S30
`S30
`
`Annals of the Rheumatic Diseases 1993; 52: S30-S38
`Annals of the Rheumatic Diseases 1993; 52: S30-S38
`
`A reappraisal of the evidence that rheumatoid
`A reappraisal of the evidence that rheumatoid
`arthritis and several other idiopathic diseases are
`arthritis and several other idiopathic diseases are
`slow bacterial infections
`slow bacterial infections
`
`G A W Rook, P M Lydyard, J L Stanford
`G A W Rook, P M Lydyard, J L Stanford
`
`The
`idea
`that
`several
`'idiopathic'
`or
`The idea that several 'idiopathic' or
`'autoimmune' diseases are in fact caused by
``autoimmune' diseases are in fact caused by
`bacteria, probably related to the mycobacteria,
`bacteria, probably related to the mycobacteria,
`which grow very slowly in the host, has been
`which grow very slowly in the host, has been
`for
`reported
`time.
`some
`The diseases
`reported for some time. The diseases
`concerned are rheumatoid arthritis
`(RA),
`concerned are rheumatoid arthritis (RA),
`sarcoidosis, the inflammatory bowel diseases
`sarcoidosis, the inflammatory bowel diseases
`(Crohn's disease and ulcerative colitis), psor-
`(Crohn's disease and ulcerative colitis), psor-
`iasis, Takayasu's arteritis, and conceivably,
`iasis, Takayasu's arteritis, and conceivably,
`'giant cell arteritides', such as polymyalgia
``giant cell arteritides', such as polymyalgia
`rheumatica. New data have increased the
`rheumatica. New data have increased the
`appeal of this hypothesis, and technical devel-
`appeal of this hypothesis, and technical devel-
`opments now make it accessible to investi-
`opments now make it accessible to investi-
`gation. The first section of this paper outlines
`gation. The first section of this paper outlines
`features
`the
`of
`accepted
`slow
`bacterial
`the features of accepted slow bacterial
`infections, and points out the parallels with
`infections, and points out the parallels with
`RA, inflammatory bowel disease, and sarcoi-
`RA, inflammatory bowel disease, and sarcoi-
`dosis, including the presence of autoanti-
`dosis, including the presence of autoanti-
`bodies, agalactosyl IgG, and arthritis. The rest
`bodies, agalactosyl IgG, and arthritis. The rest
`of the paper analyses these similarities
`in
`of the paper analyses these similarities in
`greater detail and reviews the evidence for two
`greater detail and reviews the evidence for two
`other crucial points: firstly, that there is altered
`other crucial points: firstly, that there is altered
`responsiveness to mycobacteria in RA (and
`responsiveness to mycobacteria in RA (and
`sarcoidosis); secondly, that mycobacteria can
`sarcoidosis); secondly, that mycobacteria can
`exist in forms which are difficult to detect by
`exist in forms which are difficult to detect by
`histological
`techniques,
`conventional
`and
`conventional histological techniques, and
`difficult to culture, but which are associated
`difficult to culture, but which are associated
`with the 'autoimmune' diseases considered
`with the `autoimmune' diseases considered
`here.
`here.
`
`Slow bacterial infections
`Slow bacterial infections
`Several
`bacterial
`notably
`the
`genera,
`Several bacterial genera, notably the
`spirochaetes (Lyme disease and syphilis) and
`spirochaetes (Lyme disease and syphilis) and
`mycobacteria,
`slowly
`the
`can cause very
`the mycobacteria, can cause very slowly
`characteristically
`evolving
`infections
`with
`evolving infections with characteristically
`varied presentation and complex evolution.
`varied presentation and complex evolution.
`These features are due in part to unexplained
`These features are due in part to unexplained
`tropisms which localise the infection in certain
`tropisms which localise the infection in certain
`sites, and in part to the 'spectrum' of immune
`sites, and in part to the 'spectrum' of immune
`responses which they can evoke. This can be
`responses which they can evoke. This can be
`dominated by T cell activity, as in tuberculoid
`dominated by T cell activity, as in tuberculoid
`or by antibody formation,
`leprosy,
`in
`leprosy, or by antibody formation, as in
`as
`lepromatous leprosy. Moreover, the nature of
`lepromatous leprosy. Moreover, the nature of
`the response can change with time, resulting in
`the response can change with time, resulting in
`extraordinarily complex sequences of
`the
`the extraordinarily complex sequences of
`classically
`manifestations
`in
`clinical
`clinical manifestations classically seen in
`seen
`untreated leprosy or syphilis.
