| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Regular Article |
a Department of Animal Development and Genetics, Uppsala University, SE-75236 Uppsala, Sweden
b Section of Medical Inflammation Research, Lund University, SE-22362 Lund, Sweden
c Department of Genetics and Pathology, Uppsala University Hospital, SE-75185 Uppsala, Sweden
d Genome Information Research Center, Osaka University, Osaka, Japan
ABSTRACT
It is well known that the transfer of immunoglobulins (Igs) from mother to young via milk contributes to the offspring's immune defense. The present study suggests that not only is IgG transmitted to progeny, but that functional maternal Ig-secreting cells (or B cells) can also be transferred to the neonate. We have used B cell-deficient (µ-/-) mice and found that a high proportion of them obtain long-lasting, partial reconstitution of their serum Ig levels if born to µ+/- mothers. In some of these serum IgG-positive µ-/- mice, Ig-secreting cells were detected in spleen and bone marrow. To ensure that cells of maternal origin were present in the progeny, µ-/- offspring born to µ+/- dams transgenic for green fluorescent protein (GFP) were used. In spleens and bone marrow from some of these µ-/-GFP-/- offspring, GFP-positive cells were detected, which demonstrated that cells of maternal origin could infiltrate the progeny. In addition, splenic Ig-secreting cells were detected in µ-/- mice that were born to µ-/- dams and transferred to a lactating µ+/+ foster dam at birth. This indicates that maternal Ig-secreting cells can be transferred postnatally via milk.
lactation, pregnancy, reproductive immunology
INTRODUCTION
As early as 1892, Paul Erlich used experimental mouse models to demonstrate that fetuses and neonates acquire protective immunity from their mothers, both in utero and postnatally, via milk [1]. During the 20th century, the area of maternal transmission of passive immunity has been extensively studied. It has been shown that it occurs in most mammalian species and involves a specific transport of immunoglobulin G (IgG) from mother to offspring. The route of and time point for antibody transport varies among different species [2], but in general, transport takes place either prenatally via the placenta or postnatally via milk. There are also species, such as mice and rats, in which some prenatal Ig-transport occurs, although most of the maternal antibodies are acquired from milk.
It is also well known that milk and colostrum from most mammalian species contain considerable numbers of viable maternal cells. Apart from a small proportion of epithelial cells, leukocytes such as macrophages and cells of the B and T cell lineage constitute the majority of the cells present in milk. In mice, the concentration of lymphoid cells in milk has been estimated to be about 106 cells/ml [3]. The significance of these milk leukocytes is not fully understood, although they are suggested to protect the gut lumen of the neonate.
We have previously studied the reproductive performance of B cell-deficient (µ-/-) mice [4]. These mice are unable to produce immunocompetent B cells or Ig-secreting cells due to a targeted mutation of the membrane exon of the IgM heavy chain [5]. During breeding of the µ-/- mice, it was observed that many of the offspring remained serum-IgG positive for a prolonged period when born to µ+/- mothers. This difference among the offspring occurred despite the fact that they were all of the same strain, were nursed by the same mothers, and in polymerase chain reaction (PCR)-screening, were shown to be µ-/-. Two possible explanations for the phenomenon described above present themselves: 1) the amount of IgG intake and half-life of ingested maternal IgG could differ considerably among individual mice, or 2) functional maternal cells of the B cell lineage might infiltrate some of the neonates, differentiate into IgG-secreting plasma cells, and continue to secrete considerable amounts of Igs over long periods of time.
During the development of B lineage cells, the expression of different surface molecules is altered. For instance, early B cell precursors (that are present also in µ-/- mice) do not express B220, while most later stages in B cell differentiation show expression of this surface molecule. During the terminal effector cell differentiation to plasma cells, however, there is a downregulation of the expression of almost all B cell-specific surface molecules that makes it difficult to detect these cells using conventional B cell antibodies.
In normal mice, the half-life of different IgG-isotypes has been reported to be in the range of 6–8 days [6], and several studies have suggested that the half-life of serum IgG is regulated by the major histocompatibility complex class I-related receptor, FcRn [7–9].
