Is There Evidence For Pathologic Heterogeneity In Ms

MS is a heterogeneous disease with respect to its clinical, genetic, radiographic, and pathological features. Variability in treatment response among patients is not well understood. The limited efficacy of T-cell directed therapies may result from a failure to abolish inflammation or intervene more specifically, since neither the trigger nor target antigen are known. Nonetheless, much of MS research has focused on identifying a single cause and therapy effective for all patients.

Heterogeneity with respect to the character and extent of the inflammatory response, the pattern of demyelination, the nature of oligodendrocyte pathology, the extent of remyelination, and the degree of axonal injury and/or loss present in MS lesions is well recognized. This pathologic variability has largely been interpreted as resulting from the variable intensity of the inciting pathologic process. Nonetheless, although there is pathologic heterogeneity in MS lesions, there is a surprising degree of homogeneity with respect to these pathologic features within a single individual, when matched for demyelinating activity (9,46,47,53).

In most experimental MS animal models of EAE (e.g., rats, pigs, and primates), T-cell mediated immune responses against brain antigens result in inflammation, but only limited demyelination. This resembles the pathology of acute disseminated encephalomyelitis (ADEM), in which perivascular inflammation is dominant with minimal, if any, perivenular demyelination (54). These observations suggest that additional pathogenic factors are necessary to produce the widespread demyelina-tion in MS, including, but not limited to demyelinating antibodies, cytokines and other soluble mediators, cytotoxic T-cells, reactive oxygen and nitrogen species, excitotoxic mechanisms, and mechanisms of primary oligodendrocyte injury (55). In vitro and in vivo data imply that MS may be an umbrella term for several different pathogenic entities that unify on the vulnerability of the myelin and oligo-dendrocyte to a variety of immune and toxic mediators. This hypothesis has several implications. First, multiple terminal effector pathways may act in parallel within a single patient to produce the MS lesion, thus there would be little chance to treat or prevent MS by attempts to interfere with a single mechanism. Second, different patients or subgroups may have distinct dominant effector pathways leading to tissue injury, which are constant over time, and thus specific therapy directed toward a specific underlying mechanism would be possible provided subgroups of MS could be defined. Third, the dominant effector pathways in different patients or subgroups may change over time, thus specific therapies would need to be administered during specific disease phases. Fourth, different dominant pathways of tissue injury may produce the MS plaque early in disease; however, patterns eventually converge to a common mechanism responsible for ongoing demyelination and axonal injury in chronic phases. This would require the development of therapies that are specific not only for different pathological subtypes, but for different targets (myelin, oligodendrocyte, axon, and neuron), and different disease phases (early vs. chronic).

Detailed neuropathological studies on large numbers of active MS lesions (n = 82) have revealed a profound heterogeneity in immunopathologic patterns of demyelination (53,56). Although all active lesions occur on a background of an inflammatory process, composed mainly of T-lymphocytes and macrophages, the lesions segregate into four dominant patterns of demyelination based on plaque geography, extent and pattern of oligodendrocyte pathology, evidence for immunoglobulin deposition and complement activation, and pattern of myelin protein loss (Figure 8).

The four patterns are:

Pattern I: Macrophage associated demyelination

Pattern II: Macrophage associated demyelination with local precipitation of immunoglobulins and activated complement (antibody associated demyelination)

Pattern III: Demyelination with primary alterations in the most distal oligo-dendrocyte processes and oligodendrocyte apoptosis (distal dying-back oligodendrogliopathy associated demyelination)

Pattern IV: Primary degeneration of oligodendrocytes in the periplaque white matter with secondary myelin destruction (primary oligodendrogliopathy).

