Aims: This reappraisal focuses on the most recent findings about the function of leptin in oncoming, development, clinical manifestations and results of multiple induration and applications of a possible leptin adversary for multiple induration patients and schemes for planing such an adversary. Organization: After an debut to leptin, we will concentrate on its function in the immune system and autoimmunity. Afterwards we will reexamine the literature around leptin and MS and eventually will discourse the relevant possible curative schemes based on the nexus between MS an leptin. Decision: Based on the available grounds schemes aimed at leptin hostility might stand for a fresh curative platform which deserved farther attending.
In 1994, leptin was discovered by Friedman and co-workers as a merchandise encoded by the ob cistron through the survey of corpulent mice [ 1 ] . The ob/ob or corpulent mouse is a mutant mouse enduring from a complex syndrome chiefly characterised by inordinate feeding, which consequences in deeply corpulent mice [ 2 ] . Leptin is a protein playing as both endocrine and cytokine consisting of 167 aminic acids and is an? -helical-bundle cytokine [ 3 ] . The construction of leptin is extremely similar to other members of this big cytokine household including growing endocrine, interleukins such as interleukin-6 ( IL-6 ) , IL-11, IL-12, granulocyte settlement exciting factor ( G-CSF ) and leukemia inhibitory factor ( LIF ) [ 4, 5 ] . Leptin is preponderantly produced by adipocytes and its go arounding degree positively correlates with white adipose tissue mass [ 6 ] . Administration of leptin to ob/ob mice additions basal metamorphosis and reduces nutrient consumption, taking to rapid weight loss [ 7-9 ] .
Leptin interacts with leptin receptor, besides known as Ob-R which is encoded by the dubnium cistron in human and has a individual transmembrane-spanning sphere [ 10 ] . Ob-R has besides been designated as CD295 ( bunch of distinction 295 ) [ 11 ] and belongs to the category I cytokine receptor superfamily [ 12 ] . Six isoforms of leptin receptor has been discovered ( Ob-Ra, B, degree Celsius, vitamin D, vitamin E and degree Fahrenheit ) : one long ( Ob-Rb ) , four short ( Ob-Ra, degree Celsius, vitamin D and degree Fahrenheit ) , and one secreted ( Ob-Re ) [ 13, 14 ] ; these are merchandises of alternate messenger RNA splice, and differ in the length of their intracellular dress suits but portion indistinguishable extracellular-binding spheres. [ 15 ] . Leptin binds to the ventromedial karyon of the hypothalamus, which is named the “ appetite centre ” [ 16 ] . Ob-Rb is present in a figure of hypothalamic nuclei [ 16 ] . The long isoform Ob-Rb has a long intracellular sphere in human and is responsible for most of the known effects of leptin through its complete intracellular tail, at which the signalling of four different tracts affecting JAKSTAT, MAPK, PI3K and AMPK can happen [ 14 ] . Ob-Rb is besides expressed by endothelial cells, CD34+ hematopoietic bone marrow precursors, monocytes/macrophages, T and B cells [ 5, 10, 17-22 ] . db/db mice possess a omission in the long isoform of the leptin receptor and therefore are immune to leptin [ 23 ] .
The short signifier ( Ob-Ra ) is much more widely expressed, frequently at higher degrees compared to long signifier, and is expressed in different variety meats such as in the choroid rete, kidney, cells of the immune system, lung and liver [ 5 ] . The short isoforms are believed to hold some signaling map and may besides be involved in leptin conveyance across the blood encephalon barrier and perchance in other, as yet unknown maps [ 24 ] .
The cytokine construction of leptin and recent grounds has indicated that it has a pleiotropic nature [ 25 ] . Probably the chief function of leptin is to modulate organic structure weight through the suppression of nutrient consumption and to increase energy ingestion by increased thermogenesis [ 26 ] . In add-on, leptin appears to be portion of the complex web that coordinates immune responses to assorted stimulations. Leptin besides balances the organic structure energy position and therefore adjusts the immune response to appropriate degrees. Immune responses are an energy-demanding procedures, and their suppression during famishment may conserve energy necessary for endurance of nucleus organic structure maps. Such interactions between energy homeostasis and the immune system appears to be bi-directional [ 27 ] .
