Lyme disease future or investigational therapies

Advancing immunology research
The role of T cells concomitant to Borrelia infection was first made in 1984, and long term persistence of T cell lymphocyte responses to B. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990. The role of Th1 and interferon-gamma (IFN-gamma) in borrelia was first described in 1995. The cytokine pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997.

Inflammation
Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-inflammatory immune process. This pro-inflammatory process is a cell-mediated immunity and results in Th1 upregulation. These studies have shown a significant decrease in cytokine output of (IL-10), an upregulation of Interleukin-6 (IL-6), Interleukin-12 (IL-12) and IFN-gamma and disregulation in TNF-alpha predominantly.

These studies suggest that the host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. IFN-gamma alters gene expression by endothelia exposed to B. burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils.

Studies also suggest suppressors of cytokine signaling (SOCS) proteins are induced by cytokines, and T cell receptor can down-regulate cytokine and T cell signaling in macrophages. It is hypothesized that SOCS are induced by IL-10 and B. burgdorferi and its lipoproteins in macrophages, and that SOCS may mediate the inhibition of IL-10 by concomitantly elicited cytokines. IL-10 is generally regarded as an anti-inflammatory cytokine, since it acts on a variety of cell types to suppress production of proinflammatory mediators.

Researchers are also beginning to identify microglia as a previously unappreciated source of inflammatory mediator production following infection with B. burgdorferi. Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis. This effect is associated with induction of nuclear factor-kappa B (NF-KB) by Borrelia.

Disregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in Borrelia infected patients. IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the more prominent symptoms experienced by patients with chronic Lyme disease. IL-6 is also significantly indicated in cognitive impairment.

Neuroendocrine
A developing hypothesis is that the chronic secretion of stress hormones as a result of Borrelia infection may reduce the effect of neurotransmitters, or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically glucocorticoids and catecholamines, the major stress hormones. This process is mediated via the Hypothalamic-pituitary-adrenal axis. Additionally Tryptophan, a precursor to serotonin appears to be reduced within the CNS in a number of infectious diseases that affect the brain, including Lyme. Researchers are investigating if this neurohormone secretion is the cause of neuro-psychiatric disorders developing in some patients with borreliosis. Antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a psycho-neuroimmunological process. Antidepressants have also been shown to suppress Th1 upregulation. These studies warrant investigation for antidepressants for use in a psycho-neuroimmunological approach for optimal pharmacotherapy of antibiotic refractory Lyme patients.

New developments
New research has also found that chronic Lyme patients have higher amounts of Borrelia-specific forkhead box P3 (FoxP3) than healthy controls, indicating that regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells. The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of pro-inflammatory cytokines from Borrelia.

The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the Borrelia bacterium is still present in the host, or in the absence of the inciting pathogen in an autoimmune pattern.

Researchers hope that this new developing understanding of the biomolecular basis and pathology of cell-mediated signaling events caused by B. burgdorferi infection will lead to a greater understanding of immune response and inflammation caused by Lyme disease and, hopefully, new treatment strategies for chronic antibiotic-resistant disease.

Lyme funding and treatment controversy
Many of the scientists involved in formulating what have become controversial Lyme diagnostic tests and treatment guidelines have been heavily involved in both bioweapons research and commercial vaccine and diagnostic test development, which the Lyme patient community views as a conflict of interest. In response to these and other concerns expressed by the expanding national community of patients, Richard Blumenthal, the Attorney General of Connecticut has launched an investigation exploring possible corruption.

To date, federal research aimed at developing treatments for chronic Lyme disease is roughly $30 million, as contrasted to a $22 billion budget for military biodefense. Scientists setting Lyme treatment and diagnostic testing policy in the United States have a well publicised history in the biodefense field, and many have recently received lucrative biodefense grants for BSL-3 and BSL-4 Labs where, critics contend, Lyme treatment research lacks transparency, accountability and focus on treatment research , though, it should be pointed out, that labs obtaining such grants are required to make their research findings publicly available via publication and focus their studies on issues pertinent to human health. Most, including scientist, contend that the new grants and centers stimulate research by bringing together experts in the field and providing a stable source of funding.

In 2003, Lyme researcher Dr. Mark Klempner was appointed head of the new $1.6 billion biodefense top-security facility at Boston University. In 2004, Lyme researcher Dr. Jorge Benach, was reportedly chosen as a recipient for a $3 million biodefense research grant, and in 2005, Lyme researcher Dr. Alan Barbour was reportedly placed in charge of a $40 million dollar new biodefense complex based at UC Irvine.

Former NIH Lyme disease program officer, Edward McSweegan has published numerous articles and letters to editorial pages relating to biowarfare topics ranging from anthrax to plague. Curiously, Mr. McSweegan's novel, Deliberate Release, is biowarfare thriller that describes the deliberate release of a germ weapon.