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The versatile roles of antibodies in Borrelia infections

Nature Reviews Microbiology volume 3, pages 411–420 (2005)Cite this article

Key Points

The tick-borne borreliae are the causative agents of relapsing fever and Lyme disease worldwide. Borrelia spirochaetes are motile, helical, microaerophilic organisms that have flagellae located within the periplasmic space, a defining characteristic of spirochaetes. The outer membrane has surface-exposed lipoproteins, which are major determinants of immunogenicity. The clinical manifestations of Lyme disease and relapsing fever can be similar, particularly those involving the central nervous system, joints and heart. Lyme disease lacks the marked and recurrent spirochaetaemia of relapsing fever, which is a more severe and rapidly developing disease. The genome of the Lyme disease spirochaete B. burgdorferi strain B31 has been sequenced and the genetic manipulation of this spirochaete has only very recently become technically feasible.

Specific antibodies fix complement on the surface of microorganisms and are typically thought to contribute significantly to the removal of microorganisms. However, although Borrelia can activate the classical and alternative pathways of the complement cascade in normal serum, many species are resistant to complement-mediated lysis. The basis of this resistance is the inactivation of complement components, which results from the binding of complement inhibitors to multiple outer-membrane proteins. Despite this evasion, circulating phagocytic cells, polymorphonuclear leukocytes and monocytes readily ingest and kill B. burgdorferi in a manner that is independent of opsonization with either antibody or complement. The spirochaetes can be killed by these cells through multiple oxygen-dependent and -independent mechanisms.

Based on the effectiveness of the antibody response to OspA that is seen in animal studies, a commercial recombinant lipidated OspA vaccine was created and sold in the United States. Although this vaccine was considered effective, indications of cross-reactivity of OspA with self-antigens limited confidence in the product. Furthermore, some antibodies to the vaccine had been shown to correlate with severe and prolonged arthritis, further prompting concerns about autoreactivity. As an additional impediment, not all vaccinated individuals developed strong immunity due to apparent signalling defects in Toll-like-receptor pathways. The vaccine has since been withdrawn from the market.

The importance of antibodies in controlling spirochaetal infections was underscored by the discovery of antibodies with directly bactericidal properties that do not require the participation of complement. The murine monoclonal antibody CB2, which is specific for OspB of B. burgdorferi, was bactericidal in the absence of complement. Agglutination is not involved, as monovalent Fab fragments also had bactericidal activity. Whereas this antibody does not show proteolytic activity against OspB, there are indications that structural changes occur in the antigen following antibody binding. Since this discovery, other complement-independent bactericidal antibodies that recognize surface-exposed proteins of different Borrelia spirochaetes have been reported.

IgM has been shown to be particularly crucial in the resolution of spirochaetaemia. The persistence of spirochaetes in the blood during the experimental infection of SCID, B-cell-deficient and secreted IgM (sIgM)-deficient mice demonstrates the absolute requirement for antibodies in resolving the infection. By contrast, the resolution of the initial peak of spirochaetaemia does not require the participation of T cells as nude, thymectomized or T-cell-depleted mice eliminate the spirochaetaemia as effectively as wild-type mice. The dispensable role of T cells in the resolution of spirochaetaemia was only recently fully addressed by experiments showing the ability of α/β-T-cell-deficient and α/β- and γ/δ-T-cell-deficient mice to clear the spirochaetaemia of relapsing fever.

Although there is undoubtedly a role for natural IgM in the immune response to Borrelia, in vivo demonstration of the infection-induced generation and specificity of a complement-independent bactericidal IgM argues that these antibodies comprise a different subset. This type of response is slowly gaining recognition as 'natural memory' that blurs the boundary between the innate immune response and the adaptive immune response.

The role of antibodies in defence against microorganisms has acquired increased significance in light of new and renewed microbial threats, both natural and man-made. Our findings, however, have uncovered a crucial role for an overlooked area of host defence and expand the increasingly versatile array of known antibody effector functions. Given the role of directly bactericidal antibodies in the tick-borne borrelioses, as well as the ability of antibodies to generate bactericidal products non-specifically, the expanding repertoire of antibody function in host defence will require inclusion of the direct bactericidal activity of antibodies.

Abstract

Antibodies are the primary weapons of the mammalian immune system that are used against the tick-borne borreliae, the causative agents of relapsing fever and Lyme disease worldwide. Some antibody responses have 'traditional' functions, whereas others are more versatile and have novel functions and modes of action. At a time when the multiple functions of antibodies are being increasingly recognized and passive immunization is being revived as therapy for infectious and other diseases, the versatile nature of the antibody response to the borreliae fits well with this antibody renaissance.

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Figure 1: The enzymatic cascade of the complement system is initiated by three distinct pathways.
Figure 2: The importance of B cells in spirochaete infection.
Figure 3: CB515 disrupts the bacterial outer membrane in the absence of complement.

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Acknowledgements

The authors are supported by grants from the National Institute of Allergy and Infectious Diseases and the Mathers Foundation.

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  1. Sean E. Connolly

    Present address: Yale University School of Medicine, Section of Immunobiology, 300 Cedar Street TAC S540, New Haven, CT, 06520, USA

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  1. Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, 11794-5120, USA

    Sean E. Connolly & Jorge L. Benach

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DATABASES

Entrez

Borrelia burgdorferi

Mac-1

OspA

OspB

Staphylococcus aureus

Vmp24

West Nile virus

Glossary

INNATE IMMUNITY

Innate immunity comprises immediate responses that are generated without the requirement for memory of, or prior exposure to, the pathogen.

ACQUIRED IMMUNITY

The antigen-specific response of T and B cells, which requires exposure to, or memory of, a pathogen. Includes antibody production and the killing of pathogen-infected cells.

TOLL-LIKE RECEPTORS

(TLRs). A rapidly growing family of receptors that recognize pathogen-associated molecular patterns that are common to large groups of microorganisms and/or viruses.

CD59

A mammalian cell-surface protein that can prevent the formation of the MAC by binding C8 and C9.

POLYMORPHONUCLEAR LEUKOCYTES

White blood cells that include neutrophils, eosinophils and basophils.

MONOCYTE

An intermediate cell type in the pathway leading from a myeloid precursor to a differentiated macrophage.

OPSONIZATION

A modification to the cell surface of a microorganism — typically the deposition of complement components or the binding of antibody — that facilitiates its ingestion by phagocytes.

DEFENSINS

Small (2–6 kDa) cationic microbicidal peptides produced by immune cells as part of the innate immune response.

ELASTASE

A trypsin-like enzyme in the granules of neutrophils.

FAB FRAGMENT

The light chain and N-terminal half of the heavy chain of an antibody after digestion by the enzyme papain. The Fab contains the antigen-binding domain of the antibody, but does not agglutinate or interact with immune cells.

PASSIVE IMMUNIZATION

Transfer of either specific antibody or immune serum into a naïve patient, thereby providing an immediate immune response to a microorganism.

CONGENIC

A strain that is produced by repeated backcrosses to an inbred strain with selection for a particular marker or chromosomal region from a donor strain.

RETICULOENDOTHELIAL CELLS

All of the phagocytic cells in the body, particularly the macrophages of the spleen, liver, and other tissues.

HOLINS

Small peptides encoded by bacteriophages that are used to penetrate the cell wall of bacteria.

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Connolly, S., Benach, J. The versatile roles of antibodies in Borrelia infections. Nat Rev Microbiol 3, 411–420 (2005). https://doi.org/10.1038/nrmicro1149

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