A. Hässig, H. Kremer, Liang Wen-Xi and K. Stampfli
Original Publication
Continuum vol.4 no.6 June/July 1997
http://www.virusmyth.com/aids/hiv/ahpathogen.htm
...
Summary - The immune system’s main function is the constant elimination of endogenous cell debris, and when necessary, the disposal of foreign structures. It seems appropriate, therefore, to complement the existing paradigm of "self and non-self" with the concept of "altered self". The concept of stress comprises a multitude of environmental assaults, all of which result in a displacement towards catabolic metabolism. This is based on the activation of the neuroendocrine stress axis hypothalamus-pituitary-adrenal glands, which results in increased production of catecholamines and glucocorticoids. The latter limit life-threatening acute phase reactions by means of the body’s own inflammatory mediators. The purpose of displacing the cytokine profiles of CD4 lymphocytes from Th1 to Th2 is to enable them to take over temporarily the inflammation-inhibiting role of cortisol until normality is re-established. In autoimmune disease a permanent Th2 displacement is a sign of persistent hypercortisolism. Failure by cortisone to arrest inflammation due to severe stress, results in hypercatabolic diseases such as AIDS, septicaemia, toxic shock syndrome and protein calorie malnutrition (NAIDS). Preventing and treating AIDS and NAIDS entails, besides removing the causes of stress, activating mesenchymal production of anabolic matrix components, eg. glycosamineglycanes, and the neutralisation of O and NO radicals, as well as inflammatory mediators from overactivated macrophages, using polyanions and polyphenols as food supplements. Septicaemia and toxic shock syndrome are, in our opinion, best treated with speedy administration of high doses of intravenous gammaglobulins.
Go here for a glossary (see bottom page)
Introduction
The immune system’s main function is to maintain the genetically determined individuality of the human body. The body consists of about 1014 cells. Daily turnover of cells through mitosis and apoptosis is around 1012 cells.(1) The immune system has, first to eliminate endogenously arising cell debris, and secondly to eliminate exogenous, foreign matter. According to the current paradigm, the role of the immune system is restricted to eliminating foreign "non-self" structures, and it does not concern itself with the body’s own "self-structures". In our opinion, we must enlarge the immune system’s role to include the disposal of a constant stream of "altered self-structures." The disposal of exogenous "non-self" structures is to be regarded as a secondary function, called upon only when the need arises. The elimination of exogenous "non-self" structures is in the main the function of B-cells, derived from bone marrow and mucosa-associated Iymph tissue (MALT), which produce humoral antibodies.(2)
...
Phase I adrenergic corticoid phase
Phase ll corticoid withdrawal phase
Phase lll spontaneous anabolic phase
Phase IV fat gain phase
The adrenergic-corticoid response
This corresponds to the acute phase response involving a neuroendocrine displacement towards sympathicotony, with production of adrenaline and noradrenaline, followed by hypercortisolism. The catabolic displacement of the metabolism is linked to the activation of proteases of the humoral system: clotting, fibrinolysis, complement and kallikrein/kinin; these in turn are powerful stimulators of the primary inflammatory cells, granulocytes and monocytes/macrophages, which in their turn produce proteases, inflammatory cytokines, O and NO radicals.(7) Lymphocytes, as secondary inflammatory cells migrate in large numbers into non-vascular space, ie. the Iymph nodes, as a result of which, turnover due to mitosis and apoptosis increases greatly. Intra-cellular nucleases and proteases are activated by apoptosis, which decompose the cell contents into fragments of DNA, RNA and proteins, which are expelled from the cell. The activated lymphocytes secrete increased amounts of lymphokines, especially IFN. This activates macrophages to produce increased amounts of O and NO radicals, as well as inflammatory mediators, IL-1 and TNFa. The level of cortisol which increases in this phase, linked with the decrease in DHEA limits the extent of inflammation during this oxidative stress condition. Cortisol has an ongoing inhibitory effect on the inflammatory lymphokines, IL-2 and IFN.(8)
The corticoid withdrawal phase
This is the transition from the catabolic metabolism to catabolic-anabolic equilibrium. While the level of cortisol is declining it is essential for inflammatory inhibition caused by cortisone to be taken over by the inflammatory inhibitor cytokines. This occurs through the temporary switch of the cytokine profile of CD4 Iymphocytes from Thl to Th2 by means of the activation of IL-4 and IL-10. This sets in train a generalised B-cell activation linked to hypergammaglobulinaemia. Cortisol is also responsible for stopping the anabolic formation of extra-cellular matrix components, such as collagen and glycosamineglycanes (GAGs) by fibroblasts. Due to the change in the cytokine profile from Thl to Th2, production of matrix is increased. The increase in production of GAGs is especially significant, because they play an important role as endogenous calcium antagonists, and, as cortisone inhibitors, in maintaining the anabolic-catabolic equilibrium.
