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Keywords:

  • autoimmunity;
  • immune tolerance;
  • inflammation;
  • leptin;
  • T cells

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

It has recently become apparent that several molecules involved in the control of metabolism also play an important function in the regulation of immune responses. Among those molecules, the adipocyte-derived cytokine leptin has been shown to significantly influence innate and adaptive immune responses both in normal and in pathological conditions. For example, levels of leptin are typically low in infection and high in autoimmunity, both systemically and at the site of inflammation. Moreover, in addition to its long-known effects on the promotion of T helper 1 immune responses and cell-mediated immunity, leptin has more recently been found capable to constrain proliferation of regulatory T cells. As such, leptin represents not only a link between metabolism and immune responses in general but also a pivotal modulator of the magnitude of selected mechanisms of peripheral immunity in relation to body fat mass. We review here the most recent advances on the role of leptin in the control of immune tolerance and critically discuss how strategies aimed at neutralizing the leptin axis could represent innovative tools for the therapy of autoimmune disorders.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

Leptin, an adipocyte-derived hormone of the long-chain helical cytokine family, represents a link between metabolism, nutritional status, and immune response (1, 2). Leptin has multiple biological effects on the control of food intake in relation to the endocrine and immune functions. The circulating concentration of serum leptin is proportional to the mass of body fat (2), and nutritional deprivation (which results in reduced fat stores and typically associates with hypoleptinemia) is often characterized by immune deficiency and increased risk of infection (1–3). Considering that congenital deficiency of leptin can associate with increased frequency of infection and related mortality (4), it was hypothesized that a low concentration of serum leptin might contribute to increased susceptibility to infection by reducing T helper (Th) cell priming and by affecting thymic function (5, 6). On the contrary, the Th1-promoting effects of leptin have been linked with clarity to an enhanced susceptibility to develop experimentally induced autoimmune disease including experimental autoimmune encephalomyelitis (EAE), type I diabetes (T1D), and antigen-induced arthritis (AIA) (4). This aspect is also of interest in relation to the well-known gender bias in susceptibility to autoimmunity. Autoimmune diseases are frequently more prevalent in females, and females are relatively hyperleptinemic, whereas males are relatively hypoleptinemic (2, 4). It has been speculated that leptin could in part contribute to the gender-biased susceptibility to autoimmunity, and some work in mice seems to support this possibility.

While more experimental evidence is needed to unequivocally define the role of leptin in several autoimmune conditions, it is nonetheless exciting that new developments in the field are leading to several new lines of inquiry. In this context, it is worth mentioning that leptin may only represent one of the many factors derived from the adipose tissue and neuroendocrine system that – in addition to playing an important function in the regulation of food intake and metabolism – also affect significantly the immune response. These mediators include adiponectin, visfatin, neuropeptide Y (NPY), and ghrelin (7).

Effects of leptin on innate and adaptive immunity and on T cell regulation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

Many studies have investigated the effects of leptin on innate and adaptive immune responses (Figure 1).

image

Figure 1. Schematic representation of the pleiotropic effects of leptin in immunity and pathogenesis of autoimmune responses. Leptin secreted by adipose tissue is involved in both innate and adaptive responses. Leptin exerts opposite effects on proliferation of effector T cells and on TRegs. More specifically, adipocyte-derived (proportional to fat mass) and T-cell-derived leptin stimulate effector T cell proliferation while costrain TRegs proliferation. These pleiotropic actions of leptin may contribute to the different autoimmune vs infectious diseases susceptibility observed in affluent countries together with the contribution of environmental, genetic, and neuroendocrine factors. HLA, human leukocyte antigens; IL-2, interleukin-2; LepR, leptin receptor; NK, natural killer; Th, T helper; TRegs, regulatory T cells.

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In innate immunity, leptin upregulates the phagocytic function of mouse macrophages/monocytes through phospholipase activation (8). In macrophages, leptin also upregulates secretion of proinflammatory cytokine such as tumor necrosis factor-α (TNF-α) (early), interleukin (IL)-6 (late), and IL-12 (8, 9). The facilitating effects of leptin on macrophages/monocyte function have been confirmed in humans. In particular, it has been shown that leptin can stimulate the proliferation of human circulating monocytes in vitro and can upregulate the expression of activation markers including CD38, CD69, CD25 (IL-2 receptor α-chain), and CD71 (transferrin receptor), increasing at the meantime the expression of already highly expressed surface markers of activation on resting monocytes, such as human leukocyte antigen-DR, CD11b, and CD11c (10).

