Pathogenesis And Future Treatment Of Systemic Lupus Erythematosus Biology Essay

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Systemic lupus erythematosus is a chronic multisystem autoimmune connective tissue disorder, which has variable clinical manifestations that range from mild to life-threatening. These can be characterised by multiple organ damage, very high titres of autoantibodies and immune complex deposition. Interestingly the former of these characteristics may precede the clinical manifestations of SLE by many years [1]. It is well recognised that the probable influence of oestrogen hormonal effect in women during childbearing years increases their chances of developing SLE by 10-15 times [2 - 5]. All of these factors contribute to the conventional belief that SLE is a disease primarily of these autoantibodies and immune complex deposition, the latter contributing to inflammation by virtue of complement activation and the engagement of complement and Fc - receptors

[6, 7] ultimately inflicting injury to a variety of organ systems (Fig1). Mediation of these inflammatory responses is characterised by the influx of various cell populations and also to a large extent by the generation of proinflammatory cytokines. The clinical manifestations in inflammatory diseases such as SLE and rheumatoid arthritis (RA) are thought to be influenced by the balance between proinflammatory and

anti-inflammatory cytokines.

Cytokines are soluble factors and are mainly produced by helper T (Th) cells. They also play a crucial role in the differentiation, maturation and activation of various immune cell types [8]. In order to monitor disease activity and predict disease severity certain cytokines may act as biomarkers [9]. Recent work for example, using microarray techniques and genetic analysis has strengthened the association between cytokine dysregulation and SLE [10]. These breakthroughs show some promise in understanding the immunoregulatory networks of autoimmune diseases, which are influenced by multiple factors, particularly in regard to these cytokines and their interactions.

Triggers

Environmental factors

Genetic predisposition

Neuroendocrine system

Gender and se hormone milieu

Immune Dysregulation

Deficient CD8+ T suppressor activities and B cell negative selection, loss of idiotypic control

Defective clearance/

apoptosis

DNA

Apoptic

cells

Excess help:

Cytokines:

Eg's. IL-6, 10, and 17

Auto -

reactive

B cells

APCss

T cells

CD4+

overactivity

AUTO Ab

PRODUCTION

Immune complex formation

Complement activation

Tissue injury

Fig 1: Immunopathogenesis of SLE [51]

Through systematic published literature, cytokines that have significant involvement in the pathogenesis of SLE and those that represent a relatively easy target for therapeutic intervention (i.e. the anti-cytokines) in the 'human model' will be reviewed.

Cytokine Productions and Cytokine Levels in Patients with SLE

Several cytokines are in involved in the pathogenesis of SLE [11] and more than 30 years ago [12] immune interferon (IFN-) was found in the serum of patients with SLE and showed a good correlation between (IFN-titres and disease activity.

T-helper cells 1 (Th1) cytokines such as IFN-, IL-12, and T-helper cells 2 (Th2) cytokines IL-4, IL-6 and IL-10 are each considered to play a role in the course of human SLE [13, 14]. Other proinflammatory cytokines such as IL-1 and tumour necrosis factor alpha (TNF [15] are also involved along with these Th1 and Th2 cytokines.

1. Interleukin 6 (IL-6)

IL-6 is a proinflammatory cytokine which is synthesized principally by moncytes, fibroblasts and endothelial cells (Fig 2). IL-6 secretion can also be found in both T and B lymphocytes [15] and its production is stimulated by IL-1, IL-2 and TNF- but subdued by IL-4, IL-10 and IL-13. In combination with type 1 interferons, one of the most important effects of IL-6 is to activate B lymphocytes and drive plasma-cell differentiation and to augment the immunoglobulin secretion [16, 17]. Additionally, IL-6 acts on multipotential progenitor cells, is a neutrophil activator as well as stimulating megakaryocytes to produce platelets. It also induces terminal macrophage and osteoclast differentiation as well as pyrexia and the production of acute phase proteins.

In total contrast to these proinflammatory effects, IL-6 is also involved in a number of unique anti-inflammatory reactions. For example, IL-1 and TNF-

stimulate the synthesis of each other as well as IL-6, however, the latter is involved in terminating this reaction as well as being involved in the upregulatory inflammatory cascade [17].

The association of IL-6 in the pathogenesis of SLE in humans is still controversial [18] although support for this association has been published using several murine models [19-21].

