Costimulatory molecules and their ligands as therapeutic targets in autoimmune disease

ARTICLE

In principle we differentiate between systemic and organ-specific autoimmune diseases [1]. The main candidates of systemic autoimmune disease are systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, chronic graft versus host disease and various forms of vasculitis. The most frequent organ specific autoimmune diseases are insulin dependent diabetes mellitus, multiple sclerosis and inflammatory bowel disease. Systemic autoimmune diseases are characterized by high affinity IgG antibodies, mostly against intracellular, including nuclear, antigens. As evident from the IgG production by B cells, T helper cells, mainly TH2 cells, are involved [2, 3]. The pathology is mainly due to deposition of antibodies at target cells or deposition of immune complexes which may occur in all vessels throughout the body. This leads to activation of complement and macrophages, the recruitment and activation of inflammatory cells and eventually to a blockade of important receptor functions [4]. Organ-specific autoimmune diseases are mediated by T cells, mainly TH cells, but a contribution of cytotoxic T cells has also been described, although mostly as a secondary phenomenon like destruction of islets by cytotoxic T cells in insulin dependent diabetes mellitus (IDDM) [5]. The dysregulation of mostly TH1 cells is manifested by delayed type hypersensitivity (DTH) reactions [6].

Important factors for the development of autoimmunity

Autoimmune diseases are caused by the immune system, the one organ of the body to defend the organism's integrity against any kind of foreign invaders. It does so by learning to discriminate between self and non-self, attacking only the latter and tolerating the former. Thus, the breaking down of self tolerance is the principle and consistent feature in any autoimmune disease [7], although the etiology varies widely and in most instances is multifactorial [8]. The occurrence of autoimmunity may reflect an imperfect nature of tolerance induction during T cell or B cell development. Taking the fact that autoimmune diseases are not observed in the neonatal period and that no deficits in intrathymic tolerance have been described so far, it is likely that the inadequate response of the immune system rather relies on a distortion of peripheral mechanisms of tolerance [9]. Notably, additional factors, besides a dysregulation of the immune system, are important for the onset of autoimmune disease. These are genetic factors, hormones and environmental conditions. Among the genes associated with autoimmunity, the strongest association has been observed with MHC, particularly MHC class II genes [10-13]. Yet, multiple non-MHC genes also contribute, these include the CD95/CD95L genes, several complement protein genes, some TCR Vbeta genes [14-18]. An involvement of hormones becomes apparent by the striking prevalence of females for systemic autoimmune diseases [19]. Dietary components, drugs, toxin, infections [20-23] and UV light are known to be also important for the exacerbation of autoimmune diseases, e.g. inflammatory skin lesions are usually limited to light-exposed areas [24]. Taken together, autoimmunity develops as a result of multiple interacting factors, which collectively lead to a failure or breakdown of self tolerance.

The primary immunological abnormalities associated with the breakdown of self tolerance

What are the lymphocyte abnormalities which cause autoimmune disease? We have stated already that rather than a defect in central tolerance, a failure of peripheral tolerance may be observed. This accounts for T cells. For B cells the question has not yet been answered [25].

A breakdown of T cell anergy can be brought about by expression of costimulatory molecules on cells normally devoid of these T cell activating molecules [26]. Expression can be induced by infections, tissue damage or local inflammations. One example is expression of the costimulatory molecule CD80 as a transgene selectively on pancreatic islet cells. Although not initiating insulitis by itself, it does so in the context of e.g. viral proteins [27]. Alternatively, T cell anergy may fail because of a deficit in regulatory costimulatory molecules like CTLA4. Mice with a targeted deletion of CTLA4 develop fatal autoimmune disease, due to the incapability of the immune system to terminate an ongoing response [28].

Similar, a failure of activation induced cell death also leads to autoimmune disease. This has become apparent in two mouse strains, lpr/lpr mice, which have a defect in the CD95 gene and gld/gld mice, which have a defect in the CD95 ligand gene. These mice die from severe systemic autoimmune disease, resembling systemic lupus erythematosus. Due to these defects the mice develop a generalized lymphoproliferation, i.e. activated CD4⁺ cells cannot be eliminated by AICD [29].

