PATHOGENESIS, PATHOLOGY AND IMMUNITY

The amount of LBS traveling through the salivary glands and invading the dermis is regarded to be relatively low, although exact knowledge of the size of the inoculum does not exist⁽²⁶⁾.

Once established in the feeding pool, the LBS multiply and start to spread outwards and downwards in the sur­rounding dermis with the help of their motility, moving through the extracellular matrix (ECM) with a speed up to 4 μm∕s and having a tendency to localize in perivascular connective tissue⁽⁴⁷⁾. The migration triggers local inflam­matory responses by macrophages and dendritic cells and, as the acquired immune response comes into play, also specific T cells, resulting in the classic lesion of erythema migrans (EM). Concurrently, the spirochaetes invade blood vessels and are disseminated through the body of their host.

After the host’s adaptive immune response becomes effective, the LBS disappear from the bloodstream and disseminate to various locations — typically the joints, tendons, fasciae, heart, muscle, urinary bladder, dermal and neural tissues. Here, they ‘hide’ in connective tissue with the help of multiple surface proteins that mediate binding to collagens and other components of the ECM. Some spirochaetes may also be found intracellularly in certain cells. These mechanisms are thought to help the LBS to escape from immune responses and thereby facili­tate long-lasting persistence and possibly protection against antibiotics(^46,48).

I n addition to the spreading through the circulation, some authors suggest that LBS also disseminate by migra­tion through connective tissue, i.e. along blood-vessel walls and perineural sheaths.

The inflammatory manifestations associated with LB result from the host’s innate and adaptive immune responses to the spirochaetes, as LBS do not have the ability to produce toxigenic molecules. The pathogenesis of the infection is linked to the genetic background of the vertebrate host and to the genotype of B. burgdorferi sl.(¹⁶).

Neurological complications in LB often result from inflammation of blood vessels supplying nerve roots and peripheral nerves in combination with the effect of the invasion of brain parenchyma(²⁶).

Acute Lyme arthritis in mice and humans results from the borrelia-induced infiltration of mononuclear cells into the synovial tissue and release of inflammatory cells and mediators to the joint cavity. It may manifest as a rather uncomplicated inflammatory arthritis without erosive damage in cartilage or synovium. In some cases the arthri­tis persists for longer periods, bearing many similarities to rheumatoid arthritis.

Lesions of LB in wild animals may be expected to share many similarities with human lesions. However, chronic skin manifestations have to our knowledge not been reported in any non-primate species. EM in humans and rabbits is an expanding, annular, erythematous skin lesion with central clearing, histologically characterized by mild superficial perivascular infiltration of the dermal intersti- tium, mainly by T lymphocytes. The human borrelial lymphocytoma consists of dense dermal infiltrates of B lymphocytes and some plasma cells centred around vessels, sweat glands and nerves. The appearance may resemble a cutaneous lymphoma. In human achrodermatitis chronica atrophicans the epidermis is frequently thinned and there is oedema and a perivascular lympho- /plasmacytic infil­trate in the superficial dermis, often accompanied by dilated blood vessels.

In humans with meningoradiculoneuritis, lymphocytic involvement of the leptomeninges, ganglia and afferent and efferent rootlets is present and a focal microglial reac­tion may be evident. In experimentally infected dogs multifocal non-suppurative meningitis, encephalitis, perineuritis and periarteritis have been found.

Histopathologic findings in Lyme carditis in primates and mice include interstitial lympho- /plasmacytic endo- carditits, myocarditis and pericarditis. The conducting system may reveal localized oedema and mild lymphocytic infiltrations of sinoatrial and atrioventricular nodes. Skel­etal myositis with infiltration of connective tissue with mononuclear leucocytes is found in several animal models of LB.

In joints with Lyme arthritis, non-specific synovitis with lymphocytic/plasmacytic infiltration, often in pseudo- follicular structures, is typically found. Exudation of neu­trophilic granulocytes and fibrin into synovial cavities often occurs. In more chronic cases the synovial villi become hypertrophic, but the disease seldom progresses to pannus formation and erosion of cartilage.

LBS may be visualized in histological sections by Giemsa, carbol-fuchsin or silver staining methods, or immunohis­tochemical or in situ hybridization techniques.

Adaptive immunity has a critical role in the control and resolution of disease. The response develops rather slowly (3—6 weeks in humans) and is directed against an increas­ingly diverse array of proteins as the infection progresses. LBS disappear from the circulation when the specific anti­body response comes into play. The protective immunity is, however, strain-specific, and spirochaetes can persist despite high titres of circulating antibodies when dissemi­nation has occurred. Relapses of disease may also occur in spite of seemingly good protection. IgG may also contrib­ute to disease pathogenesis by increasing the severity of inflammation. A variety of innate and adaptive T-cell subsets also participate in the immune response to B. burgdorferi, although their roles remain poorly defined.