Leptin and the immune system
Leptin and its receptors are independently regulated cistron merchandises: the ob cistron encodes for leptin, while the db cistron encodes for the leptin receptor. Mice with homozygous mutants in the leptin cistron are designated ob/ob and mice homozygous for mutants in the leptin receptor cistron are designated as db/db. The diverse functions for leptin in mammalian physiology are clearly shown by the complex syndromes exhibited by leptin-deficient ( ob/ob ) mice and deficient leptin receptor mice ( db/db ) . These mice are non merely corpulent, but besides show unnatural generative map, endocrine degrees, lesion fix, bone construction, and immune map [ 20, 28-32 ] . In add-on, both ob/ob and db/db mice suffer from thymic wasting and hold reduced Numberss of go arounding lymph cells [ 33-35 ] . Impaired T cell unsusceptibility in these mice points towards a direct consequence of leptin on T lymphocytes [ 29 ] , which may reflect CD4+ and CD8+ T cells express functional leptin receptor ( s ) [ 36, 37 ] . Leptin concentrations lowered by famishment appear to correlate with impaired immune responses in mice [ 38 ] . Since disposal of leptin to ob/ob but non db/db mice prevented immune disfunction, a cardinal function for leptin as an immune system regulator has been proposed [ 29, 39 ] .
Several writers have reviewed recent findings on leptins relationship with the immune system and autoimmune diseases [ 40-50 ] . Leptins effects on adaptative immune responses have been more extensively investigated compared to innate unsusceptibility. In vitro surveies have shown that leptin enhances proliferation of go arounding blood T lymphocytes in a dose-dependent mode [ 36, 37 ] . Addition of physiological concentrations of leptin to a Mixed Lymphocytes Reaction ( MLR ) induces a dose-dependent addition of the proliferation of CD4+ T cell [ 21 ] . Sing that inborn lack of leptin increases the frequence of infections and related mortality [ 51 ] , it was hypothesized that a low concentration of serum leptin may advance increased susceptibleness to infection by cut downing T assistant cell priming and by impacting thymic map [ 21, 29 ] . Leptin appears to impact the T assistant ( Th ) subsets, switching the balance towards the T assistant one ( Th1 ) subtype by exciting production of the Th1 proinflammatory cytokines such as, IL-2, interferon gamma ( IFN- ? ) , tumour mortification factor alpha ( TNF- ? ) , and IL-18, and decreases production of the Th2 cytokines: IL-4, IL-5 and IL-10 [ 36, 37 ] . These effects are non observed in T lymph cells from db/db mice, back uping the construct that this consequence is straight mediated by leptin receptors, expressed on T lymphocytes [ 48 ] .
Leptin besides influences other immune cell types. Peritoneal macrophages from ob/ob mice display a lower phagocytic activity, compared to macrophages from normal mice, and when leptin was administered, the phagocytic activity was restored [ 52 ] . Furthermore, the production of granulocyte macrophage settlement exciting factor ( GM-CSF ) , granulocyte colony-stimulating factor ( G-CSF ) [ 53 ] and the proinflammatory cytokines such as, TNF- ? , IL-6 and IL-12 [ 52 ] by murine macrophages is enhanced after intervention with leptin. It has besides been shown that leptin induces TNF- ? , IL-6 and IFN- ? production by resting human peripheral blood mononuclear cells ( PBMCs ) and enhances the release of these cytokines from stimulated PBMCs [ 54 ] . In human neutrophils, leptin appears to intercede its effects indirectly, likely affecting the release of TNF- ? from monocytes [ 55 ] which activates chemotaxis of lymph cells and monocytes [ 56 ] , to sites of redness [ 56, 57 ] . Furthermore, in ob/ob mice, Numberss of intraepithelial lymph cells ( IELs ) are reduced and these IELs exhibit decreased IFN- ? secernment, while the lamina propria mononucleate cells of these mice show increased programmed cell death [ 58 ] .