`untreated leprosy or syphilis.
`When the antibody response is dominant
`When the antibody response is dominant
`these infections can be accompanied by a
`these infections can be accompanied by a
`reactive arthritis, by autoantibodies including
`reactive arthritis, by autoantibodies including
`rheumatoid factor, and by strikingly raised
`rheumatoid factor, and by strikingly raised
`immunoglobulin G
`agalactosyl
`of
`levels
`levels of agalactosyl immunoglobulin G
`(Gal(O)). This pattern of disease mimics
`(Gal(0)). This pattern of disease mimics
`features of the 'idiopathic' or 'autoimmune'
`features of the 'idiopathic' or `autoimmune'
`disorders, particularly RA.
`disorders, particularly RA.
`
`When the T cell mediated response is
`When the T cell mediated response is
`prominent in
`slow bacterial
`a
`infection,
`prominent in a slow bacterial infection,
`autoantibody formation can be less striking,
`autoantibody formation can be less striking,
`and the disease process generates T cell
`and the disease process generates T cell
`dependent granulomata with variable degrees
`dependent granulomata with variable degrees
`of central necrosis. This necrosis is seen in
`of central necrosis. This necrosis is seen in
`tuberculosis and in the gumma of tertiary
`tuberculosis and in the gumma of tertiary
`syphilis, and overlap with the histological
`syphilis, and overlap with the histological
`appearance of rheumatoid skin nodules has
`appearance of rheumatoid skin nodules has
`often been noted. However, necrosis is not a
`often been noted. However, necrosis is not a
`feature of infections due to Mycobacterium
`feature of infections due to Mycobacterium
`intracellulare and M malmoense in the cervical
`intracellulare and M malmoense in the cervical
`lymph nodes of children, and the histology of
`lymph nodes of children, and the histology of
`these infections more closely resembles that of
`these infections more closely resembles that of
`sarcoidosis.
`sarcoidosis.
`Slow bacterial infections have a predilection
`Slow bacterial infections have a predilection
`for the lungs (tuberculosis), skin (leprosy, M
`for the lungs (tuberculosis), skin (leprosy, M
`ulcerans, M marinum), and gut. The ability of
`ulcerans, M marinum), and gut. The ability of
`mycobacteria to infect the gut deserves further
`mycobacteria to infect the gut deserves further
`emphasis. Some variants of M avium (myco-
`emphasis. Some variants of M avium (myco-
`bactin dependent), including the organism
`bactin dependent), including the organism
`known as M paratuberculosis, cause a chronic
`known as M paratuberculosis, cause a chronic
`granulomatous intestinal infection in cattle,
`granulomatous intestinal infection in cattle,
`goats, and deer, and recently a similar disease
`goats, and deer, and recently a similar disease
`has been described in monkeys.' With loss of
`has been described in monkeys.' With loss of
`CD4 T cells in HIV infected persons, a limited
`CD4 T cells in HIV infected persons, a limited
`number of serotypes of mycobactin indepen-
`number of serotypes of mycobactin indepen-
`dent M avium can cause similar appearances in
`dent M avium can cause similar appearances in
`the human intestine.2 Such infections with
`the human intestine.' Such infections with
`conventional mycobacteria are in many ways
`conventional mycobacteria are in many ways
`similar to the inflammatory bowel disease
`similar to the inflammatory bowel disease
`spectrum.3 In fact sarcoidosis, Crohn's disease,
`spectrum.' In fact sarcoidosis, Crohn's disease,
`and RA tend, like the established slow bacterial
`and RA tend, like the established slow bacterial
`infections, to affect the lungs, skin, and gut.
`infections, to affect the lungs, skin, and gut.
