Dermatology Online Journal

A review of the role of neutrophils in psoriasis and related disorders
Peter J Aronson MD
Dermatology Online Journal 14 (7):

Department of Dermatology, Wayne State University. paronson@med.wayne.edu

Abstract

The extensive literature about the role of neutrophils in psoriasis is reviewed. Neutrophils appear early in new psoriasis lesions. Neutrophil function can be modulated by T lymphocytes and by monocytes. Neutrophils in turn can modulate function of these cells. Many psoriasis associated pro-inflammatory molecules including angiopoetin-1, cathelicidins, CCR6, CD15, CD40, CD40L, CD69, CXCL10, Fas ligand, folic acid pathways and associated molecules (homocysteine, NF-kappaB, VCAM-1 and VEGF), GM-CSF, IFN-gamma, interleukins 1beta, 4, 6, 8, 12, 15, 17, 20, 22BP and 23, Leukotriene B4, S100A7-9 and S100A12, Sphingosine 1-Phosphate, TGF beta -1, and TNF-alpha all affect, are secreted by or are affected by neutrophils. Clinical triggers of psoriasis, drugs that help psoriasis, drugs that flare psoriasis, psoriasis associated disorders, disorders treatable with therapies used to treat psoriasis, and side effects of many psoriasis therapies can be explained at least in part by the interplay between these disorders and drugs and neutrophils.

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Introduction

Neutrophils are the first to be recruited to a site of infection or a diseased state. They are effector cells that kill bacteria or destroy affected tissues. Neutrophils produce reactive oxygen species and anti-microbial peptides. They are involved in the production of chemokines in response to a variety of stimulants including LPS, TNF-alpha, and IFN-gamma, thereby contributing to immunomodulation [1].

An intermittent exudate of fluid and of leukocytes, both neutrophils and lymphocytes, are seen in the epidermis in early psoriasis (the squirting papilla) [2, 3]. This early histology has been reconfirmed several times [4, 5].

After tape stripping a psoriasis patient, the sequence of events in early psoriasis is as follows:

1. Langerhans cell-lymphocyte interaction

2. Neutrophil presence

3. Basal keratinocyte changes [6]

Psoriatic patients have increased numbers of circulating neutrophils. (Psoriatics with arthritis have the greatest number). Activated psoriatic serum with bacterial extracts sometimes increases chemotaxis. Psoriatic serum at low concentration (1%) stimulated random migration of normal human polymorphs [7].

Neutrophils are thus recognized as a component of psoriasis, but their role in the pathogenesis of the disease, its triggers, associated disease, and complications of the disease have not been comprehensively delineated.

Methods

A review of recent associations and function of neutrophils to other inflammatory cells, proinflammatory molecules related to psoriasis, psoriasis triggers, genes and disease associated or related with psoriasis, and side effects of psoriasis treatments is performed. Specifically the review focused on the relation of neutrophils to proinflammatory molecules related to psoriasis, psoriasis triggers, psoriasis associated genes, diseases associated with or related to psoriasis, psoriasis therapies, and side effects of psoriasis treatments. In so doing it is not to be inferred that lymphocytes, monocytes and macrophages do not also provide a vital role in the pathogenesis of psoriasis.

Results: Review of the literature

Other inflammatory cells and neutrophils

Neutrophil function can be modulated by T lymphocytes

Approximately 2.5 percent of CD4(+) T cells in normal peripheral blood produce CXCL8 (IL-8). Supernatants from CXCL8(+) T cells are strongly chemotactic for neutrophils, CXCR1, and CXCR2 transfectants. Neutralization experiments indicate that chemotaxis is mainly mediated by CXCL. In acute generalized exanthematous pustulosis (AGEP) T cells produced large amounts of the monocyte/neutrophil-activating cytokine GM-CSF, and the majority of T cells release IFN-gamma and the proinflammatory cytokine TNF-alpha. Furthermore, apoptosis in neutrophils treated with conditioned medium from CXCL8(+) T cells can be reduced by 40 percent. Finally, data suggests that CXCL8-producing T cells facilitate skin inflammation by orchestrating neutrophilic infiltration and ensuring neutrophil survival, which leads to sterile pustular eruptions [8].

CXCL8-producing T cells regulate sterile, polymorphonuclear neutrophil-rich skin inflammations. A pronounced infiltration of neutrophils and of predominantly CD4+ T cells was observed in skin biopsies from pustular psoriasis, Behçet disease, and acute generalized exanthematous pustulosis, with infiltrating T cells strongly positive for CXCL8 and the chemokine receptor CCR6. Skin-derived T cell clones from pustular skin reactions were positive for CCR6 but negative for CCR8 and secreted high amounts of CXCL8 and GM-CSF, often together with IFN-gamma and TNF-alpha after in vitro stimulation. CXCL8/GM-CSF-producing T cells can orchestrate neutrophil-rich pathologies of chronic autoinflammatory diseases like pustular psoriasis and Behçet disease [9].

Neutrophil functions can be modulated by monocytes

Monocytes stimulated with bacterial lipopolysaccharides (LPS) release mediators that induce increased responses of human granulocytes. Psoriatic patient monocytes can stimulate neutrophil chemotaxis, phagocytosis, and O2 production without addition of LPS and this effect is inhibited by cyclosporin A. supernatants (sMS, or conditioned media). The sMS from unstimulated psoriatic monocytes significantly enhanced neutrophil chemotaxis and superoxide anion production. The enhancing factors are protein in nature and require ongoing protein synthesis. The neutrophil function-enhancing factors derived from psoriatic monocytes are in part cytokines, including TNF and GM-CSF [10].

Macrophage, Th17 cell associated proteins and neutrophils

Neutrophils are influenced and influence ThP-1(macrophage), Th1, Th2, and Th17 lymphocytes and their cell products including TGF-beta, IL-17, IL-22, and IL-23 [11]. Th1 cells can be defined by production of IFN-gamma and IL 17. Th0 cells are defined by production of both IFN-gamma and IL-4 and IL17. Th2 is defined by production of both IL-4 and IL-10 but not IFN-gamma but not IL17. ********** Therefore, T cells types Th1 and Th0 both produce IL-17 [12]. Discussion of how these cytokines and other inflammatory factors influence and are influenced by neutrophils especially in psoriasis and related disorders is discussed below.

Psoriasis associated ions and pro-inflammatory molecules

Angiopoietin-1

Angiopoietin-1 (Ang-1) is the primary agonist for Tie2 tyrosine kinase receptor (Tie2). Tie2 receptors are expressed in several cell types, including neutrophils. Ang-1-Tie2 signaling induces a chemotactic effect in neutrophils. Ang-1 inhibits the secretion of tissue inhibitor of matrix metalloproteinase (TIMPs). Aberrant expression and activity of Tie2 in vascular and non-vascular cells may result in the development of psoriasis [13].

Tie2 receptors are expressed in several cell types, including endothelial cells, epithelial cells, monocytes, and neutrophils. Ang-1-Tie2 signaling induces a chemotactic effect on neutrophils. In addition, this signaling pathway induces the secretion of metalloproteinases (MMPs). Ang-1 inhibits the secretion of tissue inhibitor of matrix metalloproteinase (TIMPs). Aberrant expression and activity of Tie2 in vascular and non-vascular cells may result in the development psoriasis. However, Ang-1 has an anti-inflammatory effect, when co-localized with vascular endothelial growth factor (VEGF) in the vasculature [14].

C5a/C5a des Arginine

Activation of the complement system results in the generation of biologically active peptides. The most active peptides are C5a and C5a des Arg generated by cleavage of the alpha-chain of native C5. C5a is a potent anaphylatoxin and can induce human polymorphonuclear leukocytes to migrate in a directed fashion, to degranulate, to undergo a burst of oxidative metabolism and to aggregate. Upon generation C5a is converted in serum and plasma to C5a des Arg with loss of the noxious anaphylatoxin activity [14].

C5a/C5 des Arg is produced through the alternative complement pathway. It is found in the epidermis, especially in psoriatic scales. It promotes neutrophil migration and activation [15].

Cathelicidins

Cathelicidins (LL-37) are major antimicrobial peptides (AMPs) of the innate immune system of the human skin. In normal non-inflamed skin these peptides are negligible.

Their expression can be markedly increased in inflammatory skin disease such as psoriasis. Immunohistochemistry analysis confirmed the presence of abundant LL-37 in the epidermis of psoriasis [16]. Psoriasis exhibits low levels of skin infections due to the presence of antimicrobial agents, including cathelicidin LL-37. LL-37 kills a broad spectrum of microbes, and activates neutrophil chemotaxis. LL-37 enhances the production of IL-8 under the control of MAPK p38 and extracellular signal regulated kinase (ERK), as evidenced by the inhibitory effects of p38 and ERK1/2 inhibitors on LL-37-mediated IL-8 production. LL-37 induced phosphorylation of p38 and ERK. LL-37 stimulates the generation of reactive oxygen species dose- and time-dependently, most probably via NADPH oxidase activation and intracellular Ca(2+) mobilization. Finally, LL-37 induces both mRNA expression and protein release of alpha-defensins, known as human neutrophil peptide 1-3. Thus, LL-37 may contribute to innate immunity by enhancing neutrophil host defense functions at inflammation and/or infection sites [17].

CCR6

The CCR6 gene encodes a beta chemokine. It is preferentially expressed by immature dendritic cells and memory T cells [18]. As stated above, CD4+ T cells have been observed in skin biopsies from pustular psoriasis, strongly positive for CCR6. Skin-derived T cell clones from pustular skin reactions are positive for CCR6 [9]. There is increased CCR6 in skin lesions of plaque psoriasis [19].

It has also been found that neutrophils incubated with supernatants of phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PHA-sup) express high levels of CCR6 mRNA. Cytokine TNF-alpha together with IFN-gamma synergistically activate neutrophils to express functional CCR6. The induction of CCR6 suggested that these cytokine-activated neutrophils have similarities with dendritic cells (DCs) that express CCR6 in an immature stage. In fact, the activation of neutrophils with TNF-alpha and IFN-gamma induced the expression of CD83, a dominant cell-surface marker of DCs. When neutrophils were activated with granulocyte macrophage-colony-stimulating factor, TNF-alpha and IFN-gamma, these cells expressed CD40 and HLA-DR in addition to CD83. Taken together, neutrophils, under appropriate conditions, can undergo a differentiation process characterized by the acquisition of new phenotypes and functions; such differentiated neutrophils may play more active roles in the adaptive immune response [20].

