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Autoimmune NZB Mice (Immunoglobulin Genetics/Igd/Hematopoiesis/Colony-Stimulating Factors/Prostaglandins) PAUL W

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Autoimmune NZB Mice (Immunoglobulin Genetics/Igd/Hematopoiesis/Colony-Stimulating Factors/Prostaglandins) PAUL W Proc. Nati. Acad. Sci. USA Vol. 76, No. 7, pp. 3464-3468, July 1979 Immunology Abnormalities in clonable B lymphocytes and myeloid progenitors in autoimmune NZB mice (immunoglobulin genetics/IgD/hematopoiesis/colony-stimulating factors/prostaglandins) PAUL W. KINCADE, GRACE LEE, GABRIEL FERNANDES, MALCOLM A. S. MOORE, NEIL WILLIAMS, AND ROBERT A. GOOD Sloan-Kettering Institute for Cancer Research, 145 Boston Post Road, Rye, New York 10580 Contributed by Robert A. Good, April 6, 1979 ABSTRACT Cloning procedures were used to study B ability of precursor cells of NZB mice to form myeloid colonies lymphocytes and progenitors of granulocytes and macrophages in response to a particular stimulus in vitro. Both of these were in NZB mice. Numbers of B cells that were detected in sheep characteristic of young NZB mice of both sexes and were also erythrocyte-containing semisolid cultures were only slightly in F1 of NZB mice mated with elevated in NZB tissues, and these were normally sensitive to partially expressed progeny inhibition by anti-,u or anti-b antibodies or prostaglandin E. NZW or CBA strain mice. However, NZB mice rapidly developed large numbers of B cells that could be cloned in the presence of lipopolysaccharide, and MATERIALS AND METHODS these included unusual anti-,u resistant cells. Numbers of mye- loid precursors in NZB bone marrow that were responsive to Animals. Allotype congenic C57BL/6.Ige mice were donated colony-stimulating activity in L-cell conditioned medium or by Noel Warner. NZB/Umc, CBA/H, (NZB X NZW)FI, (NZB endotoxin serum were at least normal, but at all ages granulo- X CBA)F1, and NZW/Umc were all produced at Sloan-Ket- cyte-macrophage precursors were poor responders in cultures tering from breeding stock obtained from the University of stimulated by WEHI-3 cell conditioned medium. Almost no Minnesota. colonies were elicited in NZB cultures with a colony-stimulating Cell Cultures. McCoy's modified 5a medium containing 15% activity moiety from WEHI-3 cells. Prostaglandin sensitivity respect to as- of myeloid precursors from NZB and CBA mice was also dif- fetal calf serum and enriched with glutamine, ferent. Codominant genetic control of these abnormalities was paragine, serine, pyruvate, and amino acids was used for all suggested by their partial expression in F1 hybrid NZB X CBA semisolid agar cultures as described (12-15). B lymphocytes and NZB X NZW mice. NZB mice expressed an unexpected IgD were cloned in the presence of 50 ,gM 2-mercaptoethanol and allotype allele. either 25 jig of Salmonella typhosa endotoxin (lipopolysac- charide; LPS) per ml or 0.1% washed sheep erythrocytes Abnormalities have been found in or attributed to T cells, (SRBC). The importance of using LPS or SRBC for achieving thymic epithelium, B cells, macrophages, and stem cells in reproducible colony numbers and a linear dose-response curve autoimmune NZB mice, and they produce high levels of is discussed in previous reports (12, 14). Cultures were examined xenotropic virus (1-6). The relevance of each of these abnor- with a dissecting microscope for the presence of colonies (ag- malities to the development of the hemolytic anemia in these gregates of >20 cells) after 6 days of incubation at 370C in a mice is not clear, but genetic studies tend to minimize the role fully humidified atmosphere of 7% CO2 in air. Granulocytic of viruses and certain hemopoietic abnormalities in the etiology macrophage progenitors were similarly cloned in the absence of disease (5, 6). A possible temporal sequence is suggested by of 2-mercaptoethanol in cultures containing an appropriate findings that B cells of NZB mice are polyclonally activated by source of colony-stimulating activity (CSA). 1 week of age, and autoantibodies with preference for sup- Granulocyte-Macrophage CSA. Stimuli used for cloning pressor T cells are detectable early in adult life (7-10). A pri- neutrophil and macrophage colonies were concentrates of mary B-cell abnormality or defects that are expressed at the conditioned medium from WEHI-3 myelomonocytic leukemia B-cell level could thus predispose to subsequent aberrant T-cell cells (WEHI-3-M) and L cells (LCCM). Both cell lines were function. On the other hand, production of antierythrocyte propagated in 75-cm2 plastic flasks in McCoy's 5a medium autoantibody may occur in the absence of significant numbers containing 2.0% fetal calf serum and 50,uM 2-mercaptoethanol. of T cells, and potential for autoimmunity is transferrable with Medium was harvested at 3- to 4-day intervals and concentrated fetal liver or bone marrow cells from NZB mice (3, 11). Some 5-fold by Amicon (Lexington, MA) UM 10 ultrafiltration. gene products influencing manifestation of autoimmunity Serum-free medium conditioned by WEHI-3 cells for 3-4 days might therefore be expressed in pre-B cells, B cells, or non- was concentrated and equilibrated with 0.02 M Na phosphate lymphoid cells capable of activating B cells. Limiting dilution buffer, pH 8.0, and then passed through DEAE-Sephadex as cloning techniques are available for enumerating and charac- described (16). This material will be subsequently referred to terizing several hemopoietic precursors as well as lymphocytes, as semipurified WEHI-3 CSA. A fourth source of CSA was and we propose that these can be of value for identifying in- serum from CBA or NZB mice taken 3 hr after an intravenous trinsic defects in various cell types and for following changes injection of 5 ,ig of LPS endotoxin. Prostaglandin E (PGE) was in these with progression of disease. Thus far, we have found donated by John Pike (Upjohn), and this was stored at 1 mM in that particular culture conditions reveal an exceptional category ethanol at -70°C. of B lymphocytes in NZB lymphoid tissues, which, unlike B cells Anti-Immunoglobulin Antibodies. Anti-IgM antibodies from many other strains, proliferate in the presence of anti-ji were collected from goat anti-mouse myeloma M 104E (ji, X) antibody. In addition, a severe abnormality was detected in the serum on an absorbent of HPC-76 (ji, K) and rendered specific The publication costs of this article were defrayed in part by page Abbreviations: CSA, colony-stimulating activities; ES, serum from mice charge payment. This article must therefore be hereby marked "ad- injected with endotoxin; LCCM, medium conditioned by L cells; LPS, vertisement" in accordance with 18 U. S. C. §1734 solely to indicate lipopolysaccharide; PGE, prostaglandin E; SRBC, sheep erythrocytes; this fact. WEHI-3-M, medium conditioned by WEHI-3 cells. 3464 Downloaded by guest on September 28, 2021 Immunology: Kincade et al. Proc. Natl. Acad. Sci. USA 76 (1979) 3465 for it-chains by repeated passage over HOP-1 (y2a, A), UPC 10 lo" (QY2a, K), and MPC 11 ('Y2b, K) immunoabsorbents. Goat anti-K I antibodies were prepared by immunizing with F(ab')2 frag- c 6ea a, ments of MOPC-460 (a, K), eluting the resulting antibodies a, * a from the HPC 76 column, and then crossabsorbing on the HOP 'a 0 0o 1 column. Polyvalent anti-Ig antibodies from rabbit anti-TEPC 0 0 ~~8 183 (w, K) serum were eluted from a protein A-Sepharose CD e, (Pharmacia) absorbent. Ascites or serum from mice bearing the H6/31 anti-IgD allotype hybridoma (17) was purchased from Sera Labs (Crawley Down, Sussex, England). These reagents specifically lysed clonable B cells from C57BL/6J tissues at a 1:50 dilution in the presence of rabbit complement (1:12) and inhibited B-cell cloning when added directly to the cultures at a 1:200 final concentration. Under the same conditions, cloning Ca of NZB or C57BL/6.Ige B cells was not significantly inhibited. 0) 0o Two other anti-IgD hybridomas produced at Stanford (18) were obtained from the Salk Institute Cell Distribution Center and maintained in RPMI 1640 medium. Culture supernates from 5 10 15 20'25 30 354045 50 the 11-6.3 hybrid cell line inhibited B-cell colony formation Age, weeks from C57BL/6 but not A/J, CBA/H, NZB, or C57BL/6.Ige FIG. 1. Clonable B lymphocytes in NZB (e) and CBA/H (0) mice at a 1:100 final dilution in the cultures. The pH of the spleens in cultures potentiated with LPS. Colony-forming units per 10-4.2 culture supernates was increased to 8.6 with concentrated spleen were calculated by multiplying numbers of total nucleated cells Tris, and the supernates were passed through the protein A- per spleen times the average incidence of colonies in four replicate Sepharose column. Approximately 3 ,tg of protein per ml of cultures of 2 X 104 cells. culture fluid was eluted from the column with glycine.HCl buffer, pH 2.8, and this was neutralized, concentrated, and that NZB B cells were completely resistant to H-6/31 hybri- dialyzed. This preparation contained only murine IgG2a by doma anti-6 antibody, whereas colony growth of A/J B cells was Ouchterlony analysis and was subsequently referred to as pure inhibited. These strains have been found to share alleles at all 10-4.2 anti-6. It was not cytotoxic for B cells with our rabbit other immunoglobulin allotype loci (21). Furthermore, A/J B complement but inhibited cloning of B cells from NZB, cells do not express the IgD specificity detected by the 10-4.2 C57BL.Ige, and CBA/H mice when added directly to the cul- hybridoma antibody, whereas both NZB and normal allotype tures. B cells of both A/J and C57BL/6 strains are negative for congenic C57BL/6.Ige strain mice do. C57BL/6.Ige mice were this specificity. A broader discussion of the expression of IgD derived from mating of NZB and C57BL/6 strains with sub- allotype alleles will be presented elsewhere (J.
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