Leptin besides appears to be a regulator of natural slayer ( NK ) cells development and activation. The db/db mice show decreased Numberss of NK cells in the liver, lien, lung and peripheral blood, and in normal mice leptin disposal increases the basal or induced lysis of splenocytes, non seen in db/db mice [ 59 ] .
Leptin and Autoimmunity
Leptin, plays a signficant function in CD4+ T cell-mediated immune responses, advancing a proinflammatory Th1 response. The Th1 heightening belongingss of leptin have been shown to increase the susceptibleness of mice to develop by experimentation induced autoimmune diseases such as type 1 diabetes melitus ( T1D ) , antigen-induced arthritis ( AIA ) and experimental autoimmune encephalomyelitis ( EAE ) , an immune-mediated theoretical account of human multiple induration [ 60 ] . Roll uping grounds suggests that leptin besides plays a polar function in the development of CD4+ T cell mediated autoimmune diseases in human including Crohns disease [ 61 ] , arthritic arthritis ( RA ) [ 62 ] , multiple induration [ 63 ] and type I diabetes mellitus ( T1D ) [ 64 ] . ob/ob mice resist initiation of several experimental theoretical accounts of inflammatory and autoimmune diseases, such as experimental arthritis [ 65 ] , T cell-mediated hepatitis [ 66 ] and ague and chronic enteric redness [ 67 ] .
In experimental mouse theoretical account systems of inflammatory intestine disease ( Crohns disease with ague and chronic inflammatory bowel disease ) , leptin-deficient ob/ob mice showed a important ( 72 % ) lower inflammatory bowel disease disease badness with a coincident lessening in proinflammatory cytokines ( IFN- ? , TNF- ? , IL-1? , IL-18 and IL-6 ) in colon cell civilization supernatants, compared to wild type mice [ 58 ] . Administration of leptin to ob/ob mice eliminates resistance to by experimentation induced Clostridium difficile ( Cadmium ) inflammatory bowel disease [ 58 ] . In this theoretical account, CD toxin A caused a terrible inflammatory bowel disease in wild type mice ; ob/ob every bit good as db/db mice appeared to be partly protected against CD toxin A-induced intestine redness [ 67 ] . In this instance, leptin disposal in ob/ob, but non in db/db mice reversed this consequence [ 67 ] consistent with dependence on leptin receptor signaling.
The organ-specific autoimmune status termed chronic idiopathic thrombocytopenic peliosis ( ITP ) is characterized by production of antibodies against thrombocyte membrane antigens which causes their enhanced decomposition by macrophages [ 68 ] . Leptin enhances in vitro secernment of IgG anti-platelet antibodies by splenocytes and PBMCs from patients with chronic ITP [ 69 ] . After depletion of CD4+ T cells, this phenomenon was no longer observed [ 70 ] . Further surveies showed that leptin could increase platelet reactive T cells [ 71 ] . These findings indicate that leptin may in some manner be related to the pathogenesis of chronic ITP and may stand for a mark for therapy [ 72 ] .
There are besides informations back uping a function for leptin in the development of rheumatoid arthritis ( RA ) . Injection of methylated bovine serum albumen ( BSA ) into the articulatio genuss of mice consequences in the development of antigen-induced arthritis. Ob/ob and db/db mice developed less terrible arthritis ( compared to wild type mice ) , with lower IL-1? and TNF- ? nowadays in articular synovial fluid in the articulatio genus and reduced degrees of go arounding methylated BSA antibody. Furthermore, decreased antigen-specific T cell proliferation, lower IFN- ? and a higher IL-10 secernment, indicate a displacement towards an anti-inflammatory Th2 phenotype [ 65 ] . Reducing leptin degrees in RA patients by fasting better the clinical marks of the disease [ 73 ] .
