A Novel Role of Complement in Mobilization; Immunodeficient Mice are Poor G-Csf Mobilizers because they Lack Complement-Activating Immunoglobulins

¹ Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, USA
² Tumor Immunobiology Program, University of Louisville, Louisville, USA
³ Case Western University, Cleveland, OH
⁴ Department of Medicine, University of Alberta and CBS Edmonton, Alberta, Canada
⁵ Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, USA; Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland.

^* To whom correspondence should be addressed. E-mail: mzrata01{at}louisville.edu.

	Abstract

Complement (C) and innate immunity emerge as important and underappreciated modulators of mobilization of hematopoietic stem/progenitor cells (HSPC). We reported that i) C becomes activated in bone marrow (BM) during G-CSF-induced mobilization by the classical immunoglobulin (Ig)-dependent pathway, and that ii) C3 cleavage fragments increase the responsiveness of HSPC to an SDF-1 gradient. Since patients suffering from severe combined immunodeficiency (SCID) mobilize poorly, we hypothesized that this could be directly linked to the lack of C activating Ig in these patients. In the current study to better elucidate the role of C activation in HSPC mobilization, we mobilized mice that lack Ig (RAG2, SCID and Jh) by G-CSF or zymosan, compounds that that activate C by the classical Ig-dependent and the alternative Ig-independent pathways, respectively. In addition we evaluated mobilization in C5-deficient animals. Mobilization was evaluated by measuring the number of CFU-GM and leukocytes circulating in peripheral blood. We found that i) G-CSF- but not zymosan-induced mobilization, was severely reduced in RAG2, SCID and Jh mice, ii) impaired G-CSF-induced mobilization was restored after infusion of purified wild type Ig, and iii) mobilization was severely reduced in C5-deficient mice. These data provide strong evidence that the C system plays a pivotal role in mobilization of HSPC and that egress of HSPC from BM occurs as part of an immune response.

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