Chronic idiopathic neutropenias and severe congenital neutropenia.
OBJECTIVE
Chronic idiopathic and severe congenital neutropenias are rare disorders for which recent discoveries have highlighted mechanisms and consequences.


RESULTS
An inflammatory bone marrow milieu has been shown to be a major contributor to the pathophysiology of chronic idiopathic neutropenia. Activated T-lymphocytes with myelosuppressive properties and pro-apoptotic mediators, such as IFNgamma, TNFalpha, Fas-ligand and TGFbeta1 result in accelerated apoptosis of granulocytic progenitor cells. Decreased levels of the anti-inflammatory cytokine IL-10 further disturb the balance between survival and pro-apoptotic mediators in chronic idiopathic neutropenia. Mutations in the HAX1 gene are associated with most cases of recessive autosomal severe congenital neutropenia, while ELA2 mutations are found in most cases of autosomal dominant and sporadic cases. The role of HAX-1 protein as a regulatory step in apoptosis provides further evidence for severe congenital neutropenia as a disorder of programmed cell death. The preleukemic character of severe congenital neutropenia, particularly for patients with need for high granulocyte colony stimulating factor dosage, was recently emphasized.


CONCLUSIONS
Chronic idiopathic (or as recent data suggest, immunologic) and severe congenital neutropenias provide intriguing models for better understanding of regulation of myelopoiesis. Similarities and differences between the two disorders might help to dissect these regulatory events.
Departments of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. jan.palmblad@ki.se
Jan
J
Palmblad
Helen A
HA
Papadaki
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001851:Bone Diseases, Metabolic / Q000209:etiology; D001853:Bone Marrow / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D002908:Chronic Disease; D018450:Disease Progression; D004198:Disease Susceptibility; D006801:Humans; D007239:Infections / Q000209:etiology; D007951:Leukemia, Myeloid / Q000209:etiology; D019272:Leukocyte Elastase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009190:Myelodysplastic Syndromes / Q000209:etiology; D009503:Neutropenia / Q000151:congenital / Q000209:etiology / Q000235:genetics / Q000473:pathology; D010024:Osteoporosis / Q000209:etiology; D011506:Proteins / Q000235:genetics / Q000502:physiology; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; D011506:Proteins; D012697:Serine Endopeptidases; C034869:medullasin; D019272:Leukocyte Elastase