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Rheumatology Advance Access originally published online on February 11, 2008
Rheumatology 2008 47(4):387-389; doi:10.1093/rheumatology/kem389
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIAL

Leptin and ANCA-associated vasculitis: a healthy link?

M. Thewissen and J. W. Cohen Tervaert

Cardiovascular Research Institute Maastricht (CARIM), Department of Internal Medicine, Division of Clinical and Experimental Immunology, Maastricht University, Maastricht, The Netherlands

Correspondence to: J. W. Cohen Tervaert, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail: jw.cohentervaert{at}immuno.unimaas.nl

Leptin is a 16-kDa peptide hormone that is mainly produced by adipocytes. It structurally resembles the pro-inflammatory cytokines IL-6 and IL-12. Leptin has been recognized as a key factor regulating body weight by inhibiting food intake and stimulating energy expenditure. In addition, leptin exerts pleiotropic actions in modulating immune responses. It activates monocytes and macrophages and contributes to the maturation and survival of dendritic cells. Importantly, leptin has also been shown to modulate the adaptive immune system, via enhancing T-cell survival and skewing T-cell differentiation towards a Th1 response. Recently, several papers demonstrated that leptin also affects homeostasis and function of CD4+CD25+ regulatory T (Treg) cells. Therefore, leptin dysregulation may be involved in the pathogenesis of autoimmune diseases such as ANCA-associated vasculitis.

Treg cells in autoimmune diseases
Autoimmune diseases are initiated by a loss of immunological tolerance to self antigens. The generation of autoreactive T and B cells is inherent to their maturation and selection processes in the thymus and bone marrow, respectively. Therefore, peripheral T-cell activation is under stringent control to limit inappropriate, self-reactive immune responses. A population of CD4+CD25+ T cells, expressing the forkhead/winged helix transcription factor ‘Forkhead box’ (FOX)P3, is believed to be a key mediator of active peripheral tolerance. Evidence for the involvement of this T-cell subset in maintaining tolerance originally came from animal models. Depletion of Treg cells exacerbated, whereas adoptive transfer of this cell population prevented a wide range of experimental autoimmune diseases [1–3]. In humans, decreased frequencies and/or defective function of Treg cells have been documented in several autoimmune diseases, including RA, multiple sclerosis (MS), SLE and diabetes mellitus type 1 [4, 5]. In contrast, the Treg population was increased in patients with ANCA-associated vasculitis, but these Treg cells were functionally defective as illustrated by a diminished capacity to suppress effector T-cell proliferation [6]. These findings indicate that a diminished ability to maintain peripheral tolerance, as evidenced by a dysfunctional Treg compartment, is critically involved in the pathogenesis of autoimmune diseases. Since leptin has been found to influence Treg numbers and function, leptin could be the missing link between dysfunctional regulation and development of autoimmune diseases.

Leptin and Treg cells
Freshly isolated Treg cells were found to constitutively express high amounts of both leptin and the leptin receptor. De Rosa et al. [7] showed that leptin signalling was involved in maintaining the anergic state of human Treg cells. In vitro neutralization of leptin resulted in Treg proliferation. In agreement with this, both leptin deficiency (ob/ob mice) and leptin receptor deficiency in mice (db/db mice) was associated with a marked increase in the number of Treg cells [8, 9]. Discrepancies, however, were observed in these studies with regard to the suppressive capability of the expanded Treg cells. In the presence of leptin neutralizing mAb, human Treg cells displayed a diminished suppressive capacity in in vitro co-culture experiments, whereas Treg cells from db/db mice showed an increased suppressive function both in vitro and in vivo.

Leptin levels in autoimmune disease
Mice lacking leptin or the leptin receptor are less susceptible for developing an experimental autoimmune disease. Leptin-deficient (ob/ob) mice are resistant to induction of both active and adoptively transferred Experimental Autoimmune Encephalomyelitis (EAE), whereas this protection is reversed by leptin administration. Also, leptin administration worsens disease course in EAE-susceptible mice strains [10]. In addition, experimental arthritis was found to be less severe in leptin and leptin receptor-deficient mice [11]. In human autoimmune settings, the leptin picture seems to be more complicated. In Th1-mediated autoimmune diseases, leptin might enhance inflammation and worsen disease course. Matarese and colleagues [9] reported on elevated leptin levels in both serum and cerebrospinal fluid of MS patients. These elevated leptin levels correlated with reduced numbers of circulating Treg cells. In contrast, a significant inverse relation between inflammation and leptin concentrations was found in patients with active RA [12].

