Correlation of Blood T Cell and Antibody Reactivity to Myelin Proteins with HLA Type and Lesion Localization in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS. The numbers of autoimmune T cells and Abs specific for proteins of CNS myelin are increased in the blood in some patients with MS. The aim of this study was to investigate whether there are correlations between the specificity of the autoimmune responses in the blood, the HLA molecules carried by the patient, and the clinical features of MS, because studies on experimental autoimmune encephalomyelitis, an animal model of MS, indicate that autoimmune responses targeting particular myelin proteins and the genetic background of the animal play a role in determining the pattern of lesion distribution. We tested blood T cell immunoreactivity to myelin proteins in 100 MS patients, 70 healthy controls, and 48 patients with other neurological disorders. Forty MS patients had strongly increased T cell reactivity to one or more myelin Ags. In these 40 patients, the most robust correlation was between CD4+ T cell reactivity to myelin proteolipid protein residues 184–209 (PLP184–209) and development of lesions in the brainstem and cerebellum. Furthermore, carriage of HLA-DR4, -DR7, or -DR13 molecules by MS patients correlated with increased blood T cell immunoreactivity to PLP184–209, as well as the development of lesions in the brainstem and cerebellum. Levels of PLP190–209-specific Abs in the blood also correlated with the presence of cerebellar lesions. These findings show that circulating T cells and Abs reactive against specific myelin Ags can correlate with lesion distribution in MS and suggest that they are of pathogenic relevance.

The Role of HLA in MS Susceptibility and Phenotype

“…5) (Greer et al 2008). These correlations were also observed in patients at the onset of clinical signs of disease (Greer et al 2008;Tuohy 1997) and in patients followed longitudinally over an 18-month period .…”

“…This valine is also present in DRB1*15:03, which is related to development of MS in people of African ancestry, but is not present in DRB1*15:02, which is not associated with development of MS in any populations (although DRB1*15:02 can present a wide variety of other myelin peptides, suggesting that other factors besides antigenpresenting ability are involved in its lack of association with MS (Finn et al 2004). In our studies of T cell responses to PLP in MS patients, we have reported that PLP can be presented by HLA-DR4 (Greer et al 1997(Greer et al , 2008. Binding assays, however, indicate that only certain subtypes of DR4 can bind the PLP peptides strongly, e.g.…”

“…In addition, we identified a small group of 8 patients, all of whom had cognitive impairment as a prominent feature of their MS and showed significantly elevated levels of T cell reactivity to two peptides of myelin oligodendrocyte glycoprotein (MOG) (Greer et al 2008). Seven of these 8 patients were positive for HLA-DRB1*15:01, which is a higher proportion than would be expected in a group of unselected MS patients, and the two MOG peptides that the patients reacted to have previously been shown to bind specifically to either DRB1*15:01 or DQB1*06:02 (Khare et al 2003).…”

Multiple Sclerosis Relapses: Epidemiology, Outcomes and Management. A Systematic Review

“…In fact, studies showed that areas of demyelination are commonly localised within previously remyelinated regions [109,110] . This inherent predisposition is likely to be determined by numerous polygenic factors, including genetic factors, such as some of the MS susceptibility factors [111] , several genes involved in the regulation of immune cell function, myelin and neural growth [112] , and genetically correlated CD4 T-cell immunoreactivity [113] .…”

Myelin proteolipid protein: An effective autoantigen and target of autoimmunity in multiple sclerosis

“…Although many studies have tested myelin-antigen-specific Tcell responses in patients with MS, only three studies have attempted to correlate T-cell autoreactivity to one [42] or several myelin proteins [47,56] with the areas in which lesions form. One of these studies [42] investigated T-cell reactivity to PLP peptides in 10 patients with monocentric monophasic demyelinating syndromes suggestive of a first attack of MS, and another [47] compared T-cell reactivity to PLP, MBP and MOG in 10 Japanese patients with the optico-spinal form of MS and 11 patients with conventional MS.…”