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Experimental Biology and Medicine 230:128-134 (2005)
© 2005 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Blood Concentrations of Th2-Type Immunoglobulins Are Selectively Increased in Weanling Mice Subjected to Acute Malnutrition

Tirang R. Neyestani* and Bill Woodward{dagger},1

* Laboratory of Nutrition Research, National Institute of Nutrition Research and Food Technology, Shaheed-Beheshti University of Medical Sciences, Tehran, Iran; and {dagger} Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada

1To whom requests for reprints should be addressed at Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada. E-mail: wwoodwar{at}uoguelph.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Male and female C57BL/6J mice, initially 19 days old, consumed a complete purified diet either ad libitum (age-matched control) or in restricted daily quantities (energy deficiency), or they consumed a purified isocaloric low-protein diet ad libitum (protein and energy deficit). In a 14-day experimental period, malnourished animals lost approximately 1.5% of their initial body weight daily. Zero-time controls, 19 days old, were also included in the study. Serum levels of Th2-type (IgG1 and IgE) and Th1-type (IgG2a and IgG3) immunoglobulins were quantified by enzyme-linked immunosorbent assay, and total IgG concentration was also assessed. Both malnourished groups exhibited high serum concentrations of IgG1 and IgE relative to the age-matched control group, whereas levels of the Th1-type immunoglobulins were unaffected. Total IgG concentration in the malnourished groups reflected the usual finding in humans (i.e., no effect or elevated). The results are consistent with the proposition of Th2-polarized immune competence in acute weanling deficiencies of energy, protein, or both.

Key Words: energy deficiency • protein deficiency • immunoglobulin • blood • mice


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Acute (i.e., wasting) prepubescent deficits of protein, energy, or both consistently produce a profound depression in acquired cell-mediated immune competence, whereas humoral competence is less predictably affected (1). This well-established observation may find some basis in the capacity to produce cytokines that regulate acquired immune competence. Broadly, Th1-type cytokines promote cell-mediated immune responses and the production of opsonizing and complement-fixing subclasses of IgG antibody that support this type of response (2), which is designed for defense against intracellular pathogens (3). By contrast, Th2-type cytokines promote production of antibodies whose main function is to provide protection in the extracellular space (3, 4). Interferon-{gamma} is the signature Th1-type cytokine and serves to polarize acquired immune responses in a cell-mediated direction (3, 5). Th2-type cytokines include interleukins (ILs) -4, -5, -6, -10, and -13. IL-4 is regarded as the primary polarizing cytokine of this group (3, 5).

The capacity of T cells to produce interferon-{gamma} is consistently depressed in rodent models of acute protein and energy deficit (1). Moreover, T cells from acutely malnourished rodents have exhibited a depressed capacity to produce interferon-{gamma} in response to antigen (6) and a polyclonal mitogen (7), while IL-4 production remained unaffected. Similarly, a Th2 shift was apparent when IL-4 and interferon-{gamma} production were assessed in vitro in mitogen-stimulated blood (i.e., recirculating) T cells from patients with rheumatoid arthritis subjected to a short-term fast (8). It is also of interest that a profoundly elevated blood IL-4 concentration is reported in a cohort of children situated below the 10th percentile of weight for age (9). Moreover, a high concentration of IL-10 has been found in the blood of weanling mice subjected to acute deficits of protein, energy, or both, according to protocols that mimic incipient kwashiorkor and marasmus (10).

