RESUMO
BACKGROUND: Two endogenous retroviral loci seem to be involved in the human disease Multiple sclerosis (MS). RESULTS: The two retroviral loci synergize in and contribute to MS (shown by ANOVA). Synergy probably means recombination or complementation of the activated viruses. Similar observations may be true for Type 1 Diabetes and Rheumatoid arthritis. In MS the genes also synergize with the immune system; this could well be a common phenomenon. CONCLUSION: We formulate various theories about the role of the viruses. Also, the concept is developing that some forms of autoimmunity should be treatable with antiretrovirals. In the case of MS, this idea is gradually gaining weight.
Assuntos
Retrovirus Endógenos/genética , Esclerose Múltipla/genética , Diabetes Mellitus Tipo 1/genética , HumanosRESUMO
The possibility that retroviruses play a role in multiple sclerosis (MS) has long been considered; accumulating findings suggest this to be most likely in the form of human endogenous retroviruses (HERVs). A genetic test series of fifty endogenous retroviral loci for association with MS in Danes showed SNP markers near a specific endogenous retroviral locus, HERV-Fc1 located on the X-chromosome, to be positive. Bout Onset MS was associated with the HERV-Fc1 locus, while a rarer form, Primary Progressive MS, was not. Moreover, HERV-Fc1 Gag RNA in plasma was increased 4-fold in patients with recent history of attacks, relative to patients in a stable state and to healthy controls.Finally, genetic variations in restriction genes for retroviruses influence the risk of MS, providing further support for a role of retroviral elements in disease.We speculate that endogenous retroviruses may activate the innate immune system in a variety of ways, involving the host proteins, TRIMs, TLRs, TREXs and STING. Observations in HIV-positive patients suggest that antiretroviral drugs can curb MS. Thus, these new findings regarding the etiology and pathogenesis of MS, suggest alternative ways to challenge autoimmune diseases.
Assuntos
Retrovirus Endógenos/genética , Retrovirus Endógenos/patogenicidade , Esclerose Múltipla/genética , Fatores de Restrição Antivirais , Proteínas de Transporte/genética , Marcadores Genéticos , Humanos , Esclerose Múltipla/virologia , Proteínas com Motivo Tripartido , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: Human endogenous retroviruses (HERVs) are suspected to play a role in the development of multiple sclerosis (MS). This suspicion has in part been based on increased expression of viral RNA or proteins or antibodies targeting retroviral products in MS patients. Recently, our group provided genetic evidence for association between the endogenous retrovirus HERV-Fc1 and MS, suggesting that HERV-Fc1 plays a role in this multifactorial disease. We have found increased expression of HERV-Fc1 in MS patients suffering from recent attack, but the underlying mechanism for association is still unknown. FINDINGS: Evidence from animal models indicates that ERV implication in the pathogenesis of diseases can be a result of extra copies of the virus in the germ line. Therefore, we investigated the genome of 81 individuals, 74 patients with MS and 7 healthy controls, by means of Southern blotting, for presence of extra HERV-Fc1 copies. The known insertion at the Xq21.33 position was readily detectable, but no additional insertions in other genomic contexts could be identified in any studied individuals. This substantiates our previous copy-number PCR findings of a 2:1 ratio of HERV-Fc1 DNA between women and men, as expected from the X-chromosome location; there was no difference between patient and control individuals. CONCLUSIONS: No additional germ line copies of HERV-Fc1 could be identified, precluding such copies to underlie the association between this provirus and multiples sclerosis.
