ferritin and L-ferritin as well as the number of ferritin positive cells may be considered helpful bio-markers to assess the severity of these patients.

Methods We analysed the bone marrow (BM) biopsies, by immunofluorescence of 10 adult MAS patients affected by rheumatic disease to assess the presence of: i. both H- and L-ferritin; ii. the number of CD68+/H-ferritin+ and CD68+/L-ferritin+; iii. the tissue pro-inflammatory cytokines, IL-1β, TNF, IFN-γ; and we correlated these data with clinical and laboratory data. Furthermore, the presence of ferritins was assessed in the sera of the same patients by western blot analysis.

Results We observed an increased tissue expression of H-ferritin and of pro-inflammatory cytokines (IL-1β, TNF, IFN-γ). Western blot analysis, in the sera, of H-ferritin mirrored data on the tissue. Furthermore, an increased number of CD68+/H-ferritin+ cells and an infiltrate of cells co-expressing H-ferritin and IL-12, suggesting an infiltrate of M1 macrophages, were observed.

Tissue H-ferritin levels correlated with the decreased counts of WBC (p=0.01) and PLT (p=0.0001); with the increased values of serum ferritin (p=0.012) and C-reactive protein (CRP) (p=0.0058); and with the tissue expression of IL-1β (p=0.006). The number of the CD68+/H-ferritin+ cells correlated with the decreased counts of WBC (p=0.03) and PLT (p=0.0007), and with the increased serum ferritin levels (p=0.0088) and CRP (p=0.049). The analyses concerning tissues L-ferritin as well as the number of CD68+/L-ferritin+ cells and the same parameters failed to show any significant result.

Conclusions We observed an increased tissue expression of H-ferritin associated with an increased expression of IL-1β. Interestingly, in the BM inflammatory infiltrate an increased number of CD68+/H-ferritin+ cells was shown. Of note, tissue expression of H-ferritin as well as the number of CD68+/H-ferritin+ significantly were associated with the hematological involvement of the disease, suggesting possible bio-markers to assess the severity of these patients.

References

  1. Ramos-Casals M, et al. Lancet. 2014;383:1503–16.

  2. Rosário C, et al. BMC Med. 2013;11:185.

References

Disclosure of Interest None declared

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