Fig 2: IL-6 producing cells and the biological activities of IL-6 [36].

IL-6 in Human SLE

Human SLE patients have been shown to have increased IL-6 [22-24] levels that are allied to disease activity [23] or anti-DNA levels [22], in some but not all studies [24].

In one study [25] SLE patients had a significantly higher frequency of IL-6 secreting peripheral blood mononuclear cells (PBMCs) compared to those of healthy controls. This may well be due to environmental factors as exposure to UV light has been shown to stimulate the monocyte/macrophage fraction of PBMCs taken from SLE patients to produce IL-6 [26]. Another interesting observation was that lymphoblastoid cells that were isolated from SLE patients exhibited high levels of IL-6 and blocking IL-6, which resulted in the inhibition of anti-dsDNA production in vitro [27]. However, using a widely applied method to study the activation of the innate immune system i.e. the in vitro stimulation of whole blood using lipopolysaccharide (LPS), IL-6 production was significantly lower in SLE patients as compared to normal individuals [28].

Unlike normal individuals, B lymphocytes from SLE patients were found to spontaneously generate large amounts of immunoglobulins (Ig). There was however, a significant reduction in this Ig production when IL-6 was blocked and this production was only restored after exogenous IL-6 administration [23]. In addition these B lymphocytes also secreted anti-ds DNA, with different B lymphocyte populations contributing to this in a number of different ways. For example, it was shown that the majority of these autoantibodies were produced ex vivo by low density B lymphocytes [29], whereas high density B cells had little effect. It was also shown that in response to IL-6, low density B lymphocytes from patients with active SLE were capable of directly differentiating into Ig secreting cells [30]. CD5 expression is also down-regulated by IL-6 via DNA methylation, which promotes activation and subsequent expansion of auto-reactive B cells seen in SLE patients [30]. The IL-6 abnormalities seen in SLE may well be due to in part to genetic differences. For example Linker-Israeli et tal [31] demonstrated that alleles of the adenosine/tyrosine (AT) rich minisatellite situated in the 3' region flanking the IL-6 gene, was associated with SLE patients of either Caucasian or African-American origin, but not of that of the control group.

It is well proven that the classical marker autoantibodies seen in SLE are anti-double stranded DNA (anti-dsDNA) antibodies and although the titre of those antibodies in the serum of SLE patients can be a reflection of disease activity in lupus nephritis, for example, their exact role remains unclear. It has been shown however, that anti-dsDNA can have a direct effect on cytokine expression in a variety of cells.

For example they can upregulate the expression of the proinflammatory cytokines IL-1 and IL-6 in endotheilial cells [32-34] and from human resting mononuclear cells they can stimulate the expression and release of IL-1, IL-6, IL-8, IL-10 and TNF [35].

IL-6 and lupus nephritis

IL-6 has been shown in several studies to have proliferative effects on mesangial cells thereby modulating injury in immunologically generated nephritis. Two studies [37, 38] demonstrated that mesangial proliferation in mesangial proliferative glomerulonephritis correlated well with the urinary IL-6 levels. Further studies demonstrated high urinary excretion of IL-6 in patients with active lupus nephritis. The levels of IL-6 were significantly elevated in those patients with proliferative lupus nephritis (World Health Organisation (WHO) Class III and IV) with concomitant high titres of anti-dsDNA antibodies [39, 40]. IL-6 levels were also found to be much higher in patients with active nephritis as compared to those patients with dormant renal disease [24, 40]. Additionally it was found that there was enhanced in situ expression of IL-6 in lupus nephritis, mainly along the renal glomeruli and tubles [41-43].

Interestingly IL-6 has also been shown to have a positive association with the Neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE). For example elevated levels of IL-6 have been reported in the cerebrospinal fluid (CSF) of patients with NPSLE, without subsequent damage to the blood-brain barrier [44-46].

To summarise, IL-6 has an important role in mediating local inflammation and insults of various tissues.

Therapeutic Implications of IL-6 in SLE

As previously stated in a number of studies, IL-6 was found to be elevated in both human and murine lupus.

IL-6 released from PBMC for example, directly correlated with disease activity and the treatment response seen in lupus nephritis patients [47].

Other studies have confirmed that there was an increased expression of the IL-6 agonistic receptor gp130 on peripheral lymphocytes in SLE patients, and that the levels correlated with overall disease activity.

