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Immunological differences between classical phenothypes of multiple sclerosis
Journal of the Neurological Sciences, 1-2, 349, pages 10 - 14
Multiple sclerosis (MS), one of the most serious inflammatory and neurodegenerative conditions, is characterized by variable clinical courses — relapsing–remitting (RRMS), primary progressive (PPMS) and secondary progressive (SPMS). Although PPMS affects only 10–15% of the patient population, its course and pathophysiological and immunological background are distinct. In this review we present and discuss main differences between different types of MS, with particular focus on the underlying immunological mechanisms.
- Immunological and pathophysiological mechanisms determining MS courses are reviewed.
- Differences between PPMS, RRMS and SPMS are presented and discussed.
- PPMS features distinct leukocyte surface expression and serum adhesion molecules.
- Current therapies are ineffective in PPMS due to intact blood–brain barrier.
- PPMS seems to be evoked by noninflammatory mechanisms.
Keywords: Adhesion molecules, AntiGM3 antibodies, Demyelination, Neurodegeneration, Primary progressive multiple sclerosis, PPMS.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with an autoimmune reaction that causes tissue injury and clinical disability, , and . MS is the most common cause of neurological disability in young adults with the age of onset usually between 20 and 40 years. It seems that disease onset and course may depend on genetic, infectious, immunological or environmental causes. Family members of MS patients are more likely to develop the disease than others in the general population. The prevalence of MS increases the closer the genetic relationship to the proband. The etiology of the disease is unknown, but different immunopathological mechanisms have been described that result in a highly heterogeneous clinical course and neuroradiological appearance.
Here we review the immunological mechanisms that reflect the difference in clinical manifestations of MS. The most important differences between forms of MS are summarized in Table 1 .
|Age of onset (years)||20–30||About 40||> 40|
|Frequency||85–90%||10–15%||50–60% of RRMS patients|
|Blood–brain barrier||Damaged||Relatively intact||Damaged|
|Serum level of adhesion molecules||Normal E-selectin||Increased E-selectin||Normal E-selectin|
|Increased L-selectin||Normal L-selectin||Increased L-selectin|
|Serum anti-GAGA4 IgM antibodies||Positive||Negative||Positive|
|Serum antiGM3 antibodies||3%||56%||43%|
|Disease-modifying therapies' beneficial effect||Good||No||Little|
2. Classification and clinical course of MS
There are two main courses of MS: relapsing–remitting (RRMS) and progressive ( Fig. 1 ). The more common course, RRMS (85–90%), characterized by clinical episodes interspersed by periods of stability, affects twice as many women than men and in 40% of patients develops into secondary progressive MS (SPMS) within ten years. Approximately 10 to 15% of patients experience a primary progressive multiple sclerosis (PPMS), which is characterized by gradual neurological dysfunction with or without exacerbations, , and . Compared with RRMS patients with PPMS have 0 mean age of onset a decade later, the disease does not show female predominance and the spinal cord is more frequently involved. Current disease-modifying therapies (DMTs) used in RRMS have little or no beneficial effect in PPMS due to the different immunological and pathophysiological mechanisms involved and .
3. Inflammation-related course of MS
The differences in the nature of the inflammatory response between RRMS and PPMS include disturbance of the blood brain barrier (BBB), and the local expression of inflammatory cytokines and chemokines as well as their cognate receptors  .
Trafficking of peripheral autoreactive leucocytes through the BBB is crucial to the pathogenesis of RRMS but not PPMS where inflammation persists in the subarachnoid compartment behind an intact or repaired BBB. The transmigration of leukocytes is mediated by selective expression of adhesion molecules, chemokines, chemokine receptors and matrix metalloproteinases. Duran et al. found that leucocyte surface expression of adhesion molecules and soluble serum levels of adhesion molecules in the peripheral blood of PPMS patients differs clearly from that of patients with SPMS or RRMS. They demonstrated increased levels of soluble ICAM-1 and L-selectin in SPMS and RRMS but not in PPMS where there is a pattern similar to that seen in healthy controls  . These findings explain why there are fewer and smaller gadolinium enhancing cerebral lesions in MRIs of patients with PPMS than in other subtypes of MS. The results also imply that disruption of the BBB occurs in SPMS and RRMS, which correlates with increased number of inflammatory lesions in the brain. Moreover, progressive forms of MS are characterized by widespread demyelination and diffuse degenerative changes throughout the entire white and gray matter in contrast to the active focal lesions mainly in the white matter occurring in RRMS and .
Heat shock proteins (HSP) are augmented as part of the stress response due to inflammation, infection, starvation, hypoxia, exercise, exposure of the cell to toxins, etc. Pronounced immune response against HSP60 or HSP70 in RRMS was not observed in PPMS and SPMS. Thus, the decrease of reactivity to HSP in progressive forms of MS is connected with the less inflammatory nature of progressive MS and may reflect the worse response to immunomodulatory therapy and .
