Hypotheses Regarding Autoimmunity in Lyme Disease and Multiple Sclerosis

by Megan Blewett

The concept of autoimmunity was first demonstrated by the work of Paul Ehrlich in 1892 and throughout its history has been highly controversial. Over half a century after Ehrlich’s experiment, in the 1950s and 1960s, mainstream immunologists were only beginning to seriously consider autoimmunity.1 In fact, early immunologists Noel Rose and Ian Mackay stated in their book Autoimmune Diseases: “…1955-1965 [was] the decade marked by the question, ‘Does autoimmunity exist?’…”.2

Today, that autoimmunity exists seems clear, though in which diseases autoimmunity is the primary culprit has still to be determined. Indeed, classifying any disease as an “autoimmune disease” should be done only after thorough consideration. A fatal immune error is a weighty matter, as the immune system is so key to the survival of an individual and the human species.

Evolutionarily, autoimmunity is hard to grasp. It is tempting to believe that the immune system is as obliged to follow the Hippocratic Oath as the doctors who study it. The first rule is always: Do no harm. However, studies have shown that autoimmunity has a genetic basis. According to immunologists Fu-Dong Shi and Luc Van Kaer, “Naturally occurring mutations in genes that cause a defect in [Natural Killer] cells … can predispose individuals towards autoimmune disease”.3 Why, then, should these individuals not have been selected against evolutionarily? How have groups with this severe, and often fatal, predisposition survived to the current day and age?

With regards to diseases such as multiple sclerosis (MS) and Lyme arthritis, which are known to have environmental components, a follow-up question becomes: Has the immune system made a fatal error and started to attack self material or is it correctly combating a stealth pathogen that we have yet to detect? The spirochetal etiological agent of Lyme disease is infamous for being difficult to spot. A similar agent could be at work in MS.

My previous geographic work supports the hypothesis that MS and Lyme share a common environmental agent. MS and Lyme co-occur in the United States; regions with high incidence of MS also have high incidence of Lyme (p < 0.001). The control diseases did not correlate with MS or Lyme distributions. Both MS and Lyme cluster around coastal regions, suggesting a marine agent. Migratory seabirds can carry avian retroviruses and spirochetal bacteria, among a range of other pathogens. While these geographic studies can only confirm a common vector, biochemical evidence suggests that MS and Lyme are in fact influenced by a spirochetal bacterium.

I will take a brief detour from autoimmunity in the following paragraphs to discuss several biochemical hypotheses regarding etiology.

The Borrelia burgdorferi bacteria are unique in their lack of lipopolysaccharide (LPS), a lipoprotein found on the surface of many other Gram-negative bacteria.4 LPS stimulates macrophages to produce interleukin-1 (IL-1), a type of signaling molecule known as a cytokine.5 Thus, if an LPS-lacking bacterium like Borrelia were at work in MS, one would expect to find low levels of IL-1 among patients.

A review of the scientific literature shows that this is in fact the case.6,7 Interleukin-10 (IL-10), another cytokine from the same class of interleukin signaling molecules, inhibits Borrelia-induced endothelial inflammation.8 Interferon-â therapy in MS patients stimulates IL-10 production and has beneficial effects.9 LPS can also induce endothelial inflammation, leaving open the possibility of LPS-containing Gram-negative bacterial etiological agents.

In addition, the plasminogen activation system and specifically tissueplasminogen activator appear to be “turned on” in MS patients.10 B. burgdorferi bacteria are plasmin-coated and activate plasminogen. B. burgdorferi can likewise degrade the extracellular matrix, including collagen,11 which is a component of the blood-brain barrier. This provides one mechanism for central nervous system infiltration in MS patients.

These geographic and biochemical similarities are just some of the points of overlap between MS and Lyme. Now, we must return to the focus of this essay: autoimmunity, or the lack thereof, in these two diseases.

Are LPS-lacking Gramnegative bacteria at the root of MS and Lyme arthritis or is autoimmunity entirely to blame? The prevailing opinion among researchers is that MS in an autoimmune disease. However, the environment clearly also plays a role in MS susceptibility. The molecular mimicry theory provides a compromise between these two points.

According to the molecular mimicry theory, MS is a post-infectious autoimmune disease resulting from an immune mix-up of a pathogenic antigen and a component of the myelin sheath. MS patients, some researchers believe, are infected by a pathogen whose antigen resembles a component in myelin. For some reason, myelin is degraded in MS patients.

Currently, researchers are investigating myelin basic protein (MBP) as the myelin target of this immune mix-up.12 Proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) are also “candidate autoantigens”.13 However, several points complicate MBP’s autoantigen status, including that elevated levels of anti-MBP antibodies do not appear to be specific to MS patients,14 nor are anti-MBP or anti-MOG antibody levels associated with the progression of MS.15 Thus, other candidate autoantigens need to be investigated.