On polymorphonuclear cells of healthy individuals, leptin stimulates the production of reactive oxygen species and chemotaxis through mechanisms that remain controversial and that may or may not involve an interaction with monocytes (11).

Finally, in natural killer cells, leptin contributes to cell development, differentiation, proliferation, activation, and cytotoxicity by means of effects mediated by phosphorylation of signal transducers and activator of transcription-3 (STAT-3) and upregulated gene expression for perforin and IL-2 (12).

In adaptive immunity, leptin has pleiotropic effects, possibly reflecting the elevated adaptability of this arm of the immune system in providing broad responsiveness toward different molecular structures through restricted recognition of peptides/major histocompatibility complex (MHC) complexes (Figure 1). The most evident effects of leptin on the modulation of adaptive immune responses have been shown in leptin-deficient mice (Lepob, also known as ob/ob mice) and in humans with congenital deficiency of leptin. In those cases, metabolic disturbances paralleled by immune abnormalities (i.e. thymic hypotrophy and reduced secretion of inflammatory cytokines) are dramatically reversed by administration of recombinant leptin (13).

In leptin receptor (LepR)-deficient, leptin-resistant Leprdb1J mice (also known as db/db mice), a role of leptin in lymphopoiesis is suggested by the finding of reduced lymphoid cell colony-forming potential under conditions that favor lymphoid expansion of bone marrow cells (3, 4).

From a physiological standpoint, during ontogeny, leptin provides a survival signal for double-positive CD4+CD8+ and single-positive CD4+CD8 thymocytes during the energy-consuming processes of T lymphocyte maturation (6) (Figure 1).

In the periphery, leptin has important effects on activation of lymphocytes. In contrast to its effects on macrophages/monocytes, leptin alone is unable to induce proliferation and activation of mature human peripheral blood lymphocytes unless it is coadministered with other nonspecific immunostimulants, in which case leptin induces early (CD69) and late activation markers (CD25, CD71) in both CD4+ and CD8+ lymphocyte compartments (5). However, the proliferative effect of leptin seems to be specific only for distinct lymphocyte subpopulations. More specifically, leptin induces proliferation of naive CD4+CD45RA+ T cells but inhibits proliferation of memory CD4+CD45RO+ T cells (5). At the functional level, leptin polarizes Th cytokine production toward a proinflammatory [Th1, interferon-γ (IFN-γ)] rather than an anti-inflammatory phenotype (Th2, IL-4) (5) (Figure 1). These effects seem to be mediated, at least in part, by promoted T lymphocyte survival and upregulated expression of antiapoptotic proteins such as bcl-X and T-bet, in addition to synergistic effects with other cytokines involved in lymphocyte proliferation and activation, possibly through common activation of STAT-3 signaling pathways (14).

Very recently, it has been reported that leptin can act as a negative signal for the expansion of human naturally occurring Foxp3+CD4+CD25high regulatory T cells (TRegs) (Figure 1) (15). De Rosa et al. showed that freshly isolated TRegs produce leptin and express high levels of LepR. In vitro neutralization with anti-leptin monoclonal antibody (mAb) following anti-CD3/CD28 stimulation resulted in TRegs proliferation. The TRegs that had expanded in the presence of anti-leptin mAb had increased expression of Foxp3 and had a partial suppressive capability that improved when the TRegs entered the cell cycle resting phase. These phenomena were secondary to the modulation of selected molecular pathways of T cell activation and anergy in the TRegs, as indicated by the downmodulation of the cyclin-dependent kinase inhibitor p27kip1 and the phosphorylation of the extracellular-related kinases 1/2 (15).

Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

Multiple sclerosis (MS) is a chronic, immune-mediated, human chronic inflammatory disorder of the central nervous system (CNS) (16). The most studied model of MS in animals is EAE, in which autoimmunity to CNS components is induced in susceptible strains of mice through immunization with self-antigens derived from basic myelin protein. The disease is characterized by autoreactive T cells that traffic to the brain and to the spinal cord and injure the myelin sheaths of CNS, with the result of chronic or relapsing-remitting paralysis (depending on the antigen and the strain of mice used) (16).

It has long been known that myelin-reactive Th1 CD4+ cells can induce and/or transfer disease, and Th1 cytokines are elevated in the CNS inflammatory lesions of EAE. In contrast, Th2 cytokines typically associate with recovery from EAE and/or protection from the disease (16).

