There is evidence for a role of vitamin A in the maintenance of both humoral antibody

responses and cell-mediated im- munity. The number and cytotoxic activity of natural killer
cells (Dawson et al., 1999; Zhao et al., 1994) is reduced in vitamin A deficiency, although
responsiveness to activation is maintained. (Dietary Reference Intakes for VitA page
130)
Vitamin A has other roles in resistance to infection. Vitamin A plays a central role in the
development of lymphocytes, white blood cells that play critical roles in the immune response.
Also, activation of the major regulatory cells of the immune system, T-lymphocytes, requires the
retinoic acid form of vitamin A.
Vitamin A deficiency is strongly associated with de- pressed immunity (Smith et al., 1987) and
therefore a combination of deficiency and infectious disease is potentially fatal, especially
among infants and children. Randomized trials in Sumatran (Tarwotjo et al., 1987) and Indian
(Rahmathullah et al., 1990) preschool-age children showed that vitamin A sup- plementation
decreased mortality due to infection by 96% and 54%, respectively.
Vitamin A increases resist- ance to infection by maintaining the integrity of the skin and
mucous membrane barriers against bacteria, viruses, and parasites. In ad- dition, vitamin A
enhances antibody produc- tion by white blood cells and increases the number and activity
of T cells.5 During child- hood, vitamin A supports growth and devel- opment of T cells in
the thymus gland. Carote- noids also can increase activity of T cells and natural killer (NK)
cells and enhance produc- tion of tumor necrosis factor alpha (Fig. 3.1).6
Vitamin A deficiency in rats reduced the absolute number of natural killer (NK) cells in
blood and to a lesser extent in spleen. The activity per NK cell was normal in blood and only
slightly, but significantly, re- duced in the spleen (Zhao et al., 1994). NK cytotoxici- ty was
increased in vitamin A-deficient rats when their production of cytokines was stimulated by
polyinos- inic acid:cytidylic acid (Ross, 1996). When vitamin A-deficient rats were fed a
retinoic acid supplement, the number of NK cells equalled those of control rats and NK
cytotoxicity was significantly elevated (Zhao & Ross, 1995). Thus, as for antibody

production, ad- equate vitamin A status is required to ensure the cor- rect pattern of cytokine
gene expression.
The neutrophils of vitamin A-deficient rats showed impaired chemotaxis, lower rate of
adhesion to path- ogenic organisms, and impaired respiratory burst activity. Neutrophil
function was restored to normal 8 days after vitamin A administration (Twining et al., 1997).
Retinoic acid was shown to stimulate, and retinalde- hyde to inhibit, the activity of protein kinase
C derived from T cells (Isakov, 1988). This enzyme has a major role in transmembrane signal
transduction and there- fore its regulation by retinoids could account for the modulatory effects
of vitamin A on T-cell function. Retinoic acid induces the expression of the RAR gene in
unstimulated cloned mouse T cells and in- creases proliferation of these cells in the presence of
antigen (Friedman et al., 1993). Cytotoxic T cells rec- ognize antigens in association with MHC
class I mol- ecules. Retinoic acid mediates the regulation of MHC class I gene expression via a
nuclear hormone receptor (Nagata et al., 1992). Expression of the intercellular adhesion
molecule-1 (ICAM-1) gene is up-regulated by retinoic acid in a RAR/RXR-dependent fashion
(Aoudjit et al., 1994, 1995). Retinoic acid can enhance the functional responses of human T
lymphocytes via transcriptional up-regulation of IL-2 receptors (Sidell et al., 1993).
Retinol is essential for proliferation of activated human B cells (Buck et al., 1990) and,
moreover, is a normal modulator of B-cell function (H. Blomhoff et al., 1992). In a study of the
effects of retinoids on B-cell immune function in newborn infants (Ballow et al., 1996), retinoic
acid enhanced the synthesis of IgM in antigen-stimulated umbilical cord blood mononuclear
cells, whereas in adult peripheral blood mononuclear cells it enhanced the synthesis of IgG. IgM
is the first antibody produced during a primary immune response and is 15 times more effective
than IgG in activating the complement cascade. Highly pu- rified T cells pre-incubated with
retinoic acid released a factor (probably a cytokine) which acted on cord blood B cells to
augment IgM synthesis.
Wiedermann et al. (1993) studied the in vivo and in vitro immune responses in vitamin Adeficient rats to parenterally administered antigens. The serum IgG and IgM antibody responses
to a T-cell-dependent antigen (-lactoglobulin) were significantly lower in the deficient rats
than in the pair-fed controls, but there were no such differences in the IgG and IgM re- sponses
to a type 2, T-cell-independent antigen (Ficoll conjugated to picrylsulphonic acid). This