The sequence of events in the metabolism during the recovery phase after surgery has recently been confirmed by Decker et al. on the basis of a temporary displacement of the cytokine profile from Thl to Th2 during cholecystectomies.(9)
The effect of persistant displacement of Thl to Th2 of the cytokine profile of the CD4 helper cells
The above describes events during persistent catabolic displacement in metabolism due to hypercortisolism: persistent B-cell activation and hypergammaglobulinaemia, which is characteristic of latent and active autoimmune disease.(10) As already mentioned, the main physiological function of cytotoxic T-cells is to dispose of "altered-self" structures, ie. cell debris left over after apoptosis. This is accompanied by constant scavenging by T-lymphocytes throughout the body. The total number of specificities of T-cells defined by their surface proteins is of the order of 1O9. This poly-specificity of the lymphocytes prevents a general, inflammatory activation of the immune system when apoptotic cell debris is being removed.(11)
...
Enduring hypercortisolism due to a persistent displacement in the cytokine profile towards Th2 is also associated with a selective decline in CD4 cells, with CD8 cells remaining constant. As Fauci originally showed, if there is a raised cortisol level in the bloodstream, part of the CD4 cells migrate into the bone marrow, where they activate B-cells. Once cortisol levels return to normal, the CD4 cells reappear in the circulation. The later idea that the selective decline in CD4 cells was due to their destruction by HIV proved the be untenable.(14) Another important indication of persistent hypercortisolism is the loss of delayed cutaneous skin reactions, while the Th2 profile is maintained. These reactions correlate closely with the Th1 profile and its inflammatory cytokines.
Hypercatabolic diseases under severe stress due to the failure of cortisol to inhibit inflammation
The Thl/Th2 displacement in cytokine profile of CD4 cells is, according to present understanding, meant to help stress-induced hypercortisolism return to normal. In cases of severe stress the function of cortisol to inhibit inflammation fails, which leads to a state of systemic hypercatabolic stress, because of overactivation of proteases and inflammatory cytokines, as well as to overproduction of O and NO radicals from granulocytes, macrophages and lymphocytes. The increased production of IFN from activated Iymphocytes is primarily responsible.(15,16) The most important examples of hypercatabolic diseases are AIDS, septicaemia, as well as protein calorie malnutrition (NAIDS = Nutritional AIDS, kwashiorkor). The increased production of IFN by activated lymphocytes causes macrophages to produce corresponding amounts of neopterin and ferritin.(l7,l8) The selective reduction of CD4 Iymphocytes, and the increase in neopterin and ferritin levels in the blood are all signs of lymphocyte and macrophage activity. Susceptibility to saprophytes is characteristic of hypercatabolic disease, as is the activation of latent pathogens and opportunists. Pneumocystis carinii pneumonia (PCP) is important in AIDS and protein calorie malnutrition. Contrary to earlier belief, it has now been classified as a ubiquitous fungus and not an opportunistic protozoon.(19)
...
Despite intensive efforts along these lines, there has been no breakthrough. The most promising treatment currently is to suppress the generalised protease activation. Early administration of high doses of antithrombin III has produced some initial successes.(7) In our opinion, speedy prophylaxis with high doses of intravenous gammaglobulins is most likely to be suitable in decisively reducing mortality.(24) The use of gammaglobulins in emergency medicine is compelling, which is independent of antibodies, to stop the activation of serine proteases and the production of proteases by phagocytes in cases of septicaemia and toxic shock syndrome.
Prophylaxis and treatment of hypercatabolic disease
Successful prophylaxis of AIDS is indicated in those who manifest a persistent displacement in their CD4 cytokines profile from Th1 to Th2.
...
The authors are grateful for the support given to this work by the Hans Eggenberger Foundation in Zurich.
Addresses of the authors:
Prof. Dr. med A. Hassig
Prof. Dr. med. Liang Wen-xi
Dr. med. K. Stampfli
Studiengruppe Ernahrung und Immunitat
Elisabethenstrasse 51
CH-3014 Berne
Switzerland
References
Lehner CF. Zellteilung in mehrzeiligen Organismen. Wie viele, wann und wo? NZZ Nov. 1995; 266:65
Hassig A, Liang WX, Stampfli K. Stress-induced suppression of the cellular immune reactions: On the neuroendocrine control of the immune system. Med Hypotheses 1996;46:55l-555
Mosman TR, Coffman RL. Thl and Th2 cells: Different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 1989;7:145-173.
Mosmann TR, Sad S. The expanding universe of T-cell subsets: Thl, Th2 and more. Immunol Today 1996;17:138-146.
Abbas AK, Murphy KM, Sher A. Functional diversity of helper T-lymphocytes. Nature 1996;383:787-793.
Moore FD. Bodily changes in surgical convalescence. Ann Surg 1953;137:289-315.
Jochum M. Mediatoren der akuten Entzundung und Proteinaseinhibitortherapie bei Polytrauma. In: Posttraumatisches Multiorganversagen. Hrsg: Nast Kol D, Waydhas C, Schweiberer L. Hefte zu Der Unfallchirurg 1996;253:77-79.
Munck AG, Guyre PM, Holbrook N. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrinol Rev 1984;5:25-44.
Decker D, Schondorf M, Bidlingmaier F, Hirner A, von Ruecker AA. Surgical stress induces a shift in the type-1/type-2 T-helper cell balance, suggesting down-regulation of cell-mediated and up-regulation of antibody-mediated immunity commensurate to the trauma. Surgery 1996;119:316-325.
...
28. Gebbers JO. Antioxidantien in der Ernahrung. Forsch Komplementarmed 1995;2:232-288.
Glossary
adrenal – gland secreting the hormone adrenaline and three classes of steroid hormones including the glucocorticoids.
adrenaline – also called epinephrine; hormone secreted by the adrenal glands and having the effect of increasing blood pressure and level of blood glucose. Its release is triggered by stress and it prepares the body for ‘fight or flight’ response.
anergic miliary tuberculosis – disseminated tuberculosis accompanied by diminished response of the immune system to antigen.
autoimmune – against the body’s own tissue.
adrenergic – activated by, secreting or characteristic of adrenaline.
anabolism – the construction of body tissues from simpler molecules –- opposite to catabolism.
antagonist – a substance that blocks the action of another substance by binding to the same receptor site.
antithrombin III – a blood protein that inactivates the blood clotting agent, thrombin.
antibody – also known as immunoglobulin – a protein produced in the blood by B lymphocytes in response to and then counteracting antigen.
antigen – any exogenous substance capable of provoking a specific immune response.
apoptosis – programmed cell death.
ATP – adenosine triphosphate, a nucleotide and principal carrier of chemical energy in cells.
catabolism – the chemical reactions within cells by which complex molecules break down to simpler molecules and energy is released.
catecholamines – a group of adrenergic amines that mimic the actions of the sympathetic nervous system.
cholecystectomy – removal of the gallbladder.
collagens – a family of fibrous proteins secreted by connective tissue cells (fibroblasts) that constitute the major proteins of extracellular matrix particularly in skin and bone.
corticoid – corticosteroid; steroid hormones secreted by the adrenal glands.
cortisol – the most important glucocorticoid hormone secreted by the adrenal gland ; its primary effect is on metabolism.
complement – a system of blood proteins which can be activated by the immune system; involved in control of inflammation and activation of phagocytes.
cytokine – proteins released by cells when in contact with antigen, acting as intercellular mediators/messengers in the generation of an immune response.
cutaneous – of the skin.
DHEA – dihydroepiandosterone.
endogenous – originating from within the body.
envelope – the lipid or glycoprotein membrane that forms the outer shell of some viruses.
exogenous – originating externally to the body.
exocytosis – the process of discharge from a cell of particles too large to be secreted via cell-wall diffusion.
ferritin – molecular complex which is the main form of storage of iron in the body.
fibroblast – connective tissue cell which secretes collagen and other substances.
folic acid – a vitamin of the B6 group concerned with the formation of blood cells and protein synthesis.
fibrinolysis – the action of the enzyme fibrinolysin in the dissolution of blood clots (thrombi).
gammaglobulin – a class of blood proteins of which most are immunglobulins.
granulocyte – category of white blood cell containing granules, including neutrophils, basophils and eosinophils.
glucocorticoid – category of steroid hormone secreted by the adrenal glands affecting carbohydrate metabolism and including cortisone, prednisolone and dexamethasone.
glucosamineglycanes (GAGs) – group of polysaccharides including heparin.
glycocalyx – cell coat.
Gram negative – result of a test in which organisms are stained; those remaining unstained are termed negative and this includes a major category of bacteria with complex cell walls.
Gram positive – the other possible result of the Gram test indicates a class of bacteria that have simple cell-walls.
heparin – a potent anticoagulant secreted by many tissues.
heparinoid – resembling or similar inaction to heparin.
humoral – pertaining to the extracellular fluids, including the blood serum and lymph.
hypercatabolic – a high level of catabolism.
hypothalamus – part of the brain coordinating functions of the autonomic nervous system and regulating body temperature. Releases neurohormones affecting, in particular, the pituitary gland.
hypergammaglobulinaemia – increased level of gammaglobulins in the blood.
IFNs – Interferons – a group of mediators which increase the resistance of cells to viral infections and act as cytokines. the three different IFNs are labelled alpha, beta and gamma, depending on from which cell type they originate. All cells produce one form of IFN.
immunoglobulin – an antibody molecule.
interleukin (IL) – secreted peptide or protein that mediates interactions between white blood cells; a type of cytokine.
inflammatory – response of a tissue to injury or infection.
intercellular – between cells.
intracellular – within the cell or cells.
lipopolysaccharides – a type of molecule which is a major component of the cell wall of Gram negative bacteria; an important antigen.
MALT (mucosa-associated lymphoid tissue) – lymphoid tissue associated with the GI tract, bronchial tree and other mucosa.
macrophages – large cells that ingest (engulf) microorganisms, foreign particles and other cells. Occur in the walls of blood vessels and in other connective tissue and are immobile, becoming actively mobile when stimulated by inflammation.
matrix – the intercellular substance of a tissue.
mesenchymal – pertaining to embryonic connective tissue.
metabolism – the chemical processes that maintain living organisms. Sub-categorised as anabolism and catabolism.
mitosis – cellular division/proliferation.
mitochondrion (pl. mitochondria) – a specialised membrane-bounded structure within each cell in which ATP is synthesised. Mitochondria contain their own nucleic acids and replicate independently.
monoclonal antibodies – antibodies produced by a single clone and which are homogeneous (identical in form).
mucosa – mucous membranes.
neopterin – a substance excreted in increased levels in certain types of disease including viral infection and graft tissue rejection.
neuroendocrine – pertaining particularly to interaction between neural (nerve) and endocrine (hormone) systems.
NO – Nitric Oxide
non-vascular – not in vascular space; not carried in a (blood or lymph) vessel.
noradrenaline – (also called norepinephrine) a catecholamine hormone with a strongly vasopressive action (constrictive of blood vessels).
nuclease – enzymes that split nucleic acids into nucleotides and other substances.
nucleotide – a molecular compound forming nucleic acid; the basic building blocks of RNA and DNA.
nucleoside analogues – molecules/drugs which in certain key ways mimic a nucleoside, a compound into which a nucleotide can be subdivided
O – oxygen radical.
oligo-specificity – specificity for few antigens.
parenterally – not through the alimentary canal (through some other route – intravenous injection etc.).
pathogen – an agent causing disease.
pathogenesis – the development of disease.
pituitary – gland at the base of the brain that regulates the level of neurohormones produced in the hypothalamus
poly-specificity – specificity for many antigens.
proteases – enzymes capable of splitting proteins into smaller molecules (polypeptides).
protozoa – a subkingdom comprising the simplest of animal life.
radical – any group of atoms that goes in and out of chemical combination together without change.
saprophyte – any organism living on dead or decaying organic matter.
septicaemia – the presence of bacteria or bacterial toxins in the blood (blood poisoning).
serine protease – a protease involved in the degradation of extracellular matrix macromolecules, including collagens.
sympathicotony – a stimulated condition of the sympathetic nervous system marked by vascular spasm and raised blood pressure.
systemic – pertaining to or affecting the body as a whole.
TNF – Tumour Necrosis Factor
vegetative – (of nervous system) functioning involuntarily or unconsciously.
virucidal – causing the inactivation or destruction of a virus
Glossary by Chris Baker