In both patterns I and II, macrophages and T-cells predominate in well-demarcated plaques that surround small veins and venules; however, pattern II lesions demonstrate the local precipitation of immunoglobulin and activated complement in regions of active myelin breakdown. The expression of all the myelin

Figure 8 (See color insert.) Immunopathological patterns of early multiple sclerosis lesions. Pattern II active lesions are well demarcated from the peri-plaque white matter (A; LFB/PAS), contain numerous macrophages (D; CD68), and are characterized by an equal loss of MOG (B) and MAG (C) immu-noreactivity. Pronounced deposition of C9neo-antigen is present on degenerating myelin sheaths and within myelin degradation products taken up by macrophages in the zone of active demyelination (E; C9neo). Pattern III lesions are ill-defined (F; LFB/PAS), contain numerous macrophages (I; CD68), and demonstrate a preferential loss of MAG (H) immunoreactivity relative to MOG (G). Apoptotic oligodendrocytes are present within active pattern III multiple sclerosis lesions (J, K: arrows; CNP-ase). Abbreviations'. LFB/PAS, luxol fast blue/periodic acid schif; MAG, myelin associated glycoprotein; MOG, myelin oligodendrocyte glycoprotein. Source: From Ref. 53.

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Figure 8 (See color insert.) Immunopathological patterns of early multiple sclerosis lesions. Pattern II active lesions are well demarcated from the peri-plaque white matter (A; LFB/PAS), contain numerous macrophages (D; CD68), and are characterized by an equal loss of MOG (B) and MAG (C) immu-noreactivity. Pronounced deposition of C9neo-antigen is present on degenerating myelin sheaths and within myelin degradation products taken up by macrophages in the zone of active demyelination (E; C9neo). Pattern III lesions are ill-defined (F; LFB/PAS), contain numerous macrophages (I; CD68), and demonstrate a preferential loss of MAG (H) immunoreactivity relative to MOG (G). Apoptotic oligodendrocytes are present within active pattern III multiple sclerosis lesions (J, K: arrows; CNP-ase). Abbreviations'. LFB/PAS, luxol fast blue/periodic acid schif; MAG, myelin associated glycoprotein; MOG, myelin oligodendrocyte glycoprotein. Source: From Ref. 53.

proteins (MBP, PLP, MAG, and MOG) are reduced similarly. Oligodendrocytes are reduced in number at the active edge, but re-appear within the plaque center. Remyelination is often extensive. Pattern I (macrophage associated demyelination) closely resembles myelin destruction in mouse models of autoimmune encephalomyelitis in which mainly toxic products of activated macrophages such as TNF-a (57) and nitric oxide (58) mediate destruction of myelin sheaths. Lesions similar to pattern II (antibody associated demyelination) are found in models of EAE, induced by sensitization with MOG. In this model, demyelination is induced by a cooperation between encephalitogenic T-cells and demyelinating anti-MOG antibodies (59). Although pattern II lesions suggest antibody (Ab) and complement mediated mechanisms may contribute to demyelination and tissue injury, definite proof is still lacking. A study describing deposition of MOG-reactive Igs on degenerating myelin sheaths in an active MS lesion (30) provides some support for this notion.

Pattern III lesions are defined by oligodendrocyte apoptosis, a marked reduction in oligodendrocytes, minimal remyelination, and early loss of MAG and 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) myelin proteins. The pronounced reduction in the expression of MAG and CNPase, myelin proteins localized to the most distal extension of the oligodendrocyte cell body—the periaxonal region—has been described in some MS lesions since the early 1980s (60,61). A similar selective loss of MAG has been described at the periphery of progressive multi-focal leukoencephalopathy lesions, a known viral infection of glial cells, particularly oligodendrocytes, in which the infected cells are unable to maintain their myelin sheaths (62). Thus, a pattern of demyelination in which the destruction of MAG precedes that of the major myelin proteins (MBP, PLP) suggests a process at the level of the oligodendroglial cell body, and is consistent with a distal dying-back oligoden-drogliopathy, in which the cell body is unable to support the metabolic demands necessary to maintain the distal axon. Ultrastructurally, this pattern is characterized by alterations in the distal-most extensions of the oligodendroglial processes, the periaxonal region, with a uniform widening of inner myelin lamellae and degeneration of inner glial loops antedating destruction of the myelin sheaths. These pathological alterations have been described in certain experimental models of toxin and viral induced demyelination, as well as in several stereotactic brain biopsies obtained for diagnosis in cases of early MS (63-65).