Some studies report that milk cells can traverse the gut epithelium in pigs [10], sheep [11, 12], rats [11], and mice [3]. It has also been shown that human milk leukocytes can infiltrate neonatal baboons [13]. The issue of transfer of milk cells in mice is, however, disputed in other studies [14–16]. Another possible route of transfer of maternal cells would be via the placenta, which has also been reported [17, 18].
This study focuses on the issue of whether a maternal transmission of functional B cells or plasma cells can occur. In order to evaluate this, we have analyzed a number of µ-/- offspring from heterozygous breedings (µ+/- x µ-/-), as well as µ-/- offspring from homozygous breedings(µ-/- x µ-/-) that were neonatally transferred to µ+/+ foster dams. We have focused on the detection of Ig-secreting cells in the spleens of serum IgG-positive µ-/- offspring and present results indicating that maternal Ig-secreting cells (or other cells of the B cell lineage) can be spontaneously transmitted to a proportion of the offspring.
MATERIALS AND METHODS
Animals
In the present study, B cell-deficient (µ-/-) mice and mice transgenic for green fluorescent protein (GFP) on NFR/N and C57BL background, as well as normal mice of both strains, were used. The outbred µ-/- mice that carry a targeted mutation in the membrane exon of the IgM heavy chain gene [5] were kindly provided by Dr. Werner Müller, Germany and were back-crossed against NFR/N for 10 generations. The GFP-positive mice harbor a transgene consisting of enhanced-GFP (EGFP) cDNA under the control of a chicken ß-actin promoter and cytomegalovirus enhancer as previously described [19]. The mice are now commercially available (The Jackson Laboratory, Bar Harbor, ME). The GFP-positive mice were back-crossed against µ-/- (NFR/N) for four generations in heterozygous breeding systems (µ+/-GFP+/- x µ-/-GFP-/-). A limited number of µ-/- and GFP+/- mice of the C57BL (B.10) strain were also investigated. The NFR/N strain mice were kept in the Animal Unit at the Department of Animal Development and Genetics, Uppsala University, Sweden, while mice of the B.10 strain were kept in the Animal Unit at the Section of Medical Inflammation Research, Lund University, Sweden. All mice had free access to water and rodent chow in a light- (12L:12D) and temperature- (22°C) controlled environment.
Polymerase Chain Reaction Screening
To identify the genotype of the Ig-positive individuals, the mice were screened as follows. DNA was prepared from tail biopsies as described by Laird et al. [20]. For PCR, 1 µl of the prepared DNA was used in a 30-µl reaction mixture containing 200 µM dNTPs (Finnzymes OY, Espoo, Finland), 0.5 µM of each primer, 0.6 U Dynazyme II DNA polymerase (Finnzymes OY), 50 mM KCl, 10 mM Tris-HCl (pH 8.8), 1.5 mM MgCl2, and 0.1% Triton X-100. The reactions were carried out for 30 cycles with a temperature profile of 2 min at 95°C, 2 min at 50°C, and 3 min at 72°C. The sequences of the primers used were: 5'-primer (MT100) = 5'-GTT CTG TGC CTC CGT CTA-3'; 3'-primer (MT2) = 5'-CCC CAC AAC CAT ACT ACC-3' After completion of the reaction, the products were separated by electrophoresis on agarose gels and detected by staining with ethidium bromide. The mutated allele gave a 1300-base pair (bp) amplified fragment and the wild-type allele a 260-bp fragment.
Cell Transplantation Procedure
Spleen cells from 4- to 5-mo-old donors were freshly prepared in PBS (pH 7.2) and adjusted to a cell concentration of 2, 20, or 200 x 106 mononuclear cells/ml. The cells were i.p. injected in a volume of 0.1 ml into 6-day-old µ-/- recipients from a µ-/- x µ-/- breeding.
Antibodies
The following antibodies were used for flow cytometry analysis: anti-B220 (RA3-6B2, biotinylated and fluorescein isothiocyanate-conjugated from Pharmingen, San Diego, CA and tricolor-conjugated from Caltag Laboratories, Burlingame, CA), anti-CD19 (1D3, phycoerythrin [PE]-conjugated, Pharmingen), anti-CD4 (RM4-5, biotinylated, Pharmingen), and anti-CD8 (53-6.7, biotinylated, Pharmingen). The concentration of the antibodies was 7.5 µg/ml in each case. Before staining with any of the abovementioned antibodies, the cells were incubated with an anti-CD16/CD32 antibody (2.4G2, Pharmingen) to prevent nonspecific Fc-receptor binding of the other antibodies.