Polyclonal lymphocyte activation by e.g. LPS in the mouse model or by bacterial products resembling LPS in the human will include the stimulation of B cells with low affinity for self, which have not been deleted [30, 31]. Polyclonal T cell activation by bacterial superantigens is also postulated to be of relevance for induction of autoimmune disease [32]. Both pathways link the onset of autoimmune disease to infections.

Another pathway by which infections may be initiating autoimmune disease is the phenomenon of immunological cross-reactivity [33, 34]. For example, rheumatic fever developing after streptococcal infections is caused by anti-streptococcal antibodies that cross-react with human myocardial proteins resulting in myocarditis. The underlying mechanisms, i.e. stretches of homology between microbial and self proteins, called molecular mimicry, is postulated but not definitively proven to support human autoimmune diseases.

Principles of therapy for autoimmune diseases

It should be pointed out that for most autoimmune diseases we still do not know the responsible antigen/epitope. It is for this reason that therapy has been symptomatic rather than causative for most of the time and in most instances, i.e. relying on the anti-inflammatory effect of corticosteroids [35] or on the application of antagonists for pro-inflammatory cytokines to block leukocyte emigration into tissue [36]. In severe cases T cell activation will be blocked by a generalized immunosuppression [37]. With further progress we may finally reach the goal of an antigen-specific therapy, allowing for e.g. oral tolerance induction [38], administration of altered peptide ligands [39] or depletion of clonotypic T cells [40]. The antigens mostly not yet being known, there is, however, an alternative, which will be less burdening than systemic interference by anti-inflammatory or immunosuppressive agents. Our rapidly increasing understanding of the functional principles of costimulatory molecules may allow for rather selective, though not specific therapeutic intervention.

Costimulation and autoimmune diseases

For T cell activation to take place, it is necessary for the T cell to receive two signals. One signal determines the antigen-specificity of the response and results from the interaction of the T cell receptor with the MHC bound antigenic peptide [41]. The second signal, termed costimulation, is provided by accessory molecules on the APC. This second signal is essential for T cell activation, e.g. provision of signal 1 in the absence of signal 2 leads to T cell anergy [42]. There are several pairs of costimulatory ­ ligand molecules, all of which have been described to be important in induction and or maintenance of a state of autoimmunity. The most well characterized are CD28/CTLA4 which bind to CD80/CD86 on APC [43] and CD40L binding to CD40 [44]. The literature on the role of these molecules in autoimmune disease has rapidly increased over the past decade, this review can only point out some of the highlights. Such a selective presentation requires stating in advance that, depending on the model system, the genetic background and the state of disease, partly opposing results have been described, e.g. the same reagent mitigating or exacerbating the disease. Those discordant findings could be well explained in nearly all instances. They reflect some of the general features of autoimmune diseases, like epitope spreading [45], the variable course from person to person and the tendency to wax and wane in severity over time, independent of any therapeutic intervention [46]. All these features suggest the operation of potent forces to downregulate autoimmune processes. Thus, depending on the state of disease, which includes the distinct requirements of naive and memory T cells for activation [47], the same intervention can interfere with an overshooting immune reaction or block downregulatory elements.

CD28/CTLA4 and their ligands CD80/CD86

CD28/CTLA4-CD80/CD86 ligand interactions represent the major costimulus on resting naive and memory T cells. Support for a contribution of this system in autoimmune disease was derived, among others, from the observation that African Americans have a significantly higher incidence of autoimmune disease compared to Caucasian Americans and display significantly higher levels of CD80 and CD86 [48]. The importance is most convincingly demonstrated by the clinical use of CTLA4-Ig for the treatment of psoriasis [49] only 7 years after a first documentation of in vivo effectiveness [50]. CD28 is constitutively expressed on the majority of T cells, Yet, its expression is dynamic, i.e. increases transiently after T cell activation. When CD80/CD86 engage the related, but higher affinity receptor CTLA4, which is expressed predominantly by activated T cells, inhibitory signals are deli- vered. CD80 and CD86 are both expressed by activated APC and both molecules bind CD28 as well as CTLA4. However, regulation of their expression is distinct and, also, they interact differently with their counterreceptors. It has been suggested that the major role for CD28 costimulation in T cell activation is the regulation of growth factors that control T cell function. The function of the CTLA4 molecule remains controversial. It has been suggested that CTLA4 delivers downregulatory signals with a blockade of critical cell cycle progression factors and inhibition of IL-2 receptor expression For not yet fully explained reasons, CD86, rather than CD80, is the dominating ligand of CD28. CD80, instead is upregulated in the late phase of response, coincidentally with CTLA4. This suggests a potential linkage between these two molecules and may explain the disease exacerbating effect of anti-B7.1 in several autoimmune disease models [51].