CD15

The carbohydrate antigen, CD15 (Le(X)), and its sialic acid rich derivative have been shown to be involved in the binding of neutrophils to the endothelial lectins, E-selectin and P-selectin. Binding of ligand to Neutrophil NCA-160, a carcinoembryonic antigen (CEA)-related glycoprotein, the major carrier of CD15 is able to trigger neutrophil adhesion events [21]. CD15+ neutrophil granulocytes were detected in 4 of 9 cases of psoriatic arthritis [22]. The very first effect of systemic therapy with the anti-psoriasis therapy fumaric acid esters is the disappearance of CD 15-positive cells in the beneath the epidermis [23].

CD40 CD40L

Expression of CD40L is significantly increased on activated T cells from patients with psoriatic arthritis, particularly those with active disease, when compared with normal individuals and patients with rheumatoid arthritis [24]. Interferon gamma (IFN-gamma) is shown to induce CD40 and CD40L expression on endothelial cells (ECs) and consequently to promote neutrophil adhesion [25]. Neutrophils were cultivated in vitro in the presence or absence of compounds modulating their survival in an attempt to characterize the expression profile of dendritic markers. CD40 expression levels were detected on the surface of the cultured neutrophils for 24 hours, then on the freshly isolated cells. There was a lower level of interferon-gamma production in the T cells co-cultured with anti-Fas antibody-treated neutrophils. This suggests that when IFN-gamma is reduced, CD40 effects are on endothelial cells and resulting neutrophil adhesion to them is opposed [26].

CD69

CD69, also known as activation inducer molecule, very early activation antigen, MLR-3 and Leu-23, is a type II transmembrane glycoprotein with a binding domain in the extracellular portion of the molecule. CD69 expression is induced in vitro on cells of most hematopoietic lineages, including neutrophils [27]. CD69 in the presence of tumor necrosis factor alpha inhibition may reduce neutrophil chemotaxis [28]. Included in the proteins increased in production by CD69 is S100A9. Ligands for CD69 and/or the anti-CD69 autoantibodies increase production of S100A9 in neutrophils [29].

CR3

Leukocyte integrin CR3 is complement receptor 3 (CD11b/CD18, α_Mβ₂) [30, 31]. CR3 mediates neutrophil localization through binding to intercellular adhesion molecule-1 [32]. CR3 is needed for psoriasis. Specifically flaky skin mice (fsn/fsn) have a prominent infiltrate of neutrophils, and microabscesses within the hyperproliferative epidermis. When the integrin α_Mβ₂ (CD11b/CD18), which mediates neutrophil localization was blocked in vivo with the M1/70 monoclonal antibody, the epidermal thickness was reduced by 31 percent, and neutrophil and T cell accumulation was diminished compared with control animals [33]. Moreover, there is another animal model resembling psoriasis, CR3 mediated, in which lymphocytes do not appear to play as much of a role as do neutrophils [34]. The murine chronic proliferative dermatitis mutation (cpdm/cpdm) is characterized by epidermal hyperplasia and hyperproliferation of in the cpdm/cpdm skin. No lymphocyte binding could be observed, but avid adhesion of neutrophils was seen. Binding of neutrophils could be blocked with antibodies against L-selectin, LFA-1, CR3 and anti ICAM-1. The cpdm/cpdm mutation has therefore characteristics of a psoriasis-like as well as a more generalized inflammatory skin condition [35]. TNF-alpha-induced neutrophil migration is a consequence of the TNF-alpha-induced up-regulation of integrin CR3 (CD11b/CD18) on neutrophil surfaces. Furthermore, TNF-alpha activity has been found to be strictly dependent on the activation of *********** ERK ½ p44, cooperating with the intracellular pathways involving Src kinases, PI3K/Akt, p38 MAPK, well known as activated in response to classical neutrophil chemoattractants (CXCL8) or priming agents (GM-CSF) [35].

CR3 promotes IL-12 [36]. Antibodies to C11b and CD18 (parts of CR3) suppress IL-12 [37]. In vitro and in vivo studies suggest that anti-CR3 treatment may act, at least in part, by directly inhibiting IL-12 production by antigen presenting cells [37].

Neutrophils in patients with acute psoriasis showed an increase in CD11b/CD18 expression [38]. Low expression of CD18 is associated with psoriasis like rash in an animal model, the CD18 hypomorphic mouse. Zero CD18 expression in contrast was not associated with inflammatory skin disease [39]. (The CD18 hypomorphic mouse does also however show that CD4+ T cells are needed for psoriasis. In this model both CD4+ and CD8+ T cells were significantly increased. Depleting the CD4+ cells cleared the rash. Depleting CD8+ cells did not.) [40]. CD18 deficiency has been described in humans [41]. This is also called Congenital Deficiency of beta 2 integrin leukocyte adhesion molecules. It is a rare immunodeficiency and is often fatal. Neutrophils are unable to bind to ligands on the endothelium, and so cannot leave the circulation during inflammation or infection [42].

CXCL10

CXCL10 I is IFN-gamma-inducible 10 kDa protein (IP-10/CXCL10) [43]. NF-kappaB induces CXCL10 expression by lipopolysaccarides plus IFN-gamma in neutrophils. In psoriasis CXCL10 recruits type 1 T cells and the production of these chemokines by keratinocytes is enhanced [44].

Folic acid pathways and homocysteine

The folic acid metabolic pathway is mediated by vitamins B2, B6 and B12. Folate functions as a methyl donor to create methylcobalamin, which is used in the re-methylation of homocysteine to methionine [45]. Folate pathways modulate methionine synthetase. This enzyme along with vitamin B12 is responsible for the conversion of homocysteine to methionine. Homocysteine can be converted to cysteine using vitamin B6 [46].

Homocysteine(Hcy) upregulates leukocyte activity, especially neutrophil activity in a number of ways. It regulates altered leukocyte expressions of CD11b/CD18 (CR3), CD14, and L-selectin on leukocytes which may be involved in homocysteine-induced leukocyte adhesion and migration. Hcy increases superoxide anion release by neutrophils to the extracellular medium. This effect is inhibited by superoxide dismutase and diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase activity Hcy increases intracellular H₂O₂ production by Neutrophils. Hcy enhances the activation and phosphorylation of mitogen-activated protein kinases (MAPKs), specifically p38-MAPK and ERK1/2. The migration of neutrophils is increased by Hcy. Hcy enhances the oxidative stress of neutrophils and underscores the potential role of phagocytic cells in vascular wall injury through superoxide anion release in hyperhomocysteinemia conditions [47].

Hyperhomocysteinemic patients have elevated levels of CXC chemokines, epithelial neutrophil-activating peptide ((ENA)-78, a regulator of PMN chemotaxis) [48], and growth-regulated oncogene (GRO)alpha (which reduces vasorelaxation and increases vascular superoxide anion) [49]. Homocysteine was significantly correlated with ENA-78 and (GRO)alpha [50]. (Homocysteine has important effects on mononuclear cell function, too. For example, hyperhomocysteinemic subjects had raised serum levels of MMP-9 and MMP-9/TIMP-1 ratio comparing healthy controls; although IL-10 markedly suppressed MMP-9 release from PBMCs in controls, no or only minor effect was seen in hyperhomocysteinemic subjects. Although IL-10 enhances TIMP-1 levels in PBMCs from both hyperhomocysteinemic and control subjects, the increase was more prominent in controls, resulting in a marked difference in IL-10-induced changes in MMP-9/TIMP-1 ratio between these 2 groups. Mononuclear cells from hyperhomocysteinemic individuals had impaired IL-10-induced STAT3 phosphorylation.) [51].

In a case-control study, patients with psoriasis had plasma homocysteine levels higher than controls. Conversely, folic acid levels were lower in patients with psoriasis compared with controls. Plasma homocysteine levels in patients with psoriasis correlated directly with disease severity (PASI) and inversely with folic acid levels. Plasma folic acid levels were inversely correlated with the PASI. No abnormalities of plasma vitamin B(6) and B(12) were found [52]. The results of a clinical trial using vitamin B(12) cream for psoriasis provide evidence that the recently developed vitamin B(12) cream containing avocado oil has considerable potential as a well-tolerated, long-term topical therapy of psoriasis [53].

Homocysteine related factors are nuclear factor KappaB (NF-kappaB), VCAM1 (vascular cell adhesion molecule 1 or CD106) and VEGF.

NF-kappaB

NF-kappaB is a transcription factor present in cells in inactive state but do not require new protein synthesis allowing for quick action. It is involved in cellular responses to stimuli (viz. cytokines) [54, 55].

In neutrophils pharmacological inhibitors of NF-kappaB demonstrated its role in the induction of the cytokine CXCL10 expression by LPS plus IFN-gamma, and by LPS or IFN-gamma in monocytes. Together, these results suggest that in neutrophils, the synergy observed between LPS and IFN-gamma toward CXCL10 gene expression likely reflects the cooperative induction of the NF-kappaB and STAT1 transcription factors by LPS and IFN-gamma, respectively, in both cell lines [56]. It also has been shown through another study that NF-kappaB inhibitors decrease Hcy-induced intracellular reactive oxygen species and VCAM-1 expression [57].

VCAM-1 (vascular cell adhesion molecule 1 or CD106)

VCAM-1 is a membrane protein that mediates leukocyte-endothelial cell adhesion and signal transduction [58]. There is enhanced expression of VCAM-1 in psoriatic lesions versus nonlesional skin [59]. TNF-alpha-induced VCAM-1 expression is regulated by MAPKs, NF-kappaB and p300 activation (in human tracheal smooth muscle cells (HTSMCs)). TNF-alpha significantly increased HTSMCs-neutrophil adhesions and this effect was associated with increased expression of VCAM-1 on the HTSMCs. It was blocked by the selective inhibitors of including calcium. TNF-alpha induced VCAM-1 expression via multiple signaling pathways. Blockade of these pathways may be selectively targeted to reduce neutrophil adhesion via VCAM-1 suppression and to attenuate the inflammatory responses in airway disease [60].

