Continuum vol.4 no.2
July/Aug 1996
HIV - can you be more specific?
Open Questions Concerning the Specificity of anti-HIV Antibodies:
Do they belong to the group of autoantibodies against cellular structures?
Prof. A. Hässig, Prof. Liang Wen-Xi, Dr. Kurt Stampfli and Dr.
H. Kremer
Summary - Two years ago the working-group of G.M. Shearer demonstrated
that antibodies in the serum of patients with lupus erythematosus and in
the serum of mice with experimentally induced lupus erythematosus are capable
of reacting specifically with glycoproteins 120 and peptides from the HIV-1
envelope. On the basis of these observations we put to ourselves the question
whether this group of anti-HIV antibodies are to be considered as autoantibodies
against cellular structures. A literature search has shown that humoral
autoantibodies occur frequently in patients with AIDS and display the same
specificities as in patients with systemic autoimmune diseases. We would
further point out that the horizontal transmission of HIV structures can
act as the trigger for alloimmune reactions, whereby in recipients with
severely suppressed cellular immune reactions "graft versus host"
reactions can appear, with the development of humoral alloimmune reactions.
Furthermore, we have shown that autoimmune reactions have to be considered
as pathological effects of a continuous inflammatory macrophage activity,
whereby the increased performance of the immune system for the elimination
of exogenous "non-self" structures is directed against endogenous
structures. In this connection, in systemic autoimmune diseases such as
lupus erythematosus the principal factor involved is the continuous hyperactivity
of the B-cell functions. Finally, we have shown that many observations
point to the fact that anti-HIV antibodies with specificity against gp120
and the associated peptides are autoantibodies against cellular actin.
Introduction
Two years ago the working group of G.M. Shearer demonstrated that autoantibodies
in the serum of patients with lupus erythematosus (an autoimmune disease),
and in the serum of mice with experimentally induced lupus erythematosus,
are capable of reacting specifically with glycoprotein (gp) 120 and peptides
of the HIV-1 envelope.(1) The formation of antibodies with anti-HIV specificity
against gp120 and the associated peptides in lupus erythematosus disseminatus
is an indication that the anti-HIV antibodies can be formed within the
framework of B-cell activations in systemic autoimmune diseases. Thus the
question arises whether anti-HIV antibodies should generally be classified
in the large group of autoimmune antibodies against cellular structures.
These are described as antinuclear autoantibodies.(2,3)
Lupus erythematosus disseminatus is the prototype of a systemic autoimmune
disease with widespread involvement of the different organ systems. This
group of diseases also includes rheumatoid arthritis, Sjögren’s syndrome,
scleroderma and mixed forms of inflammatory diseases of the connective
tissues. In these diseases, as a result of an activation of polyclonal
B-cells, one finds a large number of humoral autoantibodies against cellular
and extracellular structures.
Humoral autoantibodies in AIDS
In their review of chronic infections and autoimmunity, M. Abu-Shakra
and Y. Shoenfeld mention that the following autoantibodies have been found
in AIDS patients: antinuclear autoantibodies, rheumatoid factors, antibodies
against erythrocytes, platelets, granulocytes and lymphocytes (T-cells),
as well as antibodies against sperms.(4) In fact, there is extensive literature
available on humoral antibodies in AIDS patients, in which autoantibodies
against actin, myosin, trinitrophenol and thymosin have also been described.(5-7)
In addition, in many works attention is drawn to the close connection between
retroviruses and autoimmune diseases, without it being possible to explain
the pathogenic mechanisms of these relationships.(8)
Horizontal transmission of HIV structures as triggering factors for
autoimmune reactions
RNA viruses which are transcribed by reverse transcriptase into the
DNA of the host genome, where they are integrated as endogenous self-structures,
are known as retroviruses.(9) For this reason the horizontal transmission
of retroviruses may be considered as the transmission of genetic structures
between individuals of the same species. The immunological reactions occurring
in retroviral infections are therefore to be considered as alloimmune reactions
and thus have to be classified as regularities of transplantation immunology.
In this respect it is seen that immune-competent recipients of transplants
react with an effective cellular immune response and thereby reject the
transplant. Moderately immunosuppressed recipients of transplants, such
as those under long-term treatment with cyclosporin, for example, are able
to live with their transplant for long periods without problems. In contrast,
transplant recipients with pronounced suppression of their cellular immune
reactions are as a rule adversely affected by the activated immune system
of the transplant, within the framework of a "graft versus host"
reaction, which at worst can lead to the death of the patient.(10) In blood
transfusions, the elimination of alloreactive genetic structures of the
donor through cellular immune reactions of the recipient is the norm. "Graft
versus host" reactions (GVHRs) are extremely rare.
Acute and chronic "graft versus host" reactions (GVHRs)
The study of GVHRs in mice that were injected with lymphocytes from
the parent animals has provided important insights into the mechanisms
involved in acute and chronic GVHRs. With the injection of donor lymphocytes
which show differences in MHC loci of Classes I and II, from the recipient
animals, an acute lethal immunosuppressive GVHR occurs in the receiver
animals, characterised by anaemia and hypogammaglobulinaemia, with increased
mortality due to increased susceptibility to infections. If the difference
between the donor lymphocytes and the recipient lymphocytes is limited
to MHC loci of Class II a chronic GVHR develops, with stimulation of the
polyclonal B-cells and the formation of humoral autoantibodies within the
framework of a lupus-like syndrome. The stimulation of the formation of
autoantibodies is due to the long-term persistence of alloreactive T-4
cells.(11)
The significance of the shift in the Th-1/Th-2 equilibrium in systemic
autoimmunisation
As we have shown in our previous studies, an acquired suppression of
the cellular immune reactions is the leading factor in the pathogenesis
of AIDS.(12) In this, the opposing behaviour of the humoral and the cellular
immune reactions plays a decisive role. Characteristic for this is the
behaviour of the cytokine profile of the Th-1 and the Th-2 cell-groups
of the CD4+ helper cells. The Th-1 cells produce primarily IL-2, IL-12
and IFNg and through them stimulate the cellular immune reactions. The
Th-2 cells produce mainly IL-4, IL-6 and IL-10, and through them stimulate
the humoral (antibody) immune reactions. The Th-1/Th-2 equilibrium of the
cytokine production of CD4+ lymphocytes is subject to the stress-induced
neuroendocrine control of the immune system. Here, the relationship between
cortisol and dehyro-epiandosterone (DHEA) plays the decisive role.
As explained earlier, the study of alloimmune reactions in rodents has
shown that systemic autoimmunisations are associated with a shift in the
Th-1/Th-2 equilibrium of the CD4+ lymphocytes. Chronic "graft versus
host" reactions show an MHC Class-II-induced activation of the B-cells
with increased IL-4 and decreased IL-2 activity. The excess of T-2 cells
triggers the formation of antinuclear autoantibodies within the framework
of lupus-like inflammatory reactions.(11)
Extensive literature is available on the activation of autoimmune reactions
within the framework of infectious and toxic inflammations.(4) We are grateful
to A. Schaffner and B. Rager-Zisman for an excellent review on virus-induced
autoimmunity.(13) Of special interest for the pathogenesis of AIDS in haemophiliacs
are recent works on the activation of autoimmune reactions in hepatitis
C.(14) The toxic induction of autoimmune reactions has for several years
been the field of research of E. Gleichmann who, with his working-group,
has shown that toxic-induced autoimmune reactions behave in the same way
as alloimmune diseases, whereby in both cases a Th-2 profile of the CD4+
helper cells plays the central role.(15)
The close connection between our retroviruses and autoimmune rheumatic
diseases gave rise to discussions as to whether endogenous retroviruses
play a role in the aetiology of these diseases. However, no conclusive
results were obtained in this respect.(16) The contrary idea, that antiretroviral
antibodies should be classified in the large group of the autoimmune antibodies
has to our knowledge not been considered up till now.
Yin-Yang shifts of macrophage activity as triggering factors for
autoimmune diseases
As already mentioned, during the last ten years it has been recognised
that in immune reactions a state of equilibrium exists between B-cell-dependent
humoral and T-cell-dependent cellular immune reactions, which in all stress
reactions is shifted in favour of the humoral immune reactions and to the
disadvantage of the cellular immune reactions. Immune competence is defined
as a state of equilibrium between humoral and cellular immune reactions.(17)
The processing of the cell fragments resulting from the continuous cell
metabolism is a permanent physiological task of the immune system. The
human organism consists of about 1014 cells.(18) The around
1012 apoptotic cell fragments that are produced daily are recognised
by the cytotoxic T-cells originating from the thymus and by the natural
killer cells, and are transmitted to the macrophages, which process them
without any signs of inflammation. The macrophage activity corresponds
to the Yin situation. It is trophotropic and anabolic (such reactions involve
the formation of body constituents).
In contrast, every stress-induced adjustment of the immune system to
the elimination of exogenous "non-self" structures by humoral
antibodies produced from B-cells is a special, temporary task of the immune
system. It is always associated with an inflammatory activation of the
macrophages. In this process the stress-induced hypercorticolism causes
a reduction of the Th-1 lymphokines IL-2, IL-12 and IFNg. In the macrophages
this causes an increased release of radicals and inflammation mediators
such as IL-1 and TNFa. At the same time this neuroendocrine situation weakens
the containment capacity of the macrophages towards their intracellular
micro-organisms. In addition, their defence against opportunistic micro-organisms
is impaired. This macrophage activity corresponds to the Yang situation.