Although an involvement of the CD28/CTLA4-CD80/CD86 costimulatory system has been described in many human and animal model autoimmune diseases, this short overview will only briefly describe some of the findings in experimental autoimmune encephalitis (EAE) an animal model of multiple sclerosis (MS), where the importance of the CD28/CTLA4-CD80/CD86 costimulatory system has been most intensively explored [52]. Manipulation of the CD28/CTLA4-CD80/CD86 costimulatory pathway can prevent the initiation of EAE, e.g. CTLA4-Ig protects against EAE induction [53]. Yet, administration of CTLA4-Ig also can lead to exacerbation of disease [54]. Taking into account that CTLA4-Ig blocks the interaction between CD80 and CD86 with both CD28 and CTLA4, this finding likely reflects the complex interactions between receptors and ligands in this costimulatory system. With CD80 plus CD86 [55] deficient mice as well as with CD28 [56] deficient mice it could be demonstrated that the molecules are required for induction of EAE. These mice were highly resistant, yet their proliferative response and induction of TH1 cytokines was unimpaired. Furthermore in myelin basic protein (MBP)-TCR transgenic, rag^­/­ mice which were crossed with CD28^­/­, no spontaneous development of EAE was observed. Again the T cells were not anergic [57], pointing towards CD28 regulating the threshold for activation rather than regulating peripheral tolerance. Besides its importance in the induction phase the CD28/CTLA4-CD80/CD86 system is also important in the effector phase of EAE. Thus, anti-CD28 Fab treatment during the first disease episode attenuated the disease and treated mice did not show any relapse [56]. The effector phase was also blocked when transferring activated T cells into CD80/C86^­/­ mice [55]. Yet, for a clinical trial it has to be taken into account that activated autoreactive T cells are less dependent on CD80/CD86 than naive T cells [58, 59]. With respect to treatment modalities it also is important to be aware of the different roles which CD80 as compared to CD86 play in initiation and/or regulation of autoimmune diseases, i.e. treatment with anti-B7.1 during induction of EAE protected mice, while anti-CD86 exacerbated disease severity [54, 60]. Anti-B7.1 skewed the autoreactive T cells from a TH1 towards the TH2 phenotype, whereas anti-CD86 skewed towards a TH1 phenotype [61]. Similar observations have been made in MS [62-64]. How can these differences be explained? It has been postulated that B7-1 costimulation provides a quantitatively stronger costimulatory signal than B7.2, which could become particularly important in autoimmune diseases taking into account that the avidity for self antigens may be low in most instances [65]. Finally, the negative regulatory role of CTLA4 in this system should be briefly commented. CTLA4 deficient mice develop a fatal lymphproliferative disorder [66, 67]. It has been suggested that CTLA4 exerts its inhibitory effect through regulation of TGF-beta production [68]. In addition there is evidence for importance of CTLA4 in the induction of peripheral tolerance [69]. Finally there is evidence thatCTLA4 skews towards TH2 responses [70], yet this may depend on the activation state of the T cells [52]. Thus, the CD28/CTLA4-CD80/CD86 costimulatory system is of importance in the induction as well as the maintenance of EAE, the individual components paying distinct and rather well defined roles which should allow for therapeutic intervention in the near future.

