ARTICLE
INTRODUCTION
Undernutrition has been associated with impairment of cell-mediated
immunity. Indeed, it predisposes to death in infectious diseases in man
and laboratory animals [1, 2]. The recent cloning of the obese
gene product, leptin, has determined fundamental insight into the understanding
of the regulation of food intake, basal metabolism and energy expenditure
[3]. Initially, leptin was considered an anti-obesity hormone. According
to this view, rising levels of leptin signal to the brain that excess
of energy is being stored as fat. This determines decrease in food intake,
increase in energy expenditure and stabilization of body weight [4-7].
Experimental evidence has shown a number of other effects of leptin on
peripheral tissues such as ovary, blood vessels, bone marrow, and more
recently T-lymphocytes [5, 8-11]. Specifically, leptin has been suggested
to function as a prominent regulator of immune system activity, linking
the function of T-lymphocytes to nutritional status. This review describes
several of the key aspects of leptin in the regulation of food intake
and T-lymphocyte functions, and summarizes the current state of knoweldge
about how these signals interact to form the complex circuit controlling
body weight and immune response.
LEPTIN AND ITS RECEPTOR
In 1994 Friedman and colleagues reported the cloning of the obese
gene and named the encoded protein leptin [3]. Leptin is a 167 amino acid
protein, synthesized and secreted primarely by adipose tissue. Structurally,
it is a long-chain helical cytokine similar to IL-6, IL-11, IL-12, LIF,
G-CSF, CNTF, and oncostatin-M [12]. Leptin has a 67% sequence homology
in species as diverse as human, gorilla, chimpanzee, orangutan, rhesus
monkey, dog, cow, pig, rat and mouse [13]. This protein is produced by
adipose tissue in proportion to fat mass and at low levels by other tissues
such as skeletal muscles, placenta and stomach [5, 14, 15]. Once released
into circulation, it subsequently acts on the brain to inhibit food intake,
stimulates thermogenesis and modulates other physiological actions [16],
including lipid metabolism [17], hematopoiesis [10], pancreatic beta cell
and ovarian function [5]. Furthermore, leptin shows a marked gender dimorphism
in serum concentrations, being higher in females than in males with the
same body fat mass [18].
A variety of stimuli can rapidly induce leptin expression and secretion
in mice and humans, for example the inflammatory mediators TNF-alpha and
IL-1 [19-21]. Indeed, leptin is produced during acute phase response and
represents an early reactant together with C-reactive protein [22, 23]
and IL-1 during systemic inflammation and fever [24-26]. Despite its heterogeneous
biological effects in extraneural tissues, the leptin receptor (Ob-R)
is expressed predominantly in the hypothalamus. It was first cloned from
mouse choroid plexus [27] and its primary structure shows homologies to
the class I cytokine receptors family, such as IL-6R, LIFR, gp130, and
G-CSFR [27, 28]. The Ob-R gene encodes for five alternatively spliced
forms: Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd and Ob-Re. Only Ob-Rb, known as the
long-form, contains several motifs required for signal trasduction,whereas
the other forms lack some or all of these motifs. The short-splice forms
of Ob-R are expressed in several tissues and seem unable to signal into
the cell. Their role is still unclear: they may function in the transport
of leptin across the blood-brain barrier and for leptin degradation [5].
Ob-Rb is usually expressed at high levels in hypothalamic neurons and
in other cell types, including T cells [11], vascular endothelial cells
[8, 9], and the CD34+ hematopoietic bone marrow precursor [10].
The binding of leptin to its receptor increases the activity of the receptor-associated
kinases of the Janus kinase family (JAK), that contributes to the phosphorylation
of the DNA-binding activity of signal trasducer and activator of transcription
such as STAT1, STAT3, and STAT5 [29, 30]. Leptin also appears to reduce
the intracellular levels of cAMP by the activation of cAMP-phosphodiesterases
[31]. STAT proteins and cAMP are very important regulators of cell cycle,
proliferation and lymphocyte functions.
Leptin's structural similarities with the helical cytokines, the great
homology of its receptor with the class I cytokine receptor family, and
the expression of the Ob-Rb on CD4+ T cells are factors currently
promoting extensive studies about the possible role of leptin in the regulation
of the T cell-mediated immune response.