4. Immunological response
4.1. Adhesion molecules
In some studies an increased level of E-selectin was found in the serum of patients with PPMS but not in the serum of those with SPMS or RRMS and . In addition, PPMS patients with an increased serum level of E-selectin had a more rapid progression of disability. Ukkonen et al.  detected increased cell surface expression of very late activation antigen 4 (VLA-4), lymphocyte function-associated antigen 1(LFA-1) and intercellular adhesion molecule 1 (ICAM-1) in the blood and cerebrospinal fluid (CSF) in PPMS patients compared with controls. In addition, the levels of ICAM-1 in the blood and CSF were higher in PPMS patients when compared with SPMS patients, while the level of vascular adhesion molecule-1 (VCAM-1) was higher only in the blood.
These results support the immunological heterogeneity of different leucocyte/endothelial cell interactions occurring in the different clinical forms of MS. This heterogeneity may in part explain the ineffectiveness of DMTs in PPMS due to the relatively intact BBB and low-grade inflammatory response, which is no longer under the control of the peripheral immune system  . In addition, anti-inflammatory therapy that influences autoreactive myelin-specific CD4 T-cells is ineffective in the PPMS suggesting that the role of T-cells in the blood is less important than in RRMS.
4.2. Anti-glycan antibodies
Serum anti-glycan antibodies have been considered as diagnostic or prognostic biomarkers in MS. Freedman et al. found that MS patients positive for one of four anti-glycan immunoglobulin M (IgM) antibodies (anti-GAGA2, anti-GAGA3, anti-GAGA4 and anti-GAGA6) had nearly twice as high the risk of progression than patients without antibodies during the 5 years of this study  . Significantly higher levels of IgM anti-GAGA4 antibodies were found in RRMS patients when normalized for total IgM compared to patients with other neurological disorders  . These IgM anti-GAGA4 antibodies specific to alpha-glucose antigens are most commonly produced by self-replenishing B1 B-cells, which play an important role in the first line of defense against invading pathogens, removal of senescent cells, cell debris and other self-antigens and . It is interesting that alpha-glucose antigens are found not only within the type IV collagen matrix of the BBB and MS plaques but also exist in several pathogenic fungi and bacteria. This homology may suggest that IgM antibodies could arise through the mechanism of mimicry targeting a cross-reactive response that disrupts the BBB. Interestingly, the presence of anti-GAGA4 antibody may differentiate between PPMS and RRMS/SPMS patients, since nearly all PPMS patients were negative for the anti-GAGA4 antibody in an assay performed by Brettschneider et al.  .
4.3. The role of B-cells
The pathological studies described below indicate the important role of B-cells and antibodies in the inflammatory demyelinating process during the different disease stages of MS. Moreover, treatment strategies that target the pathogenic humoral immune response are effective in RRMS; these include intravenous immunoglobulins, plasma exchange or rituximab, which is a monoclonal antibody that depletes the CD20 + B-cells, , , , , , , , , and .
The formation of lymphatic-like tissue can be found in the meninges in patients with SPMS but not PPMS or RRMS  . These structures are dense clusters of B-cells and plasma cells, which surround areas that resemble germinal centers and contain dendritic cells  . Certain chemokines and cytokines such as CXCL13, lymphotoxin and BAFF (B-cell activating factor) are expressed in chronic inflammatory MS lesions and may be involved in the homing of B-cells and the formation of these structures. In addition, CXCL13 up-regulates membrane lymphotoxin LTα1β2 on B-cells, promoting the development of follicular dendritic cells and thus the production of CXCL13 itself  . CXCL13 causes a chronic intrathecal B-cell response sustaining the inflammatory process in the CNS. This chemokine also seems to have an important role in RRMS as higher levels have been detected in the CSF during relapse  . Furthermore, we have recently found that the CXCL13 CSF level is inversely correlated with the duration of disease in PPMS (unpublished data). In addition, PPMS patients have decreased mRNA levels of CXCR5 (the receptor for CXCL13), CCL5 (RANTES) and its receptor CCR3 in peripheral mononuclear blood cells (PMBCs) compared to RRMS patients, which might reflect the paucity of the inflammatory response, , and .
The clinical trial on rituximab, a chimeric monoclonal antibody selectively depleting CD20 + B cells, showed that early treatment of PPMS delays in time to confirmed disease progression in younger patients who had gadolinium-enhancing lesions. These findings confirm that pharmacological depletion of B cells may be beneficial in a subgroup of PPMS patients with significant inflammatory activity  and . Ocrelizumab is a fully humanized monoclonal antibody which compared to rituximab bind different but overlapping epitopes of CD20 molecule causing depletion of B lymphocytes. It will be interesting to see if PPMS patients will benefit from ocrelizumab treatment in the ongoing phase III study  .