A few other examples of autoimmune disease where a significant contribution of the CD28/CTLA4-CD80/CD86 costimulatory system has been described will only briefly be mentioned. Thus, CD28^­/­ mice are resistant to collagen induced arthritis [71] and experimental autoimmune myocarditis is strongly mitigated in CD28^­/­ mice [72]. In autoimmune oophoritis antibody production is significantly reduced by CD28 blockade although T cell expansion is unimpaired [73]. Experimental autoimmune glomerulonephritis, a model system of Goodpasture's syndrome, can be mitigated by treatment with CTLA4-Ig as well as with a mutated CTLA4-Ig only binding to B7.1 [74]. Furthermore, the development of autoimmune lupus in MRL-Faslpr mice is prevented by depletion of CD80/CD86 [75]. Finally it should be mentioned that modulation of the CD28/CTLA4-CD80/CD86 costimulatory system has also been explored in great detail in various models of insulin dependent diabetes mellitus [54, 76, 77], which provided further evidence for the distinct activities of B7.1 versus B7.2.

CD40-CD40 ligand

The CD40-CD40L molecules, which belong to the TNF- TNF-R family [78], are activation induced costimulatory molecules [44] that extend and enhance T cell expansion, promote T cell differentiation and mediate collaborative interactions between T cells and B cells [44]. CD40/CD40L interactions promote IL-1, IL-6 and GM-CSF production in monocytes and IL-12 secretion in monocytes and dendritic cells [79]. Furthermore, ligation of CD40 leads to association with members of the TRAF family [80], which, besides other activities, affects the cell cycle and cdk genes and upregulates the survival factors bcl-2 and bcl-XL [81]. CD40L is mainly expressed by activated CD4⁺ cells. Crosslinking of CD40L generates costimulatory signals that upregulate IL-4 and ICAM-1 expression [82, 83]. The most important aspect of CD40-CD40L interaction, is likely to be its interrelationship with the CD28 costimulatory pathway, i.e. an initial CD40-CD40L interaction leads to upregulation of CD80/CD86 which enhances the costimulatory activity of APC. Thus the CD28-B7 and the CD40-CD40L pathways are interrelated and synergistic [84-86].

The early observation that mutations of the CD40L gene are responsible for a human severe immunodeficiency has stimulated further research to characterize this costimulatory system aiming to exploit its properties therapeutically [87, 88]. Thus, in EAE and inflammatory bowel disease (IBD) pathological overproduction of IL-12 could be prevented by blocking CD40-CD40L interactions [89, 90]. Also, several in vivo studies lend further support to the interrelationship between the CD40-CD40L and the CD28-B7 costimulatory systems. Thus, it has been described that EA myasthenia gravis (EAMG) has a differential requirement for CD28 and CD40L. While CD28^­/­ mice are less susceptible and TH cells are skewed to the TH₁ phenotype, CD40L^­/­ are completely resistant and show a strong reduction in TH1 as well as TH2 cytokines [91]. In autoimmune oophoritis the interplay between CD28 and CD40L becomes even more obvious. Deficiency of each of the molecules blocks antibody production. Only when both molecules have been deleted has an additional blockade in activation and expansion of autoreactive T cells been observed [73]. In autoimmune glomerulonephritis, CD40L could be shown to be critical for induction of the disease, but not for its maintenance [92]. Furthermore, anti-CD40L prevents diabetes in NOD mice, which show a strong reduction in IFN gamma and IL-2 production, yet, as revealed by transfer experiments, there was no evidence for upregulation of regulatory T cells [93].

CD44 isoforms

CD44 comprises a set of transmembrane glycoproteins, whose members differ by glycosylation [94] and by insertion of up to ten variant exons between exon 5 and exon 6 of the CD44 standard isoform (CD44s) [95]. CD44s is expressed on many tissues and cells including the vast majority of leukocytes. Although expression is constitutive, levels of expression are regulated, e.g. increased during lymphocyte activation. In contrast to CD44s, expression of CD44 variant isoforms on leukocytes is rare and in most instances transient during the activation process [96]. CD44 is the major receptor for hyaluronan [97]. Yet, as evident from its functional activities, it also recognizes cell surface molecules, these cellular CD44 ligands being not yet defined. CD44 has been described to serve as a lymphocyte homing receptor [98] and to be involved in lymphocyte maturation [99], traffic [100] and activation [101, 102]. With respect to the latter aspect, we could demonstrate recently that CD44 functions as a costimulatory molecule in much the same manner as CD28 [103] by recruiting phosphotyrosine kinases towards the immunological synapse, which significantly lowers the threshold for initiating signal transduction via the TCR/CD3 complex [104]. Notably, the costimulatory function of CD44 accounts for T cell activation as well as for activation induced cell death (apoptosis). The association of those functions to distinct CD44 isoforms is not yet known. However, as outlined below, there is evidence that functional activities of distinct CD44 isoforms are selective and mostly non-overlapping.