It has been shown that leptin is involved in both the induction and in the progression of EAE (17, 18). Genetically, leptin-deficient Lepob mice are resistant to induction of both active and adoptively transferred EAE. This protection is reversed by leptin administration and associates with a switch from Th2- to Th1-type responses and IgG1 to IgG2a isotype switch. Similarly, in susceptible wild-type C57BL/6J mice, leptin worsens disease by increasing IFN-γ release and IgG2a production (17).

Importantly, a surge of serum leptin anticipates the onset of clinical manifestations of EAE (18). The peak of serum leptin correlates with inflammatory anorexia, weight loss, and the development of pathogenic T cell responses against myelin (18). Lymphomononuclear infiltrates in the CNS of EAE mice indicate in situ production of leptin in active inflammatory lesions, thus representing a significant local source of leptin (18). Systemic and/or in situ leptin secretion was instead lacking in EAE-resistant mice. Taken together, these data suggest an involvement of leptin in CNS inflammation in the EAE model of MS. In the human disease, it has been reported that the secretion of leptin is increased in both serum and cerebrospinal fluid (CSF) of naive-to-treatment patients with MS, an aspect that positively correlates with the secretion of IFN-γ in the CSF and inversely correlates with the percentage of circulating TRegs– a key subset of lymphocytes involved in the suppression of immune and autoimmune responses that is reduced in patients with MS as compared with healthy matched controls (19). Of note, the number of peripheral TRegs in patients with MS inversely correlates with the serum levels of leptin, suggesting a link between the number of TRegs and leptin secretion (19). Considering that TRegs are generated in the thymus, it is not known whether peripheral leptin or that produced in the perithymic adipose tissue could affect TRegs generation/function in autoimmunity-prone subjects. This aspect is not defined yet and is object of current extensive investigation.

In any case, the fact that increased leptin secretion occurs in acute phases of MS and correlates with CSF production of IFN-γ is of possible interest for the pathogenesis and clinical follow-up of patients with MS. As mentioned before, increased leptin secretion is present both in the serum and in the CSF of patients with MS and does not correlate with body mass index (BMI) (19). The increase of leptin in the CSF is higher than in the serum, suggesting possible secondary in situ synthesis of leptin in the CNS and/or an increased transport across the blood–brain barrier following enhanced systemic production.

A recent gene microarray analysis of Th1 lymphocytes from active MS lesions has shown elevated transcripts of many genes of the neuroimmunoendocrine axis, including leptin (20). Leptin transcripts were also abundant in gene expression profiles of human Th1 clones, confirming that leptin gene transcription is induced concomitantly with the polarization toward Th1 responses – which are often involved in T-cell-mediated autoimmune diseases including MS. Moreover, in situ secretion of leptin near inflammatory T cells and macrophages was observed in active EAE lesions (18). A possible explanation for the in situ elevated levels of leptin in the CSF of patients with MS could be the inflammatory cell itself, as suggested by studies with autoreactive human myelin basic protein (hMBP)-specific T cells from patients with MS that produced leptin and upregulated the expression of leptin receptor after activation (18, 19). Both anti-leptin and anti-leptin receptor-blocking antibodies reduced the proliferative responses of the hMBP-specific T cell lines to antigen stimulation, underlying a possibility of leptin-based intervention on this autocrine loop to block autoreactivity (18, 19).

Finally, recent reports (21) have shown increased secretion of serum leptin before relapses in patients with MS during treatment with IFN-β, and a capacity of leptin to enhance in vitro secretion of TNF-α, IL-6, and IL-10 from peripheral blood mononuclear cells of patients with MS in acute phase of the disease but not in patients with stable disease (21). In view of all these considerations, we suggest that leptin could be one of the many proinflammatory factors that act in concert to promote the pathogenic (autoreactive) Th1 responses targeting neuroantigens in MS.

Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

Increased serum leptin levels and leptin resistance have typically been associated with obesity – more commonly associated with human type II diabetes rather than TID – and have not conferred increased risk to development of the latter (22).

