A Brief Historical Perspective on the Pathological Consequences of Excessive Type I Interferon Exposure In vivo

Crow, Yanick J.; Lebon, Pierre; Casanova, Jean‐Laurent

doi:10.1007/s10875-018-0543-6

Cited by 25 publications

(23 citation statements)

References 63 publications

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“…The pathogenic process in SLE must require high IFNAR availability and signaling (35). This would explain the reason why only a minor fraction of IFN-a-treated patients succumbed from SLE (2,19,20,24,25), why only lupusprone mice develop SLE upon continuous IFN-a exposure (28)(29)(30), and why type I IFN showed somewhat protective effects on SLE (36,37).…”

Section: Discussionmentioning

confidence: 99%

“…ystemic lupus erythematosus (SLE) is a prototypical autoimmune disease presenting with erythematosus skin rash and characterized by the presence of serum autoantibodies, such as anti-dsDNA Ab. Previous studies have shown that IFN-a can be a principal driver of SLE (1)(2)(3)(4). IFN-a was upregulated in sera and cerebrospinal fluids of patients with SLE (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

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Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus

Akiyama

Tsumiyama

Uchimura

et al. 2019

The Journal of Immunology

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The cause of systemic lupus erythematosus (SLE) is unknown. IFN-a has been suggested as a causative agent of SLE; however, it was not proven, and to what extent and how IFN-a contributes to the disease is unknown. We studied the contribution of IFN-a to SLE by generating inducible IFN-a transgenic mice and directly show that conditional upregulation of IFN-a alone induces a typical manifestation of SLE in the mice not prone to autoimmunity, such as serum immune complex, autoantibody against dsDNA (anti-dsDNA Ab), and the organ manifestations classical to SLE, such as immune complex-deposited glomerulonephritis, classical splenic onion-skin lesion, alopecia, epidermal liquefaction, and positive lupus band test of the skin. In the spleen of mice, activated effector CD4 T cells, IFN-g-producing CD8 T cells, B220 + CD86 + cells, and CD11c + CD86 + cells were increased, and the T cells produced increased amounts of IL-4, IL-6, IL-17, and IFN-g and decreased IL-2. In particular, activated CD3 + CD4 2 CD8 2 doublenegative T cells positive for TCRab, B220, CD1d-teteramer, PD-1, and Helios (that produced increased amounts of IFN-g, IL-4, IL-17, and TNF-a) were significantly expanded. They infiltrated into kidney and induced de novo glomerulonephritis and alopecia when transferred into naive recipients. Thus, sole upregulation of IFN-a is sufficient to induce SLE, and the double-negative T cells expanded by IFN-a are directly responsible for the organ manifestations, such as lupus skin disease or nephritis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus

Akiyama

Tsumiyama

Uchimura

et al. 2019

The Journal of Immunology

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“…These observations can be linked to the unexpectedly high prevalence of atherosclerosis and cardiovascular disease in patients with SLE 90. In a more general perspective, it is clear that there are several detrimental effects on cells and tissues that are exposed to IFN for an extensive period of time 91Figure 4. summarises the effect of various IFNs on different cell types 14 25 92 93…”

Section: Introductionmentioning

confidence: 99%

Interferon pathway in SLE: one key to unlocking the mystery of the disease

2019

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SLE is characterised by an activation of the interferon (IFN) system, which leads to an increased expression of IFN-regulated genes. The reasons behind the IFN signature in SLE are (1) the existence of endogenous IFN inducers, (2) activation of several IFN-producing cell types, (3) production of many different IFNs, (4) a genetic setup promoting IFN production and (5) deficient negative feedback mechanisms. The consequences for the immune system is a continuous stimulation to an immune response, and for the patient a number of different organ manifestations leading to typical symptoms for SLE. In the current review, we will present the existing knowledge of the IFN system and pathway activation in SLE. We will also discuss how this information can contribute to our understanding of both the aetiopathogenesis and some organ manifestations of the disease. We will put forward some issues that are unresolved and should be clarified in order to make a proper stratification of patients with SLE, which seems important when selecting a therapy aiming to downregulate the IFN system.

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“…Although SLE has long been suspected to be caused by some type of autoimmune responses, the details of its etiology have remained elusive. Interferon (IFNα) has been proposed to be a principal driver of SLE (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), however, it has also been reported that IFNα can sometimes be protective against SLE (17,18), IFNα treatment itself does not induce anti-Sm Ab, which is considered diagnostic of SLE (1,16,19,20), and monoclonal anti-IFNα Ab therapy is only modestly effective in treating SLE (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

A Newly Generated DOCK8-expressing T Follicular Helper Cell Type, aiCD4 T Cell, Causes Systemic Lupus Erythematosus: Self-Organized Criticality Theory

Shiozawa

Tsumiyama

Sakurai

et al. 2020

Preprint

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Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease of unknown cause. We show here that a novel T follicular helper cell type expressing the guanine nucleotide exchange factor DOCK8 on the cell surface causes SLE. These cells, which we have designated autoantibody-inducing CD4 T (aiCD4 T) cells, are generated after resuscitation from anergy following strong TCR stimulation by antigen. When mice normally not prone to autoimmune disease were repeatedly immunized with an antigen such as OVA, they generated DOCK8+ CD4 T cells. These DOCK8+ CD4 T cells, in vivo and also upon transfer to naïve mice, induced a variety of autoantibodies and lesions characteristic of SLE. TCR repertoire analyses showed that a substantial number of novel TCR repertoires were generated in the DOCK8+ CD4 T cells, which induced novel autoantibodies upon transfer to naïve mice. DOCK8+ CD4 T cells are localized in splenic red pulp, the space immunoreactive against a variety of antigens, and specifically increased in the peripheral blood of SLE patients in association with disease activity. Anti-DOCK8 antibody treatment ameliorated the lesions induced by DOCK8+ CD4 T cells and in lupus model (NZB x W) F1 mice. Thus, when CD4 T cells are overstimulated by an external disturbance, i.e., repeatedly stimulated with antigen, to levels that surpass the system’s self-organized criticality, these cells express DOCK8 on the cell surface and acquire autoreactivity via TCR re-revision at the periphery. These DOCK8+ CD4 T cells subsequently induce a variety of autoantibodies and SLE.

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A Brief Historical Perspective on the Pathological Consequences of Excessive Type I Interferon Exposure In vivo

Cited by 25 publications

References 63 publications

Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus

Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus

Interferon pathway in SLE: one key to unlocking the mystery of the disease

A Newly Generated DOCK8-expressing T Follicular Helper Cell Type, aiCD4 T Cell, Causes Systemic Lupus Erythematosus: Self-Organized Criticality Theory

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