The pathogenesis of lyme neuroborreliosis: from infection to inflammation

Abstract

This review describes the current knowledge of the pathogenesis of acute Lyme neuroborreliosis (LNB), from invasion to inflammation of the central nervous system. Borrelia burgdorferi (B.b.) enters the host through a tick bite on the skin and may disseminate from there to secondary organs, including the central nervous system. To achieve this, B.b. first has to evade the hostile immune system. In a second step, the borrelia have to reach the central nervous system and cross the blood-brain barrier. Once in the cerebrospinal fluid (CSF), the spirochetes elicit an inflammatory response. We describe current knowledge about the infiltration of leukocytes into the CSF in LNB. In the final section, we discuss the mechanisms by which the spirochetal infection leads to the observed neural dysfunction. To conclude, we construct a stringent concept of the pathogenesis of LNB.

Figure 1

Mechanisms of the borrelia to evade the immune system. Borrelia are recognized by immune cells through TLR2 and CD14 and attacked by complement and antibodies. Therefore, the borrelia downregulate their surface proteins, hide in the extracellular matrix, and use complement-neutralizing proteins like Salp, CRASPs, or ISAC/IRAC or induce the formation of immune complexes by secreting soluble antigens to be protected from recognition and subsequent killing.

Figure 2

The inflammatory B-cell response in the CSF in response to the CNS infection. Borrelia are recognized by monocytic cells (1), which produce the B-cell–attracting chemokine CXCL13 (2). B cells immigrate into the CSF (3) and mature to plasma cells (4). These plasma cells can produce B.b.-specific antibodies (5) that can eventually destroy the invaded spirochetes (6).

Figure 3

The neural dysfunction in neuroborreliosis. Three principal mechanisms that lead to the injury of neuronal cells: (1) the secretion of cytotoxic substances by leucocytes and glial cells, (2) direct cytotoxicity, and (3) autoimmune-triggered processes through molecular mimicry.

Figure 4

Borrelia adhere to neuronal cells. Borrelia (arrows) are attached to cells of the neuronal cell line B50. The borrelia (B. garinii) were visualized using an OspA monoclonal antibody.