ANIMAL MODELS
The mutation of the leptin gene or of the leptin receptor gene causes
obesity in mice weighing three times more than normal mice, even when
pair fed with the same diet, and showing a five-fold increase in body
fat content [5]. Both leptin deficient (ob/ob) and leptin receptor
deficient (db/db) mice display many abnormalities seen in starved
animals, including decreased body temperature, hyperphagia, decreased
energy expenditure, decreased immune function, and infertility [5]. Ob/ob
mice are unable to produce functional leptin because of a non-sense mutation
of the obese gene resulting in the synthesis of a truncated protein,
that is apparently degraded in the adipocyte [32]. In db/db mice
the mutation of the Ob-Rb gene creates a new splice donor that inserts
a premature stop codon into the Ob-Rb 3'-end, resulting in the replacement
of the Ob-Rb long isoform by the short Ob-Ra isoform [33]. The study of
this mutation has already established the Ob-Rb long isoform as being
critical for leptin function [28].
From an immunological point of view, leptin deficient mice have been
described to display reduced cellularity in spleen and thymus, in the
cell-mediated pro-inflammatory immune response, and in antibody production
[34]. Similar evidence has been found also in db/db mice [35, 36].
In these mice increased infection susceptibility and reduced ability to
reject primary allogeneic skin grafts have been described. These immune
defects could partially be considered as consequence of immunosuppressive
effects of diabetic hyperglycemia and high cortisol levels present in
these animals. Food restriction experiments that reduce plasma cortisol
and hyperglicemia, are not able to reverse these immune defects. Leptin
replacement completely restores a normal immune response in these mice,
suggesting that leptin defect is directly involved in these immune system
abnormalities [11].
Studies on ICAM-1/Mac-1 knockout mice reveal other important aspects
[37]. These mice show many immunological defects and altered migration
of lymphocytes and monocytes from the blood stream into peri-pheral tissues.
Furthermore, they present increased infection susceptibility and reduced
T cell activation under antigen specific stimulation. Interestingly, late
in their life they develop obesity with increased body weight and body
fat percentage, even when they are fed with the same diet as the normal
littermate controls. This obesity seems to be due to the role of leucocytes
in the regulation of fat deposition in the periphery and of their defected
migration. These results can be considered as a "reverse image" of what
we have observed about the influence of the adipose tissue, producing
leptin, on the lymphoid tissue. In other words, lymphocytes can be affected
in their functions by adipocytes and in turn lymphocytes and monocytes
can influence fat deposition in the peri-phery with their presence in
the tissues. Consequently, the immuno-endocrine cross-talk can be very
important for the adipocyte-lymphocyte homeostasis.
PHYSIOLOGICAL ROLE OF
LEPTIN:
OBESITY VERSUS STARVATION IN IMMUNE FUNCTION OF RODENTS AND HUMANS
Initially the obese gene product, leptin, was considered an anti-obesity
hormone. According to this view, increasing leptin serum concentrations
signal to the brain and other sites that excess energy is being stored
as fat, and this means that there is enough food availability. This signal
determines increased energy expenditure, decreased food intake, and stabilization
of body weight. This mechanism may contribute to the long-term stabilization
of body weight over time in many animals. Over the last few years increasing
evidence supports the alternative view that leptin signals to the brain
that energy stores are sufficient [16]. Starvation is well known to threaten
survival of individuals, and numerous systems have been developed to defend
against it. Starvation induces reduction of fertility, of basal metabolism,
decrease in thyroid and sex hormones, and finally activation of the stress
response trough the hypothalamic-pituitary-adrenal axis (HPA) [38]. All
these systems are engaged to save energy for vital functions such as central
nervous system and heart metabolism. In this context plasma leptin levels
are dynamic, rise and fall according to the body fat, and the energy state
changes. Acute fasting leads to a rapid reduction in plasma concentrations
in both humans and mice, that is disproportionate to the reduction in
body fat that results from the starvation [39]. Food consumption has the
opposite effect on plasma leptin levels [40]. In response to feeding or
administration of gastrin, leptin is rapidly secreted by stomach where
it is produced and stored [14]. This results in acute elevation of leptin
levels, that seem to be necessary for the correct reproductive and immune
function, together with the basal adipocytes-derived leptin. Reproductive
and immune systems can be rapidly tuned, and modulated by the presence
of leptin mainly because they are less immediately essential systems compared
to vital functions such as brain and heart.
