PATHOGENESIS

The pathogenesis of Lyme disease shows a correlation in its early stages with levels of viable bacteria at the site/s of inflammation. In the later stages, however, it exhibits hallmarks of an autoimmune disease.

OspC, Dbp and Erythema Migrans

As was discussed above, the ospC locus varies considerably between strains of B. burgdorferi . Studies have shown that only a few particular sequences of the OspC protein are associated with disseminated disease. The development of the characteristic bulls-eye lesion, erythema migrans, is a result of the spirochete migrating through dermal tissue and other tissue matrices. This migration is accomplished by binding to human plasminogen, which is the precursor of plasmin (or fibrinolysin), a proteolytic enzyme that dissolves the fibrin in blood clots.

Homing of B. burgdorferi to specific tissues is mediated by binding to specific host integrins and extracellular matrix proteins. For example: Dbp, or decorin-binding protein, a protein expressed by B. burgdorferi , allows it to bind host decorin molecules. Decorin is a glycosaminoglycan (a polysaccharide containing amino sugars, often complexed with a protein) associated with collagen: it is found in various tissue, including skin and joints.

OspA, Molecular Mimicry, and the Induction of Autoimmunity

It has been demonstrated that antibodies raised against epitopes of OspA are cross-reactive with neural tissue antigens. Analysis with cDNA sequences from brain tissue has allowed researchers to identify three identical sequences on the OspA protein. Two of these sequences appear to function as cross-reactive epitopes, and immunohistochemical tests have shown these cross-reactive epitopes are present in neurons of the brain, spinal chord and dorsal root ganglia. [9]

IMMUNE EVASION MECHANISMS 

Inactivation of Complement

For any systemic pathogen to successfully establish infection in a mammalian host, it must first overcome the barriers of the innate immune system that are present in serum. A particularly powerful component of the innate immune system is the complement system, a set of serum proteins that, when activated—either by antibody-antigen complexes, by PAMPs (pathogen-associated molecular patterns), or by lectins—can lead to formation of a “membrane attack complex” and subsequently to lysis of the pathogen. Below these three pathways are outlined. Note that all three converge on the molecule C3.

The Classical, Alternative, and Lectin Complement activation pathways and the effect of Factor H on the alternative pathway complement cascade..

Pathway showing Borrelia's resistance to complement activation.

Borrelia burgdorferi has at its disposal two classes of molecules—the Erps (Osp E /F- r elated p roteins) and the CRASPs (complement acquiring surface proteins) which allow it to evade the complement system. Erps and CRASPs, which are membrane-bound molecules, bind certain key components of the complement system, Factor H and FHL-1, respectively. [6]

Recombination of the variable major protein like sequence (vls) gene locus

The vls locus, which maps to the linear plasmid lp28-1 (discussed above), encodes a 35-kDA surface lipoprotein with six variable regions that shield the conserved regions from the immune system. The function of the protein is still undetermined, but it is thought to be important in immune evasion, since loss of lp28-1 leads to decreased infectivity in mammalian hosts.

The vls locus consists of the vlsE expression site and 15 silent cassettes arranged in tandem. A gene conversion event inserts segments of the 15 silent cassettes into the expression site, leading to the expression of a new variant of the 35-kDa lipoprotein. It is thought that the (humoral) immune system can not keep up with this mechanism of antigenic variation, which permits B. burgdorferi to establish persistent infection. [7]

Horizontal gene transfer by bacteriophages

The cp32 circular plasmid encodes a bacteriophage that participates in transfer of genetic information from one strain of B. burgdorferi to another. This genetic exchange is thought to play a role in the generation of new antigenic variants. Horizontal/lateral transfer by the cp32 phage has been demonstrated not only in B. burgdorferi sensu stricto, but also between the three members of B. burgdorferi sensu lato, and even between these and other members of the Borrelia genus that do not cause Lyme disease. [8]