CD44 isoforms have been described to be upregulated in a large variety of autoimmune diseases, like rheumatoid arthritis, glomerulonephritis, Sjögren's syndrome, EAE, IDDM and inflammatory bowel diseases [105-130]. Having defined that expression of CD44v6 exon products is observed frequently during lymphocyte activation irrespective of the activation inducing agent, while expression of CD44v7 was nearly exclusively observed on PBMC of patients with autoimmune disease [102, 111, 131], we initially concentrated on the elaboration of function activity of this particular CD44 variant isoform. We could demonstrate that it is important in TH1 and TH2 mediated DTH reactions, whereas anti-CD44v6 interferes selectively with TH1 reactions. This is due to the fact that CD44v6 is mainly expressed by CD8⁺ cells, the antibody directly interfering with CD8⁺ T cell-mediated effector functions. Instead, CD44v7 is expressed on ­ rather small ­ portions of APC, B cells and CD4⁺ T cells, the antibody blockade apparently being more efficient at the level of the APC than the T cell, i.e. a DNFB-induced TH1-mediated as well as a FITC-induced TH2-mediated DTH reaction were inhibited, although the effect was stronger in TH1-mediated reactions [131]. Moreover, blockade of CD44v7 prevents and cures a TNBS-induced fatal pancolitis [132, 133], mice with a targeted deletion of CD44v7 are resistant to the induction of this autoimmune disease and IL-10 knockout mice, which spontaneously develop a lethal colitis, become resistant upon a concomitant deletion of CD44v7 [134]. The strong effects of CD44v7 are probably due to two mutually supporting, though distinct mechanisms. First, CD40-CD40L interactions are the initial stimulus to provoke CD44 [135], precisely CD44v7 [134], expression on APC. This is accompanied by IL-12 secretion and by downregulation of IL-10 production [131-134]. As described for the CD40/CD40L induced effect on the CD28/CD86 system, the CD40/CD40L induced expression of CD44v7 also has a bearing not only on the APC but on a CD44v7 ligand bearing CD4⁺ T cell population which becomes resistant to apoptosis [134]. Thus, CD44v7 provides an initiating trigger for TH1-mediated autoimmune reactions by supporting an overshooting IL-12 production and sustains the disease state by preventing activation induced cell death.

Besides the activation induced upregulation of CD44v6 and the autoimmune disease associated expression of CD44v7, we also noted a rather selective expression of CD44v3 on PBMC of patients with autoimmune disease [111, 113]. CD44v3, but not CD44v7, was also expressed on infiltrating cells in skin associated autoimmune diseases. Notably, at the site of the infiltrate, CD44v3 was also seen in allergic skin reactions and in both disease groups on endothelial cells [136]. Besides CD44v3, CD44v10 was the only additional CD44v isoform which was expressed on infiltrated cells and, albeit weakly, on endothelial cells. Furthermore, expression of CD44v10 was restricted to selected autoimmune diseases of the skin, while expression of CD44v3, although to a varying degree, was a general feature of skin-infiltrated leukocytes. Also, CD44v3 and CD44v10 are expressed on distinct leukocyte subpopulations. CD44v10 is predominantly expressed by activated monocytes, which express high amounts of TH1 proinflammatory cytokines [136]. Accordingly, blockade of CD44v10 leads to a most impressive mitigation of TH1 DTH reactions, with very few infiltrating cells and a significant reduction of edema formation [137]. There is, however, no evidence that in DTH reactions, initiated by haptens or as a consequence of an overshooting TH1 reaction in organ-related autoimmune disease, CD44v10 functions as a costimulatory molecule, i.e. CD44v10 apparently triggers effector functions of monocytes, not their APC related activities. Whether this implies a soluble ligand for CD44v10, e.g. a chemokine, remains to be explored. The fact that CD44v10 was expressed at least on some activated endothelial cells would be well in line with the hypothesis offering a means of recruiting (endothelial cells) and retaining (infiltrate) inflammatory cells via CD44v10 bound chemokines. Similarly, it has been described that in EAE the temporal and spatial expression of chemokines marks the hallmark in the pathogenesis, i.e. the emigration of T cells and monocytes to the central nervous system [138]. Finally, it should be mentioned that we also do not yet know the selective trigger initiating CD44v10 expression on monocytes during an autoimmune or allergic immune reaction.

