Neutrophil elastase in cyclic and severe congenital neutropenia

Abstract

Mutations in Neutrophils and monocytesNeutrophils (also known as "polymorphonuclear leukocytes" and "granulocytes") are terminally differentiated cellular components of the innate immune system that constitute about 35% to 75% of the population of peripheral leukocytes. 1 They kill bacterial and fungal pathogens through phagocytosis and are armed with an arsenal of proteases, antimicrobial peptides, and reactive oxygen species. 2 They also participate in the inflammatory response and produce cytokines, eicosanoids, and other signaling molecules. 3 Monocytes, constituting about 5% to 10% of peripheral leukocytes, are the circulating progenitors of tissue macrophages and dendritic cells and arise in the bone marrow from common myeloid progenitors shared with neutrophils. 4 "Neutropenia" refers to a deficiency in numbers of neutrophils. The normal neutrophil count fluctuates and varies across human populations and within individuals in response to stress and infection but typically well exceeds 1500/L 5 , and neutropenia is usually categorized as severe when the cell count is below 500/L. Common causes of neutropenia include cancer chemotherapy, autoimmune diseases, drug reactions, and hereditary disorders. 6 Among the latter, neutropenia may occur as one component of a number of inherited syndromes diversely featuring morphologic abnormalities of neutrophils, immunodeficiency, involvement of other lineages or pancytopenia, metabolic abnormalities, and systemic findings. This review, however, focuses on the 2 primary genetic forms of neutropenia: cyclic neutropenia (also known as "cyclic hematopoiesis") and the Kostmann syndrome of infantile agranulocytosis, more commonly referred to as "severe congenital neutropenia" (SCN), where mutations of the ELA2 gene, encoding the neutrophil granule serine protease, neutrophil elastase (NE), have proved to be the nearly exclusive or most common cause, respectively. Cyclic neutropeniaIn cyclic neutropenia, the peripheral-blood neutrophil and monocyte counts oscillate in opposite phase to one another with an average 21-day frequency. 6 Peak neutrophil counts tend toward somewhat subnormal values, although they can also be in the normal range. Infections, including aphthous stomatitis, periodontitis, and typhlitis, can arise during the nadir of the cycle, when the neutrophil count drops below 500/L and approaches zero. The infectious flora may differ from what is encountered with acquired neutropenia, suggesting a functional deficiency in neutrophils extending beyond that of low numbers. Cyclic neutropenia is transmitted by autosomal dominant genetics but, as with other often lethal dominant disorders, sporadic cases commonly arise from new germ line mutations. In a remarkable anecdote, a girl with the disease served as a hematopoietic stem cell donor for her sister, who did not have cyclic neutropenia but who was rather suffering from acute lymphoblastic leukemia 7 ; the bone marrow transplantation cured the sibling of leukemia, but it transferred cyclic hematopoiesis to her, ...

Ajuba Functions as a Histone Deacetylase-dependent Co-repressor for Autoregulation of the Growth Factor-independent-1 Transcription Factor

“…Severe congenital neutropenia (SCN) is characterized by a lack of neutrophils and subsequent recurrent bacterial and fungal infections (38). SCN is most commonly associated with mutations in elastase 2, neutrophil (ELA2), but mutations in GFI1, HAX1, and WAS have also been reported (39 -41).…”

The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

“…31 The precise mechanism by which the knockout phenotype is formed has not yet been revealed. Collectively, the information available suggests that the disruption of either AP-3, 15,16 serglycin, 31 or NE (by mutations in cyclic neutropenia) 41 may perturb intracellular NE trafficking, suggesting intricate sorting. In addition, our findings also suggest that CD63 is involved in proNE trafficking.…”

Current Diagnosis and Treatment Models of Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Lymphadenitis Syndrome

“…Cyclic neutropenic episodes occur every 18-24 days and the absolute neutrophil count falls below 500/mm 3 during the attack. Promyelocytic arrest is detected in the bone marrow, and attacks do not respond to steroid therapy (24). Many monogenic autoinflammatory diseases may emerge with regular attacks and mimic or coincide with PFAPA syndrome.…”

“…There are studies recommending a single dose of betamethasone (0.3 mg/kg) at the onset of fever as an alternative to this treatment (23). In some recent uncontrolled studies, low-dose (0.6 mg/ kg/g) prednisolone therapy has also been shown to improve the symptoms (24). The most frequently reported side effects of glucocorticoid therapy are restlessness and sleep disturbance.…”