In non-obese diabetic mice ( NOD ) theoretical account, used to analyze type 1 diabetes ( an autoimmune pancreatic inflammatory disease, which destroys? -cells ) , there is a pro-dromal addition in serum leptin degrees prior to development diabetes ( in females ) . Injection of leptin besides accelerates autoimmune mediated lysis of? -cells and increases IFN- ? production by peripheral T cells. These events support leptin as advancing the development of type 1 diabetes through activation of Th1 responses [ 74 ] . It has been found that natural leptin receptor mutations of the NOD/LtJ strain of mice ( named NOD/LtJ-db5J ) show reduced susceptibleness to T1D [ 75 ] . In general, adult females have higher go arounding leptin degrees than work forces [ 76 ] which may assist explicate their greater to leaning to develop autoimmune diseases [ 77 ] , leads to the decision that sexually dimorphic leptin concentrations constitute the footing of higher rates of autoimmunity in females [ 49 ] .
Leptin and multiple induration
MS, an autoimmune neurodegenerative upset most frequently affects in younger ( and female ) grownups. While the exact causes of MS remain unknown, MS pathophysiology is thought to affect complex interactions among familial, environmental and immunologic factors [ 78 ] . Relapsing-remitting MS, the most common signifier of MS, is more common in females [ 79 ] . MS therefore is an illustration of an autoimmune disease whose patterned advance and badness depends on increased degrees of many cytokines and chemokines.
It has long been known that myelin-reactive Th1 CD4+ cells might take part in pathogenesis of MS and Th1 cytokines are elevated in the CNS inflammatory lesions of EAE [ 80 ] . In contrast, lift of Th2 cytokines are typically associated with recovery from EAE every bit good as protection from MS disease [ 81 ] . As mentioned before, leptin is known to switch immune responses towards the Th1 mutual opposition. One of the most convincing findings showing the critical function of leptin in the initiation of EAE was presented by Matarese et al [ 82 ] . A rush in serum leptin degrees has been shown to predate the clinical oncoming of EAE manifestations [ 83 ] . Genetically ob/ob mice resist disease initiation in both active and adoptively transfer theoretical accounts of EAE. This protection is reversed by leptin disposal and is associated with a switch from Th2 to Th1 type responses every bit good as an IgG1 to IgG2a isotype switch. Similarly, in susceptible wild-type C57BL/6J mice, leptin worsens EAE disease by increasing IFN- ? release and heightening IgG2a production. These findings suggest that leptin is both needed for development of EAE, and probably besides human MS.
Research workers have besides examined links between leptin and MS [ 84-86 ] . Leptin is elevated up to 6.5-fold higher in acute/active MS compared to chronic, soundless MS [ 87 ] . In acute stages of MS, leptin secernment and CSF production of IFN- ? were increased [ 44 ] . In acute MS, leptin secernment was increased in both the serum and in the CSF of patients with MS ; nevertheless this did non correlate with organic structure mass index ( BMI ) [ 86 ] . The addition of leptin in the CSF was higher than that in the serum, bespeaking a possible secondary site of leptin synthesis within the CNS and/or the enhanced conveyance of leptin across the blood vascular barrier following its systemic production [ 85 ] . Increased secernment of leptin into the serum has besides been prior to backslidings in patients with MS ( during intervention with IFN- ? ) , and leptin has the capacity to heighten the secernment of TNF- ? , IL-6, and IL-10 from peripheral blood mononucleate cells of patients with MS in vitro during the acute stage of the disease ; this does non happen in patients with stable disease [ 88 ] . It has been reported that leptin secernment is increased in both serum and cerebrospinal fluid ( CSF ) of treatment-naive MS patients ; CSF leptin is positively correlated with the secernment of IFN- ? in the CSF and is reciprocally related to the fraction of go arounding regulative T cells. These tolerogenic cells are indispensable for care of anergy and are relatively reduced in patients with MS. Importantly, the figure of peripheral Treg cells in MS patients reciprocally correlates with the serum degrees of leptin, proposing a nexus between the figure of Treg cells and leptin secernment [ 86 ] . T cells from MS patients which are autoreactive to human medulla basic protein ( hMBP ) -specific produced leptin and up-regulated the look of leptin receptor after activation [ 44, 63, 86 ] . Up-regulation of the Ob-R in mononucleate cells is seen in relapsingremitting MS ( RRMS ) patients during backsliding, but is non seen in remittal or controls [ 89 ] . This determination suggests that Ob-R may play a function in the pathogenesis of MS by up-regulating the immune response in the acute stage of the disease [ 89 ] .