On the basis of the foregoing line of argument, it has been proposed recently that the immune depression associated with acute deficits of protein and energy reflects a Th2-polarized immune competence (i.e., a regulated pathophysiology rather than a biologically trivial disintegrative phenomenon; Ref. 10). Independent evidence downstream of cytokine production and levels is desirable in connection with this model and, inasmuch as Th1- and Th2-type cytokines are key regulators of immunoglobulin class switching (4), the blood immunoglobulin profile is relevant for this purpose. In particular, it has been established for many years that the blood concentration of IgE class antibody is high in acutely malnourished children (11), and this characteristic appears independent of intestinal worm infestation (9). IgE is a quintessential Th2-type immunoglobulin in humans and mice (2). Likewise, IgG1 is a Th2-supported subclass in the mouse, whereas IgG2a and IgG3 are selectively promoted by interferon-{gamma} in this species (4). The objective of this investigation was to determine whether the blood IgE and IgG subclass profiles of weanling mice subjected to pathologies mimicking either marasmus or incipient kwashiorkor would prove consistent with the Th1/Th2 imbalance model of immune depression in acute malnutrition.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and Facilities.
Male and female C57BL/6J mice were used from an in-house breeding colony derived from animals purchased several years earlier from the Jackson Laboratory (Bar Harbor, ME). This colony is maintained under conventional conditions, but incoming air is filtered, each cage is supplied with a filter lid, and positive pressure is maintained relative to the adjoining corridor. According to periodic analysis of sentinel mice maintained in cages without filter lids, the colony is free of common viral pathogens as well as Mycoplasma pulmonis and intestinal parasites. Caging and housing conditions were exactly those as described previously (12–15), and the investigation was approved by the Animal Care Committee of the University of Guelph in accordance with the guidelines of the Canadian Council on Animal Care.

Diets, Feeding Protocols, and Experimental Design.
Mice were weaned at 18 days of age and acclimated for 1 day with free access to the complete purified diet described elsewhere (16). A typical proximate analysis for this diet is 92.3% dry matter, 18.8% crude protein, 8.1% ether extract, 2.6% ash, 3.1% crude fiber, and 17.0 kJ/g gross energy (13). At 19 days of age, each mouse was randomly allocated to one of four experimental groups; namely, an age-matched control group that consumed the complete diet ad libitum, a group that consumed the complete diet in restricted daily quantities, a group that was given free access to a low-protein purified diet, and a zero-time control group (the latter was examined at 19 days of age to permit discrimination between diet- and ontogeny-related phenomena). The quantity of diet given to mice in the restricted intake group was calculated daily as described previously by this laboratory (12) with a view to achieving a loss of 1.5%–2% of initial body weight per day for the 14-day experimental period. As described elsewhere (13, 15), the purified low-protein diet contained 0.6% crude protein (as fed) and was prepared by replacing most of the egg white (80% crude protein; U.S. Biochemical, Cleveland, OH) of the complete diet with an equal weight of cornstarch (St. Lawrence Starch, Port Credit, Canada).

During the acclimation and experimental periods, animals were housed individually in cages without filter lids. In addition, all animals had free access to clean tap water, and coprophagy was permitted. The three groups other than the zero-time control were maintained on their respective regimens for 14 days (i.e., from 19 through 33 days of age). Sample sizes were 8, 6, 8, and 7 for the age-matched control, zero-time control, low-protein, and restricted intake groups, respectively, and each sample was made by pooling 4–10 mice. Pooling was maintained within sexes, and a pooled sample constituted a single degree of freedom for the purpose of statistical analysis. Similar numbers of males and females were included in each group. At the end of the 14-day experimental period, or at 19 days of age (zero-time control group), blood was taken from each mouse and the carcasses were stored at –20°C to await analysis.

Blood Collection.
After measurement of body weight, blood was taken from the orbital plexus of each mouse under CO2 anesthesia as described previously (17), and the animals were sacrificed by cervical dislocation without recovering consciousness. The blood was allowed to clot at room temperature for 30–45 mins, and the resulting serum was stored at –80°C.

Serum Immunoglobulin Assays: Immunological Reagents.
Standards for mouse IgG, IgG1, IgG2a, and IgG3 were purchased from Sigma-Aldrich Canada (Oakville, ON), and mouse IgE was obtained from PharMingen (Mississauga, ON). Gamma chain–specific goat anti-mouse immunoglobulins (affinity-purified IgG; Sigma-Aldrich) served as the capture antibodies for assays of IgG and its subclasses, whereas rat anti-mouse IgE (clone R35-72, IgG1, epsilon chain–specific; PharMingen) was used as the capture antibody in the assay of IgE. Horseradish peroxidase–conjugated, Fab-specific goat anti-mouse IgG (affinity-purified IgG; Sigma-Aldrich) and biotin-conjugated rat anti-mouse IgE (clone 35–118, IgG1, epsilon chain–specific; PharMingen) fulfilled the role of second antibody, as appropriate, such that an avidin-conjugated horseradish peroxidase reagent (PharMingen) was also required in the IgE assay.