There appears to be an inhibitory effect of dietary polyphenolic antioxidants, such as trans-resveratrol (found in red wines) and hydroxytyrosol (HT)(the latter found in olive oil) [57], that are known inhibitors of NF-kappaB-mediated VCAM-1 induction. Nutritionally relevant concentrations of RSV and HT - but not folate and vitamin B6 - reduce Hcy-induced VCAM-1 expression [61].

Relevant to the above one published study used a honey mixture group consisting of 1:1:1 honey, beeswax, and importantly olive oil topically on psoriasis patients. Five of 8 psoriasis patients showed a significant response to the honey mixture [62].

Figure 1	Figure 2
Figure 1. Psoriasis patient with Hhcys (16.9 umol/L) Figure 2. Same patient (PASI 81, Hcy 14.8 umol/L) on 12 weeks of folic acid 7-8 mg. Vitamin B6 100 mg, Vitamin B12 1 mg, resveratrol 20-37.5 mg daily for 10 weeks, 4 oz red muscadine wine, topical extra virgin olive oil and topical ceramide cream followed by 4 weeks of only folic acid, B12, B6 and muscadine.

VEGF

Vascular endothelial growth factor and vascular endothelial growth factor receptor-3 (VEGF and VEGF-R3) expression in psoriatic and nonlesional skin is significantly high in epidermis and dermis. There was significant concordance between VEGF and VEGF-R3 expressions in psoriatic lesions while no expression is observed in normal epidermis [63, 64]. Transient depletion of neutrophils suppressed VEGF-induced angiogenesis, indicating that circulating neutrophils contribute to VEGF-induced focal angiogenesis [65].

Expression of VEGF is increased by homocysteine [66].

In certain patients (those with peripheral arterial disease or DM), folic acid and B vitamins administration results in significant reduction of plasma levels of homocysteine and also VEGF. Moreover, VEGF and mRNA expression in leukocytes was down-regulated in all patients after B vitamins and folate treatment. Lowering of homocysteine with B vitamins and folic acid therefore results in reduction of plasma levels of VEGF leukocytes in patients with PAD or DM [67]. Both of these diseases are increased in psoriasis (see below).

Fas Ligand

Fas ligand is most commonly viewed as a transmembrane protein that when trimerized leads to cell death. In other words, Fas forms the death inducing signalling complex upon ligand binding [68].

However, Fas/FasL has other functions. Fas/FasL signaling is an essential early event in the induction of psoriasis by activated lymphocytes and is necessary for induction of key inflammatory cytokines including TNF-alpha and IL-15 which in turn influence neutrophils [69].

The inhibition of neutrophil migration is related to the capacity of FasL and HLA-I molecules contained in RBC supernatants to induce in vivo TGF-beta1 synthesis by neutrophils [70]. Fas ligand (FasL) expression may provoke a destructive granulocytic response. sFasL is a potent neutrophil chemoattractant and, given that it induces little apoptosis, the dominance of sFasL over mFasL may mean that graft-infiltrating neutrophils will survive to mediate inflammation. Neither sFasL nor mFasL produced neutrophil activation as assessed by chemiluminescence assay. This suggests that neutrophils recruited to an inflammatory site by FasL will be activated by mechanisms other than Fas/FasL signaling [71]. Fas/FasL signaling is necessary for induction of key inflammatory cytokines including TNF-alpha and IL-15 [72].

GM-CSF

When PMNs were activated with granulocyte macrophage-colony-stimulating factor, TNF-alpha, and IFN-gamma these cells and endothelial cells expressed CD40 promoting endothelial adhesion [73].

IFN-gamma

IFN-gamma-inducible protein-10 is called CXCL10 [74]. NF-kappaB demonstrated its role in the induction of CXCL10 expression by LPS plus IFN-gamma in neutrophils [71]. The effect of CXCL10 in psoriasis has already been discussed above in the section on CXCL10 [43].

Interleukins

IL-1beta

Multiple proteins increase their production by the CD69 signaling. One is S100A9 calcium binding protein (see S100A9 section below) [29]. S100A9 induces IL-1beta production from neutrophils [29]. The expression of IL-20 (see below) was rapidly induced by proinflammatory stimuli, including IL-1beta [75].

Elafin, an elastase inhibitor produced by keratinocytes, is overexpressed in the subcorneal region of skin affected by psoriasis, a major feature of which is epidermal infiltration by neutrophils. Treatment with IL-1 beta resulted in 2.6-fold stimulation of elafin secretion. This suggests that inflammatory mediators such as IL-1 beta (or TNF-alpha) secreted by dermal neutrophils may be involved in over-expression of elafin in keratinocytes; this could protect the epidermis from degradation by dermal neutrophil infiltration [76].

IL-4

Interleukin-4 is diminished in psoriatic skin. Some recent reports demonstrate a favorable role of IL-4 in the treatment of psoriasis [77].

Upon a single high dose of UVB irradiation of psoriatic lesional skin, IFN-gamma expression is decreased, whereas IL-4 expression is enhanced. The IL-4 protein detected in situ upon UVB exposure of normal skin was not associated with T cells but with infiltrating neutrophils. IL-4-positive cells co-expressed elastase and CD15, but not CD3 [78].

IL-6

Neutrophils promoting activity by mice defective for both G-CSF and GM-CSF requires IL-6. IL-6 is thus shown to be an alternative pathway to granulocyte production [79, 80].

Psoriasin activates neutrophils to produce a range of cytokines and chemokines including interleukin-6 (IL-6), IL-8/CXCL8, tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4 and MIP-3alpha/CCL20. Psoriasin induces phosphorylation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase (ERK) both of which are required for the production of cytokines. Moreover, psoriasin stimulates the generation of reactive oxygen species from neutrophils, most likely via nicotinamide adenine dinucleotide phosphate oxidase activation. Psoriasin enhances messenger RNA expression of alpha-defensins, termed human neutrophil peptides (HNP) 1 to 3, and induces their extracellular release [81].

IL-8

Cytokine levels were compared in aqueous extracts of stratum corneum from psoriatic lesions and normal heel. A neutrophil chemoattractant was found in all lesional extracts, and was demonstrated to be mainly interleukin-8 (IL-8) using a specific neutralizing antiserum. Interleukin-8 is therefore the only biologically active cytokine shown in this study to be elevated in psoriatic lesional extracts and may therefore play a role in the pathogenesis of the disease [82].

Lesional basal layer psoriatic scale contains chemoatracts IL-8 with migrating PMNs. C3b is found on cell membranes of subcorneal keratinocytes. It is thought that intraepidermal migration of PMNs takes place according to the concentration gradient of IL-8 followed by C3b guidance [83].

Human keratinocytes were cultured in the presence of various cytokines and chemotactic activity of the supernatants were assessed. TNF-alpha stimulation produced directed migrational responses for both neutrophils and T-lymphocytes. Eighty percent of neutrophil migration induced by the TNF-alpha treated keratinocyte cell supernatants could be inhibited by anti-interleukin-8 (IL-8) serum. Using the same antibody, IL-8 was immunoprecipitated from the supernatants of TNF-stimulated 35S-labelled keratinocytes [84].

IL-12

Polymorphonuclear neutrophils (PMNs) have been shown to produce and to release numerous cytokines, in particular upon IL-12 stimulation. The effect of IL-12 was time- and concentration-dependent, and IL-12 combinations with IL-2, IL-15, IL-18 or LPS were highly synergistic. Under IL-12 stimulation highly purified neutrophils are able to secrete IFN-gamma. The IFN-gamma produced by PMNs was biologically active, as demonstrated by its ability to induce TNF-alpha synthesis by PMNs themselves [85].

In a model of bacterial infection, Bovine PMNs were shown to secrete IL-12 (and TNF-alpha, IL-1beta, IL-12, IL-8 and IFN-gamma) in response to LPS [86].

IL-15

Among its several activities, IL-15 stimulates the expression of IL-17 by T cells [87]. In a mouse model, IL-15 was shown to play an important role in antigen-induced neutrophil migration during inflammation, triggering a sequential OVA, IL-15, IL-18, MIP-2, MIP-1alpha, TNF-alpha, LTB(4) and neutrophil migration signaling cascade [88].

IL-17

Normal neutrophils migrate to tissues where they become apoptotic and are phagocytosed by macrophages and dendritic cells. This curbs phagocyte secretion of IL-23, a cytokine controlling IL-17 production by Tn cells [89].

Th1 cells can be defined by production of IFN-gamma and IL-17. (Th2 is defined by production of both IL-4 and IL-10 but not IFN-gamma but not IL17 *********). Th17 cells (Th1/Th0) produce IL-17 [12].

Psoriasis is now known to be a mixed Th1 and Th17 inflammatory environment [90].

IL-18

Chemoattractants such as platelet activating factor can stimulate human neutrophils to activate the mitogen-activated protein kinase (MAPk) homologue 38-kD murine MAP kinase homologous to HOG-1 (p38) MAPk [91].

Caspase-1 belongs to the group of inflammatory caspases and is the activating enzyme for the proinflammatory cytokine IL-18. Interestingly, increased caspase-1 activity in lesional compared with non-lesional psoriatic skin is seen. Secretion of active IL-18 is mediated through a p38 MAPK/caspase-1-dependent mechanism, whereas secretion of proIL-18 was mediated by a p38 MAPK-dependent but caspase-1-independent mechanism [92].

IL-18 enhances the IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of NF-kappaB, STAT1, and IFN-regulatory factor (IRF)-1 [44].

IL20

IL-20 is thought to be a key cytokine in the pathogenesis of psoriasis [93]. Hcy activated chemicals p38 mitogen-activated protein kinase (MAPK) [47] as well as inhibitory kappaB kinase-NF-kappaB signaling pathways are crucial for IL-20 expression. By electrophoretic mobility shift assay two kappaB-binding sites were identified upstream from the start codon in the IL-20 gene. In rheumatoid arthritis anyway IL-20 and its receptors were expressed in the synovial membranes and rheumatoid arthritis synovial fibroblasts (RASFs). IL-20 induced RASFs to secrete IL-8. It promoted neutrophil chemotaxis [94].

