Sanyal Ratna, Polyak Maria J, Zuccolo Jonathan, Puri Mandip, Deng Lili, Roberts Luc, Zuba Ania, Storek Jan, Luider Joanne M, Sundberg Ellen M, Mansoor Adnan, Baigorri Eva, Chu Michael P, Belch Andrew R, Pilarski Linda M, Deans Julie P
Department of Biochemistry and Molecular Biology, and Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Departments of Medicine and Oncology, University of Calgary, Calgary, Alberta, Canada.
Immunol Cell Biol. 2017 Aug;95(7):611-619. doi: 10.1038/icb.2017.18. Epub 2017 Mar 17.
MS4A4A is a member of the membrane-spanning, four domain family, subfamily A (MS4A) that includes CD20 (MS4A1), FcRβ (MS4A2) and Htm4 (MS4A3). Like the first three members of this family, transcription of MS4A4A appears to be limited to hematopoietic cells. To evaluate expression of the MS4A4A protein in hematopoietic cell lineages and subsets we generated monoclonal antibodies against extracellular epitopes for use in flow cytometry. In human peripheral blood we found that MS4A4A is expressed at the plasma membrane in monocytes but not in granulocytes or lymphocytes. In vitro differentiation of monocytes demonstrated that MS4A4A is expressed in immature but not activated dendritic cells, and in macrophages generated in the presence of interleukin-4 ('alternatively activated' or M2 macrophages) but not by interferon-γ and lipopolysaccharide ('classically' activated or M1 macrophages). MS4A4A was expressed in the U937 monocytic cell line only after differentiation. In normal bone marrow, MS4A4A was expressed in mature monocytes but was undetected, or detected at only a low level, in myeloid/monocytic precursors, as well as their malignant counterparts in patients with various subtypes of myeloid leukemia. Although MS4A4A was not expressed in healthy B lymphocytes, it was highly expressed in normal plasma cells, CD138+ cells from multiple myeloma patients, and bone marrow B cells from a patient with mantle cell lymphoma. These findings suggest immunotherapeutic potential for MS4A4A antibodies in targeting alternatively activated macrophages such as tumor-associated macrophages, and in the treatment of multiple myeloma and mantle cell lymphoma.
MS4A4A是跨膜四结构域家族A亚家族（MS4A）的成员，该家族包括CD20（MS4A1）、FcRβ（MS4A2）和Htm4（MS4A3）。与该家族的前三个成员一样，MS4A4A的转录似乎仅限于造血细胞。为了评估MS4A4A蛋白在造血细胞谱系和亚群中的表达，我们制备了针对细胞外表位的单克隆抗体，用于流式细胞术。在人类外周血中，我们发现MS4A4A在单核细胞膜上表达，但在粒细胞或淋巴细胞中不表达。单核细胞的体外分化表明，MS4A4A在未成熟但未活化的树突状细胞中表达，在白细胞介素-4存在下产生的巨噬细胞（“交替活化”或M2巨噬细胞）中表达，但在干扰素-γ和脂多糖（“经典”活化或M1巨噬细胞）存在下不表达。MS4A4A仅在分化后在U937单核细胞系中表达。在正常骨髓中，MS4A4A在成熟单核细胞中表达，但在髓系/单核细胞前体及其在各种亚型髓系白血病患者中的恶性对应物中未检测到或仅检测到低水平。尽管MS4A4A在健康B淋巴细胞中不表达，但在正常浆细胞、多发性骨髓瘤患者的CD138+细胞以及套细胞淋巴瘤患者的骨髓B细胞中高度表达。这些发现表明，MS4A4A抗体在靶向交替活化的巨噬细胞（如肿瘤相关巨噬细胞）以及治疗多发性骨髓瘤和套细胞淋巴瘤方面具有免疫治疗潜力。