Serum Immunoglobulin Assays: Procedures.
Serum immunoglobulin concentrations were determined by means of a standard sandwich enzyme-linked immunosorbent assay technique using 96-well microplates (Costar 3797; Fisher Scientific Ltd., Nepean, ON). Briefly, each assay was performed using 0.01 M phosphate-buffered saline (PBS; pH 7.2) as coating buffer, 0.05% Tween-20 in PBS as washing buffer, and 1% bovine serum albumin fraction V (Roche Diagnostics, Laval, QC) in PBS as blocking buffer. Appropriate concentrations of capture antibody were determined for each assay in preliminary studies, and plates were coated for 1 hr at 37°C, followed by blocking for 30 mins at room temperature. Samples and standards were incubated in coated wells for 1 hr at room temperature. The developing solution for assays of IgG and its subclasses contained 250 mg/l O-phenylenediamine (Sigma-Aldrich) and 3.5 mM H2O2 in phosphate-citrate buffer adjusted to pH 5.0. The substrate solution for the IgE assay contained tetramethylbenzidine and was used exactly according to the instructions of the manufacturer (catalog numbers 2606 KC and 2607 KC; PharMingen). The color reaction was allowed to proceed for up to 30 mins at room temperature and, following acidification with sulfuric acid, optical density readings were taken at 490 nm (IgG and its subclasses) or at 450 nm with correction at 570 nm (IgE) using a Vmax Kinetic Microplate Reader (Molecular Devices Corp., Menlo Park, CA). All readings used to generate data for this investigation fell within the linear portion of the standard curves, each of which had an R2 value exceeding 0.97. Intraassay coefficients of variation were used to assess the reliability of each assay, and ranged between 3% and 6%. Detection limits, estimated as described elsewhere (18), ranged from 0.04 to 0.1 µg/ml for the assays of IgG and its subclasses, and from 0.03 to 0.6 ng/ml for the assay of IgE. Finally, use of spiked samples revealed detection efficiencies close to 100% (range, 94%–117% in several tests of each assay).

Carcass Analysis.
The concentrations of dry matter and its two main components, crude protein and lipid, were measured as described elsewhere (13).

Statistical Analysis.
The SAS system for Windows (version 8.2) was used for statistical analysis (19), and a predetermined upper limit of probability of P ≤0.05 was applied for statistical significance. Data were subjected to two-way ANOVA followed, if justified, by the resulting statistical probability (i.e., P ≤0.05), by Tukey’s Studentized Range test. The analyses were conducted with diet (including the zero-time control group) and sex as the main effects. Data sets that failed to exhibit normal distribution according to each of the four tests applied by the SAS program (P ≤0.05) were subjected to transformation to bring them into conformity with this basic assumption of parametric testing.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The Malnutrition Protocols Produced Wasting Disease from Either Energy Deficit or Combined Protein and Energy Deficit.
Growth indices are shown in Table 1Go. Initial body weights did not differ among groups, and the age-matched control group exhibited gains of fat and lean tissue that were comparable to outcomes reported previously (13–15, 20). The two malnutrition protocols produced comparable weight loss. However, mice subjected to restricted intake exhibited a greater loss of carcass lipid than the group fed the low-protein diet and, consequently, experienced a greater loss of carcass energy. Conversely, greater loss of lean tissue was apparent in the group fed the low-protein diet than in the restricted intake group. Both malnutrition protocols induced low food intake, including low intake on a body weight basis (not shown). This was by design in the case of the food intake restriction protocol, but reflected the classic response to consumption of an imbalanced diet where the low-protein protocol was concerned. Therefore, as discussed elsewhere (15), the low-protein diet produced a deficiency of energy as well as of protein, whereas the restricted intake protocol produced a deficiency of energy only. According to this short list of key characteristics, the weight loss pathologies produced in this investigation were comparable to the pathologies produced previously in connection with discussions demonstrating that the low-protein and restricted intake protocols impose pathologies closely mimicking, and relevant to, the well-defined human conditions of incipient kwashiorkor and marasmus (12, 14, 15, 20, 21).


