International Immunology

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International Immunology, Vol. 11, No. 6, 995-1000, June 1999
© 1999 Japanese Society for Immunology

Requirement of IL-5 for induction of autoimmune hemolytic anemia in anti-red blood cell autoantibody transgenic mice

Toshio Sakiyama², Koichi Ikuta, Sazuku Nisitani³, Kiyoshi Takatsu¹ and Tasuku Honjo

Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Sakyo-ku, Yoshida, Kyoto 606-8501, Japan
¹ Department of Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan

Correspondence to: T. Honjo

	Abstract

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IL-5, IL-10 and lipopolysaccharide (LPS) are known to activate B-1 cells in vivo in normal mice and anti-red blood cell autoantibody transgenic mice (HL mice). To assess the exact role of IL-5 in proliferation and activation of peritoneal B-1 cells, we analyzed IL-5 receptor chain-deficient HL (IL-5R^–/– x HL) mice generated by the cross between IL-5R^–/– and HL mice. In IL-5R^–/– x HL mice, Ig-producing B-1 cells in the peritoneal cavity were negligible, although the total number of B-1 cells in the peritoneal cavity were as many as 30% of that in HL mice. Moreover, LPS- or IL-10-induced differentiation of B-1 cells into antibody-producing cells was severely impaired in IL-5R^–/– x HL mice. We also used in vivo 5-bromo-2'-deoxyuridine labeling to estimate the proliferation of B-1 cells in IL-5R^–/– mice. The absence of IL-5R did not affect spontaneous proliferation of peritoneal B-1 cells. However, induced proliferation of peritoreal B-1 cells by oral administration of LPS was markedly impaired in IL-5R^–/– mice. These results suggest that IL-5 is required for activation-associated proliferation of B-1 cells but not for their spontaneous proliferation and support the idea that IL-5 plays an important role on the induction of autoantibody production from B-1 cells.

Keywords: autoimmune hemolytic anemia, IL-5

	Introduction

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B-1 cells, a subpopulation of B cells, are suggested to be associated with autoimmune diseases because the number of B-1 cells is increased in certain autoimmune mouse strains (1). B-1 cells are distinguished from conventional B cells (B-2 cells) by several characteristics such as expression of surface antigens (i.e. CD5⁺, IgM^high, IgD^low, B220^low, Mac-1⁺ and CD23^–), a preferential localization in the peritoneal and pleural cavity, self-replenishing activity, production of autoantibodies, and contribution to mucosal immunity (2–5). Since B-1 cells in irradiated mice can be reconstituted by the transfer of fetal liver cells but not bone marrow cells, B-1 cells seem to have distinct progenitor cells from conventional B cells (6). In anti-red blood cell (RBC) autoantibody (H and L chains) transgenic mice (HL mice), peripheral B-2 cells are clonally deleted by spontaneous exposure to RBC but B-1 cells in the peritoneal cavity escape from clonal deletion and expand (7). Under conventional conditions, about one-half of the HL mice suffer from autoimmune hemolytic anemia, for which peritoneal B-1 cells are responsible because depletion of peritoneal B-1 cells by RBC injection cures autoimmune anemia in HL mice (8). However, no HL mice suffer from anemia under specific pathogen-free or germ-free conditions (9). We have found that autoimmune anemia can be induced by the change of breeding environments to conventional conditions or by oral administration of lipopolysaccharide (LPS) in HL mice (9,10). Taken together, enteric bacteria are suggested to activate peritoneal B-1 cells and to induce production of the autoantibody in HL mice.

IL-5 and IL-10 are mainly secreted by activated T_h2 cells and involved in activation of peritoneal B-1 cells because administration of IL-5 and IL-10 activated peritoneal B-1 cells and induced autoimmune anemia in HL mice (11). Since IL-5 receptor chain (IL-5R) is expressed in most peritoneal B-1 cells (12), IL-5 transgenic mice show a remarkable increase in the number of peritoneal B-1 cells, the levels of serum IgM, IgE and IgA, and in vivo production of polyreactive IgM autoantibodies against single-stranded DNA, double-stranded DNA, cardiolipin and TNP (13). On the other hand, IL-5R-deficient (IL-5R^–/–) mice showed a reduced number of peritoneal B-1 cells and lower serum concentrations of IgM and IgG3 (14). Therefore, IL-5 may be involved in various steps of peritoneal B-1 cell development, but the exact role of IL-5 at different stages of B-1 cell differentiation is not clear.