Finely tuned cognate immune response requires large-scale clonal expansion
of cells and antibody-synthesis. The inhibition of this system can be
important in saving energy stores during starvation. Rapid fall in leptin
levels seems to block the optimal function of CD4+ T cells.
Leptin replacement during starvation is able to blunt the immunosuppression
associated to food deprivation; indeed DTH inflammatory response reduced
during fasting can be restored with leptin replacement during starvation
(Table 1) [41].
In humans, obesity is rarely associated with genetic deficiency in the
leptin system [42]. Indeed, the vast majority of obese humans do not have
mutations in the leptin or leptin-receptor genes, but have high levels
of circulating leptin because of their increased body fat mass [43]. By
analogy with type II diabetes mellitus, these individuals may have functional
leptin resistance, an impaired central and peripheral responsiveness to
circulating leptin [5]. More recently, a few obese gene mutations
in members of a Turkish family [44] and mutations in the leptin receptor
in a French family with massive obesity and reproductive abnormalities
have also been described [45]. The classical hypercortisolaemia, cold
intolerance and severe diabetes of ob/ob mice are not observed
in leptin deficient humans. Interestingly, these patients show alterations
in immunity, probably related to low total T cell counts and functionally
impaired cell-mediated immune response, resembling that observed in ob/ob
mice. Furthermore, the dramatic reduction in leptin levels significantly
predisposes these people to death the infectious diseases in early childhood.
Indeed, the idea that the reduced survival is due to leptin deficiency
is supported by observing very high frequency of death of the leptin-deficient
children compared to normal weight children in the youngest generation
of the same Turkish family, all raised in the same enviroment and with
the same access to nutrients [44].
Low body weight in humans and rodents has been associated with increased
frequency of infectious diseases and they are the most common cause of
secondary immunodeficiency worldwide [2, 46]. In humans, low body weight
and consequent low leptin levels are typically present in two conditions:
anorexia nervosa and malnutrition, both associated with immune deficits
[46, 47]. It is problematic to completely dissect all the potential factors
involved in these conditions. In fact they range from the broad consequences
of protein caloric malnutrition [48] to deficiency of single micronutrients,
such as zinc [49], selenium [50], vitamins A [51], C, and E, all necessary
for immune fuction. To these elements must now be added the potential
effects of leptin deficiency. Leptin seems to be a key mediator of the
immune suppression induced by starvation, directly acting on CD4+
T cell functions and indirectly affecting the presence of other hormones.
Indeed, it prevents the raising of glucocorticoids produced during starvation
and the falling of growth hormone and thyroid hormones [38], each of which
may mediate immune suppression indirectly [41]. Both leptin and micronutrients
deficits have been associated with delayed development of the immune system
during fetal growth [52] and this also causes extreme increase in frequency
of death for infections early in life [1]. Since 1810 Menkell linked malnutrition
to lymphoid tissue atrophy, mainly affecting the thymus, and nutritional
thymectomy became a common medical term [53-55]. Leptin also prevents
thymic atrophy if administred during starvation [56].
Linked to a functional but not real leptin deficiency is the most common
form of human obesity, associated to central/peripheral leptin resistance
[5]. Epidemiological studies show increase in infection frequency in these
patients mainly affecting the respiratory and urinary tracts [57, 58].
Many factors contribute to this, such as the alteration in the normal
dynamics in lungs ventilation and in urinary flow from kidneys due to
the excess in body fat. Another of these factors can also be the leptin-receptor
desensitization expressed on CD4+ T-lymphocytes due to the
very high leptin levels, finally perceived from T cells as a condition
of leptin deficiency. This as well as the real leptin deficiency observed
in malnutrition or genetic leptin deficiency, can cause many of the immune
deficits observed in each of these pathologic conditions.