IL22

IL-22 is preferentially produced by Th17 cells and mediates the acanthosis induced by IL-23. IL-23 or IL-6 can directly induce the production of IL-22 from both murine and human naive T cells. Transforming growth factor-beta, although crucial for IL-17 production, actually inhibits IL-22 production. IL-mediates ******** IL-23-induced acanthosis and dermal inflammation through the activation of Stat3 (signal transduction and activators of transcription 3) in vivo [95]. The biological activity of IL-22 is modulated by IL-22-binding protein (IL-22BP), which is considered a natural antagonist of IL-22.

Treatment of mice with IL-22BP-Fc 4 h before sepsis induction led to enhanced accumulation of neutrophils [96]. Among many types of WBCs including monocytes and macrophages IL-22BP mRNA is expressed in neutrophils [97].

IL-22 mRNA expression is up-regulated in psoriatic skin lesions compared to normal skin, whereas IL-22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were similar. Circulating IL-22 levels are significantly higher in psoriatic patients than in normal subjects. T cells isolated from psoriatic skin produce higher levels of IL-22 in comparison to peripheral T cells isolated from the same patients. Supernatants of lesional psoriatic skin-infiltrating T cells induce an inflammatory response by normal human epidermal keratinocytes, resembling that observed in psoriatic lesions [98].

IL23

IL-23 induces differentiation to IL-17-producing pathogenic Th17 cells [99]. Acanthosis is induced by IL-23 and mediated by IL-22 [95]. IL-23 or IL-6 can directly induce the production of IL-22 from both murine and human naive T cells. Transforming growth factor-beta, although crucial for IL-17 production, actually inhibits IL-22 production. IL-mediates IL-23-induced acanthosis and dermal inflammation through the activation of Stat3 (signal transduction and activators of transcription 3) in vivo [95].

IL-23 also regulates granulopoiesis in a regulatory feedback loop through IL-17A-producing neutrophil regulatory (Tn) cells. To test the role of IL-23 in the homeostatic regulation of circulating neutrophil numbers, researchers measured blood neutrophil numbers in p40-deficient (IL12b-/-) mice and found them reduced compared with wild-type mice. IL12b-/-Itgb2-/- mice, lacking beta2-integrins, IL-12, and IL-23 showed significantly blunted neutrophilia compared with Itgb2-/- mice. Treatment of both IL12b-/- and IL12b-/-Itgb2-/- mice with IL-23, but not IL-12, restored circulating neutrophil counts. Serum levels of IL-17A were readily detectable in Itgb2-/- mice, but not in IL12b-/-Itgb2-/- mice, suggesting that IL-17A production is reduced when IL-23 is absent. These results suggest a prominent role of IL-23 in the regulation of granulopoiesis and the prevalence of IL-17A-producing neutrophil regulatory cells [100].

Leukotriene B4 (and low calcium)

Topical application of LTB4 produces intraepidermal microabscesses and induces hyperproliferation. Furthermore, LTB4 has been determined in biologically active amounts in psoriatic skin lesions. Despite the importance of LTB4 in psoriasis. ******* It has been shown that human epidermis can contribute significantly to LT formation by transcellular LT synthesis. By this mechanism, LTA4 released from activated leukocytes is further transformed into LTB4 in the keratinocytes by the LTA4 hydrolase. Transcellular metabolism may be of importance in psoriasis where neutrophils migrate into the epidermis, because in human neutrophils the LTA4 hydrolase has been shown as the rate-limiting step in LTB4 formation [101].

Keratinocytes when incubated with low calcium medium possess the capacity to generate leukotriene B4 in the epidermis when provided leukotriene A4 thereby amplifying the inflammatory processes occurring during neutrophil exocytosis [102].

Magnesium

There is some evidence (from intrapartum studies) that reduction in neutrophil functional activity is directly correlated with serum magnesium levels [103].

Magnesium is useful in activating CR3.A monomeric C3bi (C3 binding region) binds directly to recombinant I-domain in a Mg (2+) dependent fashion. CR3 appears to be inactivated by removing tightly bound Mg (2+) from a cryptic site in CR3 and activated by magnesium binding [103]. Moreover, binding of neutrophils can be blocked with antibodies against CR3 [104].

Metalloproteinases

Neutrophils constitute a high source of metalloproteinases (MMPs) [105]. There is overexpression of MMP-2 in uninvolved and involved psoriatic epidermis [106].

VEGF overexpression correlates with a metalloproteinase (MMP-2) expression. Total MMP-2 expression of healthy skin is significantly lower in respect to the MMP-2 psoriatic skin [107].

Homocysteine (50-1,000 micromol/L) significantly increases the production of MMP-2 in a dose-dependent manner. Added extracellular magnesium decreased the homocysteine-induced MMP-2 secretion [108].

Hcy-induced activation of AT1 receptor involves MMP-9 and collagen type-1 modulation using ERK-1/2 and STAT3 signaling cascades [109]. In addition, (at least in brain studies) MMP-9 activity was attenuated after neutrophil depletion, suggesting that neutrophil is an important source of MMP-9 [65].

S100A7-A9 and A12

Microbicidal protein psoriasin is a multifunctional modulator of neutrophil activation. Psoriasin (S100A7) has been found to be overexpressed in psoriasis. In addition to its microbicidal activities and chemotaxis of neutrophils reported previously. Psoriasin activates neutrophils to produce a range of cytokines and chemokines including interleukin-6 (IL-6), IL-8/CXCL8, tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4 and MIP-3alpha/CCL20. Furthermore, psoriasin induces phosphorylation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase (ERK) both of which are required for the production of cytokines and chemokines as evidenced by the inhibitory effects of p38 and ERK inhibitors on psoriasin-mediated neutrophil activation. Moreover, psoriasin stimulates the generation of reactive oxygen species from neutrophils [110].

In psoriasis a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. There is downregulation of psoriasin by IFN-gamma, as well as the downregulation of psoriasin. In contrast, IFN-gamma had no suppressive effect on S100A8 (calgranulin A) or S100A9 (calgranulin B). IFN-gamma is an important activator of the STAT1. Psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway [111].

S100A8, S100A9 and S100A12 are calcium-binding proteins expressed in the cytoplasm of phagocytes. They are rapidly secreted by activated monocytes or neutrophils [112]. S100A8 is a low-molecular-weight calcium-binding protein, highly sensitive to oxidation. S100A9 associates with S100A8 in neutrophils and abnormally differentiated keratinocytes (human psoriasis) [113].

S100A12, also called EN-RAGE (extracellular newly identified receptor for advanced glycation end products binding protein) or calcium-binding protein in amniotic fluid-1, is a ligand for RAGE. It has been shown that S100A12 induces adhesion molecules such as VCAM-1 and intercellular adhesion molecule-1 in the vascular endothelial cell and mediates migration and activation of monocytes/macrophages through RAGE binding and that infusion of lipopolysaccharide [114]. S100A12 is also secreted by activated granulocytes. It binds to the receptor for advanced glycation end products which induce NF-KappaB-dependent activation of endothelium. Local expression of S100A12 in inflamed synovial tissue suggests role in psoriatic arthritis (PsA) even to the point of being useful as serum marker for PsA activity [113].

Sphingosine 1-phosphate (S1P )

Sphingosine 1-phosphate (S1P) levels in cells and, consequently, its bioactivity as a signaling molecule are controlled by the action of activity of S1P phosphatase 2 (SPP2). Sphingosine 1-phosphatase 2 was found to be highly up-regulated by inflammatory stimuli in a variety of cells including neutrophils (and endothelial cells). Silencing of SPP2 expression in endothelial cells, in turn, led to a marked reduction of TNF-alpha-induced IL-1beta mRNA and protein and to a partial reduction of induced IL-8. Up-regulation of SPP2 was detected in samples of lesional skin of patients with psoriasis, an inflammatory skin disease [115].

STAT 3

Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with IL-6, EGF, and many other cytokines/growth factors. Signal transducer and activator of transcription 3 activation contributed to skin wound healing, keratinocyte migration, hair follicle growth, and resistance to UV irradiation-induced apoptosis. Signal transducer and activator of transcription 3 was consistently activated in epidermal keratinocytes in human psoriatic lesions, which has been assumed to recapitulate a condition of persistent wound healing reaction [116].

Normal neutrophil development requires G-CSF signaling, which includes activation of Stat3. Two isoforms, Stat3alpha and Stat3beta, are expressed in myeloid cells. Gene expression profiles of G-CSF-stimulated, Stat3alpha-overexpressing 32D cells with those of cells with normal Stat3alpha expression revealed novel Stat3 gene targets, which may contribute to neutrophil expansion and improved survival [117].

TGF-beta1

Inhibitory activity of neutrophil migration is due to transforming growth factor (TGF)-beta1 contained in the supernatants that desensitize neutrophils to subsequent chemotaxic stimulation [118].

TNF-alpha

TNF alpha regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF alpha targets, that attract many cells including neutrophils [119].

Many genes associated with psoriasis affect both folic acid and neutrophil function

IL-2 and IL-4

IL-2 -330*G and IL-4 -590*C alleles significantly increased in psoriasis patients, especially late-onset psoriasis [120].

IL-15

There is evidence for the important role of IL-15 genetic variants in the pathogenesis of psoriasis, probably by increasing interleukin production and inflammation in the lesions of psoriasis [121]. The role of IL-15 in neutrophil migration has been previously discussed [82].

IL-23R

The IL-23R gene is strongly associated with psoriasis. Three studies show that individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased psoriasis risk [122]. IL-23 and the following step in the psoriasis cascade IL-17 subverts the inflammatory program of neutrophils [123].

MTHFR

Genetics of psoriasis and the Hcy metabolism pathway also appear related because of detection of mutation of site C677V of MTHFR in 39 psoriatics by PCR-RFLP [124].

PSORS1

The main marker allele for the psoriasis associated gene PSORS1 is HLA-Cw6 [125].

Figure 3
Figure 3. A 14 year-old with biopsy proven acne fulminans

This marker is most highly found in the population with susceptibility to early-onset psoriasis [126]. HLA-Cw6 is associated with another neutrophilic disorder, namely, acne fulminans [127].

