Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase

Abstract

Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candi- Lyme disease is caused by the tick-borne spirochete Borrelia burgdorferi and can involve multiple organs including the joints, heart, skin, and nervous system. 1 Lyme arthritis is a consequence of bacterial invasion of joint tissue and results from localized inflammation triggered by persistent infection. 2,3 Arthritis develops weeks to months after transmission from an infected tick and is characterized by edema, inflammatory cell infiltration, and hyperproliferation of synovium. 1,4,5 In most individuals, arthritis will resolve after clearance of the bacteria, however, a subset of individuals with the most severe inflammatory arthritis have been documented to develop treatment-resistant arthritis that does not respond to antibiotic therapy. 6,7 It is suspected that in these individuals progression to an autoimmune-mediated arthritis more similar to rheumatoid arthritis has occurred. Susceptibility to treatment-resistant arthritis is associated with HLA-DR1*0401, a major histocompatibility complex (MHC) class II allele also associated with rheumatoid arthritis. 6,8,9 These studies suggest that there are two distinct stages of Lyme arthritis; an acute inflammatory arthritis dependent on bacterial invasion and persistence in joint tissues and a chronic, treatment-resistant arthritis that may represent a transition to a rheumatoid-like disease.

Interval-Specific Congenic Lines Reveal Quantitative Trait Loci with Penetrant Lyme Arthritis Phenotypes on Chromosomes 5, 11, and 12

“…We reported previously that penetrant Lyme arthritis phenotypes were seen in reciprocal Bbaa2-Bbaa3 ISCL (12). Compared to B6 mice, B6.C3-Bbaa2-Bbaa3 mice displayed increased arthritis severity at 4 weeks following B. burgdorferi infection, whereas C3.B6-Bbaa2-Bbaa3 mice had less severe arthritis than infected C3H mice.…”

The expanding role of NADPH oxidases in health and disease: no longer just agents of death and destruction

“…In support of these observations, pharmacological agents that destroy or inhibit the production of ROS, such as apocynin [186,187], methotrexate [188] and DPI (diphenyleneiodonium) [189], can suppress the development of inflammation and symptoms associated with arthritis. In contrast, Crandall et al [190] recently reported that the pathogenesis of Lyme arthritis is independent of NADPH oxidase activity. Thus the role of NADPH oxidase in arthritis appears to be complex and may depend on the type of disease.…”

IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses

“…Studies using genetically modified mice indicate that manipulation of many host cytokines known to have dramatic effects on clearance of other bacterial pathogens, such as IL-4, IFN-␥, and IL-12, did not produce statistically significant effects on spirochetal clearance (54 -56). Similarly, mice deficient in their abilities to generate NO or reactive oxygen intermediates develop tissue pathology and bacterial loads similar to those in wild-type mice (57)(58)(59), suggesting that these vital components of phagocyte-mediated host defenses are not of central importance for controlling B. burgdorferi numbers in vivo.…”