Selective loss of a subset of T helper cells in active multiple sclerosis.

Rose, Lynn M.; Ginsberg, Arthur; Rothstein, Ted L.; Ledbetter, Jeffrey A.; Clark, Edward A.

doi:10.1073/pnas.82.21.7389

Cited by 104 publications

(30 citation statements)

References 36 publications

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“…We have assumed in this study, as other investigators have done in studies of other disease states ( 17), that marker-function relationships that have been established in healthy subjects hold true during disease; however, this may need to be established by direct observation. On this point, the significant association of the HI: SI ratio with RF and antibodies to collagen in synovial fluid and, to a lesser degree, with ESR, is indicative of a functional relevance of the increased HI : SI ratio.…”

Section: Discussionmentioning

confidence: 99%

“…CD4+ 2H4+ cells induce CD8+ cells and provide little help for immunoglobulin production, and are thus designated a suppressor inducer (SI) subset (14). The HI subset corresponds functionally to T lymphocytes that are identified by the UCHLl monoclonal antibody (15), and the SI subset corresponds to those previously defined b y sera from patients with juvenile rheumatoid arthritis (JRA), i.e., CD4-t JRA+ (16), and by the common leukocyte antigen, Lp220 (17).…”

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confidence: 99%

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Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis

Emery

Gentry

Mackay

et al. 1987

Arthritis & Rheumatism

154

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New monoclonal antibodies allow CD4 lymphocytes to be categorized into helperhnducer (HI) CD4+ 4B4-t, and suppressor inducer (SI) CD4+ 2H4+ subpopulations. Blood and synovial lymphocytes from 30 patients with rheumatoid arthritis (RA), 13 patients with other articular diseases, and 24 control subjects were exposed to these monoclonal antibodies and analyzed by flow cytometry. CD4:CDS ratios were similar for the 3 groups. In RA patients, there was a depletion of SI cells in blood and synovial fluid, and the ratio of HI cells to SI cells was elevated, particularly in the synovial lymphocytes. These data provide new evidence for T cell dysregulation in the perpetuation of RA. Submitted for publication November 10, 1986; accepted in revised form February 23, 1987. lymphocytes in blood (the T cell ratio) have been inconsistent (1-7); most reports show no marked abnormality. Studies of synovial fluid lymphocytes have generally shown a lower CD4: CD8 ratio in synovial fluid than in blood (1-3,5-7), with a slight excess of CD4-positive cells. Immunohistology shows a patchy predominance of CD4+ lymphocytes in the synovial membrane (8,9). However, counts of cells bearing the CD4 and CD8 lymphocyte markers would not closely reflect lymphocyte function, because each of these cell populations is heterogeneous. On the other hand, a functionally relevant lymphocyte subset(s) might be identifiable in RA because depletion of blood lymphocytes by thoracic duct drainage (lo), lymphocytapheresis (1 l), or total lymphoid irradiation (12) effects remission.Newer monoclonal antibodies, to antigens specified as 4B4 and 2H4, could provide a better correlation between the numeric and functional aspects of T lymphocyte activity. The 4B4 and 2H4 antigens are present on T lymphocytes, B lymphocytes, and some monocytes; about 40% of blood lymphocytes are positive for each antigen. The molecular weights of 4B4 and 2H4 are 135 kd and 190 kd, respectively. Within the CD4 subset, anti-4B4 and anti-2H4 identify reciprocal subpopulations. In vitro, CD4+ 4B4 + lymphocytes augment immunoglobulin production and antigen-driven responses, and are thus designated a helperhnducer (HI) subset (13). CD4+ 2H4+ cells induce CD8+ cells and provide little help for immunoglobulin production, and are thus designated a suppressor inducer (SI) subset (14). The HI subset corresponds functionally to T lymphocytes that are identified by the UCHLl monoclonal antibody (15), and the SI subset corresponds to those previously

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis

Emery

Gentry

Mackay

et al. 1987

Arthritis & Rheumatism

154

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“…The function of memory CD4 ϩ T cells, unlike memory B (4) and CD8 ϩ T cells (5), is to produce cytokines that in turn influence the functions of effector cells and the outcome of an immune response (6). Recent studies have identified memory and naive CD4 ϩ T cells based on the differential expression of CD45 isoforms (CD45RA and CD45R0 for naive and memory CD4 ϩ T cells, respectively) and other markers (7)(8)(9)(10) and have characterized several functional differences between these two subsets of CD4 ϩ T cells (11,12).…”

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confidence: 99%

Augmentation in Expression of Activation-Induced Genes Differentiates Memory from Naive CD4+ T Cells and Is a Molecular Mechanism for Enhanced Cellular Response of Memory CD4+ T Cells

