A Novel Autoantibody Induced by Bacterial Biofilm Conserved Components Aggravates Lupus Nephritis

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple autoantibody production and often affects the kidneys, known as lupus nephritis. However, the mechanism underlying lupus nephritis development is unclear. Biofilms that protect bacteria from stress are ubiquitous in almost every environment. Here, we identified that a conserved peptide (HU1) derived from DNABII proteins, one of major bacterial biofilm components, was specifically recognized by sera from about 47% patients with SLE. Moreover, the serum anti-HU1 levels showed a significant positive correlation with lupus nephritis occurrence. Presence of antibodies against HU1 in pristane-induced mice aggravated lupus nephritis, although these antibodies also attenuated bacterial biofilm formation. We further identified that antibodies against HU1 cross-recognized protein disulfide isomerase (P4HB) located on the renal cell surface and inhibited the activities of this enzyme. Our findings reveal a novel mechanism underlying the development of lupus nephritis triggered by bacterial biofilms.

Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus: Novel Insights into Mechanisms and Promising Therapeutic Strategies

“…Biofilms are considered to be a membrane in which the bacterial community produces an extracellular matrix and wraps itself (53), which can protect bacteria from the host immune response (54) and enable bacteria to develop drug resistance (55). The main structure of biofilms is amyloid protein rich in b-folding, which is associated with human autoimmune diseases (56)(57)(58). Curli fibrils in Salmonella enterica serovar Typhimurium (S. Typhimurium) amyloid could combined to the DNA in bacterial, and these complexes could promote biofilm formation, also contributing to SLE pathogenesis (57).…”

“…The above two studies suggest that bacterial proteins that interact with DNA may cause loss of immune tolerance to autoantigens and induce the production of autoantibodies, leading to SLE pathogenesis. Interestingly, a recent study by Fu et al (58) suggested that DNABII proteins interacting with DNA in biofilms may not directly contribute to anti-dsDNA production but other mechanisms may be involved. Sera from patients with SLE specifically recognize the DNAB II protein-derived HU1 peptide in bacterial biofilms.…”

“…Interestingly, a recent study by Fu et al. ( 58 ) suggested that DNABII proteins interacting with DNA in biofilms may not directly contribute to anti-dsDNA production but other mechanisms may be involved. Sera from patients with SLE specifically recognize the DNAB II protein-derived HU1 peptide in bacterial biofilms.…”

“…Anti-HU1 aggravates the progression of lupus nephritis (LN) in patients with SLE and a pristane-induced lupus murine model. Although anti-HU1 antibodies can inhibit biofilm formation by Staphylococcus aureus , it is accompanied by cross-reactivity with the autoantigen P4HB on the glomerular cell membrane to induce LN ( 58 ).…”

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

“…The cross-reactivity of P4HB with anti-DENV nonstructural protein 1 (NS1) antibodies may play a role in DENV infection-induced autoimmunity [ 108 ]. In some SLE patients, antibodies against the HU1 bacterial peptide recognized P4HB as an autoantigen on the membrane of renal cells, inducing lupus nephritis [ 109 ]. Thus far, polymorphisms in P4HB have not been related to complex diseases.…”