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  		Table 1. Initial and Final Body Weights, Food Intakes, and Carcass Compositionsa
 
The Malnutrition Protocols Selectively Supported High Serum Concentrations of IgG1 and IgE.
Serum total IgG concentrations are shown in Figure 1Go together with the concentrations of IgG1, IgG2a, and IgG3. An ontogeny-related fall in concentration of IgG and its subclasses, discernible by comparison of zero-time and age-matched control groups, was apparent except for the minor IgG2a component. The same outcome pertained to the major subclass, IgG2b (mean ± SD: 291 ± 59.5 vs. 121 ± 48.4 µg/ml, P < 0.001, two-tailed Student’s t test), which was outside the purview of this investigation. Total IgG concentration in the blood serum was high relative to age-matched controls in the group fed the low-protein diet, but it was unaffected by the restricted intake protocol. The blood IgG1 level was high in both malnourished groups when compared with the age-matched control. By contrast, no effect of weight loss pathology was apparent on the serum concentrations of either IgG2a or IgG3. In addition, no differences in serum concentration of IgG or its subclasses were discernible between the two malnourished groups. Finally, sex was without influence on the concentration of IgG or its subclasses (P > 0.50), and the effect of diet on IgG1 concentration was independent of sex (P for interaction = 0.73).



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  		Figure 1. Concentrations of IgG and three subclasses, IgG1, IgG2a, and IgG3, in the blood serum of weanling C57BL/6J mice. Male and female mice, initially 19 days old, were given free access to a complete purified diet (group C) or to a low-protein diet (group LP), or were fed the complete diet in restricted daily quantities (group R). The feeding period was 14 days. A zero-time control group (B) was examined at 19 days of age. Sample sizes were 6 (B), 8 (C), 8 (LP), and 7 (R), and each sample was formed by pooling blood within sexes from 4 to 10 mice. Bars represent mean values and, in the case of IgG3, are antilogs from log-transformed data. Within each graph, bars not sharing an upper-case letter differ (P ≤ 0.05) according to Tukey’s Studentized Range test. Pooled SEM = 36.81 (IgG), 8.80 (IgG1), 0.16 (IgG2a), and 0.40 (IgG3).

 
Serum IgE concentrations are shown in Figure 2Go. No influence of ontogeny was apparent on this index, an outcome consonant with the selective transport of IgG across the intestinal epithelium of the suckling rodent (22). The malnourished groups exhibited high serum concentrations of IgE relative to the age-matched control group, but did not differ from one another in this characteristic. No sex effect was apparent on blood IgE concentration (P = 0.48), nor was the influence of diet dependent on sex (P for interaction = 0.64).



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  		Figure 2. Concentrations of IgE in the blood serum of weanling C57BL/6J mice. Male and female mice, initially 19 days old, were given free access to a complete purified diet (group C) or to a low-protein diet (group LP), or were fed the complete diet in restricted daily quantities (group R). The feeding period was 14 days. A zero-time control group (B) was examined at 19 days of age. Sample sizes were 6 (B), 8 (C), 8 (LP), and 7 (R), and each sample was formed by pooling blood within sexes from 4 to 10 mice. Bars represent mean values and are square roots of data transformed as X2. Bars not sharing an upper-case letter differ (P ≤ 0.05) according to Tukey’s Studentized Range test. Pooled SEM = 0.24.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present investigation reveals high concentrations of Th2-type immunoglobulins (IgE and IgG1) in the blood of weanling mice subjected to acute deficits of either energy or both protein and energy, whereas levels of Th1-type immunoglobulins (IgG2a and IgG3) remain unaffected. This finding is made in metabolically dissimilar experimental pathologies that are relevant to marasmus and incipient kwashiorkor (i.e., the restricted intake and low-protein protocols, respectively; Refs. 12, 14, 15, 20). Moreover, this outcome exhibits no sex dependence, and inclusion of a zero-time control in the experimental design permits discernment of the phenomenon as more than a biologically trivial delay in weanling ontogeny. Therefore, the results of this investigation point to the proposition made elsewhere (10) of a Th2-polarized immune competence in acute malnutrition reflective of physiological regulation rather than disintegration. It is particularly important that the primary outcome measure of this investigation is downstream of cytokine production and was assessed independently of immunologically polarizing antigenic pressure.