These informations strongly suggest a cardinal function for leptin in thepathogenesis of CNS redness in both EAE and MS. Therefore, leptin hostility may offer a new intervention option for MS patients.
It has been shown that barricading leptin signalling with either anti-leptin antibodies or with a recombinant mouse leptin receptor steerer, prior to or following the induction of EAE, reduced grounds of clinical disease, with decreased disease patterned advance, fewer backslidings, less grounds of proteolipid protein 139-151 medulla peptide-induced T cell proliferation, and increased transition to a Th2 cytokine secernment profile [ 90 ] . CD4+ T cells recovered from mice which had been injected with leptin blockers showed lowered responses to PLP139151 peptide, ( measured as the accretion of intracellular cyclin-dependent kinase inhibitor p27 ( p27Kip-1 ) ) . Diminished responses induced by leptin encirclement were associated with a decrease in extracellular signal-regulated kinase 1/2 ( ERK1/2 ) phosphorylation, proposing that ERK1/2 activity regulates the etiology of EAE and possibly besides human MS [ 91 ] .
Both anti-leptin and anti-leptin receptor barricading antibodies reduced the proliferative responses of the hMBP-specific T cell lines to antigen stimulation, bespeaking the possibility of utilizing leptin-based intercessions to end this autocrine cringle and block autoreactivity [ 86 ] .
Pharmacological suppression of leptin utilizing several categories of receptors adversaries reduces clinical induction, patterned advance, and subsequent backslidings in both primary or passively transferred EAE [ 90 ] . These reactions were correlated with a important suppression of delayed-type hypersensitivity reaction against PLP139151 peptide, reduced CD4+ T cell activation, and an elevated IL-4 and IL-10 production in response to dispute with medulla antigens. Foxp3, a marker for Treg cells and a cardinal regulator of immune tolerance, is more intensely expressed by CD4+ T cells from mice in which leptin map had been neutralized, proposing that they had switched to the Treg phenotype. Lower T cell reactivity might stand for care of p27Kip-1, ( a pro-anergy factor ) or decreased phosphorylation of regulative tyrosine residues on ERK1/2 and STAT6. These happening provide a mechanistic footing leting for clinical intercession in EAE ( and perchance in human MS ) , which would work leptin signaling in the design of curative agents to handle MS ( and perchance other chronic inflammatory provinces ) [ 90 ] . Leptin neutralisation deeply alters intracellular signalling of myelin-reactive T cells, increasing the figure of regulative T cells which improve the class of EAE [ 92 ] .
Divers actions of leptin discussed earlier on many organ systems and immune maps suggest that efforts to barricade leptin signalling in vivo should be carefully evaluated as it may do unwanted, off-target effects. The chief concern in the development of leptin-based curative schemes for autoimmune diseases, like MS remains that complete leptin/leptin receptor obstruction might interfere with leptins hypothalamic organic structure mass modulating function. Indeed, intervention of mice with the S120A/T121A leptin mutation ( which acts as leptin adversary ) induces important weight addition by impacting repletion. Weight addition in S120A/T121A treated mice besides indirectly implies that the mutation besides functions centrally and is actively transported across the blood-brain-barrier [ 93 ] .
