Introduction
Lyme disease has proven to be one of the most invasive, persistent, and intractable worldwide plagues of the 21st century.^1-3 The application of classical antibiotics has been only partially successful. One major problem in diagnosing Lyme disease has been the development of adequate detection capability. An attempt to make an inroad against these formidable obstacles has been the exploitation of a little-known aspect of the immune system known as "complement factor H," making it possible for the first time to describe a mechanism whereby Lyme disease and other specific infectious agents possibly may be controlled. A detailed description of this component of the immune system, along with its mode of operation as applied to the Lyme disease causative organism, Borrelia burgdorferi, is described.

Immune Complement System
Nature has devised a very clever and efficient way of killing bacteria and other invading microorganisms. An elaborate set of nine proteins, comprising what is known as the "complement system," has been developed to combat the threat of invasion and infection by microorganisms. Foreign organisms, by nature, carry on their surfaces chemical groups and arrangements of proteins, polysaccharides (poly-sugars), or combinations of these two substances that are not normally present on the surface of human cells. The immune system recognizes these "antigens," as they are called, as not belonging to the human family. Another protein in the shape of a Y, the antibody, is custom-fabricated by the immune system to match exactly the chemical characteristics and structure of the antigen.

1. Certain proteins of the complement are then assembled in a specific manner on the antigen-antibody complex thus formed. The presence of an antigen-antibody complex on the surface of a cell signals the complement system that a foreign organism is present that should be destroyed. The final stage of this assembly is the formation of the complement system's killing machine, namely, the membrane attack complex (MAC). Four proteins of complement assemble on the cell surface in a specific pattern, thereby forming a basic unit that binds to a fifth component that is polymerized with additional such components, forming a cylinder or circular pore in the membrane of the organism under attack. This pore allows electrolytes (salts) and water to freely enter and leave the cell, causing it eventually to burst (lyse). (For a detailed drawing of this process as well as electron micrographs of bacterial membranes, please see http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=imm.figgrp.188.)⁴

Complement Regulation by Factor H
One component of the complement system is a protein called factor H, which has a regulatory function.⁵ Essentially all cells of the body bind factor H, preventing the assembly of complement proteins on the cell surface.⁶ Complement components assemble only on antigen-antibody complexes. Since the body does not normally generate antibodies against itself unless cells have been modified or altered in some fashion (chemical, bacterial, or viral infection, injury, etc.), complement components will not aggregate at cell surface sites protected by factor H.

In contrast, foreign cells, bacteria, mycoplasma, and viruses do not typically have on their surfaces a binding site for factor H. The surfaces of foreign organisms are antigenic and will elicit a response from the immune system, because they are recognized as non-self. Antibodies will be developed and bound to the antigens present on their surfaces. The complement components will assemble on the antigen-antibody complexes thereby generated and will destroy the invaders through the action of the MAC (see Chart 1, a 93 KB .pdf).

Factor H consists of a single strand of protein that, because of the nature of the amino acids along its length, is capable of folding back upon itself, thereby forming bunches, similar to beads on a string. The total number of beads on the string of a single molecule of factor H is 20.⁷ Complement itself, when assembled, consists of an aggregate of separate long chains, all bound to a single point of attachment. Apparently, factor H interferes with normal assembly by mimicking one of the long chains, thus preventing proper complement assembly.⁸

Microorganism Protection from Immune Surveillance
Certain bacteria and viruses, including the Lyme disease causative agent, have exploited the protection afforded from the deleterious effects of the complement system by carrying a binding site on their surfaces for factor H.⁹ This site is typically antigenic and recognized by the immune system as non-self. Normally, without bound factor H, antibodies would be developed against the antigenic site, complement would assemble on the antigen-antibody complex, and cell lysis would eventually occur. The organism protects itself from complement assembly and immune surveillance by binding the host's factor H, thereby thwarting the immune system. The surface binding site for factor H is known as "outer surface protein E" (OspE).¹⁰ Through an elaborate gene-swapping process, the structure of the surface antigen OspE may change, based on external conditions and the degree to which the spirochete is threatened.¹¹ Regardless of this surface variability, OspE is always able to bind factor H.

The known bacteria that have developed this system of immune protection include the causative agents for gonorrhea, meningitis, pneumonia, and the Lyme disease spirochete Borrelia burgdorferi.⁹ The virus responsible for human immunodeficiency disease (HIV) has also developed this protection from immune destruction⁵ and may account for some of the difficulty encountered in treating this disease. Other pathogenic bacteria and viruses may have also developed this capability but remain unknown (see Chart 2, a 102 KB .pdf).

Combating HIV by Antibodies to Factor H Binding Site
As indicated, the virus responsible for HIV protects itself from the immune system by binding human serum factor H to antigenic sites (gp41, gp120), thereby affording immune protection by disallowing assembly of complement components at the would-be antigen-antibody complex.⁵ Through the administration of antibodies to the factor H binding site, the protection afforded by factor H binding is removed and the virus is subject to immune attack from complement assembly.⁵ As far as is known, this technique has not been applied to pathogenic bacteria (including the Lyme spirochete) that have achieved immune protection through factor H binding (see Chart 2, a 102 KB .pdf).

If the Lyme disease spirochete did not have the ability to bind a factor H mimic of its own generation and thereby afford protection from the immune system, the components of complement would assemble at the antigen-antibody complex, and lysis of the organism would occur as with other bacteria through the action of the MAC. Since serum factor H is always present, this event does not occur, allowing the Lyme disease spirochete to remain an extremely difficult organism to control.