PSORS4

The PSORS4 locus was mapped by our group to chromosome 1q21, within the Epidermal Differentiation Complex. This cluster contains 13 genes encoding S100 calcium-binding proteins, some of which (S100A7, S100A8 and S100A9) are known to be up-regulated in individual patient keratinocytes in psoriatic patients [128].

SPP2

Bandshift analysis using oligonucleotides spanning predicted NF-kappaB sites within the SPP2 demonstrated that SPP2 is an NF-kappaB-dependent gene. Notably, up-regulation of SPP2 was detected in samples of lesional skin of patients with psoriasis [115].

Remember the NF-kappaB-related induction of VCAM-1 by homocysteine (Hcy) [57]. *********

TGF-beta-1

TGF-beta-1 gene polymorphism is also associated with early onset psoriasis vulgaris [129].

VDR

Neutrophils express functional vitamin D receptors (VDR) [130]. The A allele of the A-1012G polymorphism is associated with down-regulation of the Th1 response, via GATA-3. The F and T alleles of Fok1 and Taq1 have been associated with increased VDR activity. A-1012G, Fok1 and Taq1 VDR gene polymorphisms were associated with response to calcipotriol. A-1012G and Fok1 were associated with susceptibility to non-familial psoriasis [131].

Clinical triggers of psoriasis

Drugs and chemicals that flare psoriasis however may or may not use neutrophil mediated pathways.

DRUGS

Alcoholism is known to flare psoriasis [132]

Hcy enhances the oxidative stress of neutrophils and underscores the potential role of phagocytic cells in vascular wall injury through superoxide anion release in hyperhomocysteinemia conditions [47]. Homocysteine levels were high in males and females at admission to hospital for alcohol detoxification. They were lower at time of discharge [133]. Serum magnesium is reduced in alcoholism [119]. Also there is evidence through prenatal studies that hypermagenemia attenuates neutrophil function [134] {fig. 4, fig.5}.

Figure 4	Figure 5
Figure 4. Alcoholic patient. Hcy level 18.1 umol/L (nl <10.4), Mg 1.2 mg/dL (nl 1.6-3) Figure 5. Same patient 2 weeks after oral MgCl 212 mg tid (Mg now 1.6 mg/dL), folic acid 5 mg, vitamin B6 100mg, Vitamin B12 1 mg. 2 weeks of calcipotriol cream.

Beta Blockers flare psoriasis

cAMP inhibits lysosomal enzyme release, beta blockade and decreased cAMP result in increased PMN enzyme release. Beta agonists attach to beta receptors in skin increasing cAMP which is responsible for keratinocyte differentiation. One associated effect of beta blockade leading to cAMP decrease would paradoxically be a decrease in intracellular calcium and keratinocyte proliferation [135]. Calcium decrease as has been shown would also increase neutrophil acitivity in the epidermis [136, 137]. One of the transcription factors activated in the liver during hyperhomocysteinemia (also associated with neutrophil activity increase [13]) was cAMP-response element binding protein [138].

However, beta blockade may flare psoriasis through mechanisms less related to neutrophils and more through Th1 lymphocytes and dendritic cells. Beta-adrenergic receptor antagonist propranolol along with peptidoglycan, combined with intradermal injection of a soluble protein, shifted the recall memory response to the Th1 type. The underlying mechanism included enhanced local expression of IFN-gamma, IL-12 and IL-23 as well as of IFN-beta and CXCR3 ligands which resulted in an increase of antigen-positive plasmacytoid dendritic cells. Dendritic cells and IL-23 were recently reported to play a central role in the pathogenesis of Th1-sustained inflammatory skin diseases such as psoriasis [137]. Propranolol like lithium increases protein tyrosine kinases in psoriatic T cells increasing their activation [135, 139].

Corticosteroid Withdrawal

Precipitating factors of psoriatic erythroderma include administration of systemic corticosteroids and the excessive use of topical steroids [140]. A strong theory exists that has no need for neutrophils. There is an epitope on keratin 17 (K17) thought to be a putative psoriasis major autoantigen recognized by T cells. In a HaCaT keratinocyte model, authors have now demonstrated that IFN-gamma and to a less extent also TNF-alpha and TGF-alpha are able to induce K17 protein expression. Hydrocortisone as well as dexamethasone increased the IFN-gamma-induced K17 over-expression. This may be a mechanism explaining the well-known rebound phenomena after abrupt withdrawal of corticosteroids in psoriasis treatment [141].

In Cushing syndrome patients with active disease had higher serum and urinary concentrations of cysteine and homocysteine than cured patients and controls. Vitamin B12 levels were significantly decreased in patients with active disease compared with cured patients and controls, whereas folic acid levels were slightly decreased in patients than in controls. CD is associated with hyperhomocysteinemia. Glucocorticoid excess, acting directly or indirectly, seems to be the most responsible for this imbalance in serum amino acid (SAA) levels. The long-term disease remission is accompanied by normalization of SAA levels [142].

Plasma homocysteine levels were studied in renal transplant recipients in the course of steroid-based or steroid-free immunosuppression. The 20 recipients on methylprednisolone (MP) plus cyclosporine (CyA) or tacrolimus (TRL) showed similar creatinine levels when compared with those on calcineurin inhibitors plus mycophenolate mofetil but significantly higher total plasma homocysteine (tHcy) levels. No differences of tHcy levels have been observed when patients were analyzed according to CyA- or TRL-based immunosuppression regardless of MP or MMF associations. This data suggest that recipients, particularly those on steroid-based immunosuppression, should receive homocysteine-lowering treatment early after transplantation [143]

In one study a total of 30 healthy young males were randomized into 3 groups of equal size; one group received adrenocorticotrophic hormone (ACTH)(1-24) 1 mg i.m. daily for 4 days, another group was treated with cortisol 50 mg i.m. t.i.d. for 4 days, while a control group was observed for 4 days. Fasting blood samples were collected before and after treatment or observation. The pattern of changes was the same for the ACTH and cortisol groups. There were significant decreases in serum concentrations of folate (23% and 24%) and cobalamines (13% and 19%) and decreases in plasma total homocysteine concentrations that did not reach significance. There were no changes in the control group. The virtually identical pattern of changes in both treatment groups suggests that the effects were mediated by cortisol [144].

Prednisone induced rises in blood lymphocyte and neutrophil concentrations. Neutrophil phagocytosis was unimparied, but bactericidal capacity, stimulated nitroblue tetrazolium reduction and neutrophil and plasma lysozyme concentrations were all depressed during treatment with prednisone [145].

Lithium flares psoriasis

Calcium levels are important for keratinocyte differentiation. Psoriatic keratinocytes lack calcium levels needed for terminal differentiation. Lithium inhibits inositol recycling needed to form phosphatidylinositol-4,5-bisphosphate [135]. Inositol 1,4,5-trisphosphate increases intracellular free calcium [146]. This leads to less calcium release and psoriasis flare [16]. This mechanism for psoriasis flare seems to easily involve neutrophil recruitment since less calcium binding could reduce S100A8 and increase leukotriene B4 [136, 137].

However, lithium may flare psoriasis through other mechanisms such as tyrosine-phosphosphorylated proteins and through protein tyrosine kinase activity [137]. Also lithium increases TNF-[alpha] not only in healthy volunteers but also in co-cultures of psoriatic keratinocytes but not ******** in co-cultures of control keratinocytes [148, 149].

Methotrexate and homocysteinemia

Methotrexate inhibits dihydrofolate reductase (DHFR) and thereby inhibits lymphocyte proliferation [150]. Methotrexate (MTX) is a most potent inhibitor of rat skin DHFR [151].

Dihydrofolate reductase (DHFR) is primarily involved in the reduction of dihydrofolate, generated during thymidylate synthesis, to tetrahydrofolate in order to maintain adequate amounts of folate for DNA synthesis and homocysteine remethylation [152].

The enzyme tetrahydrofolate reductase converts homocysteine to methionine [153]. That homocysteinemia occurs with low dose methotrexate is not in dispute but its toxicity is. One study showed that low-dose MTX treatment in RA patients leads to an increased plasma homocysteine level. Concomitant folate supplementation with either folic or folinic acid decreases the plasma homocysteine level and consequently protects against potential cardiovascular risks. No relationship was found between the change in homocysteine concentration and the presence or absence of the C677T mutation in the MTHFR gene. Homocysteine metabolism was not associated with efficacy or toxicity of MTX treatment [154]. Another author stated that both folate and folinic acid reduce methotrexate toxicity and the discontinuation rate, and decrease methotrexate-induced hyperhomocysteinemia. Folate is less expensive, more secure and easier to handle than folinic acid. The efficacy of methotrexate probably decreases slightly, but the benefit outweighs the risk [155].

Evidence exists that specific polymorphisms of enzymes involved in folate metabolism could be useful in predicting clinical response to methotrexate in patients with psoriasis. Reduced folate carrier (RFC) 80A allele and the thymidylate synthase (TS) 3'-untranslated region (3'-UTR) 6 bp deletion were associated with methotrexate-induced toxicity. This was not the case when patients with palmoplantar pustular psoriasis were not included in the analysis. Stronger associations between specific polymorphisms and methotrexate-induced toxicity and discontinuation were found in a subanalysis of patients on methotrexate not receiving folic acid supplementation [156].

Non-steroidal anti-inflammatory drugs can flare psoriasis [157, 158]

Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase and bovine liver dihydrofolate reductase. The activity of the transformylase in BMCs taken from healthy humans was positively correlated with BMC folate levels. These results are consistent with the hypothesis that the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound [158]. Reduction in DHFR may reduce available folate for homocysteine remethylation leading to the occasional psoriasis flare [153, 159].

