Expansions of CD4+CD28– and CD8+CD28– T cells in Granulomatosis with Polyangiitis and Microscopic Polyangiitis Are Associated with Cytomegalovirus Infection But Not with Disease Activity

Bucchia

Arthritis & Rheumatology

et al. 2019

Objective. To compare the effects of rituximab (RTX) and conventional immunosuppressants (CIs) on CD4+ T cells, Treg cells, and CD8+ T cells in antineutrophil cytoplasmic antibody-associated vasculitis (AAV).Methods. A thorough immunophenotype analysis of CD4+, Treg, and CD8+ cells from 51 patients with AAV was performed. The production of cytokines and chemokines by CD8+ T cells stimulated in vitro was assessed using a multiplex immunoassay. The impact of AAV B cells on CD8+ T cell response was assessed using autologous and heterologous cocultures.Results. CD4+ and Treg cell subsets were comparable among RTX-treated and CI-treated patients. In contrast, within the CD8+ T cell compartment, RTX, but not CIS, reduced CD45RA+CCR7-(TEMRA) cell frequency (from a median of 39% before RTX treatment to 10% after RTX treatment [P < 0.01]) and efficiently dampened cytokine/chemokine production (e.g., the median macrophage inflammatory protein 1α level was 815 pg/ml in patients treated with RTX versus 985 pg/ml in patients treated with CIs versus 970 pg/ml in those with active untreated AAV [P < 0.01]). CD8+ T cell subsets cocultured with autologous B cells produced more proinflammatory cytokines in AAV patients than in controls (e.g., for tumor necrosis factor-producing effector memory CD8+ T cells: 14% in AAV patients versus 9.2% in controls [P < 0.05]). In vitro disruption of AAV B cell-CD8+ T cell cross-talk reduced CD8+ T cell cytokine production, mirroring the reduced CD8+ response observed ex vivo after RTX treatment.Conclusion. The disruption of a pathogenic B cell/CD8+ T cell axis may contribute to the efficacy of RTX in AAV. Further studies are needed to determine the value of CD8+ T cell immunomonitoring in B cell-targeted therapies.

Section: Resultssupporting

confidence: 48%

Dampening of CD8+ T Cell Response by B Cell Depletion Therapy in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Bucchia

Arthritis & Rheumatology

et al. 2019

Arthritis & Rheumatology

“…We and other investigators have shown that the presence of a latent CMV infection influences the clinical course and outcome of rheumatoid arthritis (RA), the prototypical T cell–mediated autoimmune disease with severe perturbations of immune homeostasis, particularly in various T lymphocyte compartments. Similar observations have been reported in other autoimmune diseases, such as psoriasis , granulomatosis with polyangiitis , Alzheimer's disease , and systemic lupus erythematosus .…”

supporting

confidence: 88%

Latent Cytomegalovirus Infection in Rheumatoid Arthritis and Increased Frequencies of Cytolytic LIR‐1+CD8+ T Cells

Rothe

Quandt

Schubert

et al. 2016

ObjectiveLeukocyte immunoglobulin‐like receptor 1 (LIR‐1) is up‐regulated by cytomegalovirus (CMV), which in turn, has been associated with premature aging and more severe joint disease in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the expression and functional significance of LIR‐1 in CMV‐positive RA patients.MethodsWe determined the phenotype, cytolytic potential, CMV‐specific proliferation, and HLA–G–triggered, LIR‐1–mediated inhibition of interferon‐γ secretion of LIR‐1+ T cells in RA patients and healthy controls.ResultsWe found increased frequencies of CD8+ T cells with CMV pp65–specific T cell receptors in CMV‐positive RA patients as compared to CMV‐positive healthy controls. CMV‐specific CD8+ T cells in these patients were preferentially LIR‐1+ and exhibited a terminally differentiated polyfunctional phenotype. The numbers of LIR‐1+CD8+ T cells increased with age and disease activity, and showed high levels of reactivity to CMV antigens. Ligation of LIR‐1 with soluble HLA–G molecules in vitro confirmed an inhibitory role of the molecule when expressed on CD8+ T cells in RA patients.ConclusionWe propose that latent CMV infection in the context of a chronic autoimmune response induces the recently described “chronic infection phenotype” in CD8+ T cells, which retains anti‐infectious effector features while exhibiting autoreactive cytolytic potential. This response is likely dampened by LIR‐1 to avoid overwhelming immunopathologic changes in the setting of the autoimmune disease RA. The known deficiency of soluble HLA–G in RA and the observed association of LIR‐1 expression with disease activity suggest, however, that LIR‐1+ T cells are insufficiently controlled in RA and are still likely to be involved in the pathogenesis of the disease.

BioMed Research International

“…Similarly, expanded CD4+ T-cell populations are also documented in patients with various autoimmune diseases, including RA [147, 148], MS [149], and Wegener's granulomatosis [150]. However, there is growing evidence that the HCMV seropositive population of the patients is causing the association with disease and is responsible for the extraordinary expansion of CD4+ CD28− T-cells [100, 148, 151–153]. …”

Section: T-cells Hcmv and Ramentioning

confidence: 99%

Human Cytomegalovirus and Autoimmune Disease

Halenius

Hengel

2014

118

Human cytomegalovirus (HCMV) represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE), systemic sclerosis (SSc), diabetes mellitus type 1, and rheumatoid arthritis (RA) is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention.