Antibody-Mediated Disease Remission in the Mouse Model of Lyme Borreliosis

Abstract

In the mouse model of Lyme borreliosis, the host immune response during infection with Borrelia burgdorferi results in the remission of carditis and arthritis, as well as global reduction of spirochete numbers in tissues, without elimination of infection (28). These events were recapitulated by passive transfer of immune serum from infected immunocompetent mice or T-cell-deficient mice to severe combined immunodeficient (SCID) mice. Previous studies have shown that immune serum is reactive against arthritis-related protein (Arp) and that Arp antiserum induces arthritis remission (16). However, although immune serum from T-cell-deficient mice induced disease remission, it was not reactive against Arp, suggesting that antibody to another antigen may be responsible. T-cell-deficient mouse immune serum was reactive to decorin binding protein A (DbpA). Therefore, DbpA antiserum was tested to determine its ability to induce disease remission in SCID mice. Antisera to Arp or DbpA induced both carditis and arthritis remission but did not significantly reduce spirochete numbers in tissues, based upon quantitative flaB DNA analysis, nor did treatment affect RNA levels of several genes, including arp and dbpA. Immunohistochemical labeling of spirochetes in hearts and joints during disease remission induced by adoptive transfer of lymphocytes, passive transfer of immune serum, or passive transfer of DbpA antiserum revealed that such treatment resulted in elimination of spirochetes from heart base and synovium but not vascular walls, tendons, or ligaments. These results suggest that Arp and DbpA antibodies may be active as disease-resolving components in immune serum but antibody against other antigens may be involved in reductions of spirochetes in tissues.Lyme borreliosis, caused by tick-borne Borrelia burgdorferi, has numerous clinical manifestations in humans, including arthritis and carditis, which undergo remission and periodic bouts of exacerbation over the course of months to years of persistent infection (42). Laboratory mice inoculated with B. burgdorferi also develop arthritis and carditis, which evolve over the course of three weeks and then undergo immunemediated remission and recurrence during persistent infection

CD4+T Cells Promote Antibody Production but Not Sustained Affinity Maturation during Borrelia burgdorferi Infection

“…IgG responses to DbpA appeared T independent, while BmpA-IgG responses were somewhat increased in CD4 T-deficient mice. Consistent with these data, a previous study with T cell-deficient TCR␤/␦ Ϫ/Ϫ mice also found a lack of T dependence of the DbpA response (20). Furthermore, repeated immunization with recombinant DbpA from cN40 failed to induce measurable CD4 T cell responses (data not shown).…”

“…DbpA-specific T cell-independent antibodies served as a control (Fig. 1C) (8,20). We utilized a method for detecting changes in the overall avidity of B. burgdorferi antigen-specific serum antibodies over time by comparing antibody binding after high-and low-stringency washes.…”

“…B cell responses are crucial for host defense against many extracellular pathogens (33), including infections with B. burgdorferi (20,34). B. burgdorferi-specific antibodies reduce B. burgdorferi tissue burden and disease manifestations, such as arthritis, myocarditis, and neuroinflammation (1-3, 20, 34).…”

“…Indeed, previous studies identified Arthritis-related protein (Arp; GenBank accession no. AF050212) of B. burgdorferi N40 to be dependent on conventional T cell help in C57BL/6 mice (20). Such antibodies were shown previously to resolve arthritis development (21).…”

CD14 Signaling Reciprocally Controls Collagen Deposition and Turnover to Regulate the Development of Lyme Arthritis

“…The ability of spirochetes to embed themselves in dense collagen bundles may offer protection from both antibodies and antibiotics. [52][53][54][55] Putting all this information together, we can speculate that CD14 not only helps in the activation of MMP-9 necessary for degradation of existing collagen but also may limit the continued production of collagen. Control of these fibrotic processes by CD14 not only leads to higher neutrophil recruitment and clearance of spirochetes but also deprives B. burgdorferi of "hide-outs" within joints.…”