Liu

Prabhu

et al. 2001

The Journal of Immunology

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In an attempt to understand the molecular basis for the immunological memory response, we have used cDNA microarrays to measure gene expression of human memory and naive CD4+ T cells at rest and after activation. Our analysis of 54,768 cDNA clones provides the first glimpse into gene expression patterns of memory and naive CD4+ T cells at the genome-scale and reveals several novel findings. First, memory and naive CD4+ T cells expressed similar numbers of genes at rest and after activation. Second, we have identified 14 cDNA clones that expressed higher levels of transcripts in memory cells than in naive cells. Third, we have identified 135 (130 known genes and 5 expressed sequence tags) up-regulated and 68 (42 known genes and 26 expressed sequence tags) down-regulated cDNA clones in memory CD4+ T after in vitro stimulation with anti-CD3 plus anti-CD28. Interestingly, the increase in mRNA levels of up-regulated genes was greater in memory than in naive CD4+ T cells after in vitro stimulation and was higher with anti-CD3 plus anti-CD28 than with anti-CD3 alone in both memory and naive CD4+ T cells. Finally, the changes in expression of actin and cytokine genes identified by cDNA microarrays were confirmed by Northern and protein analyses. Together, we have identified ∼200 cDNA clones whose expression levels changed after activation and suggest that the level of expression of up-regulated genes is a molecular mechanism that differentiates the response of memory from naive CD4+ T cells.

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“…Although examining lymphokine production by the progeny of single activated T cells obtained after limiting dilution technique can yield an approximate estimate of precursor frequency, the potential remains for changes in pattern of lymphokine production during the multiple replications of cells required by this technique. As an alternative to these approaches, we (20), respectively, followed by negative selection with indirect panning using plastic Petri dishes coated with goat anti-mouse IgG (Tago) (21). The purity of all T-cell subsets was >95% as determined by immunofluorescent flow cytometry after indirect staining with the appropriate mAb.…”

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Restricted production of interleukin 4 by activated human T cells.

Lewis

Prickett

Larsen

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

121

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Interleukin 4 (IL-4) is secreted by activated T cells and pleiotropically modulates both B-and T-lymphocyte function. In murine helper (CD4+) T-cell clones IL-4 production appears to be regulated independently of interferon Y and interleukin 2. To determine whether production of these lymphokines is also differentially regulated in uncloned human T cells, we studied lymphokine production *iy normal human peripheral T cells and T-cell subsets after ii vitro polyclonal activation. After maximal induction of lymphokine expression, IL-4 mRNA was detectable in <5% of CD41 and 1-2% of unfractionated T cells, whereas '33% and 60% of CD4' cells expressed detectable mRNA for interferon y and interleukin 2, respectively. This finding correlated with dramatically lower production of IL-4 mRNA and protein than of interferon rand interleukin 2 by peripheral blood and tonsillar T cells. The helper-inducer (CD4' CD45R-) T-cell subset, which significantly enhances in vitro immunoglobulin production, accounted for the preponderance of IL-4 mRNA accumulation and protein production by CD41 T cells; nevertheless, cells with detectable IL-4 mRNA constituted <10% of the CD4' CD45R-subset. Limitation of IL-4 production to a comparatively small population of normal human T cells could selectively regulate the effects of this lymphokine in T-cell-mediated immune responses; such selective regulation may be a fundamental mechanism for restricting the potentially pleiotropic effects of certain tymphokines to appropriate responder cells.Interleukin 4 (IL-4) is a T-cell lymphokine that modulates lymphocyte function by promoting B-cell growth, regulating immunoglobulin isotype expression, and promoting T-cell growth and cytotoxicity (1)(2)(3)(4). Interferon y (IFN-'y) (5,6) and, to a lesser extent, interleukin 2 (IL-2) (6, 7), which are primarily produced by activated T cells, also have pleiotropic effects on lymphoid cells. In certain cases all three lymphokines may have similar or synergistic activities, such as the enhancement of T-cell-mediated cytotoxicity (4,8), whereas in other situations, such as the regulation of immunoglobulin isotype expression by IL-4 and IFN-y, differential or antagonistic effects have been demonstrated (2, 9, 10).These in vitro findings raise the question as to how lymphokine production by activated T cells is regulated in vivo to result in an integrated effective immune response. One mechanism to facilitate distinct T-cell effector functions would be to limit the production of a lymphokine to a particular subtype ofT cells. Such segregation ofCD4' T-cell lymphokine production has been proposed by Mosmann and co-workers (11, 12) from the observation that most murine CD4' clones produce either IL-4 or IFN-y and IL-2 in a mutually exclusive fashion. However, most human CD4' T-cell clones do not appear to conform to this pattern (9, 13), and there is evidence that the patterns of lymphokine production obtained in clones may be influenced by the conditions used during the cloning process (14). In addition, c...

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Selective loss of a subset of T helper cells in active multiple sclerosis.

Abstract: ABSTRACT

Cited by 104 publications

References 36 publications

Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis

Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis

Augmentation in Expression of Activation-Induced Genes Differentiates Memory from Naive CD4+ T Cells and Is a Molecular Mechanism for Enhanced Cellular Response of Memory CD4+ T Cells

Restricted production of interleukin 4 by activated human T cells.

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