Continuum vol.4 no.6
June/July 1997
Pathogenesis of human suppression in hypercatabolic diseases:
AIDS, septicaemia, toxic shock syndrome and protein calorie malnutrition
A. Hässig, H. Kremer, Liang Wen-Xi and K. Stampfli
Summary - The immune systems 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
bodys 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 systems 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 bodys own "self-structures". In our
opinion, we must enlarge the immune systems 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)
Cannon and Selyes concept of stress, which goes back to the 1930s,
includes a variety of external assaults, all of which result in displacing
cell metabolism towards catabolism. Several causes of stress must be distinguished:
they can be psychic, toxic, infectious, traumatic or nutritional in origin,
and the extent of metabolic displacement is determined by the sum of the
contributing factors. Stress responses of limited duration are necessary,
even vital, in special situations such as "fight or flight".
Enduring stress responses, however, are destructive.(2)
A stress-induced catabolic displacement in metabolism depends on the
activation of the neuroendocrine hypothalamus-pituitary-adrenal axis. The
endocrine-induced metabolic displacement is linked to the sympathicotonic
displacement of the vegetative nervous system. The heightened production
of adrenaline by the adrenal gland, and noradrenaline by sympathicotonic
nerve endings, has the effect of concentrating cell metabolism to provide
quickly available energy supplies, ie. glucose, to ready muscles to fight
or take flight. The function of glucocorticoids produced in the adrenal
cortex is to limit the effect of life-threatening overactivation of the
neuroendocrine stress axis. The increase in cortisol together with the
corresponding decline in dihydroepiandrosterone (DHEA) has the ongoing
effect of suppressing T-cell dependent cellular immune responses. This
is due to the counteracting activation of B-cell dependent humoral immune
responses.(2)
Accounts by Mosmann and Coffman of the counteracting cytokine profiles
of CD4 helper lymphocytes provide strong support for the described counteracting
behaviour of the cellular and humoral immune responses.(3) They showed
that CD4 helper cells could be differentiated into two groups, which they
called Th1 and Th2. Th1 cells secrete mainly IL-2, IL-12 and IFN which
stimulate cellular responses; Th-2 cells however, produce mainly IL-4,
IL-6 and IL-10 which stimulate humoral immune responses. Research into
the numerous functions of CD4 helper cells has expanded considerably in
recent years; although their actual functions in anabolic and catabolic
metabolic mechanisms remain poorly understood.(4,5) Surgery is an ideal
means of studying short-term stress responses regarding the relative immune
performance of T and B-cells. In 1953 in his classical work on the course
of surgical stress reactions Moore described four phases following major
surgery.(6)
- 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)
As we have shown in our paper on parenterally transmitted hepatitis
viruses, those that have an envelope prevent being eliminated by the hosts
immune system, because they incorporate some of the bodys own structures
into their envelopes.(12) As a result the hosts immune system becomes
unable to eliminate them. Its only response is an autoimmune one. The oligo-specificity
of these immune responses to the bodys own structures having uniform "altered-self"
specificity triggers systemic inflammatory responses.
From the foregoing, we must distinguish between physiological, poly-specific
and pathological oligo-specific autoimmune reactions. Prevention and treatment
of the latter is limited to disposal of "altered-self" structures,
by removing hypercortisolism and by strengthening anabolic metabolism.
Using virucidal chemotherapy to treat virus-induced autoimmune diseases
is quite inappropriate, because it is not possible to eliminate the pathogen
completely from the body. The best that can be achieved is a return to
a symptomless carrier state.
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)
AIDS and protein calorie malnutrition are diseases in which the sum
total of all causes of stress have brought the body to an irreversible
hypercatabolic state. In AIDS, a major stress factor is the psychological
effect of the medical death sentence pronounced after a diagnosis of "HIV
positive"; in addition, there is the stress of chronic hepatitis B
and C infection. On top of this comes the toxic stress of drugs (opiates,
poppers etc). Central to the deadly endgame is long-term treatment with
nucleoside analogues and folic acid inhibitors, which drastically reduce
the ability of mitchondria to produce ATP, the primary energy source for
all metabolic processes.(20) With children suffering from kwashiorkor,
stress is due mainly to malnutrition, and most of them die from PCP and
anergic miliary tuberculosis.(21)
Septicaemia and toxic shock syndrome following trauma, burns and major
surgery manifest themselves only a few days after the event. Lipopolysaccharide
intoxication from gram-negative bacteria is the main problem. In one-quarter
of cases intoxication is due to toxins from gram-positive germs, ie. staphylococci.
The disease process is dominated by activation of proteases from the humoral
system, which in turn produce other proteases, inflammatory cytokines,
O and NO radicals from granulocytes and macrophages.(7) Lymphocytes, too,
are activated and their mitotic and apoptotic turnover is increased massively.
They reinforce the exocytotic activity of macrophages by increasing the
output of IFN. It is easy to pass a point of no return in this group of
hypercatabolic conditions, beyond which the outcome is always fatal. Treatment
up till now has been aimed at dealing with immunological neutralisation
of bacterial toxins and neutralising inflammatory cytokines by monoclonal
antibodies and receptor antagonists.(22,23)
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.
It is essential to counteract catabolic activation of the immune system
with anabolic treatment. This can be done directly and successfully by
increased production of extra-cellular matrix by fibroblasts. It is most
important to activate the synthesis of glycosamineglycanes (heparin, heparinoids)
by augmenting available GAG precursors. It has been shown that extra-cellular
sulphated hetero-polysaccharides greatly enhance the synthesis of GAGs.(25)
GAGs are incorporated into the glycocalyx of the cell surfaces and reduce
the flow of calcium into the cell, and inhibit binding of cortisone to
its intra-cellular receptors.(26,27) In practice, this means taking cartilage
extracts such as chondroitin sulphate and/or agar from algae as food supplements.
It is also essential to counteract the raised exocytosis of O and NO
radicals and inflammatory mediators from activated macrophages, for which
plant antioxidants ie. flavonoids and tannins, are appropriate. These polyphenols
bind to excess radicals, sequester excess iron and reduce the increased
activation of proteases in catabolic conditions.(28) It is most important
to note that the numerous plant antioxidants contained in, for example,
the Tibetan herbal product Padma 28, far exceeds that in vitamins C and
E and in beta-carotene.(28)
In preventing AIDS it is highly desirable to remove the causes of stress
as far as possible, and it should be noted that in those at risk who are
frequently infected with hepatitis, treatment with antioxidants such as
Padma 28 is so effective as to make the patients survive as symptomless
carriers.(28)
In cases of septicaemia and toxic shock syndrome following trauma, burns
and major surgery emphasis must be laid on prevention rather than treatment.
It is our considered opinion that rapid administration of high doses of
intravenous gammaglobulin is essential. *
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
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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 bodys 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