David Zagzag - Interview

Lyme Disease Picture of David Zagzag"Lyme borreliosis, caused by infection of the spirochete Borrelia burgdorferi, is a multi-system disorder usually contracted by a tick bite," explains Dr. Zagzag. "The disease has three typical stages.

"First, constitutional upset and rash (erthema migrans); second, carditis, arthritis and a meningopolyneuritis; and last, chronic skin (acrodermatitis chronica atrophica), arthritic, and neurological symptoms.

"Peripheral nerve manifestations are of varying patterns and include cranial (facial) nerve involvement, plexopathy, multifocal neuropathy and, rarely, a severe generalized neuropathy similar to Guillain-Barre Syndrome. In the third stage, mild distal sensorimotor neuropathy and carpal tunnel syndrome frequently present."

"The pathogenesis of Lyme Disease involving the central nervous system remains unclear1," Dr. Zagzag says. "It has been hypothesized that the influx of inflammatory cells to the central nervous system is at least in part responsible for the clinical symptomatology affecting these patients."

Dr. Zagzag explains that nerve biopsies2, 3, 4 show perivascular infiltrates of lymphocytes and plasma cells around small endoneurial, perineurial and epineurial blood vessels. Although there is no frank necrotizing vasculitis, endateritis obliterans is occasionally seen. Spirochetes are probably present in small numbers and have been identified in other tissues, but have not been observed in peripheral nerve. At autopsy, lymphocytes and plasma cells have been observed infiltrating autonomic ganglia.

"SDF-1α, also known as CXCL12, is a ligand of the chemokine receptor CXCR4, also known as fusin,5" states Dr. Zagzag. "Knockout mouse experiments demonstrated that CXCR4 and SDF-1α are required for normal embryonic development of the nervous, gastro-intestinal, hematopoietic, and cardiovascular systems.6 For example, SDF-1α is chemotactic for CD34+ progenitor cells, induces proliferation of B-cell progenitors, and regulates leukocyte and endothelial precursor migration.7

"We hypothesize that the up-regulation of SDF-1α in pathological tissues of the central and peripheral nervous system (CNS, PNS) tissue is responsible for the attraction of CXCR4 inflammatory cells and that the molecular basis for this recruitment is the SDF-1α / CXCR4 pathway."

In this study, Dr. Zagzag and Dr. David Younger, the co-investigator, propose to investigate the expression of the ligand SDF-1α and its chemokine receptor CXCR4 in cerebrospinal fluid (CSF) and blood of patients with early, midterm, and late stages of Lyme disease.

To do this, they will test samples of blood and CSF already collected for non-research purposes from patients at different stages of the disease. Using a test called "ELISA," they will check for the presence of SDF-1α. Also, whenever a muscle or nerve biopsy is performed, samples will be stained for SDF-1α and CXCR4 to access their relationship in patients with Lyme disease. Lastly, they will test the effect of SDF-1 α on migration of a specific kind of T-cells.

"We hypothesize that the amount of SDF-1α in diseased tissues of the central and peripheral nervous systems is responsible for the attraction of inflammatory cells," says Dr. Zagzag. "The results of this study will clarify the role of SDF-1α and CXCR4 in Lyme Disease. "

Dr. Zagzag believes that this study will help to add to the existing knowledge base about Lyme disease. "There are still a lot of unanswered questions about the pathogenesis of this disease when it affects the nervous system, and therefore in the therapeutic modalities administered to patients," he says. "It is my opinion that if the pathophysiological processes leading to patients suffering could be elucidated, a targeted therapy with better outcomes could be developed."