The following antibodies were used for ELISA: goat antimouse IgG (U.S. Biochemicals, Cleveland, OH) and peroxidase-conjugated goat antimouse Ig (cat. no. A0412; Sigma Chemical Co., St. Louis, MO).
The following antibodies were used for enzyme-linked immunospot (ELISPOT) assay: goat antimouse IgG (U.S. Biochemicals) and peroxidase-conjugated goat antimouse Ig (Sigma no. A0412).
Enzyme-Linked Immunosorbent Assay
A sandwich ELISA was performed basically as described by Engvall [21] to determine serum IgG levels. In brief, goat antimouse IgG (U.S. Biochemicals) was coupled to immunoplates overnight. After coating with albumin (Sigma), various concentrations of purified IgG (Sigma), control sera, and test sera were added to the plate. The presence of IgG was visualized by peroxidase-conjugated goat antimouse IgG (Sigma). The color of the product was then measured in a spectrophotometer at 492 nm.
Enzyme-Linked Immunospot Assay
The number of IgG-secreting cells in spleens and bone marrow was determined by ELISPOT analysis. Nitrocellulose filter plates (Millititer HA, Bedford, MA) were soaked with PBS for 30 min. The plates were then coated overnight at 4°C with goat antimouse IgG, appropriately diluted in PBS. After five washes with PBS, the filters were blocked with 5% fetal calf serum (FCS) in PBS at 37°C for 30 min. Single-cell suspensions were prepared in 10 ml PBS (pH 7.2). After 10 min of sedimentation, followed by a wash in PBS, the cells were resuspended in RPMI medium supplemented with glutamine, 5% FCS, 2-mercaptoethanol (50 µM), penicillin, and streptomycin, and the cell concentration was adjusted to 2.5 x 105 or 10 x 106 cells/ml. The two dilutions of freshly isolated cells (100 µl) were added to the wells and incubated at 37°C in 5% CO2 atmosphere overnight. After nine washes with 0.05% Tween in PBS and one final wash with PBS, the filters were incubated for 2 h at room temperature with peroxidase-conjugated goat antimouse Ig. Spots were visualized by the precipitating substrate 3-amino-9-ethyl-carbazole (Sigma), counted under a light microscope, and expressed as spots per spleen or spots per femur. In the initial ELISPOT experiments, half of the cell suspensions were pretreated with the translation inhibitor cycloheximide (50 µg/ml) to exclude the possibility that spots in the assay were the result of passively released Fc-receptor-attached IgG molecules.
Flow Cytometry
Single-cell suspensions were prepared as for ELISPOT analysis, but instead of being resuspended in RPMI medium, cells were resuspended in PBS (pH 7.2) supplemented with 0.5% FCS and 0.05% NaN3 thatfrom now on will be referred to as fluorescence-activated cell sorter (FACS)-buffer. Cell concentration was adjusted to 10 x 106 cells/ml and 1 x 106 cells were incubated with fluorochrome-conjugated antibodies for 30 min. Following two washes in FACS-buffer, cells were resuspended in 1 ml FACS-buffer. In cases where biotinylated antibodies were used, cells were first incubated with the biotinylated antibody for 30 min, washed two times in FACS-buffer, and then incubated with fluorescein avidin D (Vector) or PE-streptavidin (Vector) for 30 min. After this, the cells were washed two times in FACS-buffer and finally resuspended. Cell suspensions were kept on ice during all incubations. Cells were preincubated with an anti-CD16/CD32 antibody to prevent nonspecific binding of antibodies to Fc receptors. A Becton-Dickinson Facscan with Cellquest 3.01 software was used for the flow cytometric analysis, and 1 x 104 or 1 x 105 cells were counted from each sample. Cells stained with an irrelevant antibody were used as the negative control. Additional positive and negative controls included in each experiment were spleen and bone marrow cells from normal (µ+/+) mice as well as from µ-/- mice originating from µ-/- x µ-/- breeding. Isotype-matched control antibodies did not change the very low levels of background staining.