There are different principles for the design of leptin adversaries. Non-specific agents which block leptin signal tracts which overlap with other systems, such as JAK-STAT, may ensue in damaging off-target effects. So far, there is no sanctioned commercially available specific leptin adversary that can be used for clinical surveies with human topics. The recent development of leptin mutant mice and proteins that interfere with leptin activity or signalling suggest the eventual possibility of leptin transition in clinical therapy of inflammatory provinces [ 94 ] . A monoclonal antibody against human leptin receptors which has a leptin adversary consequence has been antecedently described [ 95 ] . This antibody inhibits proinflammatory actions of leptin by barricading peripheral immune actions of leptin and leptin-induced initiation of TNF- ? by human monocytes, and T cell proliferation [ 95 ] . The Deoxyribonucleic acid sequence encoding this antibody has been cloned, and different signifiers of barricading antibody ( Fab and ScFv ) produced with similar barricading efficaciousness as the whole antibody, a first measure towards a curative antibody. The greatest advantage of recombinant antibody ( rAb ) engineering is that rAbs can be manipulated genetically to give specific belongingss ( e.g. humanized conjugated with other molecular motives, etc ) and more significantly bring forthing bifunctional molecules which can at the same time adhere to at least two different ligands, one of which is cell-/tissue-specific, allowing encirclement of leptin receptors on a specific mark tissues.
The adipose tissue and neuroendocrine system besides secretes factors which like leptin besides modulate thermal consumption and metamorphosis besides affect influence immune position. These go-betweens include adiponectin, visfatin, neuropeptide Y ( NPY ) , and ghrelin [ 96 ] . Ghrelin, a endocrine stimulated by NPY and Agouti-related peptide ( AgRP ) , ( a neuropeptide produced in the encephalon ) , is secreted chiefly by the tummy and besides by the little bowel, pancreas and thyroid [ 97 ] . Ghrelin is secreted when blood degrees of leptin and glucose bead, and stimulates appetite. It is normally increased before repasts, decreased after nutrient consumption [ 98 ] stimulates the anterior pituitary secretory organ to release growing endocrine, and is a biological antagonistic to leptin. Ghrelin besides has suppressive effects on leptin-induced secernment of inflammatory cytokines every bit good as a powerful consequence on Thymus map [ 99 ] . In worlds, ghrelin blocks leptin-induced secernment of Th1 cytokines by T cells [ 100 ] , and in mice, suppresses EAE through decrease of messenger RNA degrees of TNF- ? , IL-1? , and IL-6 in spinal cord cellular infiltrates and microglia [ 101 ] . Therefore, ghrelin may besides stand for an endogenous adversary of leptin, and therefore happen usage in the intervention of MS.
Adequate nutrition is a requirement for bring forthing appropriate immune responses against occupying pathogens. Conversely, sufficient energy shops may be one of the factors required for long-run, damaging immune reactions, like those observed in autoimmune diseases. Therefore, leptin can be considered as a nexus between the immune tolerance, metabolic province, and autoimmunity. Leptin, as an inflammatory cytokine, may be responsible for equilibrating immune responses between immunosuppression and autoimmunity, ( Fig. 1 ) with higher go arounding leptin degrees predisposing persons to autoimmune diseases, while low serum leptin cut downing autoimmunity, but increase susceptibleness to infection [ 26 ] . As early leptin research has chiefly focused on the functions of leptin on organic structure weight ordinance, less attending has yet been given to the development of leptin adversaries specifically designed for its peripheral immune-regulating effects. Based on the available grounds in the literature, leptin receptor hostility might stand for an of import and fresh curative attack for handling autoimmune diseases, including MS. Development of monoclonal antibodies against the leptin receptors that block leptin signalling in specific tissues or variety meats could be a promising hereafter tool for many immune mediated chronic inflammatory conditions [ 95 ] .
The writers affirm that they have no known viing involvements.
All writers participated in different parts of the readying of the manuscript.
The writers would wish to thank graduate office of Isfahan University for support of this survey, J.S. Alexander and A. Minagar supported by US Department of Defense Grant ( MS090035 ) .
Figure 1. Leptin part to immune responses in MS susceptibleness. Low Calories intake leads to low degrees of leptin production. Low leptin is associated with a Th2 cytokine polarisation with lower degrees of inflammatory cytokines, elevated degrees of ghrelin and adipocytokines stamp downing automimmunity. High leptin degrees intensify immune responses which increase MS susceptibleness including CD4/CD8 cell, monocyte, macrophage activation and proliferation and strong activation of Th1 cytokines.