ReviewInfluence of Peripheral inflammation on the progression of multiple sclerosis: Evidence from the clinic and experimental animal models
Introduction
Multiple sclerosis (MS) is a chronic inflammatory disorder of the brain and spinal cord characterized by demyelination and remyelination events, accompanied by loss of sensory and motor functions. With time remyelination becomes incomplete and leads to persistent symptom accumulation. MS shows a heterogeneous clinical course, but the vast majority of the patients present relapsing‐remitting (RR) episodes from the onset, eventually leading to secondary progressive (SP) MS, that worsens the patients' quality of life (Bradl and Lassmann, 2009, Weiner, 2008). A minority of patients exhibit primary progressive (PP) MS, which is characterized by a constant decline from the onset with no recovery in their neurological functions (Bradl and Lassmann, 2009, Dutta and Trapp, 2011).
Although MS is an autoimmune disease, its etiology is still unclear. Many people now believe it to be of multifactorial origin. Epidemiological studies have clearly shown that both genetic and environmental factors influence MS incidence, suggesting that people with certain genetic risk factors, are more likely to develop the disease given specific features of their surroundings (reviewed in Compston and Coles, 2008). Infections and other pro-inflammatory events have been postulated as possible triggers of the pathology and/or of relapsing episodes, and some authors have hypothesized that the autoimmune response could be a consequence of a primary central pro-inflammatory event (Barnett and Prineas, 2004).
Although therapeutic interventions are able to reduce the frequency of new relapsing episodes, they fail to reduce disability or influence the progressive phase of the disease. Moreover, second generation drugs are usually powerful immunological treatments that may induce serious adverse secondary effects. Questions have been raised about the safety of the long term use of these drugs (reviewed in Chataway and Miller, 2011). Immunomodulatory treatments that were demonstrated to be beneficial in the relapsing form of the disease have very little effect in progressive phases. These data might indicate that both the pathogenesis and the immunological mechanisms are different between relapsing and progressive MS (Kutzelnigg et al., 2005). In addition, the same authors demonstrated that SPMS and PPMS patients had generalized inflammation in the whole brain along with cortical demyelination and diffuse white matter injury. These characteristic signs of PPMS and SPMS patients are rare in the acute or relapsing stage (Kutzelnigg et al., 2005).
MS is described primarily as an inflammatory autoimmune disease (Lindquist et al., 2011, Lucchinetti et al., 2004). Multifocal inflammation, mainly in the white matter of the brain and spinal cord, is associated with the RR phase of the disease, while the progressive period has been related to the events of axonal loss and neurodegeneration (Slavin et al., 2010). Like most autoimmune disorders, unveiling the role of the different inflammatory components is essential, but has been proven to be a challenge.
Lymphocytes and macrophages have been considered as the principal pathological players for years, since they were the main cell type found in MS plaques. It is well established that activated T cells entering the CNS drive at least part of the immune mediated damage (Frohman et al., 2006, Hafler et al., 2005). Inflammatory cells in progressive MS patients were observed in perivascular cuffs, while their location in the parenchyma is sparse. In addition, lymph follicle-like structures are formed in the meninges and perivascular spaces (Bradl and Lassmann, 2009, Kutzelnigg et al., 2005). The germinal centers of this follicle are composed of B cells and a network of dendritic cells. On the contrary, both perivascular and parenchymal infiltration by immune cells are seen in acute and relapsing MS lesions (Bradl and Lassmann, 2009).
In the past years, several subtypes of T cells have been implicated in the pathology of MS.
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CD4 + T helper 1(Th1) cells have been considered key players in both MS pathology and experimental autoimmune encephalomyelitis (EAE) pathology for a long time due to the fact that most histopathological and clinical conditions could be explained by the involvement of these cells and their leading cytokine IFN-γ (Leibowitz et al., 1966). In fact, adoptive transfer of myelin specific Th1 cells is a very potent inducer of EAE, whereas IFN-γ has been found in MS lesions and its administration has exacerbated MS pathology by triggering relapses (Gold, 2011, Panitch et al., 1987).
- (2)
In the early 2000s novel CD4 + T helper 17 (Th17) cells became highly associated with EAE because mice deficient of interleukin 23 (IL-23), the main interleukin 17 (IL-17) stimulator, were found to be resistant to the induction of the pathology (Cua et al., 2003). Since then more evidence has supported the involvement of these cells in MS pathology, including their presence in the inflamed CNS of EAE animals (Pepper et al., 2010), and the fact that IL-17 is one of the main up-regulated cytokines in MS patients (Lock et al., 2002).
- (3)
Gamma delta (γδ) T cells have also been implicated in MS pathology since they were found in active MS acute lesions and in the cerebrospinal fluid (CSF) of early diagnosed patients (Shimonkevitz et al., 1993, Wucherpfennig et al., 1992). In the EAE animal model high amounts of IL-17 producing γδT cells were found during the induction phase of the pathology (Sutton et al., 2009). They were also implicated in an exacerbation of autoimmunity because of their ability to restraint regulatory T cell (Treg) activity (Petermann et al., 2010).
