More MS news articles for Jan 2002

T Cells, Cytokines, and Autoantigens in Multiple Sclerosis

Current Neurology and Neuroscience Reports 2001 1: 263-270
Bruno Gran MD and Abdolmohamad Rostami MD, PhD
Department of Neurology, 3400 Spruce Street, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104-4283, USA.


In multiple sclerosis (MS), inflammatory demyelination in the central nervous system is thought to be initiated by T cells that recognize myelin antigens. T cells are the main regulators of acquired immunity and are involved in the pathogenesis of several organ-specific autoimmune diseases. This review provides an overview of recent studies on the role of T cells in autoimmune demyelination. Because autoreactive T cells are normally present in the mature repertoire of T cells in the blood and lymphoid organs of MS patients, but also in normal controls, particular attention is devoted to the mechanisms of activation and the functional phenotype of such T cells in patients with MS. The role of cytokines as effector molecules and the main candidate antigens are also discussed.


Molecular mimicry

The specific mechanisms by which cross-recognition of similar antigens by T-cell receptors may occur have evolved in parallel with the sophisticated knowledge accumulated in the past 15 years on how T cells recognize peptide antigens [8]. The initial view was that homology in the amino acid sequence of foreign and self antigens was required in order for cross-recognition to occur [9]. Subsequently, Wucherpfennig and Strominger [10] showed that only amino acids that contact the HLA molecule and the T-cell receptor (TCR) were required to be conserved. Systematic studies that utilized single and multiple amino acid-substituted altered peptide ligands derived from major myelin antigens showed an even more remarkable flexibility in the recognition of antigens by TCR [11,12]. It was proved that, at least in certain cases, no amino acid sequence homology was required for cross-recognition of antigens by a single TCR to occur [13]. Most recently, the use of highly complex mixtures of peptides (ie, synthetic peptide combinatorial libraries) has allowed the extensive exploration of flexibility and degeneracy in TCR antigen recognition [14]. The identification of foreign antigen-derived ligands, that can activate myelin-reactive T-cell clones with much higher potency than myelin peptides, has further supported the view that molecular mimicry may often occur in vivo [14]. The emerging picture is that molecular mimicry may be very common, so that other facilitating factors (eg, decreased costimulation requirements of autoreactive T cells) must be present at the same time for the induction of autoimmunity [8].


Which Antigens are Recognized by Autoreactive T Cells?

The main candidate autoantigens in MS are listed in 1. MBP, PLP, and myelin oligodendrocyte gylcoprotein (MOG) have been studied most extensively. The encephalitogenic potential of MBP, the second most abundant protein in CNS myelin, has been discussed previously [27]. PLP, the most abundant protein in CNS myelin, has also been studied in detail in both EAE and MS [1]. Recently, Pender et al. [36] analyzed the relationship of T-cell reactivity to three immunodominant peptides of PLP with disease activity in five patients with relapsing-remitting MS. Monthly limiting dilution assays were performed for 12 to 16 months to measure the frequencies of circulating T cells proliferating in response to PLP(41-58), PLP(184-199), and PLP(190-209). The response to an immundominant peptide of MBP (82-100) and a control antigen, tetanus toxoid, was also measured. In comparison with four control patients, MS patients showed more frequent surges of T cells reactive to PLP(184-209), which, in some cases, preceded clinical relapses. In one patient, the frequency of T cells reactive to the same peptide correlated with the total number of gadolinium-enhancing MRI lesions.

Myelin oligodendrocyte glycoprotein, a quantitatively minor component of CNS myelin, has received considerable attention in MS immunology for several reasons. Unlike MBP and PLP, it is present in the CNS, but not in peripheral myelin. It is also a membrane protein that may be more accessible than other myelin proteins to specific antibodies, and in certain mouse strains and nonhuman primates, it induces autoimmune demyelination that is pathologically very similar to MS [37]. Moreover, anti-MOG antibodies can markedly increase demyelination in MOG-induced EAE, and have been found in MS lesions [2]. Recent studies that addressed the role of other interesting candidate antigens in MS are listed in 1.


Cytokines Produced by Cells Involved in Central Nervous System Autoimmune Demyelination

Upon activation by specific antigens, autoreactive T cells can produce proinflammatory cytokines, some of which may exert a toxic effect on myelin. TNF-ã has been shown to be present in MS lesions and to be toxic in vitro for oligodendrocytes [38]. Interesting new data have appeared on the role of TNF in EAE and MS. Transgenic mouse models have shown that overexpression of TNF-á can lead to spontaneous inflammatory demyelination or increase severity of EAE induced by immunization. Knockout models have suggested that, in MOG-induced EAE, TNF-receptor 1 (TNFR1) signaling is critical in mediating demyelination, although CNS inflammation can develop in its absence. TNFR1 may also be involved in disease resolution, by mediating apoptosis of infiltrating T cells present in the lesions. A very severe clinical course of EAE in TNFR2-knockout mice compared with wild-type animals has suggested a protective role for TNFR2 signaling [39]. IFN-ã is another Th1-type cytokine for which a proinflammatory role in MS has been postulated [40]. However, studies in knockout mice have shown that IFN-ã is not essential for the induction of EAE with MOG(35-55), but is in fact involved in its down-regulation [41]. In contrast, IL-12, a key inducer of Th1-type T-cell responses, is necessary for the development of EAE [42].

Autoreactive T cells can also produce anti-inflammatory and immunomodulatory cytokines, such as IL-4, IL-5, IL-10, and TGF-â. The latter cytokine effectively suppresses EAE [43] by a mechanism that involves inhibition of IL-12 signaling [44]. Among immunomodulatory cytokines, IL-13 and TGF-â were particularly effective in down-regulating EAE induced by adoptive transfer of a PLP-specific T-cell clone [45].

To further add to the complexity of the role of T cells in MS and EAE, recent studies have suggested that cytokines and growth factors secreted by autoreactive T cells may be beneficial for CNS repair.


Chemokines and the Recruitment of Effector Cells

In addition to the production of cytokines, another functional consequence of T-cell activation in the CNS is the recruitment of other effector cells, such as CD4, CD8 T cells, monocytes, neutrophils, and B cells. Production of chemokines in the inflammatory microenvironment creates chemical gradients that promote the migration into the CNS of these cell types. The role of chemokines and their receptors in MS was reviewed recently by Zhang et al. [48] and is summarized in 2.



Studies in basic T-cell receptor immunology have provided evidence that supports a role for molecular mimicry in the activation of autoreactive T cells in patients with MS. Because T cells reactive to myelin antigens are also found in normal patients, it seems likely that other factors, such as genetic susceptibility, influence the activation of such cells in MS patients. Exposure to environmental factors, such as viruses cross-recognized by autoreactive T cells, may provide a link between genetic susceptibility and initiation of myelin damage. If MBP as well as other myelin antigens (1) are primary targets of autoimmune demyelination, decreased costimulation requirements for the activation of autoreactive T cells may well play a role in the initiation of the disease. Finally, cytokines appear to play a major role as effector molecules in mediating autoimmune inflammatory damage. However, their reliability as surrogate markers of disease activity is still far from matching the data provided by MRI.

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