Here we report that anti-RBC Ig-producing B-1 cells are undetectable in the peritoneal cavity of IL-5R^–/–xHL mice, although they contain 30% of the peritoneal B-1 cells as compared with HL mice. In addition, LPS- or IL-10-induced differentiation of peritoneal B-1 cells into antibody-producing cells was strongly impaired in IL-5R^–/–xHL mice. Furthermore, B-1 cells in IL-5R^–/– mice showed a similar level of spontaneous proliferation to that in normal mice but their LPS-induced proliferation was severely impaired. Taken these results together, IL-5 plays an important role in differentiation and activation-associated proliferation of peritoneal B-1 cells but not in their spontaneous proliferation.

The influence of IL-5 on development and differentiation of B-1 cells into antibody-producing cells was investigated in IL-5R^–/–xHL mice generated by the cross between IL-5R^–/– and HL mice, because an overwhelming number of B-2 cells makes it difficult to examine the B-1 cell-derived antibody-producing cells in IL-5R^–/– mice. In HL mice, almost all B-2 cells are deleted by spontaneous exposure to RBC and the incidence of autoimmune anemia correlates well with the number of anti-RBC Ig-producing B-1 cells in the peritoneal cavity (7). In fact, almost all B cells in the spleen, bone marrow, lymph nodes and blood are deleted in IL-5R^–/–xHL mice (data not shown) as well as HL mice (7). In the peritoneal cavity of IL-5R^–/–xHL mice, almost all B cells were B-1 cells which lost the expression of surface IL-5R (data not shown). Both the total number and percentage of peritoneal B-1 cells in 8-week-old IL-5R^–/–xHL mice were significantly lower than those in HL mice (Table 1). By 13 weeks the number of peritoneal B-1 cells almost doubled in IL-5R^–/–xHL mice as reported previously in IL-5^–/– mice (14). By contrast, the number of peritoneal T cells was unaltered in IL-5R^–/–xHL mice as compared with that in HL mice (data not shown). These results suggested that IL-5 may not be essential but play some role in the development of peritoneal B-1 cells in HL mice.

View this table: [in this window] [in a new window]   Table 1. Reduction of peritoneal CD5+ B cells in IL-5R–/– x HL mice

 
We next examined the role of IL-5R in differentiation of B-1 cells into antibody-producing cells in IL-5R^–/–xHL mice. We collected peritoneal washout cells from 10-week-old IL-5R^–/–xHL mice and measured the number of anti-RBC Ig-producing cells by the ELISPOT assay. To our surprise, anti-RBC Ig-producing cells in the peritoneal cavity were undetectable in IL-5R^–/–xHL mice (Table 2), whereas they contained ~1.3x10⁵ peritoneal B-1 cells per mouse. The amount of anti-RBC antibody in the serum was also below the detectable level.

View this table: [in this window] [in a new window]   Table 2. LPS- or IL-10-induced anemia in IL-5R–/– x HL mice

 
In IL-5R^–/–xHL mice, however, we observed some increase in the number of anti-RBC Ig-producing cells and serum level of anti-RBC Ig after oral administration of LPS. But these increased values were still below the level of unstimulated HL mice (Table 2). The number of Ig-producing cells per B-1 cells in IL-5R^–/–xHL mice after LPS stimulation was one fifth of that in HL mice. Similarly, only a slight increase of anti-RBC Ig-producing cells was observed after IL-10 injection in IL-5R^–/–xHL mice. Neither LPS nor IL-10 increased the number of B-1 cells in IL-5R^–/–xHL as well as HL mice. By contrast, administration of LPS or IL-10 to HL mice induced a marked increase of anti-RBC-producing cells in the peritoneal cavity with reduction of hematocrit values as shown before (10,11). These data indicate that IL-5 plays an important role in LPS- or IL-10-induced differentiation of B-1 cells into antibody-producing cells in vivo. There may be another factor that can replace IL-5, albeit weakly, because LPS or IL-10 administration had weak responses in IL-5R^–/–xHL mice. This is in agreement with the observation that the number of peritoneal B-1 cells reaches almost the normal level in aged IL-5R^–/– mice (14).

To determine whether IL-5 is involved in proliferation of peritoneal B-1 cells in vivo, normal mice (C57BL/6) and IL-5R^–/– mice were fed with 5-bromo-2'-deoxyuridine (BrdU) water and their BrdU incorporation into peritoneal B-1 cells was compared. After 20 days of BrdU labeling, peritoneal cells were stained for IgM and CD5, or IgM and IgD, fixed and then stained for BrdU incorporation. In the peritoneal IgM⁺ cells of normal mice, the percentage of BrdU⁺ cells within IgM⁺ CD5⁺ B cells (4.2/[36.8 + 4.2] = 10.2%) was in good agreement with that of BrdU⁺ cells within IgM⁺ IgD^low B cells (4.7/[37.6 + 4.7] = 11.1%) (Fig. 1A). Subsequently, we examined the effect of LPS on B-1 cell turnover in normal mice. Since peritoneal B-1 cells were effectively activated by oral administration of LPS but not by systemic injection of LPS (10), BrdU and LPS were given to normal mice in drinking water. After 20 days of BrdU and LPS administration, the number of CD5⁺ B cells (3.83x10⁵) did not increase significantly as compared with that (3.60x10⁵) in unstimulated mice. However, the percentage (9.3/[35.7 + 9.3] = 20.7%) of BrdU⁺ IgM⁺ CD5⁺ B cells in the peritoneal IgM⁺ cells, which again agrees with that of BrdU⁺ IgM⁺ IgD^low peritoneal B cells, was almost twice as high as that in unstimulated mice, indicating that enteric LPS induced proliferation of peritoneal B-1 cells (Fig. 1A and B). The absence of increase in cell number despite of BrdU incorporation could be due to the loss of B-1 cells in the peritoneal cavity by differentiation and migration.