FEATURES OF IMMUNOREGULATORY
ROLE OF LEPTIN: RELEVANCE FOR CD4+ T CELL FUNCTION AND THYMIC
HOMEOSTASIS
The first evidence of a possible involvement of leptin in the modulation
of the immune system derives from the study of its structure and of its
receptor. As previously shown, leptin belongs to the vast class of long
helical cytokines and its receptor is homologous to the class I cytokine
receptors [5]. These similarities suggest the possible role of leptin
in immune system homeostasis. Furthermore, the analysis of the immune
functions of both ob/ob and db/db mice shows impaired in
vitro T cell-mediated immunity with low IL-2 and IFN-gamma production
and decreased DTH responses in vivo, as compared to normal, age
matched littermate controls. Chronic leptin replacement in ob/ob
mice restores the T cell function, increasing the secretion of the pro-inflammatory
cytokines IL-2 and IFN-gamma as well as the DTH response in vivo.
These effects are not seen when leptin is injected into db/db animals
that lack the leptin receptor, suggesting that leptin may have a direct
and specific effect on T cells [11, 34-36].
Leptin's effects on human CD4+ T-lymphocytes have been extensively
investigated in vitro. Addition of physiological concentrations
of leptin to mixed-lymphocyte reactions (MLRs) induces a marked dose-dependent
increase in the proliferative responses of highly purified CD4+
T-lymphocytes. Both human naive (CD45RA+) and memory (CD45RO+)
CD4+ T cells express Ob-Rb mRNA. Differential effects of leptin
have been shown on proliferative responses and cytokine profiles of these
two T-lymphocyte subsets. In the presence of leptin naive cells increase
their proliferative responses and IL-2 secretion, while memory cells show
substantial increase in IFN-gamma together with suppression of IL-4 secretion
despite little effect on the proliferative responses. These results indicate
that leptin may bias T cell responses towards a Th1 pro-inflammatory phenotype.
None of the in vitro actions of leptin is seen when T-lymphocytes
from db/db mice are used, confirming the specificity of these effects
on T cell responses (Table 1)
[11].
Pro-inflammatory cytokines such as IFN-gamma can upregulate adhesion
molecules and certain accessory molecules can bias T cell response towards
the production of specific cytokines. Human PBMCs and murine splenocytes
when incubated with leptin alone for 36-48 hours show marked cellular
clumping but not when performed with db/db mice cells. These effects
were mainly due to increased expression of the adhesion molecules ICAM-1
(CD54) and VLA-2 (CD49b) on CD4+ T cells (Table
1) [11].
In normal individuals, nutritional deprivation affects immune function
and also rapidly reduces the amount of circulating leptin in mice and
humans [38, 39]. DTH-response in normal mice results markedly reduced
when 48 hours starvation is imposed at priming with the antigen. Exogenous
leptin replacement during the 48 hours starvation is able to completely
reverse this inhibition. These findings demonstrate that the presence
of leptin in the microenvironment where immune responses take place is
necessary for priming of T cells (Table
1) [11]. Clinical trials involving starvation to modulate the pro-inflammatory
immune response in human autoimmune diseases have been recently reported
[59, 60]. Rheumatoid arthritis (RA) patients after 7 days starvation and
then refeeding, showed a significant decrease in erythrocyte sedimentation
rate, C-reactive protein level, joint count, CD4+ and CD8+
counts and expression on T cells of activation markers (CD69) together
with increase in IL-4 secretion. Starvation in RA patients determined
a marked reduction of leptin levels with concomitant decrease in activation
of CD4+ T cells and an increase in the number and/or the function
of IL-4 producing Th2 cells. This confirms that factors such as leptin
associated with loss of body weight during acute starvation, appear to
have an inhibitory effect on CD4+ T-lymphocyte activation when
they are dramatically reduced.
Lymphoid atrophy is a well recognized consequence of nutritional deprivation.
The thymus is particularly sensitive to food deprivation and has been
designated the "barometer of malnutrition" [53-55]. Leptin seems to play
a pivotal role in the pathogenesis of starvation-induced thymic atrophy.
Indeed, 48 hours acute starvation in normal mice, causes a dramatic fall
in the total thymocyte count particularly affecting the CD4+
CD8+ double positive and the CD4+ CD8
single positive compartments when compared to ad-libitum fed mice
[56]. Leptin replacement during starvation completely protected against
these starvation induced changes in thymocyte numbers and subpopulation
proportions (Table 2) [56]. The
reduction in thymic size and cellularity is related structurally to a
loss in the cortical thymocytes with an increase in the number of apoptotic
cells. These effects were completely blunted by leptin injection. Also
splenic CD4+ lymphocytes seem to be sensitive to starvation;
leptin treatment also restored T cell counts in this organ [56].