Leptin and ANCA-associated vasculitis
In this issue of Rheumatology, Kümpers and colleagues studied for the first time ghrelin and leptin levels in ANCA-associated vasculitis (WG, microscopic polyangiitis) [13]. Like leptin, ghrelin exerts immune modulatory effects in addition to metabolic and neuroendocrine actions. In contrast to leptin, ghrelin seems to display inhibitory effects on inflammatory processes. Unexpectedly, leptin levels were decreased, whereas ghrelin levels were increased in patients with active ANCA-associated vasculitis. However, both leptin and ghrelin levels normalized during follow-up after immunosuppressive treatment. The authors detected a positive correlation between ghrelin levels and disease activity, whereas leptin levels correlated negatively with disease activity. Similar results have been reported for leptin and ghrelin levels in AS [14]. Both AS and WG are frequently accompanied by anorexia and weight loss. Since leptin levels correlate positively with the amount of adipose tissue, the observed decreased leptin levels in AS and WG may have been a consequence of wasting.

Microbial infections are thought to play an important role in the pathophysiology of both ANCA-associated vasculitis and AS. In ANCA-associated vasculitis, several lines of evidence point towards a two-hit process, in which ANCAs together with pro-inflammatory stimuli, most likely of infectious origin, are sufficient for the development of full-blown disease [15]. Chronic nasal carriage of Staphylococcus aureus was found to increase the risk for disease relapse in ANCA-associated vasculitis and Klebsiella infection has been implicated in the pathogenesis of AS [16, 17]. It has been documented that the risk of infection and death is highest when energy reserves are not sufficient. Accumulating evidence points out that leptin may play an important role in the regulation of the immune system in energy-deficient states. In humans, congenital leptin deficiency has been associated with childhood infections and early mortality and a reduced Th1 immunity, all of which could be reversed by leptin administration [18]. The exact mechanism by which low or absent leptin levels increase susceptibility to infections is not completely understood. Leptin absence may trigger Treg proliferation and thereby reduce defence against microbial infections. On the other hand, in the absence of leptin a Th2 cytokine profile may be favoured, which is detrimental for immunity against microbes. In ANCA-associated vasculitis, leptin levels are decreased and correlate negatively with disease activity. In addition, circulating Treg cells are increased in ANCA-associated vasculitis patients both during active disease (unpublished observation) and during remission. In the remission phase, these Tregs have been demonstrated to be functionally defective [6]. Whether the Treg population is also dysfunctional during active disease, has not been properly studied yet. We hypothesize that decreased leptin levels may result in an increased susceptibility to infections. Infections may trigger autoimmunity in (genetically) susceptible individuals, e.g. by molecular mimicry. Otherwise, Th2 cells induced by low leptin levels may enhance autoantibody production and infections may exacerbate the autoimmune response by toll-like receptor triggering or other mechanisms [19].

Conclusions

Both high and low levels of leptin might contribute to autoimmune diseases (Fig. 1). Low leptin levels result in a Th2 skewing and an increased risk for microbial infection and thereby increase the risk for disease induction and/or disease relapses. In contrast, high leptin levels favour Th1 immune responses and negatively affect Treg cells and peripheral tolerance. Altogether, it is clear that leptin levels should be maintained within the ‘normal’ range. Whether leptin levels predict disease flare or whether normalizing leptin levels exert beneficial effects on disease activity needs further study.


Figure 1
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  		FIG. 1. Immune modulatory actions of leptin. Infection, Treg cells, autoantibodies and Th1 skewing have all been implicated in the pathophysiology of autoimmune diseases. Directly, via modulation of the Treg population, alteration of the cytokine balance, or enhancement of autoantibody production or indirectly via influencing susceptibility to microbial infections, leptin can contribute to autoimmune disease pathogenesis.

 
Without doubt, leptin is an important modulator of T-cell function. Both in vitro and in vivo studies support involvement of leptin in the pathophysiology of autoimmune diseases such as ANCA-associated vasculitis. However, the relation between leptin levels and ANCA-associated vasculitis proposed here may be oversimplified. Besides leptin, other potentially interesting factors, such as neuropeptide Y, visfatin and apelin, may be involved. These molecules are implicated in the regulation of food intake and metabolism, but may in addition exert immune modulatory actions. In addition, macrophage inhibitory cytokine-1 (MIC-1), is a newly defined regulator of appetite that is involved in tumour-induced anorexia [20]. MIC-1 might be critically involved in weight loss and appears to be another interesting target for further research in ANCA-associated vasculitis.

Disclosure statement: The authors have declared no conflicts of interest.

References

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Accepted 21 December 2007


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