Taking this into account it has been suggested that gp130 could be a useful biomarker to monitor both the activity of disease and subsequent treatment responses in those patients [48].

Using murine models where the success of IL-6 antagonism is well proven, a phase 1 dose finding study was set up to evaluate the use of a monoclonal antibody tocilizumab (Anti-IL-6 R Ab) in human SLE patients [49]. A total of sixteen patients with moderately active disease as defined by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), (i.e. a SELENA - SLEDAI score of between 3 and 10 or active glomerulonephritis) were given tocilizumab in one of three doses (2 mg/kg in 4 patients, 4 mg/kg in 6 patients, and 8 mg/kg in 6 patients) twice weekly for 12 weeks. Patients were then monitored for an additional 8 weeks [50].

There was a notable reduction in inflammatory markers, auto-antibody levels and in disease activity (SELENA-SLEDAI from 9.5 at baseline to 5.5 at 20 weeks) with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Unfortunately almost all the patients developed a significant dose-related neutropenia with concomitant high rates of infections [50].

Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serological responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.

2. Interleukin 10 (IL-10)

The cytokine IL-10 is mainly produced by lymphocytes and monocytes. It also impedes the activation of antigen presenting cells (APCs) and down-regulates the expression of co-stimulatory molecules such as major histocompatibility complex class II (MHC II) and B7 expression [51]. IL-10 also inhibits T cell function by diminishing the expression of other proinflammatory cytokines such as TNF IL-1, IL-6, IL-8 and IL-12 [52, 53]. As well as these inhibitory functions IL-10 boosts B cell mediated proliferation, thereby increasing survival, proliferation, differentiation and immunoglobulin class switching, resulting in increased antibody secretion, which promotes the inflammation seen in SLE [54].

In particular the production of IL-10 and TNF two mutually associated cytokines play a complex and opposite role in these systemic inflammatory responses that has been found to be deregulated in SLE patients (Fig3).

All these findings, plus the addition of environmental influences are suggestive of a combination between genetic and disease-induced events. IL-10 and TNF for example, have been linked to SLE and genetic polymorphorisms at the promotor regions of both these genes [55] is associated with their over production, particularly that of IL-10 [56].

Fig 3: Interactions of IL-10 and TNF in SLE [55].

DC, dendritic cells; Mø (APCs), antigen presenting cells; Stat, signal transducer and activator of transcription.

However, previous studies of a much larger magnitude which included patient family members with increased IL-10 production [57], failed to confirm this association [58].

Increased IL-10 production might also explain B cell hyperactivity and autoantibody production, two of the main indicators of the immune dysregulation seen in SLE. In line with this; the association between IL-10, disease activity, immune complexes isolated from the serum of SLE patients as well as monoclonal anti-dsDNA antibodies, induced IL-10 production in healthy monocytes [35, 59]. IL-10 might also regulate DCs and T cell function, by promoting Th2 deviation of the overall immune response (see Fig 1) [60].

Therapeutic Implications of IL-10 in SLE

Although one of the major factors in regard to the above is still the absence of a therapeutic agent which is suitable for long-term administration in human patients with SLE, IL-10 was the first cytokine to be blocked [64], which has led to use anti-IL-10 antibody in the treatment of this disease [61].

An over-production of IL-10 has been demonstrated in murine models of SLE [62]. Using continuous early-onset therapy with an anti-IL-10 antibody however, delayed autoimmunity in NZB/W mice and improved their overall survival rate from 10 to 80% [63]. In a pilot study using an anti-IL-10 murine monoclonal antibody (MoAb), which neutralizes human IL-10, Llorente et al. [64] evaluated the clinical efficacy and safety of this antibody in a total of six patients with steroid dependent SLE.

The treatment consisted of administering 20mg/day of MoAb intravenously for a total of 21 consecutive days. The patients were then followed up monthly for a total period of 6 months. The therapy was well tolerated in all six patients and although all had significant improvement of their cutaneous lesions and/or joint symptoms during MoAb administration, they also developed antibodies against it.

This study not only suggests that the use of MoAb may be of benefit in the management of refractory SLE, but that a much larger, randomized and blinded study using a humanized anti-IL-10 MoAb is required. Such an agent might soon be available [61].

3. Interleukin 17 (IL-17)

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