Ob/ob mice present marked reduction in thymic cellularity particularly
affecting CD4+ CD8+ double positive cells. Leptin
treatment of ob/ob mice has a significant impact on the thymus.
Specifically, it increases the total thymocyte counts and the single subpopulations
of thymic cells. Furthermore, leptin treatment in vivo reduced
the level of apoptosis in thymocytes from ob/ob mice to that observed
in normal wild-type control mice [56]. These results are also confirmed
in vitro by dexamethasone-induced apoptosis assays of normal mice
thymocytes. Addition of exogenous leptin to the cultures during the assay
completely prevented thymocyte apoptosis. The ability of leptin to protect
against thymic athrophy also seems to involve a direct anti-apoptotic
mechanism. Whether these protective effects are mediated directly by leptin
action on the thymus or by reduction of glucocorticoids both in starved
animals or ob/ob mice, needs further investigations and cannot
be excluded [61]. However, reduced leptin concentrations are pivotal also
in explaining starvation-induced lymphoid atrophy.
A NOVEL ROLE FOR ADIPOSE TISSUE IN LYMPHOID ORGAN
HOMEOSTASIS
The increasing evidence regarding the role of leptin in bone marrow
precursor development [10] and T cell function [11, 56], can support a
novel view about the role of adipose tissue in the final balance of the
T cell-mediated immune response. Adipocytes so far have been mainly considered
as long term energy storage sites and as producers of cholesterol for
steroid hormones synthesis. Adipose tissue is also present anatomically
to protect many organs surrounding different districts of the body. Its
presence has been mainly associated with its metabolic function and not
with the important role of contributor for the T cell function and homeostasis.
With the discovery of the novel effects of leptin on T-lymphocyte functions,
it is possible to consider the adipose tissue, that surrounds lymph nodes,
thymus and bone marrow, no longer just as a protective and energetic tissue
but as a dynamic structure necessary for T cell activities. Its proteic
product, leptin, creates a permissive microenvironment, that enables the
immune system to function and to sustain an optimal pro-inflammatory immune
response [11]. Heavy reduction in the adipocyte mass and consequently
in leptin levels, determines the release of a negative signal, that impairs
T cell priming and the production of pro-inflammatory mediators, such
as IFN-gamma, necessary for the induction of a Th1 response. These findings
give to adipose tissue a very important role not only in metabolism and
steroidogenesis but also in the immune response. Conversely, leucocytes
are belived to contribute to the adipose tissue metabolism, for their
ability to influence fat deposition and the developement of obesity [37].
Better understanding of the cross talk between adipocytes and lymphocytes
and the increasing mass of information on novel activities of these two
cellular compartments will shed more light in the future on the complex
immuno-endocrine network of the body.
CONCLUSION
CONCLUDING REMARKS
The large number of studies performed to analyze the interactions among
nutritional state, cytokines, and immunity indicate the extreme complexity
of this cytokine network. Clinical trials are testing the efficacy of
administration in humans of leptin as anti-obesity hormone [62]. Recent
evidence from the literature shows that recombinant leptin in obese subjects,
in which leptin resistance reigns, does not determine great weight reducing
effects [63]. As expected, its efficacy seems to be higher in obese subjects
with genetic leptin deficiency, representing a minority of the obese population
[64]. With the increasing evidence of leptin effect on T cell, only clinical
research will decide whether administration of leptin to malnourished
or immunosuppressed individuals will be of therapeutic benefit. Beyond
these cases, it remains uncertain whether leptin will find greater use
in the treatment of obesity or in immunosuppressed individuals. Given
leptin's multiplicity of activities [65-68] we belive that in the future,
additional and unexpected consequences of leptin influences on immune
function will emerge.
Acknoledgements. We would like to thank Dr. Antonio Di Giacomo,
Dr. Veronica Sanna for critical reading of the manuscript. We are also
particularly indebted to Prof. Serafino Zappacosta and Dr. Silvia Fontana
for their constant enthusiastic support. The work is supported by the
AISM (Associazione Italiana Sclerosi Multipla).
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