Peripheral Blood and Granuloma CD4+CD28− T Cells Are a Major Source of Interferon-γ and Tumor Necrosis Factor-α in Wegener’s Granulomatosis

Komocsi, A.; Lamprecht, Peter; Csernok, Elena; Mueller, Antje; Holl‐Ulrich, Konstanze; Seitzer, Ulrike; Moosig, Frank; Schnabel, A; Gross, Wolfgang L.

doi:10.1016/s0002-9440(10)61118-2

Cited by 195 publications

(184 citation statements)

References 38 publications

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“…Other investigators have observed differences in the expression of chemokines and chemokine receptors across disease subsets (42,43). In addition, some studies are consistent with confinement of critical cytokine production to certain T cell subsets, and recruitment of such cells (particularly CD28-negative T cells) into granulomatous lesions of patients with WG (44,45).…”

Section: Discussionmentioning

confidence: 60%

Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial

Stone¹

2003

Arthritis & Rheumatism

361

153

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Objective. To report baseline data on 180 patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET), and to examine demographic and clinical differences between patients with limited disease and those with severe disease.Methods. Definitions of limited and severe disease were agreed upon by consensus of the investigators at a pretrial meeting and were incorporated into the protocol as a stratification criterion. These data were applied prospectively to the WGET patient cohort, based on clinical features and the intention to treat patients according to disease activity. Data related to disease onset, date of diagnosis, clinical features, antineutrophil cytoplasmic antibody assays, tissue biopsy findings, and other medical history were collected on a baseline medical history form. Physician-investigators from each center participated in the development of this form, and all were certified in its use prior to the start of the trial. Selected data on patients who were screened for the trial but were not enrolled were also collected.Results. Several significant differences between the limited and severe disease subsets were observed. Patients with limited disease were nearly a decade younger at disease onset compared with patients with severe disease. Thirty-three percent of patients with severe disease were women, compared with 58% of those with limited disease. Despite their younger age at symptom onset, patients with limited disease tended to have longer disease duration, a greater likelihood of experiencing exacerbation of previous disease following a period of remission, and a higher prevalence of destructive upper respiratory tract disorders at the time of enrollment (e.g., saddle-nose deformity). Patients with limited WG were less likely than those with severe disease to have antibodies to either proteinase 3 or myeloperoxidase. Patients with severe disease had a higher likelihood of previous thyroid disease, particularly either Graves' disease or Hashimoto thyroiditis, suggesting the possibility of different pathogenetic factors within these disease subsets. Other observed differences between these subsets, such as the greater frequency of alveolar hemorrhage in the severe disease group, were related to the a priori definitions of limited and severe disease.Conclusion. There are significant differences between patients with limited WG and those with severe WG with regard to sex, age, the likelihood of recurrent disease, the risk of damage in certain organ systems, and, possibly, etiologic factors. These differences (and perhaps other differences that are currently unrecognized) in patient subsets may have implications for mechanisms of pathogenesis, prognosis, response to treatment, and the design of future clinical investigations.

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Section: Discussionmentioning

confidence: 60%

Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial

Stone¹

2003

Arthritis & Rheumatism

361

153

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“…These T cells have undergone clonal expansion in vivo, have lost the expression of CD40L, are highly proinflammatory, and express a variety of killer Ig-like receptors (10 -14). An expansion of CD4 ϩ CD28 null T cells was also reported for patients with other autoimmune diseases (13,15), HIV-and CMV-infected individuals (16), and people suffering from coronary disease (17). Although the role of these cells in disease pathology is not clear, CD4…”

Section: T He Cd4mentioning

confidence: 55%

CD4+CD28null T Cells in Autoimmune Disease: Pathogenic Features and Decreased Susceptibility to Immunoregulation

Thewissen

Somers

Hellings

et al. 2007

The Journal of Immunology

167

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To determine the role of expanded CD4+CD28null T cells in multiple sclerosis and rheumatoid arthritis pathology, these cells were phenotypically characterized and their Ag reactivity was studied. FACS analysis confirmed that CD4+CD28null T cells are terminally differentiated effector memory cells. In addition, they express phenotypic markers that indicate their capacity to infiltrate into tissues and cause tissue damage. Whereas no reactivity to the candidate autoantigens myelin basic protein and collagen type II was observed within the CD4+CD28null T cell subset, CMV reactivity was prominent in four of four HC, four of four rheumatoid arthritis patients, and three of four multiple sclerosis patients. The level of the CMV-induced proliferative response was found to be related to the clonal diversity of the response. Interestingly, our results illustrate that CD4+CD28null T cells are not susceptible to the suppressive actions of CD4+CD25+ regulatory T cells. In conclusion, this study provides several indications for a role of CD4+CD28null T cells in autoimmune pathology. CD4+CD28null T cells display pathogenic features, fill up immunological space, and are less susceptible to regulatory mechanisms. However, based on their low reactivity to the autoantigens tested in this study, CD4+CD28null T cells most likely do not play a direct autoaggressive role in autoimmune disease.

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“…ϩ CD28 Ϫ cells, present in granulomas, seem to contribute to production of IFN-␥ and TNF-␣ (77,78). These cells show evidence of an effector-memory phenotype, oligoclonality, and replicative senescence, suggesting that they are the product of antigen exposure but not necessarily MPO or PR3 (78,79) (reviewed in [80]).…”

Section: Cd28mentioning

confidence: 99%

Anti-Neutrophil Cytoplasm-Associated Glomerulonephritis

Morgan

Harper

Williams

et al. 2006

Journal of the American Society of Nephrology

107

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Wegener's granulomatosis, microscopic polyangiitis, and renal limited vasculitis are associated with circulating anti-neutrophil cytoplasm antibodies and are an important cause of rapidly progressive glomerulonephritis. This review gives an account of recent advances in the understanding of the pathogenesis underlying these conditions and how these may lead to future treatments. Consideration is given to recent clinical trials in the management of anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitides.

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Peripheral Blood and Granuloma CD4+CD28− T Cells Are a Major Source of Interferon-γ and Tumor Necrosis Factor-α in Wegener’s Granulomatosis

Cited by 195 publications

References 38 publications

Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial

Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial

CD4+CD28null T Cells in Autoimmune Disease: Pathogenic Features and Decreased Susceptibility to Immunoregulation

Anti-Neutrophil Cytoplasm-Associated Glomerulonephritis

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