Confocal Laser Scanning Microscopy
A confocal laser scanning microscope Leica TCS-SP (Leica Microsystems, Heidelberg, Germany) was used for detection of GFP+ cells in suspension, as well as in nonfixed cryosections (10 µm). For excitation of the GFP, the 488-nm line of an Ar laser was used and the GFP-specific fluorescence was detected in an emission window of 500–550 nm. Any autofluorescence present in the sample was detected by altering the emission window up to 700 nm and any cells displaying fluorescence in both in the shorter and longer wavelengths were disregarded. A transmission image of the sample was collected simultaneously with the fluorescence image and the two images were merged and subsequently mounted in Adobe Photoshop 5.0.2.
Statistical Analysis
Statistical differences in serum IgG levels in mice injected with different amounts of spleen cells and differences in results from flow cytometric analysis of spleen lymphocyte populations were tested using a two-tailed Mann-Whitney U-test (**P < 0.01; ***P < 0.001).
RESULTS
B-Cell-Deficient Mice Can Exhibit Serum-IgG and Splenic IgG-Secreting Cells
During breeding of NFR/N µ+/- females and µ-/- males, we found that some of the offspring that were µ-/- as determined by PCR (Fig. 1) were nevertheless positive for serum IgG at 3 mo of age (Table 1; nos. 1–4). These serum IgG-positive mice were further investigated by FACS analysis for B220+ cells (B cells). None of the mice had levels of splenic B220+ cells above the low background levels seen in serum IgG-negative µ-/- mice from µ-/- x µ-/- breeding (Table 1). Similarly, elevated levels of B220+ cells were not found in ascites fluid, para-aortic lymph nodes, bone marrow, or thymus, compared to the same µ-/- controls (not shown). Interestingly, however, one of the four serum IgG-positive mice harbored splenic IgG-secreting cells that were detectable in an ELISPOT assay (Table 1; no. 4).
|
|
We then wanted to investigate this phenomenon in older mice, and consequently, five µ-/- offspring born to µ+/- dams were analyzed for expression of CD19 on splenic lymphocytes, as well as for levels of serum IgG and number of IgG-secreting cells in spleen and bone marrow from femur (Table 1; nos. 5–9) at 18 wk of age. Four out of these five mice displayed detectable levels of serum IgG as well as IgG-secreting cells in both spleen and bone marrow, while one of them (Table 1; no. 6) had clearly detectable serum IgG levels, although IgG-secreting cells could not be detected in spleen and bone marrow. Despite this, splenic cells expressing CD19 (B cells) were not found in any of the mice (Table 1; no. 5–9).
To ensure that the abovementioned results were not NFR/N strain specific or dependent on the conventional animal house environment, the entire spleens of 9-mo-oldµ-/- mice of the C57BL-strain born to µ+/- dams in a specific pathogen-free environment were investigated by ELISPOT assay. These µ-/- offspring displayed 40–140 IgG-secreting cells per spleen, while µ-/- from µ-/- mothers did not have any detectable IgG-secreting cells. For comparison, the µ+/- control mice displayed 13 000–80 000 splenic IgG-secreting cells. This shows that the same pattern could be observed in another mouse strain and in a cleaner environment.
Because the addition of the translation inhibitor cycloheximide to the cell suspensions in the ELISPOT experiments decreased the appearance of spots by more than 70%, the possibility that spots in the assay were the result of passively released Fc-receptor-attached IgG molecules was excluded.
Maternal Lymphocytes Can Be Transmitted to the Offspring
To investigate directly the possibility that cells of maternal origin are transferred to the µ-/- offspring, female µ+/-GFP+/- mice were mated with µ-/- males. In 3 out of 11 resulting µ-/-GFP-/- offspring, GFP+ cells were detected using confocal scanning laser microscopy at a frequency estimated to 1 of 105 cells, in spleen and bone marrow up to 24 wk after birth (Fig. 2 and Table 2). Cells of maternal origin were, therefore, present in the offspring. In these mice, the same pattern as displayed by the other mice investigated was observed, i.e., no elevation of the number of splenic B220+ cells as compared to the µ-/- control (from µ-/- x µ-/- breeding), despite the presence of IgG-secreting cells (Table 2).