The value of the blood profile of IgE, IgG1, IgG2a, and IgG3 as a marker of Th1- or Th2-biased immune competence in the mouse is apparent from examination of diverse experimental systems. For example, interferon-{gamma} knockout mice exhibited low serum concentrations of IgG2a, whereas levels of IgG1 and IgE were unaffected and, conversely, IL-4 knockout animals exhibited the reciprocal immunoglobulin profile (23). Similarly, the lupus-like autoimmune MRL mouse was found to over-express interferon-{gamma} relative to IL-4 and IL-10 and, in parallel, to exhibit high blood levels of IgG2a and IgG3 and low concentrations of IgG1 (24). In addition, high serum levels of IgE and IgG1, together with low levels of IgG2a, are reported in a murine model of antibiotic-induced Th2-biased immune competence (25). These findings are consistent with earlier reports that interferon-{gamma} selectively induces murine IgG2a and IgG3 subclass switching in vitro, whereas IL-4 selectively promotes class switching to IgG1 and IgE (4). By contrast, the serum IgG2b concentration of the mouse is variously reported to reflect Th1 polarity (23), Th2 polarity (26), or neither (24). Moreover, transforming growth factor-ß appears to be the decisive switch factor for murine IgG2b as it also is for IgA (4). A broad evidence base, therefore, supports the interpretation of the blood profile of IgE and the three IgG subclasses that were selected for this investigation as an index of Th1/Th2 balance at a systemic level, at least if important confounding influences on these immunoglobulins can be eliminated from consideration.

The suckling rodent selectively absorbs intact IgG until gut closure occurs during the period between 16 and 20 days of age (22). Consequently, the ontogeny-related decline in serum concentration of IgG and its major subclasses (this investigation) is attributable to turnover of milk-derived immunoglobulin subsequent to weaning. This raises the possibility that the high concentration of IgG1 sustained by the malnourished animals is a biologically trivial consequence of decreased turnover. Indeed, a prolonged half-life is reported for IgG (27) as well as for other proteins (28) in the blood of acutely malnourished humans. However, no basis can be cited for a subclass-specific impact on blood IgG turnover. Therefore, the simplest interpretation of the present results pertaining to IgG subclasses remains focused on the Th2-biased character of the serum immunoglobulin profile. Importantly, these results were obtained in the context of normal or elevated blood total IgG concentrations as are usually (1), although not always (29), reported in humans with acute malnourishment. Previous documentation of the effect of acute protein deficits, energy deficits, or both on blood IgG subclasses appears unavailable.

A high concentration of blood IgE has long been recognized as characteristic of acute protein and energy deficiencies in humans (11). This phenomenon has frequently been attributed to concurrent intestinal worm infestation, but blood IgE levels remained high in a cohort of malnourished children despite long-term antihelminthic drug therapy (9). The present investigation extends this observation to experimental animal systems in which, according to routine and frequent monitoring, intestinal worm infestation is not a factor. Both experimental protocols examined herein elicit the characteristic malnutrition-associated elevation in blood glucocorticoid levels (30), which in turn, would be expected to up-regulate IgE synthesis and levels (31). It is reasonable to view the high blood IgE levels found in acute protein deficits, energy deficits, or both in this investigation as intrinsic to these experimental pathologies and reflective of the prevailing Th1/Th2 balance.

Acute malnutrition consistently reduces cell-mediated immune competence while exerting a less predictable influence on the capacity to generate antibody responses (1). The results of the present investigation are relevant to this phenomenon because they lend support to the concept of a Th2-polarized immune competence in acute protein and energy deficiencies. Implications may also accrue in relation to Th1-skewed disorders such as several autoimmune pathologies. For example, subtotal fasting at a level of 215 kcal per day is reported to alleviate symptoms of rheumatoid arthritis (8). Such an intervention cannot be recommended for routine therapeutic purposes, but an understanding of immune regulation in acute protein and energy deficiencies may contribute toward improved therapeutic modalities for Th1-biased conditions. The concept of a Th2-polarized immune competence in acute malnutrition is supported by the results of this investigation and has both fundamental and clinical implications.


   Acknowledgments
 
We thank Mrs. Lyn Hillyer for preparing the figures. T.R.N. performed the laboratory bench work and prepared the first draft of the manuscript. Any intellectual property herein specific to immunoglobulins is shared equally by T.R.N. and B.W.


   Footnotes
 
This work was supported by funds awarded to B.W. by the Natural Sciences and Engineering Research Council of Canada.

Received for publication August 17, 2004. Accepted for publication October 29, 2004.


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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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