View larger version (69K): [in this window] [in a new window]   Fig. 1. In vivo BrdU incorporation by peritoneal B-1 cells of normal mice. (A) Flow cytometric analysis of peritoneal B cells of normal mice (C57BL/6) fed without BrdU (left), with BrdU (middle) or BrdU plus LPS (right) in drinking water. Mice were fed with BrdU (Sigma, St Louis, MO) at a concentration of 2 mg/ml or LPS at a concentration of 30 µg/ml in drinking water. Drinking water was protected from light during the experiment and was changed every 3 days. After 20 days of drinking, peritoneal washout cells were first stained for IgM, then for CD5 (upper) or IgD (lower). For simultaneous flow cytometric detection of cell surface markers and BrdU incorporation, we modified the published method (19); the Fix and Perm cell permeabilization kits (Caltag, Burlingame, CA) were used at the stage of cell fixation and permeabilization. After surface staining, cells were washed and resuspended in 100 µl of PBS. Cells were mixed with 100 µl of Reagent A (fixation medium) and incubated for 15 min at room temperature. After washing with PBS, cells were resuspended in 100 µl of Reagent B (permeabilization medium) and incubated for 15 min at room temperature. Cells were washed, then incubated in 100 µl of 0.15 M NaCl and 4.2 mM MgCl2 (pH 5.0) containing 100 Kunitz units DNase I (Takara Biomedicals, Tokyo, Japan) for 15 min at 37°C. After washing, cells were incubated with anti-BrdU–FITC (PharMingen) and analyzed by a FACSCalibur. Cells were gated for sIgM+ lymphocytes. Results of one representative mouse are shown. The percentages of cell numbers in each quadrant within sIgM+ lymphocytes are indicated. (B) Effect of enteric LPS on CD5+ and CD5– peritoneal B cells of normal mice. Peritoneal cells were isolated from normal mice without and with LPS administration (open and closed bars respectively). Percentages of BrdU labeling for IgM+ CD5+ and IgM+ CD5– B cells in the absence (or presence) of LPS were 10.7 ± 0.8% (19.7 ± 1.3%) and 9.7 ± 1.3% (10.4 ± 1.0%) respectively. Numbers (percentages) of CD5+ peritoneal B cells from normal mice without and with LPS drinking were 3.60 ± 0.86x105 (44.0 ± 8.9%) and 3.83 ± 0.62x105 (43.6 ± 7.5%) respectively. Data represent mean ± SD values from three mice. Statistical analysis was done by the t-test.

 
By contrast, enteric LPS did not alter the turnover of peritoneal B-2 cells (IgM⁺ CD5^– or IgM⁺ IgD^high B cells) (Fig. 1B), although peritoneal B-2 cells showed a similar level of BrdU incorporation in unstimulated mice to that of peritoneal B-1 cells as reported previously by others (15,16). It is worth noting that the level of BrdU incorporation into B-2 cells does not necessarily indicate their proliferation in the peritoneal cavity, because newly developed B-2 cells can migrate from bone marrow. Selective effects of enteric LPS on peritoneal B-1 cell proliferation was confirmed by analyzing BrdU labeling of B cells in Peyer's patches, mesenteric lymph nodes, spleen and peritoneal cavity of normal mice at different time intervals (Fig. 2). After 10 and 20 days of BrdU drinking, cell suspensions from these tissues were stained and analyzed as described above. BrdU labeling of B cells (mostly B-2 cells) from Peyer's patches, mesenteric lymph nodes or spleen was not augmented by oral administration of LPS. However, peritoneal B-1 but not B-2 cells increased BrdU labeling by oral administration of LPS (Figs 1B and 2). These results showed that enteric LPS selectively enhanced proliferation of peritoneal B-1 cells.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Appearance of BrdU-labeled IgM+ B cells in the peritoneal cavity, Peyer's patch, mesenteric lymph node and spleen during continuous administration of BrdU (open circle, dashed line) or BrdU plus LPS (closed circle, solid line). Mice and cells were treated and analyzed as described in Fig. 1. Peritoneal B cells were divided into two groups by expression of CD5. Vertical bars indicate mean ± SD.