|
|
Splenic IgG-Secreting Cells Can Be Transferred to the Offspring via Milk
We then mated µ-/- females with µ-/- males and transferred 10 newborn µ-/- pups to a lactating µ+/+ foster mother of the same strain. At the age of 50 days, 7 of the 10 offspring had detectable levels of serum IgG (Table 3). In two of these, IgG-secreting cells were detected in the spleen by ELISPOT assay (Table 3; nos. 28 and 29). This suggests that at least some of the maternal IgG-secreting cells had been transferred postnatally, via the milk. Again, no increase in the B220+ cell population was detected (Table 3).
|
Adoptive Transfer of Adult Spleen Cells to Neonatal µ-/- Mice Mimics the Pattern Observed in µ-/- Mice Born to µ+/- Mothers
We then wanted to investigate whether adult cells entering the circulation of neonatal mice could give rise to the unexpected pattern of lack of detection of B220+ cells, despite detectable levels of serum-IgG and Ig-secreting cells. Neonatal µ-/- mice were, therefore, subjected to experimental transfer of spleen cells from adult µ+/+ donors. In a separate experiment, µ-/- neonates were injected with 0.2 x 106, 2 x 106, or 20 x 106 spleen cells to determine to what extent the number of cells administered could affect the serum IgG levels. The experiment showed that i.p. injection of 20 x 106 spleen cells caused a long-lasting normalization of serum-IgG levels (Fig. 3).
|
Five additional µ-/- neonates were then i.p. injected with 20 x 106 spleen cells, and at 3 mo of age all of them showed the presence of splenic IgG-secreting cells and four out of five had detectable serum IgG levels (Table 4 and Fig. 4c). As with the spontaneously transferred mice (Table 1 and Fig. 4d), none of these reconstituted mice had significant levels of B220+ spleen cells as compared to the B cell-deficient control (Table 4). The splenic proportions of CD4+ (28.2 ± 18.1%) and CD8+ (6.9 ± 4.1%) T cells in the mice subjected to adoptive transfer of spleen cells did not differ from that of the controls (CD4+: P = 0.387 when compared to µ-/- controls and P = 1.0 when compared to NFR/N [µ+/+] controls; CD8+: P = 0.053 when compared to µ-/- controls and P = 0.051 when compared to NFR/N [µ+/+] controls). In two of the recipients, the cell composition of ascites fluid, para-aortic lymph nodes, bone marrow, and thymus were investigated. None of these mice showed proportions of B220+ cells exceeding the background levels of B cell-deficient controls (data not shown).
|
|
In a similarly designed experiment, we subjected 6-day-old neonatal µ-/- mice to adoptive transfer of 20 x 106 spleen cells from adult µ+/+GFP+/- donors. Five weeks after transfer, the mice were sacrificed and the spleens were cryosectioned. Examination of the sections by confocal microscopy revealed that the transferred cells were more abundant in marginal zone regions of the spleen (Fig. 5). A scattered and more sparse distribution of GFP+ cells was observed in the red pulp as well as in the white pulp.
|
DISCUSSION
The present study demonstrates that maternal cells of the B cell lineage (Ig-secreting cells or their precursors) can be spontaneously transmitted to B cell-deficient offspring. The results also show that the maternal transmission of cells could occur via milk.
The question of whether spontaneous transmission of viable lymphocytes from mother to offspring can occur is considered to be controversial and the observation that functional maternal plasma cells can survive for several months in the offspring has not, to our knowledge, been reported previously. There are some reports, however, concerning transmission of maternal cells to neonates [17, 18, 22, 23], as well as transmission of fetal or placental cells to the mother [24–30], although most of these reports refer to species other than mice. In severely combined immunodeficient mice, however, it has been shown that xenotransplanted human B cells can be transmitted from mother to offspring [31].
