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
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
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
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
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
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
(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
are recycled by the host (see
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
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
is destroyed in the same manner as described above5 (see
Chart 5, a 51 KB .pdf).
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