TY - JOUR
T1 - A unique form of haptoglobin produced by murine hematopoietic cells supports B-cell survival, differentiation and immune response
AU - Huntoon, Kristin M.
AU - Russell, Lisa
AU - Tracy, Erin
AU - Barbour, Karen W.
AU - Li, Qingsheng
AU - Shrikant, Protul A.
AU - Berger, Franklin G.
AU - Garrett-Sinha, Lee Ann
AU - Baumann, Heinz
N1 - Funding Information:
This work was supported by the National Institute of Health grants DK033886 to HB, R01 CA104645 to PAS, R01 AI085127 to LG-S and P30CA16056 ( Roswell Park Cancer Institute's Cancer Center Support Grant) and by a Lupus Research Institute Grant to L.G.-S. We thank Dr. Yanping Wang for providing experimental resources to analyze expression of murine haptoglobin and for generating DC cultures; Dr. Kelvin Lee and Cheryl Rozanski for providing mouse DC cultures; Dr. Sandra Buitrago-Sexton and the staff of the animal facility at RPCI for animal care; Barbara Owczarczak for help in dissecting 100s of mouse spleens; and Dr. Paul Wallace and his team at the flow cytometry for assistance in cell analyses.
PY - 2013/10
Y1 - 2013/10
N2 - Haptoglobin (Hp), an acute phase reactant and major hemoglobin-binding protein, has a unique role in host immunity. Previously, we demonstrated that Hp-deficient C57BL/6J mice exhibit stunted development of mature T- and B-cells resulting in markedly lower levels of antigen-specific IgG. The current study identified leukocyte-derived pro-Hp as a relevant mediator of an optimal immune response. Reconstitution of Hp-/- mice with Hp+/+ bone marrow restored normal immune response to ovalbumin. Furthermore, transplanting a mixture of bone marrow-derived from B-cell-deficient and Hp-deficient mice into Rag1-/-/Hp+/+ recipients resulted in mice with a defective immune response similar to Hp-/- mice. This suggests that Hp generated by the B-cell compartment, rather than by the liver, is functionally contributing to a normal immune response. Leukocytes isolated from the spleen express Hp and release a non-proteolytically processed pro-Hp that uniquely differed from liver-derived Hp by not binding to hemoglobin. While addition of purified plasma Hp to cultured B-cells did not alter responses, pro-Hp isolated from splenocytes enhanced cellular proliferation and production of IgG. Collectively, the comparison of wild-type and Hp-deficient mice suggests a novel regulatory activity for lymphocyte-derived Hp, including Hp produced by B-cells themselves, that supports in vivo survival and functional differentiation of the B-cells to ensure an optimal immune response.
AB - Haptoglobin (Hp), an acute phase reactant and major hemoglobin-binding protein, has a unique role in host immunity. Previously, we demonstrated that Hp-deficient C57BL/6J mice exhibit stunted development of mature T- and B-cells resulting in markedly lower levels of antigen-specific IgG. The current study identified leukocyte-derived pro-Hp as a relevant mediator of an optimal immune response. Reconstitution of Hp-/- mice with Hp+/+ bone marrow restored normal immune response to ovalbumin. Furthermore, transplanting a mixture of bone marrow-derived from B-cell-deficient and Hp-deficient mice into Rag1-/-/Hp+/+ recipients resulted in mice with a defective immune response similar to Hp-/- mice. This suggests that Hp generated by the B-cell compartment, rather than by the liver, is functionally contributing to a normal immune response. Leukocytes isolated from the spleen express Hp and release a non-proteolytically processed pro-Hp that uniquely differed from liver-derived Hp by not binding to hemoglobin. While addition of purified plasma Hp to cultured B-cells did not alter responses, pro-Hp isolated from splenocytes enhanced cellular proliferation and production of IgG. Collectively, the comparison of wild-type and Hp-deficient mice suggests a novel regulatory activity for lymphocyte-derived Hp, including Hp produced by B-cells themselves, that supports in vivo survival and functional differentiation of the B-cells to ensure an optimal immune response.
KW - Acute phase response
KW - Immunoglobin production
KW - Inflammation
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U2 - 10.1016/j.molimm.2013.03.008
DO - 10.1016/j.molimm.2013.03.008
M3 - Article
C2 - 23548836
AN - SCOPUS:84877591387
SN - 0161-5890
VL - 55
SP - 345
EP - 354
JO - Molecular Immunology
JF - Molecular Immunology
IS - 3-4
ER -