Our results indicate that long-lived IgG-secreting plasma cells (or possibly a small number of precursor or memory B cells) could be spontaneously transmitted to the offspring and contribute to the maintenance of detectable levels of serum-IgG for several months. The difficulty of detecting a splenic B220+ or CD19+ B cell population in any of the ELISPOT-positive µ-/- mice born to µ+/- dams favors the view that it is actually long-lived plasma cells that are transmitted. In a recent publication, Slifka and coworkers have examined the issue of plasma cell longevity and estimate their life span to be more than 1 yr in mice [32]. In addition, a study on adoptive transfer of B cells in adult µ-/- mice shows that the majority of injected B cells die shortly after injection and that only 0.7–2.4% of the transferred B cells can be detected in the spleens and lymph nodes of the recipients 9 days after injection [33]. We assume, therefore, that it is long-lived plasma cells (and possibly a small number of memory B cells) that survive in the neonatal mice. Another observation that supports the likelihood that the cells transmitted are plasma cells or mature B cells, rather than precursor cells, is that adoptive transfer of spleen cells from old donors generally results in a more efficient plasma cell reconstitution than cells from young donors (data not shown).
The very low numbers of maternal cells found in some of the µ-/- offspring may explain why no clear-cut correlation between serum Ig levels and the number of ELISPOTs can be observed. It has been shown that one plasma cell can secrete 10 000 Ig molecules per second [34, 35]. This means that even very small numbers of plasma cells could produce amounts of serum IgG that are clearly detectable in an ELISA, although it could be extremely difficult to find the actual cells. In addition, it seems as though the Ig-secreting cells home to different lymphoid tissues in different individuals: in our experiments, Ig-secreting cells are found in spleen in some individuals and in bone marrow in others. It should also be pointed out that only a limited part of the total amount of lymphoid tissue in each mouse has been screened for presence of maternal cells. It is likely, therefore, that a higher proportion of the mice actually harbor maternal cells but in tissues other than those investigated.
It is worth noting that the very low numbers of Ig-secreting cells in the spontaneously transferred mice, make immunohistochemical detection of the cells difficult, particularly because the surface marker most commonly used for identification of plasma cells (CD138) would also be expected to be expressed by the endogenous pre-B cells [36]. It is also well known that flow cytometry is not normally sensitive enough to detect cells that appear at extremely low levels. This means that even though B220+ or CD19+ cells were not detected in µ-/- mice born to µ+/- mothers, we cannot exclude the possibility that maternally transmitted progenitor B cells or memory B cells (instead of terminally differentiated plasma cells) could have differentiated and eventually given rise to the observed phenomenon. It seems more likely, however, that plasma cells with their low antigenicity (due to the downregulation of surface antigens) could more easily survive in the neonate.
A transmission of immunocompetent maternal cells of the B cell lineage to the offspring could have an important physiological role to play, in the sense that the offspring would be provided with antibodies that would be most likely directed against common environmental pathogens, over a long period of time. If the neonate is immunodeprived or immunodeficient, such an antibody production might be essential for its survival.
The actual mechanism of maternal plasma cell and/or B cell infiltration in the offspring remains unknown. It appears that the maternal cells could be transferred postnatally via the milk, because a proportion of the offspring born to serum IgG-negative dams, but nursed by normal dams, displayed detectable numbers of splenic IgG-secreting cells (Table 3). One possibility could be a physiological mechanism of transmission, involving integrins or other cell-adhesion molecules that would allow some cells of maternal origin to penetrate and enter the fetal or neonatal circulatory system. It is also possible that parts of the reconstitution noted in some of the experiments (Tables 1 and 2) could be the result of transfer of cells over the placental barrier in utero or of loss of the placental barrier at birth. It cannot be excluded, however, that the transmission of cells via the milk is dependent on epithelial damage caused by gastric or intestinal inflammatory reactions, because the risk of pathogen-associated inflammatory reactions could be expected to be higher in immunodeficient mice as compared to normal mice. The fact that there is a considerable variation in IgG levels and number of Ig-secreting cells among the B cell-deficient pups may suggest that the transfer of maternal cells is accidental rather than physiological. It is of importance to note that the relevance of transfer of maternal Ig-secreting and/or B cells in normal mice remains unclear.
In µ-/- mice, the B cell and plasma cell compartments are not occupied by endogenously produced cells. The conditions for acceptance of transferred, long-lived cells of the B cell-lineage could, therefore, be expected to be more favorable than in normal mice, provided that immune reactions toward B cell-specific antigens are not evoked. A few normal offspring born to GFP+ dams were also investigated, but no GFP+ cells were detected in these individuals (data not shown). This does not necessarily mean that maternal cell transmission cannot occur in normal mice but implies that the frequency may be lower. It cannot be excluded, however, that the frequency of spontaneous transmission is the same in all mice, but that the destruction of transferred cells could be higher in phenotypically and immunologically normal mice.