The molecular mimcry theory has also been applied to Lyme arthritis, a chronic condition affecting about 10% of all Lyme patients.16 Some researchers argue that Lyme arthritis is in fact a post-infectious autoimmune disease. Synovial samples from sufferers of this antibiotic-resistant form of Lyme disease do not test positive for B. burgdorferi DNA, suggesting that infection persists even after spirochetal infection.17

One of the most widely accepted autoantigens in Lyme disease, following the molecular mimicry theory, is the human Lymphocyte Function Antigen-1 (hLFA1alpha), which contains a peptide similar to the B. burgdorferi outer surface protein A (OspA) from amino acids 165-173.18,19,20 Thus, antibiotic-resistant Lyme arthritis may, like MS, be a result of an immune recognition error.

However, Dr. Steven Phillips has pointed out that B. burgdorferi bacteria are very hard to detect and may still be present in Lyme arthritis patients.21,22 Thus, Lyme arthritis has yet to be definitively classified as an autoimmune or chronic condition.23 MS faces similar classification difficulties. Until better detection methods are applied, elucidating the molecular mechanisms of “post-infectious” diseases will be very difficult.

Further research must be performed to better understand the mechanisms of Lyme arthritis and its commonalities with MS.

1. Silverstein AM. Autoimmunity versus horror autotoxicus: The struggle for recognition. Nat Immunol 2001;2:279-281.

2. Rose NR, Mackay IR (eds). The Autoimmune Diseases. New York: Academic Press; 1985.

3. Shi F, Van Kaer L. Reciprocal regulation between natural killer cells and autoreactive T cells. Nat Rev Immunol 2006;6:751-760.

4. Kinjo Y, Tupin E, et al. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 2006;7:978-986.

5. Wier DM, Stewart J. Immunology. New York: Longman Group Limited; 1997.

6. Rudick RA, Ransohoff RM. Cytokine secretion by multiple sclerosis monocytes. Relationship to disease activity. Arch Neurol 1992;49:265-270.

7. Feakes R, Sawcer S, et al. Interleukin 1 receptor antagonist (IL-1ra) in multiple sclerosis. J Neuroimmunol 2000;105:96-101.

8. Lisinkski TJ, Furie MB. Interleukin-10 inhibits proinflammatory activation of endothelium in response to Borrelia burgdorferi or lipopolysaccharide but not interleukin-1beta or tumor necrosis factor alpha. J Leukoc Biol 2002;72:503-511.

9. Byrnes AA, McArthur JC, Karp CL. Interferon-â therapy for multiple sclerosis induces reciprocal changes in interleukin-12 and interleukin-10 production. Ann Neurol 2002;51:165-174.

10. Cuzner ML, Opdenakker G. Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. J Neuroimmunol 1999;94:1-14.

11. Coleman JL, Roemer EJ, Benach JL. Plasmin-coated Borrelia burgdorferi degrades soluble and insoluble components of the mammalian extracellular matrix. Inf Imm 1999;67:3926-3936.

12. Bogdanos DP, Smith H, et al. A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics. Clin Dev Immunol 2005;12:217-224.

13. Hellings N, Baree M, et al. T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls. J Neurosci Res 2001;63:290-302.

14. Mazzanti B, Vergelli M, et al. T-cell response to myelin basic protein and lipidbound myelin basic protein in patients with multiple sclerosis and health donors. J Neuroimmunol 1998;82:96-100.

15. Kuhle J, Pohl C, et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 2007;356(4):371-378.

16. Lengl-Janssen B, Strauss AF, et al. The T helper cell response in Lyme arthritis: differential recognition of Borrelia burgdorferi outer surface protein A in patients with treatment-resistant or treatment-responsive Lyme arthritis. J Exp Med 1994;180:2069-2078.

17. Carlson D, Hernandez J, et al. Lack of Borrelia burgdorferi DNA in synovial samples from patients with antibiotic treatment-resistant Lyme arthritis. Arthritis Rheum 1999;42:2705-2709.

18. Guerau-de-Arellano M, Huber BT. Development of autoimmunity in Lyme arthritis. Curr Opin Rheumatol 2002;14:388-393.

19. Gross DM, Forsthuber T, et al. Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science 1998;281:703-706.

20. Gross DM, Huber BT. Cellular and molecular aspects of Lyme arthritis. Cell Mol Life Sci 2000;57:1562-1569.

21. Phillips SE, Mattman LH, et al. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Infection 1998;26:364-367.

22. Phillips SE, Burrascano JJ, et al. Chronic infection in ‘post-Lyme borreliosis syndrome’. Int J Epidemiol 2005;34:1439-1440.

23. Phillips SE, Harris NS, et al. Lyme disease: scratching the surface. Lancet 2005;366:1771.