Antibodies made to the binding site for factor H prevent factor H from binding to the surface. In the case of the Lyme disease spirochete, the antigenic site (OspE) is variable as dictated by previous therapies and attempts to kill the organism. However, it has been demonstrated that the serum of Lyme disease patients contains antibodies to the spirochete. Whether these antibodies are sufficient to successfully bind to and destroy the organism following the administration of antibodies to the factor H binding site (OspE) remains to be seen (see Chart 3, an 89 KB .pdf).

Normal Mechanism of Virus Destruction
There is one major difference between the destruction of a bacterial cell and a virus by the immune system. That difference lies in the absence of a membrane or wall surrounding the virus. It is true that some viruses have a "membrane" surrounding the outer protein coat but this membrane is not of the virus (there are no viral genes to specify it) but has been borrowed from the host to mask or disguise itself for protection from the immune system. The normal or classical mechanism for bacterial (cellular) destruction by the complement system is the formation of the MAC, a protein pore that is inserted into the cell wall of the organism, leading to cell rupture and death.⁴ Since the virus does not have such a wall surrounding it, another mechanism must be used by the immune system to destroy viruses. Since viruses are foreign to the body, the immune system recognizes it as non-self and makes antibodies against the antigens found on the surface protein. These antibodies bind to the antigens on the surface, forming an antigen-antibody complex. Certain components of the complement system (C3b and C4b) assemble on this complex and attach the virus to a white blood cell known as a phagocyte. A phagocyte is a blood cell capable of engulfing particles and destroying them internally.¹²

A particle near a phagocytic cell is surrounded by an extension of the cell membrane that eventually surrounds it. The membrane of the cell detaches from the surface (now internal) and becomes a "bubble" (phagosome) formed by the cell's own membrane, which contains the entrapped particle. Within the phagocytic cell are other bubbles called lysosomes, which contain a variety of digestive enzymes on their inner surfaces. The phagosome merges with the lysosome and becomes a single bubble known as a phagolysosome. The engulfed particle (virus) is now within a sealed chamber containing, on its inner surface, digestive enzymes that are capable of reducing the virus to its constituents (amino acids, nucleotides, etc.). The phagolysosome containing the digested virus moves to the outer membrane of the phagocytic cell and merges with it. The contents of the phagolysosome then empty into the surrounding medium and are recycled by the host (see Chart 4, a 51 KB .pdf).

Destruction of HIV by Antibodies to Factor H Binding Site
As shown in Chart 2, HIV binds the host's factor H, affording protection from the assembly of complement components C3b and C4b, and eventual attachment to a phagocytic blood cell, marking it for destruction. This protection is achieved by disallowing the binding of antibodies to HIV made by the host against antigens found on the HIV. Because the antigen-antibody complex does not form, complement cannot assemble and the virus is spared from destruction.

When antibodies to the human factor H binding site (antigens gp41, gp120) are administered, factor H is displaced. HIV antibodies already present in the serum of the host or additional HIV antibodies bind to the antigenic sites on HIV. This antigen-antibody complex will now bind complement components C3b and C4b, attaching the virus to a phagocytic cell. Once attached, the virus is destroyed in the same manner as described above⁵ (see Chart 5, a 51 KB .pdf).

Notes
1. Bradford RW, Allen HW. Current research in Lyme disease. BRI Report #42. Chula Vista, California: Bradford Research Institute; June 1992.
2. Bradford RW, Allen HW. Lyme disease, potential plague of the twenty-first century. BRI Report # 73. Chula Vista, California: Bradford Research Institute.
3. Bradford RW, Allen HW. Biochemistry of Lyme disease: Borrelia burgdorferi spirochete/cyst. BRI Report #74. Chula Vista, California: Bradford Research Institute.
4. Janeway CA, Travers P, Walport M, Shlomehik MJ. Immunobiology. New York: Garland Publications; 2001. Available at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=imm.figgrp.188. Accessed March 10, 2007.
5. Stoiber H, Pinter C, Siccardi AG, et al. Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55). J Exp Med. 1996;183:307-10.
6. Jozsi M, Manuelian T, Heinen S, et al. Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology. Histol Histopathol. 2004;19:251-8.
7. Aslam M, Perkins SJ. Folded-back solution structure of monomeric factor H of human complement by synchrotron x-ray and neutron scattering, analytical ultracentrifugation and constrained molecular modeling. J Mol Biol. 2001;309:1117-38.
8. Kask L, Villoutreix BO, Steen M, et al. Structural stability and heat-induced conformational change of two complement inhibitors: C4b-binding protein and factor H. Protein Science. 2004;13:1356-64. Available at: http://www.proteinscience.org/cgi/reprint/ps.03516504v1.
9. Kraiczy P, Hellwage J, Skerka S, et al. Complement resistance of Borrelia burgdorferi correlates with the expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins. J Biol Chem. 2004;279:2421-9.
10. Lam TT, Nguyen TP, Montgomery RR, et al. Outer surface proteins E and F of Borrelia burgdorferi, the agent of Lyme disease. Infect Immun. 1994;62:290-8.
11. Bykowski T, Babb K, von Lackum K, et al. Transcriptional regulation of the Borrelia burgdorferi antigenically variable VisE surface protein. Bacteriol. 2006;188:4879-89.
12. The adaptive immune system. Available at: http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/viruses/viruses.html. Accessed March 10, 2007.