It is ergotropic and catabolic and is generally described as an acute-phase
reaction.
The Th-1 cytokine profile of the CD4+ lymphocytes corresponds to the
Yin situation of the macrophage activity, while the TH-2 profile corresponds
to the Yang situation of this activity.(19)
According to what has been said, autoimmune diseases are to be understood
as being the pathological effects of a continuous inflammatory macrophage
activity, in which the increased performance of the immune system is directed
towards endogenous structures.
In systemic autoimmune diseases such as lupus erythematosus disseminatus
the persistent hyperactivity of the B-cell functions is the principal factor
responsible for these conditions.
From what has been said, it emerges that there is much that speaks for
the fact that the close association between retroviral diseases and autoimmune
diseases is due to the same mechanism of a continuous hyperactivity of
the B-cell functions. It should therefore be worthwhile to seriously address
the question whether the anti-HIV antibodies can retain the individual
identity accorded them up until now, or whether they should be classified
in the large group of humoral autoantibodies against cellular structures.
In this respect, clarification of the relationship of the retroviral proteins
to the endogenous proteins plays a central role.
Relationships of the glycoprotein gp120 of the HIV envelope to actin
In their work on the occurrence of anti-HIV antibodies with specificity
against gp120 and the accompanying peptides in patients with lupus erythematosus
disseminatus, the working-group of G M Shearer has shown that these antibodies
differ from the anti-DNA autoantibodies of these patients.(1) As a result
of this the question of the specificity of this autoantibody population
remained unanswered. The following arguments serve to indicate that these
could be anti-actin autoantibodies. Glycoprotein 120 and protein 41 are
generally considered to be fission products of protein 160, which is found
in virally infected cells but not in the infectious virus itself. Protein
120 is found only on the surface of protrusions occurring with the exocytosis
of virus-like particles, but not in the released particles themselves.(20)
Thus the question arises whether these glycoproteins, which are described
as envelope proteins of the retroviruses, are endogenous proteins. In the
first description of the human immunodeficiency viruses (HIVs) by the working-group
of L Montagnier, they mentioned the possibility that "the 45k protein
may be due to contamination of the virus by cellular actin, which was present
in immunoprecipitates of all the cell extracts".(21) In fact, the
oxidation of cellular sulphydryl groups leads to the polymerisation of
actin, so that the binding of anti-actin autoantibodies has been suggested
as a sensitive method for the indication of a lymphocyte activation.(22-25)
Anti-actin antibodies are found in healthy individuals, but also especially
in patients with autoimmune diseases. In the latter cases their antibody
profile speaks against cross-reactivity with viral antigens. In all probability
they are natural autoantibodies.(26) They are particularly common in patients
with chronic forms of hepatitis, where they play the same role as disease
indicators as do the anticardiolipin antibodies in syphilis.(14)
In order to explain the relationship of the demonstration of anti-HIV
antibodies to viral or non-viral endogenous structures it seems to us to
be essential to address, on a sound basis, the question of the anti-actin
activity of anti-HIV antibodies against the envelope proteins of HIVs.
Based on these considerations, the sine qua non of an HIV infection
in a case of AIDS is in our opinion invalid. Pathogenically, stress-induced
suppressions of the cellular immune reactions are to be placed at the beginning
of the process. Besides the weakening of the defences against latent infections
and opportunistic micro-organisms, the impairment of the thymus-dependent
immune functions causes an activation of the polyclonal B-cells, which
in turn gives rise to autoimmune reactions with increased production of
humoral autoantibodies. The increase in the anti-HIV antibody level is
to be understood as a marker of this activation of the polyclonal B-cells.
Therefore efforts aimed at the prevention of AIDS have to be directed primarily
towards the correction of stress-induced suppressions of the cellular immune
reactions, whereby suppression of the inflammatory activation of the macrophages
is the most important objective.(27)
Finally, we would like to draw attention to the fact that at the time
when the working-groups of L Montagnier and R.C. Gallo were developing
the anti-HIV antibody test, it was widely believed that any synthesis and
release of reverse transcriptase was an indication of the active production
of retroviruses. Today, however, we know that RNA-controlled DNA polymerases
fulfil certain physiological functions, for example as telomerases in the
stabilisation of the extremities of chromosomes.(28) It is therefore of
interest to consider this particular viewpoint in a critical examination
of the development of these tests at that time. *
The authors are grateful for the support given to this work by the
Hans Eggenberger Foundation in Zurich.
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