Assuntos
Variações do Número de Cópias de DNA , Retrovirus Endógenos/genética , Células Germinativas/patologia , Células Germinativas/virologia , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Southern Blotting , Feminino , Humanos , MasculinoRESUMO
We studied the importance of certain polymorphisms on human chromosome 19q13.3 for drug sensitivity in human tumor cell cultures. NCI60 is a panel of 60 established tumor-derived cell lines, which have been tested for their sensitivity to tens of thousands of different drugs. Here we investigate the correlations between the responses of the NCI60 cells to different anticancer drugs and their respective alleles of five DNA polymorphisms located in a cancer-related chromosomal area. One polymorphism, located in the 5' noncoding region of the gene ASE-1, alias CD3EAP, proved to be associated with drug sensitivity (P = 0.025). The same polymorphism has previously been associated with treatment response of multiple myeloma after bone marrow ablation. The polymorphism ASE-1-e1 was of importance for the drug response in the human cancer cell lines investigated and could eventually become important for individualized drug treatment in humans.
Assuntos
Linhagem Celular Tumoral/efeitos dos fármacos , Cromossomos Humanos Par 19/genética , Resistencia a Medicamentos Antineoplásicos/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Cromossomos Humanos Par 19/ultraestrutura , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Éxons/genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , RNA Polimerase I , Proteínas RepressorasRESUMO
Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte antigens is reported for multiple sclerosis. We speculate the possibility that recombinants or mixed viral particles are formed and that the resulting viruses stimulate the innate immune system, thereby initiating the autoimmune response.
Assuntos
Artrite Reumatoide/virologia , Diabetes Mellitus Tipo 1/virologia , Retrovirus Endógenos/genética , Loci Gênicos , Esclerose Múltipla/virologia , Proteínas Virais/genética , Artrite Reumatoide/genética , Autoimunidade , Diabetes Mellitus Tipo 1/genética , Feminino , Redes Reguladoras de Genes , Estudos de Associação Genética , Marcadores Genéticos/genética , Predisposição Genética para Doença , Genótipo , Humanos , Imunidade Inata , Masculino , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We recently described that the autoimmune, central nervous system disease, multiple sclerosis (MS), is genetically associated with the human endogenous retroviral locus, HERV-Fc1, in Scandinavians. A number of dominant human genes encoding factors that restrict retrovirus replication have been known for a long time. Today human restriction genes for retroviruses include amongst others TRIMs, APOBEC3s, BST2 and TREXs. We have therefore looked for a role of these retroviral restriction genes in MS using genetic epidemiology. We here report that markers in two TRIMs, TRIM5 and TRIM22 and a marker in BST2, associated statistically with the risk of getting MS, while markers in or near APOBEC3s and TREXs showed little or no effect. This indicates that the two TRIMs and BST2 influence the risk of disease and thus supports the hypothesis of a viral involvement.
Assuntos
Esclerose Múltipla/genética , Retroviridae/genética , Desaminases APOBEC , Fatores de Restrição Antivirais , Proteínas de Transporte/genética , Citidina Desaminase , Citosina Desaminase/genética , Retrovirus Endógenos/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Antígenos de Histocompatibilidade Menor , Proteínas Repressoras/genética , Proteínas com Motivo Tripartido , Ubiquitina-Proteína LigasesRESUMO
We have previously described the occurrence of multiple sclerosis (MS) to be associated with human endogenous retroviruses, specifically the X-linked viral locus HERV-Fc1. The aim of this study was to investigate a possible association of the HERV-Fc1 locus with subtypes of MS. MS patients are generally subdivided into three categories: Remitting/Relapsing and Secondary Progressive, which together constitute Bout Onset MS, and Primary Progressive. In this study of 1181 MS patients and 1886 controls we found that Bout Onset MS was associated with the C-allele of the marker rs391745 near the HERV-Fc1 locus (pâ=â0.003), while primary progressive disease was not. The ability to see genetic differences between subtypes of MS near this gene speaks for the involvement of the virus HERV-Fc1 locus in modifying the disease course of MS.
Assuntos
Retrovirus Endógenos/genética , Marcadores Genéticos , Esclerose Múltipla/genética , Sequência de Bases , Primers do DNA , Genes Ligados ao Cromossomo X , Humanos , Esclerose Múltipla/classificaçãoRESUMO
We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis.