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THE SCIENCE OF CHRONIC FATIGUE SYNDROMES |
Chapter 6
We can now try to elaborate upon the science of these syndromes, realising that this is work in progress.
We will now proceed to look in some detail at elements that need understanding so that we can look at the patterns that connect them.
This is written with more technical data than I first intended.
From time to time I will try to summarize the crucial information.
IDENTIFYING ABNORMALITIES AND EXPLAINING MECHANISMS.Here we are operating in medical models, drawing upon scientific methods.
This chapter is largely about genes and viruses.
The most likely explanations relate to the following factors:Genetic vulnerability.
It would be difficult to adequately describe the range of gene research which is being undertaken in this early part of the 21st century, but I want to mention the following,Genes, which shape gene products such as functional protein and enzyme activity levels.
Genes, which shape lipid profiles.
Genes, which shape immune responses. (MHC genes commonly described as HLA, genes which code for cytokines and for their receptors and probably an array of genetic polymorphisms relating to substances in cascades of events along complex immune pathways.)
Genes have times of being activated such that their products come into action.
Germ cell DNA in the ovum and sperm carries information from one generation to the next.
In somatic cells the genes carry out their functions in every nucleated cell.
Somatic mutations in these cells can have minor or major, as well as short term or long term consequences for those cells and for the whole organism.
The ongoing work on the complete human genome is already bearing fruit in very many diseases.
Major Histocompatibility Complex
Study of HLA and major histocompatibility complex (MHC) molecules, is revealing intriguing links with specific disorders.
The term histocompatibility arose in the context of grafts (and acceptance or rejection) between members of a species.
By international agreement HLA is the logo for human MHC.
MHC can be used as a term to cover the genes and gene products.
The MHC genes are located on the short arm of chromosome 6.Class I molecules are expressed on virtually all cell surfaces and are products of 3 reduplicated loci: HLA-A, HLA-B and HLA-C.
Class II molecules are restricted in expression to B-lymphocytes, dendritic cells, macrophages, monocytes, antigen-activated T lymphocytes, and to epithelial and endothelial cells that have been activated by interferon. They are products of closely linked genes in the HLA-D region.
Class III molecules are the C4, C2 and Bf components of complement.
Complement is a cascading series of plasma enzymes, regulatory proteins and proteins capable of cell lysis. Complement activity is involved in the opsonization of bacteria, and some fractions are potent mediators of immune cell activation (e.g. C5a is a potent chemo attractant for neutrophils and monocyte-macrophages.)
I will expand on the immunological mechanisms on P 31.
One illustration is the discovery that four environmental exposures may increase the emergence of type1 diabetes in people possessing certain HLA haplotypes.
These are exposures to
(1)Certain coxsackie B viruses,
(2) Beta casein A1 from cow's milk,
(3) Exposure to cereals such as wheat (this latter at specific times of development such as before 4 months of age)
(4) Vitamin D deficiency during pregnancyEnvironmental stress.
Chemicals including pesticides, industrial products, intoxicants and anaesthetics may cause severe, moderate or subtle effects on cellular chemistry especially contributing to cell membrane abnormalities in mitochondria. These changes may be evident quickly or may not emerge or be detected for months, years or even decades.DNA itself is susceptible to injury, particularly in rapidly dividing cells.
Many experts suggest that injury to mitochondria is important.
Mitochondria are the cytoplasmic organelles, which provide 80% of the energy of eukaryotic cells.The mitochondrial DNA is 10 times more susceptible to mutation than nuclear DNA, and mitochondrial membranes are susceptible to oxidative injury.
One thing that appears to be protective of nuclear DNA is the time it rests in a folded form in between times of cell replication.There is some evidence that immune responses can be suboptimal in mammalian cells when pesticides and some industrial products are present in very low concentrations.
Yet other environmental chemicals appear to be hormone disrupters (eg oestrogen disrupters) or diverters of steroid hormones into unwanted pathways.
This is pertinent to recent and long-standing controversies such as hormone replacement therapies.
There are reasons to be alarmed about the extensive exposure of all living systems on the earth to these chemicals!
This requires us to ask all industries and their support systems, to act for all of the people on the earth, rather than just for their shareholders.
A transparency and honesty, which has been hitherto unknown on earth, is needed.
Scientists, who are beholden to multinational or national corporate organizations, could blaze a trail of friendship to knowledge and commitment to integrity to bring about a new and healing era of our earth.
David Suzuki has blazed a trail in creating and maintaining awareness of ecology.
PATHOGENS
At the beginning of the following material on micro-organisms, I remind the reader that we are looking at the earliest forms of life, including their evolution and genetics, and sometimes, living pieces which have emerged such as viruses.
The first forms of life are likely to be primitive bacteria, which emerged on the earth some 3.8 billion years ago.
All organisms which have arisen since, live in the presence of and interact with the organisms called prokaryotes.
In chapters to come, I will elaborate on prokaryotes.
Celera, the private team that completed the human genome project, describe the genome as a dynamic and vibrant ecosystem.
This lifestyle diversity owes itself to the ability to trade RNA and DNA.
Elisabet Sahtouris writes" To this day, every bacterium on this planet can trade bits of DNA with any other it can contact."
What an amazing contribution to our understanding of evolution!
Although I refer to pathogens (disease causing agents), I am attentive to the potential for organisms to give rise to certain kinds of injury in the host, albeit as a survival mechanism for themselves, or to coexist in a non-damaging way.
Micro-organisms may evolve into complementary and benign roles and are probably essential to many ecological balances.
VIRUSES
A virus is a very simple infective agent consisting of a nucleic acid surrounded by one or more proteins and in some cases an outer membrane envelope.It is crucial to appreciate the wide range of consequences of this simple form of life on all the other forms of life.
Viruses can only replicate themselves inside cells as they lack ribosomes or enzymes for high-energy phosphate generation, or for carbohydrate, protein or lipid metabolism.
They may have a few, up to several hundred, genes.
Many of these genes are able to inactivate or modulate immune system mechanisms.Enteroviruses, Coxsackie, hepatitis A, influenza and polioviruses are all RNA viruses.
Hepatitis B and Herpes Family Virus (HSV1 and 2, varicella-zoster, Epstein Barr virus (EBV) and cytomegalo virus (CMV) as well as HHV6 types A and B, HHV7 and 8,) and parvovirus are DNA viruses.
Parvoviruses are the smallest DNA viruses. Some are autonomous, while others are not.
Parvovirus B19 (an autonomous virus) depends upon cellular DNA replication and requires the virus-coded Rep protein.
Interestingly, another non autonomous parvovirus, adeno-associated virus (AAV) requires helper viruses of the adenovirus or herpes family for replication, and may be a safe human gene vector because its Rep protein causes its integration at a single chromosomal site.
This should alert us to the interplay in living systems, including one virus affecting another,
Viruses of the lentivirus and retrovirus groups are not purely RNA or DNA viruses as they are enveloped RNA viruses with two identical sense-strand genomes and associated reverse transcriptase and integrase enzymes.
They reverse transcribe themselves into partially duplicated double-strand DNA copies and integrate with the host genome as part of their replication strategy. Human immunodeficiency virus (HIV) does this.
Viruses, which cause similar illnesses, may have different ways or degrees in which they do so.
I want to illustrate this, because too often people (even health practitioners) tend to generalize about viruses.Hepatitis A virus is a picornavirus. It causes an acute illness, which is usually mild and never progresses to chronic illness.
Hepatitis B virus is a DNA virus, now classified as a hepadenavirus, and its genome codes for four sets of viral products. Each gene and gene products and effects have been measured.
As an example, the x gene codes for a small protein that can transactivate transcription of both viral and host cellular genes.The host gene which produces interferon , and the gene which produces class1 MHC molecules are activated by this viral gene activity.
It exists inside and outside the liver in the infected individual, contains its own DNA polymerase, and is associated with acute and chronic hepatitis, and hepatocellular carcinoma.
In the infective phase this virus is found in all bodily fluids.
Also a variety of acute and chronic autoimmune disorders are seen in many cases of hepatitis B.
Hepatitis C virus is distinct, classified as a flavivirus, has at least 6 genotypes and usually a quite insidious course with some 50% of those infected showing low grade hepatitis.
Interestingly, many cases experience ongoing chronic fatigue.Research in virology has accelerated and we are rapidly reaching sufficient knowledge of all stages of viral activity and replication, to plan management strategies.
This has led to development of a range of antiviral drugs.
Unfortunately these therapies often fail to cure the infected person.
The Government may have restrictions in PBS listing in the indications, such that the drugs are too expensive for most people.
Herpes viruses.
The following viruses are in this family
HHV1 (Herpes simplex virus, HSV1) (classically cold sores and dendritic ulcers of the cornea) (probably present in 60% of most communities)
HHV2 (Herpes simplex type2, HSV2) (usually causes genital herpes)HHV3 (varicella-zoster), (causes chickenpox and shingles,) (98% of western populations)
These 3 herpes type viruses have a predilection for skin and neural cells.The other herpes viruses tend to target immune cells (B and T lymphocytes).
HHV4 Epstein Barr virus (EBV) (Causes infectious mononucleosis/glandular fever) (80% of Western populations are infected by young adulthood years.)
This virus infects B-lymphocytes.HHV5 Cytomegalovirus (CMV)(glandular like fever like illness except in immunocompromised individuals where it causes many serious and even fatal conditions.) (50-75% prevalence in Western populations)
Human CMV encodes more than 200 genes and the function of these genes has been gradually revealed by research.
Some of these genes are able to subvert immune mechanisms. (See below)
HHV6 types A and B, (Infantile roseola is usually caused by the B strain, but both can sometime cause more serious diseases.) HHV6B is probably carried by 100% of people)There is evidence that the HHV6A strain is associated with some cases of CFS. (Ablashi et al)
W John Martin has the following to say about HHV6
"Twenty years after the discovery of Epstein-Barr virus (EBV) a new
herpes virus was reported by Salahuddin and his associates. This new virus was isolated from Patients with AIDS and other lymphoproliferative disorders and was eventually named as human herpes virus type-6 (HHV-6).
HHV-6 is the smallest of herpes viruses (170 kb) and has been classified as beta-herpes virus. HHV-6 has been reisolated by many laboratories and a
consensus conference has classified them into subgroups A and B. The subgrouping is based on restriction endonuclease sites, and biological and Immunological characteristics.Antibody to HHV-6 and therefore, possible exposure/infection is detected in <80% individuals in the Western world. From all indication it appears that the infection by HHV-6 takes place very early in life after the acute phase the virus becomes
dormant to be activated at a later time. HHV-6 can be reactivated by the
usual factors e.g., immunological and environmental .HHV-6 is exclusive T-cell tropic, induces and up regulates CD4
receptors and cytokine expression, enhances the killing of cells infected
with other lytic viruses such as HIV-1.There is evidence for the association of HHV-6 with at least three lymphoproliferative
diseases; causative agent for childhood disease Roseola (Exanthem subitum)a febrile illness in young children, and EBV- and CMV- negative cases
of mononucleosis in young adults. This is an important pathogen that
can initiate pathologies mentioned before, it may also be a cofactor in
several other diseases such as AIDS, cervical carcinoma, and oral carcinomaHHV-6 is reactivated in infectious diseases, proliferative
disorders, and immune deficiencies "A variety of pathogens either co-infect the same cell or are present
in the same environment.
The type and level of viral antigens as well as specific T cell activations for example and the duration of their presence in that milieu can be important factors that may give rise to a particular disease.Whereas HHV-6 and HIV-1 may give rise to AIDS-like disease, HHV-6 in conjunction with HPV may result in malignancy of the cervix. HHV-6 becomes latent after the initial infection and can be reactivated by a variety of viruses and vice versa. Interaction between the viruses may take place after the reactivation of these agents."
HHV7 and 8. These appear as significant in some malignant diseases.
HHV8 has been identified in Kaposi sarcoma and multiple myeloma.
Immune cells (lymphocytes and macrophages) are major targets in HHV4-9
Herpes virus and immune system evasion.
Members of this family of viruses are capable of interfering at many levels of immune function, as follows.
Impairment of
(1) Antibody recognition of viral epitopes,
(2) Presentation of viral peptides by major histocompatibility complex (MHC) class1 and 2 molecules,
(eg Human and murine CMV both encode a set of glycoproteins known as immunoevasins which prevent presentations of antigenic peptides by MHC class 1 pathways.)
(3) Recruitment of immune effector cells,
(4) Complement activation, and alsoBy existing in latent forms, and extending the time window for viral replication and spread.
As well viruses appear to make decoy molecules with cytokine action (eg EBV can make an IL10 called vIL10)
Human cytomegalovirus can live in haemopoietic progenitor cells, fibroblasts, smooth muscle cells, endothelial cells, epithelial cells, monocytes, and granulocytes.
In the acute stages lytic effects are seen, but latent presence in monocytes is not lytic.
Most DNA viruses (except for pox viruses) need to enter the cell nucleus for their DNA to be transcribed by cellular RNA polymerase II. Most also depend upon the cell for messenger RNA synthesis and processing.
Tropisms: Many viruses seem to have a predilection for certain cell types. For example, herpes type I and II live in skin and nerve cells, respiratory syncytial virus in respiratory epithelium, EB virus in B-lymphocytes and polio virus in anterior horn cells.
Quite complex processes lead to 10-1000 infectious progeny.
Pathology results from damage to host cells, including induction of apoptosis, but also a variety of other responses including proliferation, of which one long-term consequence can be malignancy (e.g. with hepatitis B and C infections).
I would like to return to Dr W John Martin as he explains one difficulty with some viruses."What are Stealth Viruses?
Viruses are submicroscopic infectious agents that replicate inside cells. Viral illnesses are normally controlled by the body's immune system acting primarily through white blood cells called lymphocytes. These cells recognize certain viral proteins that provide the antigens targeted by specific lymphocytes, leading to an anti-viral inflammatory response.Not all viral proteins, however, can function as antigens for effective anti-viral immunity. Indeed, for many viruses, only a very few proteins are involved in lymphocyte recognition of virally infected cells. Loss of these critical antigenic proteins can allow a virus to essentially go unrecognized by the cellular immune system. When such viruses have managed to retain the capacity to damage cells, they can potentially cause a persistent infection resulting in a prolonged illness.
The viral nature of such an illness is usually overlooked because of the absence of overt inflammation. Atypically structured cell-damaging (cytopathic) viruses were initially identified in patients with the chronic fatigue syndrome and in patients with more severe neurological and neuropsychiatric illnesses.
The term "stealth" was introduced to highlight their basic property of evading effective immune recognition, and also because they had gone unrecognized by the medical community.
Detection of Stealth Viruses
Stealth-adapted viruses can be most readily detected using specialized, semi-quantitative, viral culture methods developed and refined over the last decade. Using these procedures, stealth viruses will typically induce a characteristic vacuolating cytopathic effect (CPE) in cultures of human and animal-derived cells.Stealth virus infected cultures can be distinguished from cultures of conventional herpesviruses, adenoviruses, enteroviruses and retroviruses, by the appearance and host range of the CPE, and also by using selective immunological and molecular probe based assays, including polymerase chain reaction (PCR) testing methods."
It seems that further independent work is needed to verify this statement by Martin, but I include his writings for he principles they convey.
As seen above, I emphasize that viral effects on the immune system include mechanisms to inactivate, deviate or down regulate components of this vital body system, and it is beyond doubt that these strange small infective agents inhabit us all and will emerge as playing more roles in our health and disease than we estimated.
BACTERIOPHAGES
Before we leave the field of virology there is a re-awakening of knowledge about viruses that specifically attack particular bacteria. With the emergence of bacteria that are resistant to antibiotics, researchers are beginning to pay attention the fact that a particular virus called a bacteriophage could kill these resistant organisms.Attention is drawn to the adverse effects of bacterial lysis by bacteriophages in some situations (eg E coli in some cases of fibromyalgia)
When we come to the later notes on bacteria we need to raise the possibility that we will be able to change the bacterial flora in safer ways than before.
The study of virology is very extensive and the above is to give some basic information about these organisms.
RESIDUAL AND DELAYED EFFECTS OF VIRAL INFECTION.It is known that viruses such as human immunodeficiency viruses. herpes viruses, E B viruses and CMV persist in the body for life. Research is needed to clarify whether there are some people who carry heavier loads of the herpes family of viruses, and have different T lymphocyte and cytokine responses contributing to some of the fatigue features.
It is already clear that there are different pathologies that emerge in some people when multiple factors operate together (e.g. In Africa E B virus is part of the reason for Burkitt's lymphoma, and in multiple myeloma and Kaposi's sarcoma, HHV8 has been isolated.)
Some researchers such as W John Martin suggest that viruses can be present and participate in pathologies, but escape detection by standard laboratory tests. They have named such viruses "stealth viruses", and these seem to be mutant versions of such organisms as CMV. This may involve mutant forms which have less antigenic proteins.I have looked at Martin's publications and find them intriguing, but the work requires validation in independent laboratories.
I therefore have added an appendage on his work after the reference section.
Some peptide sequences in CMV may be triggers for evoking autoimmune responses.
There is interest in the poliomyelitis virus sometimes giving a delayed post polio syndrome. Perhaps the delayed effect is a subtle residual vulnerability in the anterior horn motor neurones that were originally infected with the virus.
In the section on therapy I will provide a little information about emerging anti viral therapies.
Mechanisms of fever
PYROGENS
In medical sciences much attention has been paid to fever and the mechanisms of generation of high temperatures. Pyrogens are substances from outside the body (exogenous) or from inside the body (endogenous), which generate fever.Exogenous pyrogens:
These are largely from micro-organisms.
a) Molecules from gram negative bacteria made of lipopolysaccharide and termed endotoxins.
b) Molecules from gram positive bacteria such as cell wall derived lipotechoic acid and peptidoglycans.
c) Some exo and endo toxins from staphylococci and streptococci act as bacterial superantigens -(polyclonal T lymphocyte activators) that bind to the variable region of T cell receptors rather than the antigen-binding region. This can result in mediator* release.
*These mediators are also called cytokines.
I will give a detailed account of these chemical messengers in the section on immunology.
Endogenous pyrogens.These are polypeptides produced by a variety of host cells, mainly monocytes and macrophages. Interleukin 1 alpha and 1 beta can be produced by phagocytic cells, endothelial cells, B lymphocytes, T (natural killer) cells, fibroblasts and some other muscle cells, also keratinocytes and glial cells. TNF alpha, interferon alpha, and IL6 are also pyrogens.
Fever can make it easier for the body to deal with micro-organisms by impairing micro-organism growth, lessening virulence and enhancing human neutrophil activity against bacteria and enhancing cytotoxic effects of lymphocytes.There is however an energy loss to the host, as a 1o C temperature increase, increases oxygen requirement by 13%, as well as increasing catabolism, and caloric and fluid requirements.
As mentioned, I will refer further to cytokines and interleukins later in this document.The next group of organisms is larger than viruses. Viruses are not referred to as cells.
Life certainly contains amazing variation.