 
Similar experiments were carried out in IL-5R^–/– mice to examine the role of IL-5 in B-1 cell proliferation (Fig. 3). The efficiencies of BrdU labeling of peritoneal B-1 and B-2 cells were similar in IL-5R^–/– mice. In addition, the efficiency of BrdU labeling of peritoneal B-1 cells was similar between normal and IL-5R^–/– mice (Figs 1 and 3), although the percentage (29.7 + 3.3 = 33%) of B-1 cells in the peritoneal B cells of IL-5R^–/– mice was slightly lower than that (36.8 + 4.2 = 41%) of normal mice. These results suggest that IL-5 may not be required for spontaneous proliferation of B-1 cells. On the other hand, the percentage of BrdU⁺ cells in the peritoneal B-1 cells was not augmented by oral administration of LPS in IL-5R^–/– mice (Fig. 3) in contrast to normal mice (Fig. 1). These data indicate that IL-5 is required for LPS-induced B-1 cell proliferation.

View larger version (61K): [in this window] [in a new window]   Fig. 3. In vivo BrdU incorporation into peritoneal B-1 cells of IL-5R–/– mice. (A) Flow cytometric analysis of peritoneal B cells of IL-5R–/– mice fed without BrdU (left), with BrdU (middle) or BrdU plus LPS (right) in drinking water. After 20 days of drinking, peritoneal washout cells were first stained for IgM, then for CD5 (upper) or IgD (lower), and fixed followed by nuclear staining for BrdU incorporation as described in Fig. 1. Cells were gated for sIgM+ lymphocytes. Results of one representative mouse are shown. The percentages of cell numbers in each quadrant within sIgM+ lymphocytes are indicated. (B) Effect of enteric LPS on CD5+ and CD5– peritoneal B cells of IL-5R–/– mice. Peritoneal cells were isolated from IL-5R–/– mice without and with LPS administration (open and closed bars respectively). Percentages of BrdU labeling for IgM+ CD5+ and IgM+ CD5– B cells in the absence (or presence) of LPS were 10.0 ± 1.4% (10.9 ± 1.2%) and 9.6 ± 0.9% (10.1 ± 1.1%) respectively. Numbers (percentages) of CD5+ peritoneal B cells from IL-5R/– mice without and with LPS drinking were 2.56 ± 0.38x105 (32.6 ± 4.8%) and 2.80 ± 0.64x105 (35.8 ± 7.2%) respectively. Data represent mean ± SD values from three mice. Statistical analysis was done by the t-test.

 
We have shown that IL-5 plays an important role in LPS-induced proliferation and differentiation of B-1 cells into antibody-producing cells. By contrast, IL-5 appears to be involved in but probably not required for spontaneous proliferation of B-1 cells because the number of B-1 cells in IL-5R^–/–xHL mice was reduced only to one-third of HL mice (Table 2). These results indicate that IL-5 regulates the terminal differentiation and proliferation of B-1 cells. Although we and others (17,18) have shown that IL-10 is involved in differentiation of peritoneal B-1 cells into antibody-producing cells, IL-10 stimulation did not fully support the differentiation of peritoneal B-1 cells into Ig-producing cells in IL-5R^–/–xHL mice. This suggests that oral LPS administration or enteric bacteria may first induce IL-10 secretion from macrophages or other cells and then this IL-10 may induce IL-5 secretion to activate B-1 cells expressing IL-5R. Thus, there can be hierarchy of cytokine action in the process of B-1 cell activation.

	Acknowledgments

 
We thank Dr H. Ishida for IL-10, Dr N. Watanabe for discussion, Ms Y. Kobayashi and T. Taniuchi for technical assistance, and Ms Y. Takahashi and T. Tanaka for preparing the manuscript. This work was supported by grants for the COE program from the Ministry of Education, Science, Sports and Culture of Japan and from the Deutsch Forschungsgeminshaft.

	Abbreviations

 

BrdU	5-bromo-2'-deoxyuridine
HL mice	anti-red blood cell autoantibody transgenic mice
IL-5R	IL-5 receptor chain
LPS	lipopolysaccharide
RBC	red blood cell

	Notes

 
² Present address: Kagoshima Medical Association Hospital, 7-1 Kamoikeshinmachi, Kagoshima 890-0064, Japan

³ Present address: Howard Hughes Medical Institute University of California, Los Angeles, 5-721 MRL, 675 Circle Drive South, Box 951662, Los Angeles, CA 90095-1662, USA

Transmitting editor: T. Watanabe

Received 25 January 1999, accepted 12 February 1999.

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Top Abstract Introduction References

 

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