This paper presents a revised version of the Illness Perception Questionnaire (IPQ-R), a recently developed and widely used quantitative measure of the five components of illness representations in Leventhal's self-regulatory model. The revised version stemmed from a need to deal with minor psychometric problems with two subscales, and to include additional subscales, assessing cyclical timeline perceptions, illness coherence, and emotional representations. Item selection was determined by principal components analyses which verified the factorial structure of the questionnaire in a sample of 711 patients from 8 different illness groups. Further analysis provided good evidence for both the internal reliability of the subscales and the short (3 week) and longer term (6 month) retest reliability. The IPQ-R also demonstrated sound discriminant, known group and predictive validity. While it is possible that the new subscales will vary in their applicability in different patient groups, the IPQ-R provides a more comprehensive and psychometrically acceptable assessment of the key components of patients' perceptions of illness.

The Revised Illness Perception Questionnaire (IPQ-R)

Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

Immunology of multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease that serves as an animal model for multiple sclerosis. Oral administration of myelin basic protein (MBP) suppresses EAE by inducing peripheral tolerance. T cell clones were isolated from the mesenteric lymph nodes of SJL mice that had been orally tolerized to MBP. These clones were CD4+ and were structurally identical to T helper cell type 1 (TH1) encephalitogenic CD4+ clones in T cell receptor usage, major histocompatibility complex restriction, and epitope recognition. However, they produced transforming growth factor-beta with various amounts of interleukin-4 and interleukin-10 and suppressed EAE induced with either MBP or proteolipid protein. Thus, mucosally derived TH2-like clones induced by oral antigen can actively regulate immune responses in vivo and may represent a different subset of T cells.

https://science.sciencemag.org/content/sci/265/5176/1237.full.pdf

Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis

Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.

CD4+CD25high Regulatory Cells in Human Peripheral Blood

CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4+CD25+ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4+CD25hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4+CD25hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4+CD25hi regulatory T cell function in patients with MS.

/pdf/loss-of-functional-suppression-by-cd4-cd25-regulatory-t-3nyj8dsmz0.pdf

Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis

MULTIPLE sclerosis is thought to be an autoimmune disease of the central nervous system mediated by T cells specific for a myelin antigen1,2. Myelin basic protein has been studied as a potential autoantigen in the disease because of its role as an encephalitogen in experimental autoimmune encephalomyelitis and post-viral encephalomyelitis3,4 and because of the presence in the blood of multiple sclerosis patients of in vivo-activated T cells reactive to myelin basic protein5. Immune involvement in multiple sclerosis has been further suggested by the association with the major histocompatibility complex class II phenotype DR2, DQwl (refs 6–9). To define the T-cell specificity toward myelin basic protein, 15,824 short-term T-cell lines were established from multiple sclerosis subjects, subjects with other neurological diseases, and normal controls. Here we report a higher frequency of T-cell lines reactive with a DR2-associated region of myelin basic protein between residues 84–102 in patients with multiple sclerosis compared with controls. A second region, identified between residues 143–168, was recognized equally in multiple sclerosis patients and controls and was associated with the DRwll phenotype. These DR2 and DRw11 associations were also observed among T-cell lines generated from family members of a multiple sclerosis patient. The immunodominant 84–102 peptide from myelin basic protein was both DR2- and DQwl-restricted among different T-cell lines. These results raise the possibility that this immunodominant region may be encephalitogenic in some DR2+ individuals.

T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis.

Multiple sclerosis (MS) is thought to be an autoimmune disease mediated by T lymphocytes that recognize myelin components of the central nervous system. In a 1-year double-blind study, 30 individuals with relapsing-remitting MS received daily capsules of bovine myelin or a control protein to determine the effect of oral tolerization to myelin antigens on the disease. Six of 15 individuals in the myelin-treated group had at least one major exacerbation; 12 or 15 had an attack in the control group. T cells reactive with myelin basic protein were reduced in the myelin-treated group. No toxicity or side effects were noted. Although conclusions about efficacy cannot be drawn from these data, they open an area of investigation for MS and other autoimmune diseases.

Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis

Objective: To assess the correlation between cognitive dysfunction and disease burden in multiple sclerosis (MS) during a 1-year period. Design: The Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis was performed at entrance and 1 year. Patients underwent at least 20 proton density (range, 20-24) and T2-weighted axial magnetic resonance imaging (MRI) brain scans except for stable patients who were scanned monthly. Magnetic resonance imaging was evaluated using computer-automated, 3-dimensional volumetric analysis. Setting: A research clinic of a university hospital. Patients: Forty-four patients with MS of the following disease categories: relapsing-remitting (14), relapsingremitting progressive (12), chronic progressive (13), and stable (5). Main Outcome Measures: The relationships between scores on the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis and 2 MRI measures (total lesion volume and brain to intracranial cavity volume ratio) were assessed using linear regression. These MRI measures were also compared with cognitive status at 1 year using analysis of variance. Results: Overall, there was no decline in mean cognitive test performance during 1 year. Significant correlations were found between baseline neuropsychological test scores of nonverbal memory, informationprocessing speed, and attention and both MRI measures. Patients with chronic progressive MS demonstrated the strongest correlations. At 1 year, change in information-processing speed and attention correlated with change in total lesion volume. The mean increase in total lesion volume was 5.7 mL for 4 patients whose cognitive status worsened compared with 0.4 mL for 19 patients who improved and 0.5 mL for 21 patients who remained stable. Conclusions: During a 1-year period mean cognitive performance did not worsen. Automated volumetric MRI measures of total lesion volume and brain to intracranial cavity volume ratio correlated with neuropsychological performance, especially in patients with chronic progressive MS. Worsening MRI lesion burden correlated with cognitive decline.

Serial Neuropsychological Assessment and Magnetic Resonance Imaging Analysis in Multiple Sclerosis

We followed 18 multiple sclerosis patients clinically and with repeated brain MRIs with and without gadolinium for over 1 year. Clinical evaluations included scoring on the Kurtzke Expanded Disability Status Scale (EDSS) and the Ambulation Index (AI) scale. There was a significant correlation between the change in EDSS or AI and the change in number of lesions on MRI and between cumulative number of lesions on MRI and cumulative change in EDSS or AI. Our findings support the validity of MRI as a measure of clinical activity and potentially as an objective quantitative outcome measure for assessing response to therapy.

Longitudinal MRI in multiple sclerosis: Correlation between disability and lesion burden

A patient in whom multiple sclerosis (MS) was ultimately diagnosed presented with a lower motor neuron syndrome involving 1 hand, with EMG evidence of denervation. Twelve other patients were subsequently identified with definite MS and asymmetric hand atrophy. These patients were studied clinically and electrophysiologically. Evidence of chronic and ongoing denervation was noted in the hands of 12 of the 13 patients; in only 3 patients could the EMG abnormalities be accounted for by peripheral nerve lesions. Thus, lesions resulting in lower motor neuron damage may occur in the central nervous system in MS patients. We suggest that demyelination in the region of the ventral root exit zone may account for these findings.

Glenn A. Mackin

Papers

T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis.

Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis

Serial Neuropsychological Assessment and Magnetic Resonance Imaging Analysis in Multiple Sclerosis

Longitudinal MRI in multiple sclerosis: Correlation between disability and lesion burden

Lower motor neuron dysfunction in patients with multiple sclerosis