With the strong enrichment of CD44v3 in dermal infiltrates it became tempting to speculate that CD44v3 may be a particular skin-associated leukocyte homing receptor. The assumption, indeed, could be verified by the transfer of draining lymph node cells after induction of a DTH reactions. Migration of the transferred lymphocytes to sensitized skin areas could be completely inhibited by a CD44v3-specific antibody [136]. This feature may explain the rather selective expression of CD44v3 in dermal infiltrates. Yet, it does not cover the whole arsenal of functional activities of this CD44 isoform. According to our data so far, CD44v3 is mainly, though not exclusively expressed on APC. Upon binding to an as yet undefined ligand on CD4⁺ cells, it triggers TH1 cytokine production, which ­ as revealed by antibody blocking studies ­ efficiently supports maintenance of an overshooting TH1 reaction in autoimmune diseases [136].

Taken together, expression of CD44v7, CD44v3 and in some instances CD44v10, all of which are CD44 isoforms not constitutively expressed on leukocytes, is initiated during leukocyte activation. Only in the case of overshooting is pathological immune reaction expression observed during prolonged periods of time and expression levels remain in a detectable range. Nonetheless, as compared to e.g. CD28/B7, these molecules are only detected in a minority of cells and at low intensity. Despite this, they can contribute efficiently to the induction and maintenance of autoimmune disease. They do so by facilitating leukocyte recruitment (mainly CD44v3, less efficiently CD44v10), by triggering effector functions of monocytes (CD44v10), by stimulation of CD4⁺ cells of the TH1 subtype (CD44v3), and by triggering activation of APC (CD44v7) as well as (directly or via ligand binding) by interference with activation induced cell death (CD44v7). Animal experiments have provided convincing evidence that blocking of these functions very efficiently mitigates or ameliorates the disease state in a variety of autoimmune alterations. Most importantly, therapeutic blocking of these molecules, most likely due to their transient and very selective expression, was not burdened by any side effects and even had no measurable negative impact on physiological immune reactions. These features make CD44v3 and, particularly, CD44v7 ideal targets of therapy. Therefore and to allow for a transfer of this knowledge into the clinic, it is urgently necessary to define the ligands of these CD44 variant isoforms and to elucidate the possible underlying mechanisms in more detail.

CONCLUSION

Costimulatory pathways of CD28/CTLA4-CD80/CD86, of CD40L-CD40 and of CD44v3, CD44v7 and their ligands are critical in regulating T cell activation and tolerance and are important in the initiation and progression of a variety of autoimmune diseases. Consequently, these pathways represent potentially powerful therapeutic targets in autoimmune diseases [60,139-145]. As far as prevalence can be given to transiently expressed costimulatory molecules or their ligands and depending on the extent and level of expression, therapeutic protocols based on interference with costimulatory pathways may not be burdened by severe side effects and can be considered as rather selective drugs. Because of the known variability in the course of autoimmune diseases it will be necessary to provide a detailed analysis of signals initiated by costimulatory molecules and their ligands in APC and effector cells to allow for choosing the appropriate target depending on the disease state of the individual patient.

Abbreviations

AICD: activation induced cell death
APC: antigen presenting cell
DTH: delayed type hypersensitivity
EA: experimental allergic
EAE: EA encephalomyelitis
EAG: EA glomerulonephritis
EAM: experimental autoimmune myocarditis
EAMG: EA myasthenia gravis
IBM: inflammatory bowel disease
IDDM: insulin dependent diabetes mellitus
MHC: major histocompatibility complex
MS: multiple sclerosis
PBMC: peripheral blood mononuclear cells
SLE: systemic lupus erythematosus
TCR: T cell receptor
TH: helper T cell.

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