Until quite recently, most of the associations of leptin with diabetes have been with two recessive obesity mutations in mice originally termed ‘obese’ (chromosome 6) and ‘diabetes’ (chromosome 4). The former abrogates expression of the leptin gene (Lepob) and the latter mutation produces a truncated signaling-defective receptor (Leprdb1J). Either mutation homozygous on the C57BL6/J background produces an identical syndrome of massive obesity and insulin resistance but with initial hyperglycemia, which is eventually compensated by pancreatic β cell expansion and remission from diabetes. On the related C57BLKS/J (BKS) background, the same two mutations produce an obesity insulin resistance syndrome that is not compensated by sustained β cell hyperplasia, thus leading to a permanent, life-shortening syndrome with aspects of both type 2 diabetes and TID (23). Hence, diabetogenesis in these monogenic obesity models appears not strictly as a function of a disturbed leptin–leptin receptor axis and the attendant insulin resistance syndrome but it seems to rather require complex interactions with multiple genes in the inbred strain background (24). Although the BKS-Leprdb1J diabetes model is generally considered to be reflective of type II diabetes, the juvenile onset of diabetes coupled with massive loss of islet β cell, as well as immunodeficiencies associated with the severe insulin resistance, has led immunologists to examine whether immune/autoimmune components are present. Indeed, some cellular and humoral immunity against islets was found (25). It was subsequently shown that the obesity-induced diabetes occurred in the presence of immunodeficiency mutations, indicating that any anti-islet immunity was a secondary feature not essential for pathogenesis (26).

In contrast to the monogenic obesity models wherein immunity, at best, plays a secondary role in diabetes pathogenesis, the nonobese diabetic (NOD) mouse clearly represents a model of T-cell-mediated autoimmune TID. Both MHC and non-MHC genes contribute to numerous immunodeficiencies in both the innate and the adaptive arms of the immune system (27). Indeed, diabetogenesis in NOD mice represents a ‘threshold’ pathway of an immune system capable of maintaining immune homeostasis if sufficiently challenged by environmental stimuli, particularly microbial agents (27). This accounts for the relative ease whereby numerous experimental immunostimulations can suppress the diabetogenic process in NOD mice (28). Balanced against the large number of treatments that retard or prevent clinical diabetes development in NOD mice is the relative paucity of treatments that precipitate spontaneous TID in juvenile females. It was, therefore, a surprise that early postnatal leptin administration at pharmacologic doses represented such a treatment (29). The simple observation that early (6-week) serum leptin levels in NOD/LtJ females were higher than that for diabetes-resistant strains led Matarese et al. (29) to test the hypothesis that leptin might be a critical endocrine contributor to the activation of diabetogenic T cells. Weekly leptin injections between 1 and 4 weeks of age, followed by more intensive treatment over the next 2 weeks, produced an astonishing ∼85% diabetes at 7 weeks of age in treated females. The treatment was specific for females; diabetogenesis in males was not accelerated. This leptin effect to accelerate diabetogenesis in females was unexpected. A previous study using stocks of NOD/Shi mice congenic for either Leprdb1J or Lepob(30) reported development of a transitory type II diabetes syndrome manifested by obesity, hyperinsulinemia, and islet hyperplasia, which nonetheless culminated in a hypoinsulinemic, insulitis-driven TID syndrome (30). One would have predicted that if endogenous leptin were critical to development or activation of autoimmune T effectors, then some diabetes-retardant or protective effects in NOD mice deficient in leptin or its long-form signaling receptor might have been expected.

Such a deviation in the NOD model was observed in a new mutation in the leptin receptor (Leprdb5J) that spontaneously occurred in the large production colony of NOD/LtJ mice at The Jackson Laboratory. A novel glycine640valine transition mutation in the extracellular domain of the NOD leptin receptor did not reduce expression of either the short isoform or long (signaling) isoform (31). STAT-3 recruitment/phosphorylation is commonly studied as the downstream target of leptin receptor activation by ligand. Leptin binding to COS7 cells transfected with mutant vs wild-type complementary DNA was reduced 50% and no activation of a cotransfected STAT-3 promoter luciferase gene was observed (M. Maamra and R. Ross, unpublished data). Like the original Leprdb1J mutation, the defective Leprdb5J mutation produced obesity and insulin resistance, but, in seeming contrast to the report using NOD mice congenic for the Leprdb1J mutation, the early-onset type II diabetes syndrome produced in NOD by the Leprdb5J mutation suppressed activation of autoimmune T effector cells (32). Indeed, in an initial incidence study, all mutant females and at least one third of mutant males spontaneously remitted to normoglycemia, with insulitis limited to the islet perimeters. Remission was correlated with massive pancreatic β cell hyperplasia. Although human CD4+ T cells reportedly express the LepR-Rb long form, only short form (LepR-Ra) was detected by reverse transcription polymerase chain reaction on purified NOD leukocytes, with receptor long form only detected on thymic and splenic stromal elements after removal of lymphocytes. When lethally irradiated wild-type NOD/Lt mice were reconstituted with bone marrow from either obese diabetic NOD-Leprdb5J or wild-type donors, destructive insulitis and a TID ensued. In contrast, when obese Leprdb5J females were recipients of marrow from either genotype, destructive insulitis was suppressed such that the syndrome remained a compensated type II diabetes in most recipients. In addition to increasing β cell mass (both by eliciting replication of preexisting β cell and neogenesis from what appeared to be centroacinar cells), the altered environment in Leprdb5J mice produced macrophages that suppressed T cell activation in vitro(32). The macrophage-secreted factor(s) remain to be identified.

