Granuloma Formation in a Cyba-Deficient Model of Chronic Granulomatous Disease Is Associated with Myeloid Hyperplasia and the Exhaustion of B-Cell Lineage

Abstract

Haematopoiesis is a paradigm of cell differentiation because of the wide variety and overwhelming number of mature blood cells produced daily. Under stress conditions, the organism must adapt to a boosted demand for blood cells. Chronic granulomatous disease (CGD) is a genetic disease caused by inactivating mutations that affect the phagocyte oxidase. Besides a defective innate immune system, CGD patients suffer from recurrent hyper-inflammation episodes, circumstances upon which they must face emergency haematopoiesis. The targeting of Cybb and Ncf1 genes have produced CGD animal models that are a useful surrogate when studying the pathophysiology and treatment of this disease. Here, we show that Cyba−/− mice spontaneously develop granuloma and, therefore, constitute a CGD animal model to complement the existing Cybb−/− and Ncf1−/− models. More importantly, we have analysed haematopoiesis in granuloma-bearing Cyba−/− mice. These animals showed a significant loss of weight, developed remarkable splenomegaly, bone marrow myeloid hyperplasia, and signs of anaemia. Haematological analyses showed a sharped decrease of B-cells and a striking development of myeloid cells in all compartments. Collectively, our results show that granuloma inflammatory lesions dramatically change haematopoiesis homeostasis. Consequently, we suggest that besides their defective innate immunity, the alteration of haematopoiesis homeostasis upon granuloma may contribute to the dismal outcome of CGD.

Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison

“…NADPH oxidases are present in all eukaryotic cells, and it is common to find several isoforms in each type of cell, a finding that strongly suggests an indispensable role in cellular biology. This is the case for HSC, which express different NAPDH oxidase isoforms ( 62 , 63 ), and recent reports support their relevance in the control of HSC biology and differentiation ( 64 – 66 ).…”

<i>Cyba</i> and <i>Nox2</i> mutant rats show different incidences of eosinophilia in the genetic background- and sex-dependent manner

“…Similarly, a Cyba mutant mouse strain exhibited the spontaneous formation of granulomas composed of macrophages in the lung and more intriguingly eosinophilic crystals in the organ [ 20 ]. Other Cyba mutant mouse strains showed a significant increase in CD11b + myeloid cells in peripheral blood and spleen [ 21 , 22 ]. However, blood eosinophilia was not observed in these Cyba mutant mice.…”