5. Pathophysiological mechanisms of neurodegeneration
5.1. Axonal degeneration mechanisms
Neurodegeneration and neuroinflammation play a key role in pathomechanism of neuronal and axonal injury resulting in permanent neurological deficit in MS. In this process axonal injury is not restricted to demyelinating plaques in the white matter but it is also observed in normal appearing white and gray matter, , , and . Many different immunological mechanisms may lead to axon injury including destruction by specific T-cells, activated microglia, invading macrophages, natural killer cells and auto-antibodies against specific antigens.
In immune-mediated mechanisms of axon damage during demyelination the dominant T lymphocytes within MS lesions are cytotoxic CD8 + T cells (CTLs)  . The recruitment of CTLs to lesion sites can undergo antigen-specific expansion and some clones of these cells may recognize and specifically injure axons due to major histocompatibility complex (MHC) class I expression on neurons and axons. Activated macrophages and microglia produce a plethora of toxic molecules which induce axonal injury. Particularly reactive oxygen and nitric oxide radicals seem to be most important in neurodegeneration inducing mitochondrial dysfunction and subsequent energy failure that can end in axon death and .
Diffuse tissue damage particularly affecting axons plays a major pathophysiological role in the progressive neurological disability seen in MS  . Lycke et al.  first explored neurofilament proteins as biomarkers of axonal degeneration. They found that CSF neurofilament light (NFL) levels were higher in patients who had suffered a relapse within three months of sampling, indicating a temporal correlation between acute inflammatory activity and neurodegeneration  . The presence of elevated intrathecal anti-NFM (neurofilament medium) IgM or IgG antibody levels is a general feature of MS regardless of clinical variables  ; however, high levels of NFL in the CSF reflect the degree of neuronal damage and are associated with a worse outcome in MS  . The level of intrathecal autoantibodies to NFL is higher in patients with progressive MS than those with RRMS  . In addition, CSF CXCL13 chemokine levels in progressive MS correlate significantly with NFL suggesting that neurodegeneration could be dependent on inflammation and humoral autoimmunity and .
Imaging studies have revealed that atrophy of gray matter begins at an early stage in the MS course and can even precede white matter lesions  . New and active focal inflammatory lesions in the white matter are mainly present in RRMS, while diffuse axon injury of the normal appearing white matter and cortical demyelination are characteristic hallmarks in progressive MS. Additionally atrophy of the spinal cord and gray matter within the brain are more prominent in PPMS compared to RRMS and . Abovementioned differences indicate that the neurodegenerative process is dominant in progressive forms of MS.
Gangliosides, a class of acidic glycosphingolipids, constitute an axonal antigen and are also minor constituents of myelin. The synthesis of pathogenic autoantibodies to gangliosides may cause an injury to neuronal tissue and induce a complex local immune process generating a lymphoid environment. Acarin and colleagues  found elevated serum antibodies against GM1, asialoGM1 and GD1a significantly more frequently in PPMS than in RRMS or SPMS. Sadatipour et al.  found that the percentage of subjects with an increased plasma anti-GM3 response was significantly higher in the PPMS (56.3%) and SPMS (42.9%) groups than in RRMS (2.9%), healthy subjects (2.6%) and subjects with other neurological diseases (14.6%). Stevens et al. found increased IgM antiGM3 antibodies in the CSF of patients with chronic progressive MS  . Increased T-cell reactivity to GM3 and GQ1b occurred significantly more often in patients with PPMS than in healthy subjects and patients with other CNS diseases. These findings suggest that ganglioside specific T-cells may contribute to the axonal damage in PPMS  .
It is unclear whether elevated antiganglioside antibodies are secondary to axonal damage or are a cause of neurodegeneration in MS  . An immune attack directed at axonal antigens could explain the progressive course of MS, as the capacity for CNS axonal regeneration is much more limited than the capacity for remyelination.
The pathophysiology of axonal injury in MS depends on the declining capacity for repair and ongoing gliosis. In addition, the progression in PPMS may be an age-dependent process modulated by an individual's genetic predisposition and environmental influences.
Noninflammatory mechanisms are postulated to be responsible for the progressive clinical disability, but little is known about the relationship between axonal degeneration and demyelination in multiple sclerosis. We hope that progress in understanding the immunological associations between inflammation and neurodegeneration will indicate novel therapeutic strategies to control the clinical disease course of PPMS form.
Conflict of interest and sources of funding statement
The authors have no financial conflict of interest.
We thank E. Kaufmann and M. Wójcicka for excellent technical assistance in our unpublished results.
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a Department of Neurology, Poznan University School of Medicine, Poland
b Department of Clinical Neuroimmunology, Poznan University School of Medicine, Poland
c Neuroimmunological Unit, Medical Research Center of the Polish Academy of Sciences, Poznan, Poland
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