Although the LepR signaling deficiencies producing obesity are predominantly associated with JAK/STAT-3-dependent pathways in the CNS, one of the many immune dysfunctions associated with impaired innate immune responses of macrophages from wild-type NOD mice is hyperphosphorylation of STAT-5. This phenotype, in turn, has been associated with their high release (which was not IL-10 suppressible) of the proinflammatory prostanoid, prostaglandin E2 (33, 34). Both freshly isolated peritoneal and bone-marrow-derived NOD macrophages from wild-type and Leprdb5J donors were analyzed in vitro for this hyperphosphorylation phenotype (D. Pomerleau and E. H. Leiter, unpublished data). Compared with wild-type NOD macrophages, it was observed greatly reduced, but nonetheless clearly demonstrable leptin-mediated STAT-3 phosphorylation in NOD-Leprdb5J macrophages (vs none in BKS-Leprdb1J macrophages). Hence, at least in Leprdb5J macrophages, an effect of leptin was observed, but one that was significantly attenuated. This attenuation was especially significant in the context of the STAT-5 hyperphosphorylation phenotype characterizing wild-type NOD macrophages. Although Leprdb5J macrophages exhibited some leptin stimulation of STAT-5 phosphorylation, it was significantly less than in wild-type NOD macrophages. Hence, one of the protective mechanisms underlying the Leprdb5J mutation may entail mitigation of the STAT-5 hyperphosphorylation defect. It is noteworthy that many non-STAT-3-dependent intracellular signaling pathways responsive to leptin are now being recognized (35, 36).

Given the findings summarized above that leptin constrains proliferation of human TRegs(15, 19) such that high concentrations can exacerbate development of autoimmunity, the T cell suppression associated with alterations in the innate immune system of leptin-resistant NOD-Leprdb5J mice might conceivably be due, in part, to a correction in the known functional impairment of TRegs(37) or invariant CD4+ natural killer T (NKT) (CD4+iNKT) cells (38) in NOD mice. However, NOD-Leprdb5J mice did not differ significantly from wild type in either percentage or total numbers of CD4+CD25+ T cells (putative TRegs) in peripheral blood or spleen (32). More recent costaining of this population with Foxp3 again showed no significant differences (E. H. Leiter, unpublished data). Similarly, we have used tetramers to stain for peripheral CD4+iNKT cells in spleen and again found no significant differences between wild-type and mutant percentages or total numbers.

Leptin in systemic autoimmunity: still an open question

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

AIA is a model of immune-mediated joint inflammation induced by administration of methylated bovine serum albumin (mBSA) into the knees of immunized mice (39). The severity of arthritis in leptin and leptin-receptor-deficient mice was reduced. The milder form of AIA seen in Lepob and Leprdb1J mice, as compared with controls, was accompanied by decreased synovial concentrations of IL-1β and TNF-α, decreased in vitro proliferative response to antigen in lymph node cells, and a switch toward the production of Th2 cytokines (39). Serum levels of anti-mBSA antibodies were also significantly decreased in the arthritic Lepob mice, as compared with controls.

Thus, in AIA, leptin may probably contribute to joint inflammation by regulating both humoral and cell-mediated immune responses. However, joint inflammation in AIA depends on adaptive immune responses, which are impaired in Lepob and Leprdb5J mice. More recent studies have investigated the effect of leptin and leptin receptor deficiency on the inflammatory events of zymosan-induced arthritis (ZIA), a model of proliferative arthritis restricted to the joint injected with zymosan A and not dependent on adaptive immune responses (40). ZIA, in contrast to AIA, was not impaired in Lepob and Leprdb1J mice. However, the resolution of acute inflammation was delayed in the absence of leptin or leptin signaling, suggesting that leptin could exert beneficial influences on the evolution of this model of arthritis (40).

