Antibody reactivity to the hres‐1 endogenous retroviral element identifies a subset of patients with systemic lupus erythematosus and overlap syndromes

Abstract

Objective. To evaluate the correlation between the presence of antibodies to an endogenous retroviral element-encoded nuclear protein autoantigen, HRES-1, and the presence of other antinuclear antibodies and HLA class I1 alleles in patients with systemic lupus erythematosus (SLE) and overlap syndromes.Methods. Antibody reactivities to native and recombinant proteins and synthetic peptides were assessed by counterimmunoelectrophoresis, enzyme-linked immunosorbent assay, and Western blotting. HLA class I1 alleles were determined by oligonucleotide typing.Results. significant association between anti-HRES-1 and anti-RNP and an inverse correlation between HRES-1 and RolLa autoantibodies in patients with SLE or overlap syndromes. Antigenic epitopes of HRES-1 and the retroviral gag-related region of the 70-kd protein component of U1 small nuclear RNP, which share 3 consecutive highly charged amino acids (Arg-Arg-Glu), an additional Arg, and functionally similar ArgILys residues, represent cross-reactive epitopes between the two proteins. Selective removal of HRES-1 antibodies from sera of HRES-l-seropositive/RNP-seropositive patients by absorption on recombinant HRES-l/glutathione-Stransferase-conjugated agarose beads had no effect on anti-RNP reactivities. A comparative multivariate analysis of HLA class I1 genes revealed a differential segregation of DQBl alleles in HRES-l-seropositive versus HRES-1-seronegative patients (P = 0.04). While a relative increase of DQB1*0402 among HRES-1-seropositive patients was noted across ethnic groups (P = 0.02), a decrease of DQB1*0201 and DQB1*0301 was found in white HRES-l-seropositive patients (P = 0.04).Conclusion. Autoantibodies to HRES-1 are detectable in a distinct subset of patients with autoimmune disease, primarily in those who do not have antibodies to Ro and La. Anti-HRES-1 and anti-RNP reactivities are mediated by cross-reactive but separate antibody molecules. HLA-DQB genes, rather than HLA-DRB or DQA genes, may have a more significant influence on generation of these antinuclear autoantibodies.A hallmark of the destructive autoimmune process in patients with systemic lupus erythematosus

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

“…HRES-1 is a transcriptionally active HERV that encodes a 28 kDa nuclear autoantigen, HRES-1/p28 and a small GTP-ase, HRES-1/Rab4. Autoantibodies to HRES-1/p28, which are found in half of the patients with SLE [23][24][25][26][27], are cross-reactive with antigens of viruses infecting patients with SLE, such as TTV and EBV [71] and the 70 kDa component of U1 snRNP [24] and may thus contribute to epitope spreading and development of anti-nuclear antibody (ANA). In turn, HRES-1/Rab4 regulates the recycling of CD4, a key component of the IS, which is abnormally assembled in T cells of patients with SLE.…”

“…Interestingly, higher expression levels in SLE lymphocytes correlate with production of U1 snRNP [57] which includes a 70 kDa protein with a region of homology to gag antigens of infectious and ERV [24,58]. The 1q42 chromosomal region that has been associated with lupus susceptibility [59] and harbors the HRES-1 ERV [27,60] is genetically unstable [61].…”

“…In addition, TTV cross-reactive lupus sera showed high binding affinity to HRES-1/p28 peptide 121-135 (DRRREGPDRSPRQPP) harboring three consecutive highly charged amino acids (RRE). This RRE triplet is repeated three times in the retroviral gag-like region of 70K U1 snRNP lupus autoantigen and represent crossreactive epitopes between the two proteins [24].…”

Exogenous Factors in Cutaneous Lupus Erythematosus

“…In lupus patients, however, antibody levels to human immunodefi ciency virus type I p24 gag proteins are increased, and endogenous retroviruses are found in sera [65][66][67] . Two studies [66,67] showed a correlation between these antibodies and specifi c antibodies and clinical features (e.g., severe discoid LE). Nevertheless, despite a large number of studies, there is as yet no conclusive evidence to support the direct linkage of LE to endogenous or exogenous retroviruses in humans.…”

Molecular Analysis of Endogenous Retrovirus HRES-1: Identification of Frameshift Mutations in Region Encoding Putative 28-kDa Autoantigen

“…Polyclonal antibodies revealed a 28-kDa protein concordant with the predicted molecular weight of the p25 protein. This product was related to the HRES-1 gag ORF (11).The serum antibody reactivity against the 2 HRES-1 peptides was tested, and the GAG p24 HTLV-1 reactivity, previously observed in autoimmune patient's sera, was subsequently related to anti-HRES-1 antibodies (11)(12)(13).…”