Immune responses to antigens of human endogenous retroviruses in patients with acute or stable multiple sclerosis

Clerici, Mario; Fusi, Marta; Caputo, Domenico; Guerini, Franca Rosa; Trabattoni, Daria; Salvaggio, A.; Cazzullo, Carlo Luigi; Arienti, Donatella; Villa, Maria Luisa; Urnovitz, Howard B.; Ferrante, Pasquale

doi:10.1016/s0165-5728(99)00123-x

Cited by 29 publications

(16 citation statements)

References 53 publications

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“…In the group of patients with active MS, much greater differences in the HERV-H/F Gag expression relative to healthy controls were detected for CD4 ϩ and CD8 ϩ T cells. This is further evidence that the HERV-H/F family may play a role in the extensive activation of the adaptive immune responses in MS (15,62). A previous study indicated that transcripts from HERV-H may play a biological role during T-cell activation.…”

Section: Discussionmentioning

confidence: 80%

“…Moreover, it has been shown that HERV peptides stimulate proliferation and immune response in MS patients with acute MS, but not in individuals with stable MS (15). HERV peptide-specific proliferation and type 1 cytokine production by PBMCs was observed in individuals with acute MS, but not in those with stable MS, in whom a type 2 cytokine profile dominates (15).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the authors observed that HERVstimulated cytokine production is supported by CD4 ϩ T helper cells. Different immune responses in patients with acute or chronic disease suggest that a cell-mediated and HERV-specific immune response is associated with MS (15). In addition, the existence of a T-cell-mediated immune pathogenicity previously confirmed in vivo with cell-free MSRV (HERV-W) virions injected into SCID mice humanized with human lymphoid grafts caused T-lymphocyte-dependent neuropathology (21).…”

Section: Discussionmentioning

confidence: 99%

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Expression of HERV-Fc1, a Human Endogenous Retrovirus, Is Increased in Patients with Active Multiple Sclerosis

Laska

Brudek

Nissen

et al. 2012

J Virol

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Multiple sclerosis (MS) is considered to be an autoimmune disease with an unknown cause and with immune system dysregulation. Among environmental factors, viruses are most often connected with the etiology of MS. Human endogenous retroviruses (HERVs) constitute 5 to 8% of human genomic DNA and have been detected as transcripts and proteins in the central nervous system (CNS) and peripheral blood, frequently in the context of neuroinflammation. HERV-Fc1, which belongs to the HERV-H/F family, has received our attention largely because of the genetic association with MS. We studied the expression of a capsid (Gag) protein of HERV-H/F origin by flow cytometry in peripheral blood mononuclear cells (PBMCs) from healthy controls and from MS patients with nonactive or active disease. There was a significant increase in HERV-H/F Gag expression in CD4 ؉ (P < 0.001) and CD8 ؉ (P < 0.001) T lymphocytes and in monocytes (P ‫؍‬ 0.0356) in PBMCs from MS patients with active disease. Furthermore, we have undertaken the first rigorous SYBR green-based absolute quantitative PCR (Q-PCR) evaluation approach to quantify extracellular HERV-Fc1 RNA viral loads in plasma from MS patients and healthy controls. We found a 4-fold increase in extracellular HERV-Fc1 RNA titers in patients with active MS compared with healthy controls (P < 0.001). These findings strengthen the link between HERV-Fc1 and the pathology of MS. The cause and biological consequences of these differential expression levels will be the subject of further investigation. HERV-Fc1 biology could be a compelling area for understanding the pathology of MS and possibly other autoimmune disorders.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Expression of HERV-Fc1, a Human Endogenous Retrovirus, Is Increased in Patients with Active Multiple Sclerosis

Laska

Brudek

Nissen

et al. 2012

J Virol

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“…There is also circumstantial evidence that HERV expression is elevated by proinflammatory cytokines (55,56). A number of studies have, indeed, shown that HERV-encoded proteins are expressed in inflamed tissues, and antibodies to HERVs in patients with autoimmune diseases such as systemic lupus erythematodes (SLE), Sjogren's syndrome, multiple sclerosis, and related dis- eases were frequently detected (46,52,(57)(58)(59)(60). These studies are often cited to support a role for HERVs in the etiology or progression of these disorders.…”

Section: Production Of Herv Particlesmentioning

confidence: 99%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

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

468

423

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Retroelements constitute a large portion of our genomes. One class of these elements, the human endogenous retroviruses (HERVs), is comprised of remnants of ancient exogenous retroviruses that have gained access to the germ line. After integration, most proviruses have been the subject of numerous amplifications and have suffered extensive deletions and mutations. Nevertheless, HERV-derived transcripts and proteins have been detected in healthy and diseased human tissues, and HERV-K, the youngest, most conserved family, is able to form virus-like particles. Although it is generally accepted that the integration of retroelements can cause significant harm by disrupting or disregulating essential genes, the role of HERV expression in the etiology of malignancies and autoimmune and neurologic diseases remains controversial. In recent years, striking evidence has accumulated indicating that some proviral sequences and HERV proteins might even serve the needs of the host and are therefore under positive selection. The remarkable progress in the analysis of host genomes has brought to light the significant impact of HERVs and other retroelements on genetic variation, genome evolution, and gene regulation.A lmost half of the mammalian genome is derived from ancient transposable elements. The two general types, (DNA)-transposons and retroelements, often regarded as ''selfish DNA parasites or junk DNA,'' encompass Ϸ2.8% and 42.2% of the human genome, respectively (1, 2). This striking finding is one of the many insights from recent large-scale sequencing projects that have provided the most valuable information in this field since the initial discovery of mobile elements in 1956 by Barbara McClintock (3, 4). Whereas DNA-transposons amplify without an RNA intermediate, retroelements rely on an RNA transcript that is retrotranscribed by a reverse transcriptase before integration in the genome. Here, we briefly review the characteristics of retroelements, their present classification, and the available evidence for their biological significance and function in normal and pathological processes. The focus is on human endogenous retroviruses (HERVs), the remnants of ancient germ-cell infections. Although most of the HERV proviruses have undergone extensive deletions and mutations, some have retained ORFs coding for functional proteins. A few families, including the HERV-K (HML-2) group, have been shown to form viral particles (5, 6), and an apparently intact provirus has recently been discovered in a small fraction of the human population, indicating a very recent acquisition (5-7). Classification of RetroelementsRetroelements constitute 90% of the Ϸ3 million transposable elements present in the human genome (1). They are split into two large groups, the non-LTR and LTR elements (Fig. 1). Two of the non-LTR members are present in extremely high copy numbers in the mammalian germ line: the short interspersed elements (SINE) with the prominent Alu and MIR repeats and the long-terminal interspersed elements (LINE) containing the...

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“…The EVI1/CCR7 gene is important in that human endogenous retrovirus (HERV) peptides in the expression of type 1 cytokine profiles in vitro of peripheral blood mononuclear cells from patients in relapsing phases of MS but not from stable MS patients have been reported. 21 Moreover, LTR16B1 of ERV3 was significantly decreased in serum of patients with relapsing MS. Downregulation of the MS-associated retrovirus has similarly been positively associated in 11 patients with response to treatment with recombinant interferon-␤. 22 Our MSA and comparative analysis of serum DNA has expanded the observation of HERV sequences in MS to include the underexpression of AT_rich repeats and LINE elements L1M5, L1MA4, L1MD, and L1MC compared with the normal database.…”

Section: Discussionmentioning

confidence: 95%

Serum DNA Motifs Predict Disease and Clinical Status in Multiple Sclerosis

Beck¹,

Urnovitz²,

Saresella³

et al. 2010

The Journal of Molecular Diagnostics

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Using recently available mass sequencing and assembly technologies , we have been able to identify and quantify unique cell-free DNA motifs in the blood of patients with multiple sclerosis (MS). The most common MS clinical syndrome , relapsing-remitting MS (RRMS) , is accompanied by a unique fingerprint of both inter-and intragenic cell-free circulating nucleic acids as specific DNA sequences that provide significant clinical sensitivity and specificity. Coding genes that are differentially represented in MS serum encode cytoskeletal proteins, brain-expressed regulators of growth, and receptors involved in nervous system signal transduction. Although coding genes distinguish RRMS and its clinical activity, several repeat sequences, such as the L1M family of LINE elements, are consistently different in all MS patients and clinical status versus the normal database. These data demonstrate that DNA motifs observed in serum are characteristic of RRMS and disease activity and are promising as a clinical tool in monitoring patient responses to treatment modalities.

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Immune responses to antigens of human endogenous retroviruses in patients with acute or stable multiple sclerosis

Cited by 29 publications

References 53 publications

Expression of HERV-Fc1, a Human Endogenous Retrovirus, Is Increased in Patients with Active Multiple Sclerosis

Expression of HERV-Fc1, a Human Endogenous Retrovirus, Is Increased in Patients with Active Multiple Sclerosis

Retroelements and the human genome: New perspectives on an old relation

Serum DNA Motifs Predict Disease and Clinical Status in Multiple Sclerosis

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