- (4)
Even though there is a lot of evidence that implicates different types of Treg cells in MS pathology, the interpretation of experimental data has been difficult due to the lack of markers. In spite of this, adoptive transfer and neutralization experiments have proven that Tregs render resistance to EAE (reviewed in Fletcher et al., 2010).
- (5)
Finally, CD8 + T cells were found in the lesions, CSF and blood of MS patients, and their CNS abundance has been positively correlated with the intensity of axon damage (reviewed in Saxena et al., 2011). In EAE, some studies have suggested a pathogenic role for CD8 + T cells (Huseby et al., 2001, Sun et al., 2001), while CD8 + Treg cells have a suppressing role (Chen et al., 2009).
The presence of B cells in recent MS plaques was first described in 1980 (Esiri, 1980), since then they were found to play a significant role in the pathology of the disease (reviewed in Wootla et al., 2011). As previously said, Baranzini et al. were able to prove that a germinal center-like reaction takes place during the immune attack against CNS structures, with the production of antibodies within the plaques (Baranzini et al., 1999, Bradl and Lassmann, 2009, Kutzelnigg et al., 2005). Some of the roles attributed to these cells in MS pathology are: myelin-specific antigen presentation (acute demyelination and contribution to MS progression), abnormal cytokine production (decreased production of IL-10 may be responsible for the activation of pro-inflammatory T cells), and the production of immunoglobulins involved in demyelination or remyelination (reviewed in Wootla et al., 2011).
Antigen presenting cells (APC) are involved in multiple stages during the pathogenesis of MS in animal models: (1) upon encountering myelin antigen they activate T cells in the lymph nodes (Bailey et al., 2007, Guermonprez et al., 2002), (2) depending on the cytokines produced they influence the resulting T cell subtype (Zhu and Paul, 2010), (3) they re-stimulate mature T cells once they are in the brain (Tompkins et al., 2002). Under non‐pathological conditions macrophages are the main MCH II expressing APCs in the CSF, but they are not the only ones able to present myelin antigens: monocytes, dendritic cells, microglia and astrocytes have also been implicated in antigen presentation in demyelinating disorders (Bauer et al., 1995, Constantinescu et al., 2005, Cudrici et al., 2007, Pattison et al., 1996).
Finally, some less specific effector cells have been related to MS. Mast cells have been associated with MS plaques since 1990 (Wootla et al., 2011), and more recently it was evidenced that these cells were involved, in high association with myelin autoantibodies, in both MS and EAE (Kruger et al., 1990, Secor et al., 2000). Mast cells are able to secrete a wide range of cytokines, and therefore influence the differentiation pattern of both T and B lymphocytes, tilting the scale towards an effector or regulatory profile. In EAE, mice lacking mast cells developed a milder form of the pathology (Secor et al., 2000), and also showed a reduced response of autoreactive T cells (Gregory et al., 2005). On the contrary, a recent report demonstrated that mast-cell deficient mice presented a more severe form of the disease (Bennett et al., 2009). Moreover, mast cells also contributed to EAE severity by interacting with other immune cells in secondary lymphoid organs (Tanzola et al., 2003).
Neutrophils are leukocytes that respond to several infectious stimuli. In the past years they have been found to cooperate extensively with the Th17 cell response by means of a chemokine-dependent reciprocal cross-talk between them. Due to the fact that neutrophils have a highly indiscriminate and histotoxic potential, their activation has to be finely regulated and consists of a priming first step prior to the fully active state. Neutrophil priming was evidenced in some inflammatory and autoimmune pathologies such as rheumatoid arthritis or autoantibody-associated vasculitis (Harper et al., 2001, Wright et al., 2010). Indeed, in MS primed neutrophils are numerous in patients (Naegele et al., 2011). Moreover, CXC chemokine receptor type 2 (CXCR2 +) neutrophils have been seen to contribute to the development of lesions in EAE and cuprizone (Carlson et al., 2008, Liu et al., 2010) models.
Cytokines are polypeptides traditionally involved in orchestrating immune responses. Taking into consideration the wide range of functions they have individually and as a complex network, fully understanding the mechanisms behind their involvement in MS pathology has been difficult (for a more detailed review see Codarri et al., 2010). Information taken from animal models has, time after time, failed to translate into the clinics; and most hypotheses had to be revised in light of the results of clinical trials.
Tumor necrosis factor alpha (TNF-α) is elevated in the CSF, serum and active lesions of MS patients, and correlates with disease progression (Maimone et al., 1991, Sharief and Hentges, 1991). Even though preclinical results in animal models were encouraging, patients treated with different TNF-α blockers deteriorated with the treatment (Anon., 1999).
Something similar was seen with interferon gamma (IFN-γ) and interleukin 12 (IL-12) therapies, where preclinical results in animal models pointed to a specific beneficial (IFN-γ) or a detrimental (IL-12) role of these cytokines, but the opposite was seen in the clinical trials (Leonard et al., 1995, Panitch et al., 1987, Willenborg et al., 1996).
The denominated IL-23/IL-17 axis, which includes interleukin 23 (IL-23), interleukin 17 (IL-17) and interleukin 21 (IL-21) among other cytokines, has been associated in the past years with MS. Although IL-23 has a vital role in the development of EAE, blocking it did not result in any significant therapeutic benefit in a clinical trial (Segal et al., 2008). Even though Th17 cells have been clearly implicated in both MS pathology and EAE pathology (see above), neutralizing IL-17 or the lack of the cytokine did not provide resistance to EAE (Haak et al., 2009, Hofstetter et al., 2005).
Taking this into consideration and many other data, it becomes clear that the comprehension of the mechanisms behind the involvement of cytokines in MS is crucial for a better and global insight into MS pathophysiology. Given the pleiotropic and multi-functional traits of cytokines we need to be careful in the interpretations of the data available from both animal model research and clinical trials.
Blood brain barrier (BBB) breakdown and inflammation appear to play a major role in the pathology of numerous neurodegenerative diseases compromising the vascular unit and inducing leukocyte migration within the brain parenchyma (Stolp and Dziegielewska, 2009). BBB disruption is a major hallmark in MS (Larochelle et al., 2011, McQuaid et al., 2009, Watzlawik et al., 2010). The entry of leukocytes into the CNS is considered an early phenomenon that induces BBB breakdown and neuroinflammation (Larochelle et al., 2011). Activated peripheral lymphocytes infiltrate the CNS and trigger an immune response that damages the myelin and eventually leads to axonal loss (Lindquist et al., 2011). Indeed, it was described that leukocyte migration modifies BBB integrity in MS lesions (Larochelle et al., 2011). However, it was also described that components of the inflammatory response contribute to the disease independent of BBB integrity (Buljevac et al., 2002, Lindquist et al., 2011). RRMS and progressive MS differ mainly in the state of the BBB. RRMS lesions are characterized by BBB breakdown which allows new lesions to flare up as inflammatory cells enter the CNS. But, the inflammation remains trapped behind a close BBB in the progressive phase of the disease (Bradl and Lassmann, 2009).
Several cytokines associated with MS are known to affect BBB integrity: (1) intravenous administration of TNF-α in mice resulted in BBB breakdown (Tsuge et al., 2010), (2) in vitro TNF-α and IFN-γ alter the architecture of junction proteins in primary cultures of BBB-endothelial cells (Alvarez et al., 2011), (3) interleukin 1beta (IL-1β) increases the vascular endothelial growth factor (VEGF) during MS relapses which in turn generates an increase in BBB permeability (Argaw et al., 2006, Su et al., 2006), and (4) IL-17 increases BBB permeability and promotes lymphocyte and monocyte migration (Kebir et al., 2007).
Section snippets
Communication between periphery and CNS
Systemic inflammatory stimuli that circulate in the blood can get into the brain, inducing the synthesis of cytokines in the CNS, which are responsible for changes in behavior and the general state known as sickness behavior (Besedovsky and del Rey, 1996, Combrinck et al., 2002, Dantzer et al., 1998, Dantzer et al., 2008, Londono and Cadavid, 2010, Pitossi et al., 1997). This sickness behavior is evidenced by fever, anorexia, fatigue, sleep and memory disturbances (Dantzer, 2004, Dantzer et
MS experimental models and systemic inflammation
Several animal models of demyelination have helped understand the pathophysiology of MS (Denic et al., 2011). As reviewed in Blakemore and Franklin (Blakemore and Franklin, 2008), animal models can be divided into two groups: those which attempt to replicate the disease as accurately as possible, like virus induced encephalomyelitis and EAE, and others that provide a more reductionist approach which allow studying specific aspects of the disease (e.g. ethidium bromide, lysolecithin, cuprizone).
Conclusions
We have reviewed evidence that some peripheral infections exacerbate the immune response in both MS experimental models and patients. Peripheral infectious agents may aggravate the symptomatology of the disease and increase the risk of relapses and remitting episodes. The importance of early treatments of infectious diseases should be taken into account in MS patients in order to improve the quality of life and progression of the disease. In addition, treatments with anti-inflammatory agents
Acknowledgments
Carina C. Ferrari is a member of the Research Career of the National Council of Scientific and Technological Research (CONICET), Argentina. Veronica Murta is a fellow of CONICET. We would like to thank Rodolfo Tarelli for the critical reading of the manuscript.
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