Mechanisms of Dysregulated Antibody Response in Lyme Disease

Abstract

Lyme disease (LD), caused by the spirochetal bacterium Borrelia burgdorferi, is transmitted by the black-legged tick Ixodes scapularis (Hu, 2016). LD is the fastest growing global tick-borne disease and annually affects >300,000 people in the U.S. alone (Steere et al., 2016). The economic impact is a staggering $1.3 billion dollars per year (Adrion et al., 2015). LD can cause long-term, debilitating symptoms, including arthritis, carditis, and neurological complications (Hu, 2016; Steere et al., 2016). A longstanding question is why antibodies produced during primary infection are not able to completely clear spirochetes or confer protective immunity (Barbour et al., 2008). Antibody titers can remain for years in some LD patients while in others, they wane over time or never develop at all (Kalish et al., 2001). Herein, we describe animal studies that reveal mechanisms behind dysregulated development of adaptive immunity and provide insights that may be relevant to human immunity to B. burgdorferi infection. Antibodies produced through B and T cell interactions either within or outside germinal centers are termed T cell-dependent (TD) whereas those produced without the aid of T cells are T cell-independent (TI). One mechanism whereby B. burgdorferi attempt to evade adaptive immunity is by continuously changing the sequence of a unique surface protein called variable major protein-like sequence (VlsE) (Norris, 2015). Such sequence variation generates a large repertoire of antigenically-distinct spirochetes that become unrecognizable to the antibodies that are mounted against a previous version of this protein. This may allow B. burgdorferi to persist for months or years if not effectively cleared through innate immune response and/or early diagnosis and treatment with antibiotics. Another defensive strategy relies on switching which immunogenic proteins are surface expressed [e.g., Outer Surface Protein A (OspA) and OspC], as spirochetes transit from one environment to another. OspA and OspC are predominately expressed when spirochetes are in the tick vs. the mammalian host, respectively. Notably, whole-proteome microarray analysis revealed that while relatively few B. burgdorferi open reading frames (~15%) encode immunogens, those that do elicit the same detectable antibodies in naturally infected humans and wild white-footed mice (Peromyscus leucopus), the predominant maintenance reservoir for B. burgdorferi (Barbour et al., 2008). Interestingly, a spectrum of disease severity has been observed in different mouse strains, reflecting their unique genetic composition, which controls the magnitude of humoral responses during B. burgdorferi infection (Weis et al., 1999). Despite strong antibody responses in animals experimentally-infected with B. burgdorferi and in many LD patients, this does not translate to robust disease-resolving and long-term immunity (Barthold and Bockenstedt, 1993; Aguero-Rosenfeld et al., 1996). In order to explore the mechanisms through which B. burgdorferi infection impacts the immune system and gain an understanding of the role of B and T cells in LD pathogenesis, researchers have conducted studies in mice lacking either or both of these lymphocyte populations. Pathologies associated with B. burgdorferi infection of mice often spontaneously resolve, although animals may never completely clear spirochetes. In contrast, after infection with B. burgdorferi, severe combined immunodeficient (SCID) and recombination activating gene (RAG)-deficient mice, both of which lack B and T cells, developed severe, persistent arthritis that remained unresolved (Hastey et al., 2012). While B cells regulate disease progression and resolution in wild-type mice (McKisic and Barthold, 2000), adoptive transfer of CD4+ T cells into RAG-deficient mice prior to B. burgdorferi infection increased arthritis and carditis severity (unless B cells were co-transferred), and CD8+ T cell transfer increased arthritis severity (McKisic et al., 2000). Conversely, adoptive transfer of serum from immunocompetent B. burgdorferi-infected mice into SCID mice ameliorated both arthritis and carditis (Barthold et al., 1997; McKisic and Barthold, 2000). Transfer of immune serum into naive recipient mice either prior to or at the time of inoculation also prevented B. burgdorferi infection (Barthold et al., 1997). Immunization of mice with late-stage LD patient sera that demonstrated strong antibody reactivity to several B. burgdorferi proteins, including OspA and B, provided partial protection against B. burgdorferi challenge (Fikrig et al., 1994). These findings reveal that humoral immune responses generated in experimentally-infected mice and LD patients play an important role in the resolution of some of the most commonly reported clinical manifestations (arthritis and carditis), which are driven principally by activation of inflammatory T cells and release of potent inflammatory mediators. Researchers found unusually strong and persistent TD and TI IgM antibody production in lymph nodes during early infection and in bone marrow later on in the course of murine infection (Hastey et al., 2012; Richards et al., 2015). IgG-secreting plasma cells, on the other hand, accumulate slowly in the bone marrow. Only about 50% of the IgG response is clearly TD and, coupled with IgM, is thought to contribute to the reduction but not elimination of B. burgdorferi from tissues (Hodzic et al., 2003). This TD repertoire of IgG contributes minimally to long-term antibody-mediated immunity, unlike the typical humoral response to bacterial pathogens (Hastey et al., 2012; Tracy and Baumgarth, 2017). To dissect the mechanisms behind this dysregulated response, Hastey et al. (2012) elucidated distinct stages of altered immune response using a mouse model of LD. In the first phase of...