observation indicates that B-cell function is not directly affected by vitamin A deficiency and the
decreased antibody response to the T-cell-dependent antigen might be due to cytokine production
by T helper cells. How- ever, the biliary IgA and the serum IgE antibodies against both antigens
were decreased in the deficient animals. In the in vitro experiments, IL-2 and IFN-levels in
supernatants from mitogen-stimulated lym- phocytes from vitamin A-deficient rats were higher
than control levels, whereas IL-6 levels were lower. Il-2 and IFN-are produced by Th1 cells,
while IL-6
is produced by Th2 cells. IgE production is depend- ent on the presence of IL-4, which is also
produced by Th2 cells. These results indicate an up-regulation of Th1 cell function and a downregulation of Th2 cell function. Despite an increase in T cell proliferation in vitro, vitamin Adeficient rats had a lower delayed- type hypersensitivity than the control rats as well as
suppressed antibody production.
Smith & Hayes (1987) reported that in vitamin A-deficient mice, the IgG1 and IgG3 responses to
a protein antigen (haemocyanin) were impaired earlier and to a greater extent than were IgM
responses. The impaired responses were attributable to fewer anti- body-secreting cells (plasma
cells) rather than to a decreased secretion rate per cell. The reduction in plasma cell number
resulted from a defect in the abil- ity of T helper cells to provide stimulatory signals to B cells
(Carman et al., 1989). The IgG responses were restored by adding retinyl acetate to the murine
diet (Chun et al., 1992). Carman & Hayes (1991) reported that the T cells of vitamin A-deficient
mice produced excess interferon-(IFN-).
Carman et al. (1992) investigated the immunologi- cal effects of vitamin A deficiency in mice
infected with the parasitic helminth Trichinella spiralis. They showed that vitamin A deficiency
shifts the immune response toward an early Th1-type response and delays the de- velopment of a
Th2-type response. The normal Th2 response to T. spiralis infection is characterized by high
levels of parasite-specific IgG antibodies and increased bone marrow synthesis of eosinophils,
the cells that specialize in killing extracellular parasites. The inap- propriate Th1 response elicits
high levels of IFN-, low Th2 and IgG-secreting cell frequencies and impaired eosinophil
production. Th2 cells secrete IL-5, which induces growth and differentiation of eosinophils;
therefore, by suppressing Th2 cell growth through ex- cess production of IFN- , one would

expect decreased eosinophil production in vitamin A deficiency. Further investigations (Cantorna

et al., 1994, 1995) confirmed that the imbalance between Th1 and Th2 responses in vitamin A
deficiency was caused by a distorted pattern of cytokine gene expression, in particular an
excessive production of IFN-and IL-12. IFN-, by antagonizing IL-4, can inhibit
proliferation of Th2 cells; it can also in- hibit B-cell proliferation, activation and immunoglobulin class switching. IL-12 stimulates the differentiation of Th1 cells. Excessive production of
IFN-w
as due to dysregulation of IFN-gene expression and excess anti- gen-presenting
capacity for IFN-stimulation. Vitamin A repletion decreased the synthesis of IFN-and IL-12,
limited the antigen presentation capacity to stimulate IFN-and increased the Th2 cell
frequency, thereby restoring the Th1/Th2 balance to normal. Retinoic acid was 100-fold more
active than retinol for restoring IgG responses in vitamin A-deficient cell cultures (Chun et al.,
1992). Retinoic acid was shown to inhibit IFN-gene transcription through its role as a ligand
for nuclear retinoic acid receptor (RAR) (Cantorna et al., 1996).

Retinoic acid increased the proliferation of granulocyte/macrophage precursor cells even in the
presence of maximally stimulating concentrations of colony-stimulating factor (Tobler et al.,
1986). Retinoids can modulate macrophage function by enhancing phagocytosis and IL-1
production (Dille- hay et al., 1988). An increase in transglutaminase activity during macrophage
activation is thought to contribute to the enhanced functional capacity of activated macrophages.
Moore et al. (1984) reported that physiological concentrations of retinoic acid specifically
induced the synthesis of transglutaminase by cultured mouse macrophages. Retinoic acid stimulated the capacity of macrophages to phagocytose and kill the unicellular parasite Trypanosoma
cruzi (Wirth & Kierszenbaum, 1986). Transglutaminase activity appeared to be involved in the
retinoid effect, because inhibition of the enzyme activity cancelled the effect. Retinoic acid at
physiological concentrations does not act alone in inducing IL-1production in human
monocytes; rather it strongly enhances phorbol ester- induced IL-1production at the level of
transcription (Matikainen et al., 1991). This effect of phorbol ester is mediated through the
activation of its cellular re- ceptor, protein kinase C. Macrophages from normal healthy donors
are usually not cytotoxic to tumour cells in vitro, but they can be rendered tumoricidal by
interaction in vitro with bacterial products, lym- phokines or vitamin A (retinyl palmitate)
(Tachibana et al., 1984). Macrophages from rats or mice receiving very high intakes of retinyl

palmitate also exhibit an increased ability to kill tumour cells (Tachibana et al., 1984; Moriguchi
et al., 1985).

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