TNF-alpha blockade is sometimes associated with pustular psoriasis flare

Patients with chronic plaque-type psoriasis occasionally develop palmoplantar pustulosis during or after discontinuation of infliximab therapy. There is a report on 120 patients from the literature who developed pustular lesions during treatment with TNF-alpha inhibitors. They identified 72 women and 36 men (several papers did not specify the gender of patients) with an age range of 13-78 years (mean 42.3 years). The primary diagnoses were rheumatoid arthritis (n=61), ankylosing spondylitis (n=21), psoriasis (n=10), Crohn disease (n=8), synovitis acne pustulosis hyperostosis osteitis (SAPHO) syndrome (n=3), psoriatic arthritis (n=2), among other diagnoses (n=15). Psoriasis (except palmoplantar pustular type) was the most common adverse effect during anti-TNF-alpha treatment (n=73), followed by palmoplantar pustular psoriasis (n=37) and psoriasis of the nail (n=6), sometimes combined in the same patient. Palmoplantar pustulosis and psoriasiform exanthema was the diagnosis in 10 patients each. A positive personal history of psoriasis was recorded in 25 patients. A positive family history was noted in 8 patients. No data about personal (n=7) or family history (n = 46) were available in a number of patients. Newly induced psoriasis was diagnosed in 74 patients whereas an exacerbation or aggravation of a pre-existing psoriasis was noted in another 25 patients. All 3 TNF-alpha inhibitors available on the market were involved: infliximab (63 patients), etanercept (37 patients), and adalimumab (26 patients). In 2 of the 5 cases on one small series, manifestation of palmoplantar pustulosis was not accompanied by worsening of plaque-type psoriasis [160].

Peripheral blood neutrophils on patients with rheumatoid arthritis (RA) and controls were obtained at baseline and during anti-TNF-alpha therapy with adalimumab. All RA patients were maintained on stable regimens of methotrexate, hydroxychloroquine, and prednisone. Baseline chemotaxis of neutrophils was significantly decreased in the RA patients compared to the controls. Two weeks after adalimumab administration neutrophil chemotactic activity was completely restored with no difference noted between RA patients and controls. The production of reactive oxygen species both in resting and in phorbol 12-myristate 13-acetate-stimulted cells was significantly higher in RA patients at baseline and was unmodified by the adalimumab. The activation antigen CD69 which was absent on control neutrophils was significantly expressed on neutrophils from RA patients at baseline but was barely detectable in RA patients on adalimumab [161]. Normalization of neutrophil function here may paradoxically may lead to a pustular flare on a TNF-alpha blocker.

Infection

Interleukin-12's protective acts against Streptococcal infection increase IFN-gamma and neutrophils. The ability of exogenous interleukin-12 (IL-12) to elicit protective innate immune responses against the extracellular pathogen Streptococcus pneumoniae was tested by infecting BALB/c mice intranasally (i.n.) with S. pneumoniae after i.n. administration of IL-12. IL-12-treated mice contained higher levels of pulmonary gamma interferon (IFN-gamma) after infection and significantly more neutrophils than infected mice not treated with IL-12. Streptococcus is associated with a psoriasis flares, especially guttate psoriasis [162]. Both IL-23 and IL-17 subverted the inflammatory program of neutrophils, which resulted in severe tissue inflammatory pathology associated with infection [163].

Helicobacter pylori infections can lead to hyper-Hcy. Chronic H. pylori infection is known to increase the pH level of the gastric juice and to decrease ascorbic acid levels, both of which will lead to a reduced folate absorption. Low folate hampers the methionine synthase reaction. This leads to an increased concentration of homocysteine in the blood, resulting in damage of endothelial cells. This in turn is associated with psoriasis. In one study psoriatic patients were without any known gastrointestinal complaints. An equal number of healthy individuals constituted the control group. The prevalence of Helicobacter pylori sero-positivity in psoriatic patients was nevertheless significantly higher than in the control group [164].

Smoking

Smoking is associated with Hcy [165]. Smoking habits are related with the increase of basal and after methionine load homocysteinemia, probably because of a decrease in B6 vitamin levels. There is a proportional effect between the number of cigarettes smoked, B6 depletion and basal homocysteinemia increase [166]. The psoriasis variant palmoplantar pustulosis can be improved after cessation of smoking [112]. Moreover, the risk of psoriasis was higher in ex- and current smokers than in those who never smoked, the relative risk estimates (OR) being 1.9 for ex-smokers and 1.7 for smokers. Smoking was strongly associated with pustular lesions [167].

Trauma

Trauma response in psoriasis is frequently associated with new psoriasis at the site, the isomorphic or Koebner phenomenon [168]. Polymorphonuclear neutrophils (PMN) are critically involved in inflammation-mediated angiogenesis which is important for wound healing and repair. CD18-deficient mice which lack PMN infiltration to sites of lesion. ******* In CD18-deficient animals, neovascularization was found to be significantly compromised when compared with wild-type control animals which showed profound neovascularization within the granulation tissue during the wound healing process. Thus, PMN infiltration seems to facilitate inflammation-mediated angiogenesis [169].

Conventional psoriasis pharmacotherapies and neutrophils

DRUGS

Calcitriol

Neutrophils express functional vitamin D receptors (VDR) [130]. Calcitriol, 1 alpha,25 dihydroxycholecalciferol (1 alpha,25 (OH)2 D3) is a natural active vitamin D3 metabolite, which has been shown to have antipsoriatic efficacy. Calcitriol (3 μg/g in white petrolatum) affects polymorphonuclear neutrophil accumulation [170].

Corticosteroids

Glucocorticoids have been shown to inhibit human neutrophil apoptosis, with implications that this might help accentuate neutrophilic inflammation [171].

Prednisolone dose-dependently inhibited the LPS-induced release of cytokines (TNF-alpha and IL-6) and chemokines (IL-8 and MCP-1), while enhancing the release of the anti-inflammatory cytokine IL-10. Prednisolone in this way attenuates neutrophil activation [172].

Glucocorticoids inhibit Fas expression in bovine blood neutrophils via glucocorticoid receptor activation, possibly contributing to the cells' increased longevity in culture [173]

Neutrophil relation to steroid enema treatment was studied in patients with distal ulcerative colitis and proctitis. Rectal release of the neutrophil (myeloperoxidase, MPO) granule constituents were measured. Released amounts of MPO. ******* Clinical activity and particularly endoscopic activity correlated well with intraluminal MPO concentrations both before and during treatment. This decline of MPO concentration was seen after 7 days of treatment [174]. In a mouse model, both dexamethasone and indomethacin inhibited in vivo acute inflammation induced by 12-O-tetradecanoyl-phorbol-13-acetate and MPO activity [175].

Cyclosporine

Psoriatic patient monocytes stimulate PMN chemotaxis, phagocytosis, and O2- production without LPS. This effect is inhibited by cyclosporine A [10]. Cyclosporine A (CsA) modulates genes from the Th17 pathway (IL-17, IL-22, genes for S100A12 and others) [220] early response genes were down regulated by CsA. More myeloid-derived genes than activated T cell genes were modulated (54 cf. to 11) [176].

Fumaric Acid

Esters of fumaric acid have a long tradition in the treatment of psoriasis. The relationship of fumaric acid, CD15, and granulocytes in psoriasis and psoriatic arthritis had already been discussed in the section on CD15 [22, 23].

Dimethylfumarate (DMF) is perceived as the main active substance of this drug. However, the molecular mechanisms of DMF action are not completely understood. DMF dose-dependently reduced superantigen-induced expression of CD25, human leukocyte antigen-DR, and cutaneous lymphocyte antigen by 27, 22, and 48 percent on CD3-positive cells, respectively [177]. However, it is also noted that an enteric-coated tablet containing DMF and calcium, magnesium and zinc salts was approved for the treatment of psoriasis in Germany and since then has become the most commonly used systemic therapy in this country (see magnesium below) [178].

Magnesium

Neutrophils in patients with acute psoriasis showed an increase in CR3 (CD11b/CD18) expression. Magnesium is useful in activating CR3. A candidate for the cryptic ligand binding site is the I-domain, a Mg (2+) binding site in the alpha chain of CR3. A monomeric C3bi binds directly to recombinant I-domain in a Mg (2+) dependent fashion. These results suggest that CR3 may be inactivated by removing tightly bound divalent cation (Mg (2+)) from a cryptic site in CR3 [37]. Magnesium is a treatment for psoriasis. The combination of seawater baths and solar radiation at the Dead Sea is known as an effective treatment for patients with psoriasis and atopic dermatitis. Dead Sea water is particularly rich in magnesium ions. In one study authors wished to determine the effects of magnesium ions on the capacity of human epidermal Langerhans cells to stimulate the proliferation of alloreactive T cells. Treatment with MgCl2, similarly to ultraviolet B, significantly reduced the capacity of epidermal cells to activate allogeneic T cells. Magnesium ions also suppressed Langerhans cells function when added to epidermal cell suspensions in vitro. The reduced antigen-presenting capacity of Langerhans cells after treatment with MgCl2 was associated with a reduced expression by Langerhans cells of HLA-DR and costimulatory B7 molecules, and with a suppression of the constitutive tumor necrosis factor-alpha production by epidermal cells in vitro. These findings demonstrate that magnesium ions specifically inhibit the antigen-presenting capacity of Langerhans cells and may thus contribute to the efficacy of Dead Sea water in the treatment of inflammatory skin disease [179]. Another study showed an increased serum Hcy concentration causes abnormal metabolism of Mg2+ in cerebral vascular muscle cells. Homocysteine (Hcy) at concentrations of from 0.05 to 1.0 mM caused dose-dependent loss of [Mg2+]i in cultured cerebral vascular smooth muscle cells. Lowering [Mg2+] resulted in elevation of [Ca2+]i and loss of [Mg2+]i. Depletion of [Mg2+]i, induced by Hcy, was potentiated by low Mg2+. However, concomitant addition of Hcy and the 3 vitamins inhibited completely the loss of [Mg2+]i. Interestingly, in the presence of low [Mg2+]o, the vitamin combination did not retard depletion of [Mg2+]i. This study is compatible with the hypothesis that suggest the need for the 3 B-vitamins, together with normal physiological levels of Mg2+, in order to prevent [Mg2+]i depletion [180]. No parallel studies exist for keratinocytes but this article suggests that elevated Hcy would act to reduce intracellular magnesium. Also there is evidence through prenatal and asthma studies that hypermagnesemia attenuates neutrophil function [181, 182].

Methotrexate

Methotrexate (MTX) inhibits random migration and chemotactic migration of PMNs to Platelet activating factor (PAF), LTB4 and PAF-induce intraepidermal accumulation of inflammatory cells in dose- and time-dependent fashion. The inhibition of PMNs activities may be part of the mechanism of MTX therapy for psoriasis [183].