It is of interest to note that the B cell-deficiency in the mice used as model animals is comparable with a certain type of agammaglobulinemia in humans that has been shown to be caused by a mutation in the IgM heavy chain gene [37]. The phenotype of individuals suffering from the disorder is identical to the phenotype of the B cell-deficient mice used in this study, i.e., in both cases, there is no detectable progression of B cell-differentiation beyond the pre-B cell stage, and consequently, there is profound hypogammaglobulinemia [5, 37]. It is tempting to speculate that the survival of these hypogammaglobulinemic babies is facilitated by spontaneous transmission of long-lived IgG-secreting plasma cells from the mother. Because the plasma cells are likely to produce antibodies against common environmental antigens, it could be expected that such a maternal cell transmission would be directly beneficial for the child.
The microchimerism that would be the result of a transfer of maternal cells to the offspring could perhaps be related to the immunopathogenesis of some autoimmune conditions. Systemic sclerosis is a disease of unknown origin with many clinical and histopathological similarities to chronic graft-versus-host disease. The disease often occurs in women after their childbearing years, and it has been suggested that fetal cells that persist in the maternal circulation for many years can give rise to a graft-versus-host disease [38, 39]. Because systemic sclerosis also occurs in women that have never been pregnant and in men, the possible role of a micropopulation of maternally derived cells would be interesting to investigate.
Although the mechanisms of maternal transmission of lymphocytes to the offspring are unknown, we believe that the findings in the present study provide new information that could be of significance in many fields of immunology and developmental biology.
ACKNOWLEDGMENTS
The authors thank Dr. Stefan Gunnarsson for help with images and confocal laser scanning microscopy, Mrs. Anita Mattsson for excellent technical assistance, and Dr. Gary Franklin for valuable criticism and language correction.
FOOTNOTES
1 This work was supported by King Gustaf V's 80-yr foundation, Alfred Östlund's, Helge Ax:son Johnson's, Hierta Retzius’, Lennander's, Magnus Bergvall's, G. & J. Kocks’, and Von Hofsten's Foundations, as well as by the Swedish Medical Research Council. 
2 Correspondence: Marie Arvola, Dept. of Animal Development and Genetics, Evolutionary Biology Centre, Norbyvägen 18A, S-752 36 Uppsala, Sweden. FAX: 46 18 4712683; marie.arvola{at}devbiol.uu.se
3 Current address: Section of Experimental Pathology, Lund University Hospital, SE-22362 Lund, Sweden.
Accepted: July 25, 2000.
Received: April 13, 2000.
REFERENCES
This article has been cited by other articles:
|
|
 |
|
  A M Stevens Microchimeric cells in systemic lupus erythematosus: targets or innocent bystanders? Lupus, November 1, 2006; 15(11): 820 - 826. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Kaplan and S. Land Influence of Maternal-Fetal Histocompatibility and MHC Zygosity on Maternal Microchimerism J. Immunol., June 1, 2005; 174(11): 7123 - 7128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Vernochet, S. M. Caucheteux, M.-C. Gendron, J. Wantyghem, and C. Kanellopoulos-Langevin Affinity-Dependent Alterations of Mouse B Cell Development by Noninherited Maternal Antigen Biol Reprod, February 1, 2005; 72(2): 460 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. HANSON, M. KOROTKOVA, S. LUNDIN, L. HAVERSEN, S.-A. SILFVERDAL, I. MATTSBY-BALTZER, B. STRANDVIK, and E. TELEMO The Transfer of Immunity from Mother to Child Ann. N.Y. Acad. Sci., April 1, 2003; 987(1): 199 - 206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Leithauser, Z. Trobonjaca, J. Reimann, and P. Moller In Situ Characterization of Genetically Targeted (Green Fluorescent) Single Cells and Their Microenvironment in an Adoptive Host Am. J. Pathol., June 1, 2001; 158(6): 1975 - 1983. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
