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Department of Human Health and Nutritional Sciences, University of Guelph, ON, Canada N1G 2W1, Fax: 519–763–5902
* E-mail: wwoodwar{at}uoguelph.ca.
Dear Editor:
Niiya et al. (1) recently reported that depressed thymus-dependent adaptive immune competence in a murine model of chronic adult protein-energy malnutrition (PEM) is at least partly attributable to "reduced frequencies" of dendritic cells and to "impaired functions" of these cells. The Ehime University group is among the few to persist in the quest for a meaningful understanding of immune competence in protein and energy deficit and the recent report from this group (1) provides evidence that the net capacity for antigen processing and presentation in support of a memory response is depressed by chronic PEM in adulthood. I must respectfully submit, however, that the experimental outcomes presented by Niiya et al. (1) cannot address questions specific to the dendritic cell or to any particular type of antigen presenting cell.
The main problem is that the investigation centered on splenic antigen-presenting cell suspensions of undefined, but surely modest, dendritic cell enrichment, and inspection of the results shown in Table 2 of Niiya et al. (1) bears out this concern. Thus, the "dendritic cell" population studied in this investigation comprised 3.1 and 2.4% of the nucleated spleen cells from fully nourished controls and malnourished animals, respectively, whereas a substantive literature has established that dendritic cells comprise only 0.5–1% of nucleated spleen cells (e.g. 2,3) in the adult mouse. Unfortunately, the enrichment procedure used by Niiya et al. (1), viz. differential centrifugation followed by adherence steps, cannot yield a highly purified dendritic cell population from the spleen of the mouse, nor does it yield a consistent enrichment. In fact, enrichment ranging from 10 to 50% is reported as representative of this procedure even when followed by lytic elimination of residual T and B cells (4) and the experience of my laboratory group concurs with this report. In short, the conclusions of Niiya et al. (1) were based on spleen cell suspensions of unknown cellular composition in which only limited dendritic cell enrichment can have been achieved.
Second, the assays applied by Niiya et al. (1) relating to antigen-presenting cell activities are not specific to the dendritic cell. Two types of assay were used, both in vitro, viz. assessment of T cell proliferation in response to hepatitis B surface antigen and assessment of constitutive cytokine production (specifically, IL-12p70 and IFN
). As the authors acknowledge, the hepatitis B surface antigen-specific proliferation assay assessed the capacity to initiate a memory cell response. Thus, any activated or resting B cells and residual macrophages found in the "dendritic cell" populations studied by Niiya et al. (1) would be potent in this assay (e.g. 5). Likewise, numerous probable nondendritic elements of these cellular populations (B cells, T cells, natural killer cells, and any residual macrophages) are well-known, high-level producers of IL-12p70 and/or IFN or will influence the production of these cytokines by dendritic cells. Application of assays lacking effector cell specificity clearly compounds the difficulties stemming from use of effector populations of undefined cellular composition.
The influence of protein and energy deficit on splenic dendritic cell numbers, assessed on the basis of currently accepted surface marker phenotype, has been reported in murine models of acute weanling malnutrition (3,6). A surprising resistance to involution was exhibited by this rapid-turnover cellular compartment, and one wonders if this outcome would extend to the more long-term forms of PEM. Further, acute deficits of protein and energy appear to impose no lasting impact on the antigen processing and presenting capacities of murine dendritic cells (individual cell basis), which remain potently capable of eliciting a primary response both in vitro and when adoptively transferred to healthy mice (6). By contrast, chronic murine protein deficiency reduced the antigen presenting capacity of the dendritic cell compartment in vitro (7), but this function was not assessed on a per cell basis as had been the intent of Niiya et al. (1). A T cell-centric research effort has prevailed vis-à-vis adaptive immune competence in PEM and Niiya et al. (1) have rightly highlighted a need to improve our research base with regard to the most potent of the antigen presenting cells. Unfortunately, interpretation of the report of Niiya et al. (1) is impossible in terms of any particular type of antigen presenting cell.
Manuscript received 20 May 2007.
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LITERATURE CITED |
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1. Niiya T, Akbar SMF, Yoshida O, Miyake T, Matsuura B, Murakami H, Abe M, Hiasa Y, Onji M. Impaired dendritic cell function resulting from chronic undernutrition disrupts the antigen-specific immune response in mice. J Nutr. 2007;137:671–5.
2. de Smedt T, Pajak B, Muraille E, Lespagnard L, Heinen E, de Baetselier P, Urbain J, Leo O, Moser M. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med. 1996;184:1413–24.
3. Konyer JE, Hillyer LM, Woodward B. Splenic dendritic cell populations of the weanling mouse involute proportionately with total nucleated cell numbers throughout acute protein and energy deficiencies except in the most advanced stages of nitrogen-to-energy imbalance. Nutr Res. 2003;23:921–31.
4. Basu A, Chakrabarti G, Saha A, Bandyopadhyay S. Modulation of CD11c+ splenic dendritic cell functions in murine visceral leishmaniasis: correlation with parasite replication in the spleen. Immunology. 2000;99:305–13.[Medline]
5. Croft M, Bradley LM, Swain SL. Naïve versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol. 1994;152:2675–85.[Abstract]
6. Zhang X, Hillyer LM, Woodward BD. The capacity of noninflammatory (steady-state) dendritic cells to present antigen in the primary response is preserved in acutely protein- or energy-deficient weanling mice. J Nutr. 2002;132:2748–56.
7. Conzen SD, Janeway CA. Defective antigen presentation in chronically protein-deprived mice. Immunology. 1988;63:683–9.[Medline]
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