In humans, patients with rheumatoid arthritis (RA) with reduced serum leptin levels induced by fasting reportedly had improved clinical and biological measures of disease activity associated with a decrease of CD4+ lymphocyte activation and a shift toward Th2 cytokine production (41). These aspects, resembling somehow those seen in AIA in Lepob mice, suggested that leptin could also influence inflammatory arthritis in humans through an influence on Th1 responses. However, the reduction of serum leptin concentration in patients with RA following a 7-day ketogenic diet did not lead to significant changes in any clinical or biological measurements of disease activity (42).

Other studies by Bokarewa et al. (43) reported increased leptin plasma levels in 76 patients with RA as compared with healthy controls. These authors found that leptin levels in synovial fluid were reduced as compared with matched plasma samples, and the difference between plasma and synovial fluid was particularly pronounced in nonerosive arthritis. The authors suggested that a local consumption of leptin in the joint could exert a protective effect against the destructive course of RA. Consistent with this hypothesis, treatment with recombinant leptin reduced both the severity of joint manifestations in Staphylococcus aureus-induced arthritis and the inflammatory response in terms of serum IL-6 levels, without affecting the in vivo survival of the bacteria (44). Contrasting results were obtained by Popa et al. (45). These authors found a significant inverse correlation between inflammation and leptin concentration in patients with active RA (although plasma leptin concentration did not significantly differ from that observed in healthy controls). The authors suggest that active chronic inflammation may lower plasma leptin concentrations (45), and also another group reported lower plasma leptin levels in patients with RA than in controls (46), without correlation with BMI, C-reactive protein, or disease activity score (46). Others groups have found that serum levels of leptin may not be increased in patients with RA and/or that a correlation may exist between leptin levels and clinical or biological signs of disease activity, whereas a positive correlation is always seen between leptin and BMI, or percentage of body fat (46).

In summary, despite methodological differences and contrasting results, these data suggest overall that leptin may influence arthritis in two opposing ways, either by enhancing the expression of Th1 cytokines or by modulating the inflammatory responses. Additional studies are needed to clarify the variability and different effects on joint damage in the different experimental settings and possible correlations between leptin and selected disease aspects.

Leptin in other conditions: immune-mediated disorders of the liver and the kidney

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

Protection of Lepob mice from autoimmunity is also observed in experimentally induced hepatitis (EIH) (9, 47). Activation of T cells and macrophages is one of the initial events during viral or autoimmune hepatitis. Activated T cells are directly cytotoxic for hepatocytes and release proinflammatory cytokines, which mediate hepatocyte damage. A well-described mouse model of T-cell-dependent liver injury is the one induced by i.v. injection of the T cell mitogen concanavalin A (Con A), which results in fulminant hepatitis. During Con-A-induced hepatitis, TNF-α is a crucial cytokine in the acute disease process because neutralization of this cytokine reduces liver damage. On the other hand, the injection of TNF-α causes acute inflammatory hepatocellular apoptosis followed by organ failure, and TNF-α thus appears to cause hepatoxicity.

Siegmund et al. (47) showed that leptin-deficient Lepob mice were protected from Con-A-induced hepatitis. TNF-α and IFN-γ levels, as well as expression of the activation marker CD69, were not elevated in Lepob mice following administration of Con A, suggesting that their resistance was associated with reduced levels of those proinflammatory cytokines, together with low percentages of intrahepatic NKT cells (which are cells that contribute to progression of this disease) (47).

Similar results were obtained in EIH induced by Pseudomonas aeruginosa exotoxin A administration (9). Also in this case, leptin administration restored responsiveness of Lepob mice to EIH, and T lymphocytes and TNF-α were required for the induction of liver injury. The authors also showed that leptin played an important role in the production of two proinflammatory cytokines in the liver, namely TNF-α and IL-18 (9). In humans, inflammatory liver disorders, such as steatohepatitis, have shown conflicting results in that leptin levels were increased or decreased according to the clinical stage, sex, and age of the patients. Thus, further investigation is needed.