In psoriatics receiving MTX, neutrophil chemotaxis is suppressed, resulting in a possible alteration in the potential pathologic activity of neutrophils commonly found in lesional skin [184]. MTX is a potent inhibitor of C5a-induced skin inflammation, and that this inhibition may be caused by a direct effect on circulating neutrophils (and monocytes) [185].

Methotrexate in therapeutic dosages inhibits PMN infiltration [186]. Synovial fluid neutrophil counts and reduces joint swelling and tenderness were studied in rheumatoid arthritis patients on methotrexate.******* There was a significant effect on neutrophil chemotaxis. The direct effects on the neutrophils diminished over time [187]. Neutrophils from patients treated with low dose methotrexate showed reduced platelet activating factor-induced chemotactic responses. MTX significantly inhibit PAF-induced eosinophil and neutrophil locomotion in a dose-dependent manner. MTX also reduced calcium ionophore-driven LTB4 generation from the neutrophils of asthmatics and attenuated PHA-induced mononuclear DNA synthesis as shown by a reduction in 3H-thymidine uptake and propidium iodide staining [188].

Retinoids

Etretinate, a metabolite of acitretin causes inhibition of neutrophil migration [189].

In all forms of active psoriasis, etretinate was found to affect first the angiogenic reaction and PMN adherence, whereas NK cell activity usually normalized only after a long-term therapy. The earliest normalization of all three parameters was noticed in pustular psoriasis, and it was correlated with the clinical improvement. In 2 cases of palmo-plantar pustular psoriasis, in 5 cases of arthropathic variety, and in 5 cases of common psoriasis, the normalization preceded clearing of the skin lesions [190].

Phototherapies (mixed effects)

One in vitro study showed that chemokinetic microdroplet migration response of human peripheral polymorphonuclear leukocytes from normal and psoriatic subjects was significantly reduced following irradiation of 12®-HETE at a concentration of 1 μg/ml in medium with 40 J.cm-2 UVA and 1.5 J.cm-2 UVB respectively [191].

Another in vivo polymorphonuclear leukocyte (PMN) and mononuclear cell (MNC) locomotion is increased in psoriasis vulgaris but remains unaltered by PUVA treatment [192].

Many studies suggest enhancement of various neutrophil activities by PUVA: Early histological changes indicate the collecting of neutrophils in the stratum corneum, mainly in the acute psoriasis. Fc gammaRIIIB (CD16) is the specific functional neutrophilic receptor, which is responsible for phagocytosis. Myeloperoxidase (MPO) is the granulocyte enzyme playing the main role in metabolic activity of neutrophils. The expression of CD16 and MPO activity were significantly higher in neutrophils of patients after PUVA [193]. Human polymorphonuclear and monomorphonuclear leukocytes (PMNs andMMNL) were exposed in vitro to 8-methoxypsoralen (8-MOP, 0.1-80 μg/ml) and/or UV-A radiation (0.03-2 J/cm2) and then analysed for the following functions: chemotaxis, bactericidal activity, and proliferation in response to mitogen stimulation. The functions of PMNs became depressed only at a high PUVA dose level (about 20 μg/ml of 8-MOP plus 2 J/cm² of UV-A), whereas with MMNL chemotaxis was inhibited at 1 microgram/ml of 8-MOP plus 2 J/cm² of UV-A and lymphocyte proliferation was diminished at 0.1 μg/ml plus 0.1 J/cm². Because with the MMNL, as compared with the PMNs, a longer time period was present between PUVA exposure and analysis, and because no difference between these cell types in trypan blue exclusion could be seen, the relative sensitivity of the MMNL functions was taken as evidence of DNA damage being a mechanism for the observed PUVA-induced effects. In short, this study showed PUVA effects are more efficient against monnuclear cells than neutrophils [194].

Upon a single high dose of UVB irradiation of psoriatic lesional skin, IFN-gamma expression is decreased, whereas IL-4 expression is enhanced. A similar type 1 to type 2 shift was found in dermal T cells derived from irradiated lesional skin as compared to unexposed lesional psoriatic skin. Investigators found recently that the IL-4 protein detected in situ upon UVB exposure of normal skin was not associated with T cells but with infiltrating neutrophils. In the irradiated skin of both healthy controls and patients, IL-4-positive cells coexpressed elastase and CD15, but not CD3. IL-4-expressing cells found in psoriatic skin after a single high-dose UVB exposure appeared to be neutrophils [195].

Photodegradation may also play a role in neutrophil activity increase in light. Photodegradation of folic acid (FA) by ultraviolet (UV) radiation is a well-documented photochemical reaction and decreased serum levels of FA have been found in patients receiving photochemotherapy (psoralen plus UVA) [196].

Disorders treatable by TNF-alpha blockade are neutrophilic and frequently hyperhomocysteinemic

Disorders with major neutrophil dysfunction are TNF-alpha modulation are ******** psoriasis, pyoderma gangrenosum, neutrophilic dermatosis. TNF-alpha inhibitors such as adalimumab have been used in the treatment these including of pyoderma gangrenosum [197]. Targeting the TNF pathway can significantly decrease Lp(a) and homocysteine levels and elevate Apo A-I and SHBG concentrations. These data support an important precursor role for high-grade inflammation in modulating these putative risk parameters [198]. Exposure of keratinocytes to IFN-gamma and TNF-alpha increased intra-cytoplasmic expression and led to partial translocation at the cell surface. Keratinocyte activation by TLR2, TLR3, and TLR4 ligands led to the nuclear translocation of NF-kappab and the release of proinflammatory cytokines TNF-alpha and IL-8 [199]. Important physiological activators of neutrophils are the cytokines interleukin-8/CXC chemokine ligand 8 (IL-8/CXCL8) [31]. The effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in 10 psoriasis patients treated for 6 months. ****** (sentence?) ****** rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-gamma-inducible protein-10 (CXCL10), and MIP-3alpha (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively [200].

Hcy enhances the oxidative stress of neutrophils, and underscores the potential role of phagocytic cells in vascular wall injury through superoxide anion release in hyperhomocysteinemia conditions [46]. Hcy elevation is associated with many of the disorders treatable or flared by anti-TNF alpha drugs (i.e., pyoderma gangrenosum and in the aurthor's experience 2 cases of a disorder sometimes associated with pyoderma gangrenosum and treatable with TNF-alpha blockade, subcorneal pustular dermatosis of Sneddon Wilkinson [201].

Figure 6	Figure 7
Figure 6. IBD patient with Hhcy on Prednisone 1-2 mg and folic acid, 5 mg, B6 100 mg, B12 1 mg daily Figure 7. Same patient off B vitamins

Figure 8	Figure 9
Figure 8. Sneddon Wilkerson patient with Hhcy (20 μmol/L) on topical corticosteroids Figure 9. Same patient 3 weeks later with topical calcipotriol cream, B6 100 mg and B12 1 mg daily (but no folic acid) added

Plasma homocysteine level did significantly increase in ankylosing spondylitis patients under sulfasalazine or MTX treatment [202].

Figure 10
Figure 10. Biopsy-proven Behçet disease patient with Hhcy

In Behçet Disease significantly higher homocysteine and lower nitric oxide and neopterin levels were observed in patients with Behçet disease compared with healthy controls [203]. To determine the effect of folic acid supplementation in Behçet disease (BD) patients with ocular involvement associated with hyperhomocysteinemia (Hhcys). Uveitis improvement was associated with decreased Hcy using folic acid 15 mg. Our results indicate that folates supplementation is useful for BD patients with Hhcys [204].

In inflammatory bowel disease (IBD) homocysteine has a crucial role in cellular stress, epigenetic events, inflammatory processes, and host-microbial interactions. Hyperhomocysteinemia might therefore influence the clinical history of IBD, including disease severity, susceptibility to particular enteric infections, and the risk for the development of colorectal cancer. Given the peculiar frequency of such deficiencies in IBD, one review states that normalizing vitamin levels should be an integral part of the management of these patients [205]. In ulcerative colitis the mean tHcy in UC patients was significantly higher than in healthy controls. Patients with active disease had higher tHcy than patients in remission. Patients with 4 or more recurrences of the disease had also higher tHcy than the others: The tHcy correlated with duration of disease. Folate and B12 levels were within their reference ranges in all subjects. Ulcerative colitis is associated with elevated tHcy concentration, particularly in the active stage, and in more recurrent types of the disease; this elevation does not seem to be prevented by a normal folate status [206].

Fourteen percent of patients with Livedoid Vasculopathy which often is a neutrophil mediated disorder had elevated homocysteine levels [207]. Vasculitis or vasculopathy was reported in 1 patient with Sjögren syndrome and was associated with MTHFR mutation but not homocysteinemia [208]. Hyperhomocysteinemia is commonly observed in Rheumatoid Arthritis (RA) patients, thus putatively accounting in part for the high rate of cardiovascular events in these subjects. Homocysteine (Hcy) is known to exert a pro-inflammatory effect putatively contributing to the progression of atherosclerotic lesions by cytokine production from several vascular cell-types. Hcy was present in synovial fluids, with a mean concentration significantly higher in RA patients than in controls. Hcy enhanced IL-6 and IL-8 production in RA synoviocytes only (up to 35%). Moreover, Hcy produced a clear-cut activation of NF-kB in rheumatoid cells only. Hcy, therefore, is thought to enhance IL-1-dependent cytokine production by rheumatoid synoviocytes at a concentration measurable in RA joints in vivo. Thus, in RA patients, Hcy may not only represent an important risk factor for the progression of cardiovascular diseases, but it may also contribute to the joint damage [209].

The association of hyperhomocysteinemia is these disorders should not be overstated. In one RA, Psoriatic Arthritis, SLE: study shows only in 25 percent of patients may the Hcy pathway be important. ******* The nature of B12 and folic acid (FA) deficiencies in a cohort of rheumatic patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and systemic lupus erythematosus (SLE). Levels of B12, FA, and parameters of anemia were recovered or examined in 276 outpatients. In those with recent findings of low serum B12 levels, further studies of serum homocysteine (Hcy), and urine methylmalonic acid (MMA) levels were performed on patients with psoriatic arthritis, rheumatoid arthritis and SLE. Low levels of serum B12 were also frequent (24%), with almost similar occurrence in the 3 disease groups. In the 15 patients with recently detected low B12 levels, Hcy and MMA were evaluated before and following B12 therapy. In 10 of them, baseline Hcy levels were high, while MMA was increased in 1 patient only. Response to B12 administration (i.e., a decrease in Hcy and/or MMA levels) was noticed in 4 patients only, suggesting that only 26 percent of the low-serum-B12 patients had true [sic] B12 deficiency [210].