The preferential loss of MAG, a hallmark of pattern III lesions, is also observed in acute white matter ischemia (66). Prominent nuclear expression of hypoxia inducible factor (HIF)-la, a specific and sensitive marker for hypoxia-like metabolic injury, also occurs in pattern III. This shared expression of HIF-la in acute ischemic lesions and pattern III MS lesions suggests that a hypoxia-like metabolic injury may contribute to the pathogenesis of inflammatory white matter damage in a subset of MS patients (67). Microarray analysis of normal appearing white matter (NAWM) from 10 post-mortem MS brains revealed upregulation of genes, such as HIF-la, known to be involved in neuroprotective mechanisms induced by hypoxic preconditioning (68). Whether this upregulation reflects an adaptation of cells to the chronic progressive pathophysiology of MS, or the activation of neuroprotective mechanisms in response to ischemic preconditioning in a subset of patients remains to be determined. Pattern III lesions are ill-defined, typically do not surround blood vessels, and do not demonstrate evidence for immunoglobulin or activated complement. The lesions are invariably associated with T-cell dominated inflammation and microglial activation. However, the quality of microglia activation is different from that observed in other MS lesions. Pattern III microglia highly express inducible nitric oxide synthase

(i-NOS), but lack other activation markers (e.g., CCR5 and CD14) (69). Since both the pattern of demyelination and microglial activation resembles that found in acute white matter infarction, pattern III lesions may develop on a background of histotoxic hypoxia, perhaps due to mitochondrial damage induced by oxygen or nitric oxide radicals.

Pattern IV lesions, the least common, are associated with profound nonapop-totic oligodendrocyte death in the periplaque white matter. Since these lesions are very rare and identified only in autopsy cases, their pathogenesis is unclear.

The frequency of immunopathological patterns in 286 demyelinating disease cases (238 biopsies; 48 autopsies) analyzed to date, reveal a distribution similar to previously published studies. (15% pattern I, 58% pattern II, 26% pattern III, and 1% pattern IV) (Figure 9) (70).

The concept of pathological heterogeneity in MS lesions is further supported by immunocytochemical studies quantifying chemokines, including cellular

Figure 9 (See color insert.) Schematic representation of the four different multiple sclerosis immunopathological subtypes based on the underlying mechanism of myelin/oligodendrocyte destruction. Patterns I and II have sharp macrophage (MU) borders, surround vessels, and show oligodendrocyte preservation and remyelination. Pattern II also has complement and Ig deposition #. Pattern III shows ill-defined MU borders, myelin associated glycoprotein loss (arrow), oligodendrocyte apoptosis, distal dying back oligodendrogliopathy with inner glial loop degeneration and limited remyelination, while IV shows oligodendrocyte degeneration in the white matter. Source: From Ref. 163.

Figure 9 (See color insert.) Schematic representation of the four different multiple sclerosis immunopathological subtypes based on the underlying mechanism of myelin/oligodendrocyte destruction. Patterns I and II have sharp macrophage (MU) borders, surround vessels, and show oligodendrocyte preservation and remyelination. Pattern II also has complement and Ig deposition #. Pattern III shows ill-defined MU borders, myelin associated glycoprotein loss (arrow), oligodendrocyte apoptosis, distal dying back oligodendrogliopathy with inner glial loop degeneration and limited remyelination, while IV shows oligodendrocyte degeneration in the white matter. Source: From Ref. 163.

expression of CCR1 and CCR5 in pattern II (n = 21) and pattern III (n = 17) lesions relative to demyelinating activity (69). Infiltrating monocytes in lesions of all patterns co-express CCR1 and CCR5. In pattern II, the number of CCR1 cells decreases, while the number of CCR5 expressing cells increases in late active versus early active regions. In contrast, CCR1 and CCR5 cells are equal in all regions of pattern III lesions and resembles the expression pattern seen in acute strokes. These data support the notion of distinct inflammatory microenvironments in pattern II and III lesions, and suggest pathological heterogeneity in MS lesions.

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