More recently, protection from autoimmunity in Lepob mice has been observed in experimentally induced glomerulonephritis (48). In this immune-complex-mediated inflammatory disease induced by injection of sheep antibodies specific for mouse glomerular basement membrane into mice preimmunized against sheep IgG, the authors observed renal protection of Lepob mice associated with reduced glomerular crescent formation, reduced macrophage infiltration, and glomerular thrombosis. These protective effects were associated with concomitant defects of both adaptive and innate immune response (testified by reduced in vitro proliferation of splenic T cells and reduced humoral responses to sheep IgG, respectively). In spite of this observed trend, in one experiment, Lepob mice developed histological injury, but these were still protected from disease, indicating that defects in the effector responses were present in Lepob mice, in line with the in vitro experiments that had indicated defective phagocytosis and cytokine production.

Finally, evidence that leptin may exert pathogenic effects in immune-mediated disorders of the kidney come from the finding that leptin is a renal growth and profibrogenic factor that contributes to endocapillary proliferation and subsequent development of glomerulosclerosis during renal damage in conditions possibly including diabetes and obesity, both characterized by high circulating leptin levels (49).

Leptin and autoimmunity: some concluding thoughts

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

Changes in diet and calorie intake and, subsequently, serum leptin concentration should be taken into account to explain the complex network connecting nutritional status and susceptibility to autoimmune and infectious diseases (1, 3, 7) (Figure 1). Animal studies provide support for this concept. In some murine models of systemic lupus erythematosus, autoimmune diabetes, and EAE, the induction and progression of disease can be prevented by starvation and/or reduced calorie intake, or by administration of nutrients, such as polyunsaturated fatty acids, which are capable of reducing inflammatory responses and leptin secretion (1, 3, 7). In humans, similar observations have been reported by Bruining (50), who described an increased incidence of autoimmunity at younger ages in affluent countries, where affluence is associated with increased postnatal growth and abundant nutrition (50). More specifically, children who developed diabetes had a greater gain in BMI in the first year of life compared with healthy siblings and the early presence of autoantibodies specific for IA-2 (pancreatic islet tyrosine phosphatase). Leptin, with its pleiotropic functions, including the promotion of Th1 responses, reduction of the apoptotic rate of thymocytes, reversal of acute-starvation-induced immunosuppression, and induction of expression of adhesion molecules [e.g. ICAM-1 and CD49b (integrin 2)] (Figure 1) (1, 3, 7), could be a good candidate in the contribution to the pathogenesis and maintenance of autoimmunity in genetically predisposed individuals. Conversely, malnutrition and nutritional deficiency might protect individuals from autoimmunity by lowering circulating leptin concentrations but predispose to infections, such as candidiasis, tuberculosis, pneumonia, and bacterial and viral diarrhea. Leptin receptor desensitization could be possibly perceived by T cells as a condition of leptin deficiency, leading to immune dysfunction in a similar manner to malnutrition and genetic leptin deficiency. Of note, the most common form of human obesity, characterized by hyperleptinemia that causes central and peripheral leptin resistance, is associated with an increased frequency of infections (Figure 1) (1, 3, 7).

Future perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References

Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic functions. Many functions of this molecule remain to be investigated. However, in view of its influence on food intake and metabolism, leptin situates at the interface between metabolism and immunity in modulating not only inflammation but also immune and autoimmune reactivity. Recently, molecules with orexigenic activity such as ghrelin and NPY (3, 7) have been shown to mediate effects opposite to leptin in the hypothalamic control of food intake and on peripheral immune responses. For example, ghrelin blocks leptin-induced secretion of proinflammatory cytokines by human T cells, and NPY ameliorates clinical score and progression of EAE (3, 7). Thus, several metabolic regulators including leptin might broadly influence vital functions not only by tuning caloric balance but also by affecting immune responses.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Effects of leptin on innate and adaptive immunity and on T cell regulation
  5. Leptin in organ-specific autoimmunity of the central nervous system: the case of multiple sclerosis
  6. Leptin in organ-specific autoimmunity of the pancreas: leptin is a classical type II diabetes susceptibility gene but also plays a role in autoimmunity to β cells
  7. Leptin in systemic autoimmunity: still an open question
  8. Leptin in other conditions: immune-mediated disorders of the liver and the kidney
  9. Leptin and autoimmunity: some concluding thoughts
  10. Future perspectives
  11. Acknowledgments
  12. References
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