Disorders associated with psoriasis are either neutrophilic or are associated with homocysteinemia

Depression

Clinical depression can be diagnosed in 32 percent of psoriatic patients according to one study [211]. Depression is associated with the Hcy pathway [210]. Findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. Treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population [212] the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients [213].

Diabetes

A multivariate logistic regression model showed that psoriasis was significantly associated with diabetes, independently of age and gender [214].

Chances for atherosclerosis, congestive heart failure, type 2 diabetes, and peripheral vascular disease were 5% for psoriasis patients [215].

While increased Hcy has also been linked to obesity at least in women and in diabetic patients with the metabolic syndrome [216-222], insulin resistance is associated with elevated plasma total homocysteine levels in healthy, non-obese subjects [222].

Women with Gestational Diabetes Mellitis in comparison to control women were characterized by higher values of homeostasis model of insulin resistance, serum triglycerides, and FFA. In women with gestational diabetes mellitis serum total Hcy correlated with vitamin B12 and folates [223].

Recently, more and more attention has been paid to the involvement of hyperhomocysteinemia in the progression of diabetic retinopathy (DR), a serious microangiopathic complication of diabetes. Clinical studies have demonstrated that MTHFR gene polymorphism can contribute to the progression of DR, especially in the patients with poorly controlled blood glucose. Furthermore, accumulating evidence suggests that homocysteine activates vascular inflammation through inflammatory cytokines, including VEGF [224].

Hyperlipidemia

Psoriasis patients have a higher prevalence of hypertriglyceridemia and abdominal obesity [225]. Though body weight, waist hip ration, and mean fat mass percentage correlate with lipid levels [226], it is to be noted that the fasting triglyceride level in the patient shown in figure 1 and 2 fell 20 percent on vitamin and resveratrol therapy while losing only about 8 pounds.

Inflammatory Bowel Disease

That inflammatory bowel disease is associated with hyperhomocysteinemia has already been discussed. The characteristic inflammatory response begins with an infiltration of neutrophils and macrophages, which then release chemokines and cytokines [219 ].

Epidemiological studies have shown that, in psoriasis patients, associated disorders may occur more frequently than expected. Such comorbidities include psoriatic arthritis, psoriatic pustular diseases, Crohn disease, and signs of metabolic syndrome, which leads to atherosclerosis with coronary heart disease [220].

Seventeen percent of the IBD patients and 10 percent of the persons without IBD had a diagnosis for at least 1 immune-mediated disease. Inflammatory bowel disease patients were more likely to have asthma, psoriasis, rheumatoid arthritis, and multiple sclerosis [227].

Lymphoma

Lymphoma incidence may be increased in psoriasis and other TNF-alpha mediated diseases. That risk varies from only slightly increased in IBD [228]. Higher in classic rheumatic disorders such as rheumatoid arthritis, systemic lupus, and Sjögren Syndrome [229]. It is clearly increased in psoriatics only with methotrexate exposure [230].

Genetic polymorphisms in the folate metabolic pathway were investigated using the DNA from a case-control study on 31 patients having malignant lymphoma. Two polymorphisms MTHFR 677 C-->T and MTHFR 1298 A-->C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5, 10-methylene-tetrahydrofolate and results in a reduced incidence of DNA double strand breakage. Methionine Synthetase 2756 A-->G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. There is a higher susceptibility for lymphoma with the MTHFR 677CC and MTHFR 1298 AA genotypes. When those harbor at least 1 variant allele in either polymorphism of MTHFR they were defined as reference. For the MS 2756 AG genotype polymorphism there was also a higher susceptibility to developing malignant lymphoma [231].

Multiple Sclerosis (MS)

Several studies associate MS with psoriasis (and rheumatoid arthritis). The most frequent autoimmune disease associated with MS is psoriasis (18% in one study)[232].

MS patients had a statistically significant more frequent coexistence of rheumatoid arthritis, psoriasis, and goiter when compared to the controls [233]. There are increased plasma homocysteine levels in MS patients [234]. Myocardial infarct, stroke and peripheral vascular disease and possibly idiopathic calciphylaxis {figs. 11, 12}

Figure 11	Figure 12
Figure 11. Remaining ankle of amputee with peripheral vascular disease and Hhcy history Figure 12. Leg ulcer patient with normal kidney, parathyroid function with calcified vasculopathy and Hhcy

Myocardial infarcts and peripheral vascular disease are more common in TNF–alpha antagonist treated diseases such as psoriasis, rheumatoid arthritis, and psoriatic arthritis [235-8]. Lowering homocysteine (Hcy) in patients with ischemic stroke prevents recurrent stroke, myocardial infarction, and death [239, 240].

Hcy appears to act through other mechanisms on organ systems. Homocysteine acts on calcium. It potentiates calcification of cultured rat aortic smooth muscle cells (Fig. 12) [241]. Homocysteinemia there is induced depletion of intracellular free Mg ions in canine cerebral vascular smooth muscle cells. This was thought to create possible relationship to atherogenesis and stroke. Specifically there are findings consistent with the hypothesis that an increased serum Hcy concentration causes abnormal metabolism of Mg2+ in cerebral vascular smooth muscle cells, thus priming these cells for Hcy-induced atherogenesis, cerebral vasospasm and stroke. These results suggest the need for the 3 B-vitamins, together with normal physiological levels of Mg2+, in order to prevent [Mg2+]i depletion and occlusive cerebral vascular diseases induced by homocysteinemia [242].

Neutrophils have a role in the pathogenesis of the acute myocardial infarction (AMI). One recent review explores the possibility that inhibition of the activity of neutrophils and inhibition of the signaling pathways related to their activity may result useful in AMI and may improve the prognosis of this pathology [243].

Impaired homocysteine metabolism seems to exist in 15-30 percent of patients with premature cardiovascular disease. Moderate homocysteinemia is a risk factor for cardiovascular disease, independent of conventional risk factors [244]. Targeting PMNs with anti Hcy folate should be selective. Folate therapy does not seem to affect early CAV onset. Sub-group analysis suggests that folate therapy may delay CAV development only in patients with baseline hyperhomocysteinemia, while it may favor CAV progression in recipients with normal baseline homocysteinemia [245].

Obesity and the Metabolic Syndrome

Obesity and the metabolic syndrome are associated with psoriasis. Metabolic syndrome was significantly more common in psoriatic patients than in controls after the age of 40 years. Psoriatic patients also had a higher prevalence of hypertriglyceridemia and abdominal obesity, whereas hyperglycaemia, arterial hypertension and high-density lipoprotein cholesterol plasma levels were similar. Although psoriasis patients appear more frequently smokers, the association of psoriasis with metabolic syndrome was independent from smoking. However there seems to be no correlation between severity of psoriasis and prevalence of metabolic syndrome [226, 246].

Some TNF-alpha drug toxicity is similar to disorders associated with homocysteine/mg (both hve effects on neutrophils)

Heart Failure

Heart failure is associated with abnormally high and low magnesium levels [247]. Intracellular Mg depletion was demonstrable in neutrophils, which may be responsible for some of the adverse clinical manifestations in heart failure patients [248].

Hepatic disorders: Primary Biliary Cirrhosis, Cholestasis

In a case controlled study of primary biliary cirrhosis there was significant associations with psoriasis (13% in cases vs. 3% in controls) [249].

In primary biliary cirrrhosis, hyper-HCY is related to hypovitaminosis and genetic predisposing factors. Increased TF and Hcy levels and signs of endothelial activation are associated with hypercoagulability and may have an important role in blood clotting activation [250].

Twenty-two patients consecutively admitted for generalized pustular psoriasis who underwent liver biological tests at the time of the attack and during the following weeks were included. Twenty patients (90%) had at least 1 abnormal biological liver parameter. Eleven patients (50%) had pronounced abnormalities: jaundice (4/22), gammaglutamyl transferase higher than 5 times the normal value (10/22), alkaline phosphatase higher than twice the normal value (7/22), and/or aminotransferases higher than 3 times the normal value (7/22). These abnormalities returned to normal range at the time of remission of pustular psoriasis, suggesting that severe liver abnormalities could be associated with severe cutaneous disease. Neutrophilic cholangitis was observed on liver biopsy [251].

Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio, and glutathione were measured. Plasma Hcy concentrations were transiently elevated by the 14th day after bile duct ligation and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. This study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic stages and in secondary biliary cirrhosis. In addition, it was observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis [251]. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis [252].

Expression of neutrophil chemo-attractant, interleukin (IL)-8, in bile duct cells is seen in reactive bile ductules with neutrophilic infiltration using in 8 cases of chronic viral hepatitis, 7 cases of liver cirrhosis (LC), 7 cases of sepsis, 11 cases of extrahepatic biliary obstruction (EBO), 3 cases of fulminant hepatitis (FH), 5 cases of primary biliary cirrhosis, and 3 cases of primary sclerosing cholangitis. IL-8 was detected in bile ductules in various diseased livers. HNP1-3-positive neutrophils were significantly dense around IL-8-positive bile ductules compared with IL-8-negative ductules in septic liver, LC, EBO, and FH. Experiments in vitro showed that cultured human biliary epithelial cells expressed and secreted IL-8 in response to lipopolysaccharide and also IL-1beta and tumor necrosis factor-alpha [253].

Multiple Sclerosis

There is increased plasma homocysteine level on average in multiple sclerosis patients [254, 255]. Magnesium oral therapy in a patient with multiple sclerosis improved MS spasticity [256].

Conclusions

Neutrophil and related pathways can help explain:

The pathogenesis of psoriasis and related disorders

The coexistence of disorders associated with psoriasis

Why certain agents flare psoriasis

Why many psoriasis drugs work

Why certain disorders are associated with the treatment of psoriasis with TNF alpha

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