`Thus although Crohn's disease is an inflam-
`Thus although Crohn's disease is an inflam-
`matory bowel disease, the lung lavages of these
`matory bowel disease, the lung lavages of these
`patients
`grossly abnormal,4 and lung
`are
`patients are grossly abnormal,4 and lung
`damage is a serious complication in some cases
`damage is a serious complication in some cases
`of RA.5 Similarly, there is evidence for gut
`of RA.' Similarly, there is evidence for gut
`abnormalities in sarcoidosis6 and RA,7 and
`abnormalities in sarcoidosis6 and RA,' and
`arthritis can occur in all of these conditions.8 9
`arthritis can occur in all of these conditions.' 9
`It should be stressed that this pattern of disease
`It should be stressed that this pattern of disease
`is quite unlike that seen in the organ specific
`is quite unlike that seen in the organ specific
`disorders of proved autoimmune aetiology
`disorders of proved autoimmune aetiology
`(such as the endocrinopathies or Myasthenia
`(such as the endocrinopathies or Myasthenia
`gravis).
`gravis).
`Whipple's disease is a rare slow bacterial
`Whipple's disease is a rare slow bacterial
`infection which illustrates particularly well the
`infection which illustrates particularly well the
`conceptual and diagnostic dilemma. This
`conceptual and diagnostic dilemma. This
`disease is associated with the presence, within
`disease is associated with the presence, within
`macrophages, of non-cultivable organisms,
`macrophages, of non-cultivable organisms,
`demonstrable by electron microscopy and
`demonstrable by electron microscopy and
`periodic
`acid-Schiff
`by
`the
`sometimes
`sometimes by the periodic acid-Schiff
`technique. The commonest symptoms at
`technique. The commonest symptoms at
`diagnosis are weight loss, diarrhoea, arthral-
`diagnosis are weight loss, diarrhoea, arthral-
`gias, abdominal pain, and skin changes. The
`gias, abdominal pain, and skin changes. The
`
`Department ofMedical
`Department of Medical
`Microbiology,
`Microbiology,
`University College
`University College
`London Medical
`London Medical
`School, London,
`School, London,
`United Kingdom
`United Kingdom
`G A W Rook
`G A W Rook
`J L Stanford
`J L Stanford
`Department of
`Department of
`Immunology,
`Immunology,
`University College
`University College
`London Medical
`London Medical
`School, London,
`School, London,
`United Kingdom
`United Kingdom
`P M Lydyard
`P M Lydyard
`Correspondence to:
`Correspondence to:
`Dr G A W Rook,
`Dr G A W Rook,
`Department of Medical
`Department of Medical
`Microbiology, University
`Microbiology, University
`College London Medical
`College London Medical
`School, 67-73 Riding House
`School, 67-73 Riding House
`St, London W1P 7PP,
`St, London WI P 7PP,
`United Kingdom.
`United Kingdom.
`
`(cid:9)
`

`

`Idiopathic diseases are slow bacterial infections: reappraisal of evidence
`Idiopathic diseases are slow bacterial infections: reappraisal of evidence (cid:9)
`
`S31
`S31
`
`infection progresses so slowly that symptoms
`infection progresses so slowly that symptoms
`can be present for 10 years before a diagnosis
`can be present for 10 years before a diagnosis
`is made. The presentation is very variable, and
`is made. The presentation is very variable, and
`the infection can mimic Crohn's disease or
`the infection can mimic Crohn's disease or
`sarcoidosis,10 or even present as a longstanding
`sarcoidosis," or even present as a longstanding
`seronegative polyarthritis."
`It has recently
`seronegative polyarthritis." It has recently
`been reported that the sequence of the gene
`been reported that the sequence of the gene
`encoding the 16S ribosomal RNA of the
`encoding the 16S ribosomal RNA of the
`organisms from a single case of Whipple's
`organisms from a single case of Whipple's
`disease most closely resembled that found in
`disease most closely resembled that found in
`Rhodococcus, Arthrobacter, and Streptomyces,
`Rhodococcus, Arthrobacter, and Streptomyces,
`and slightly less closely resembled the sequence
`and slightly less closely resembled the sequence
`found in mycobacteria.'2
`found in mycobacteria."
`
`Reactive arthritis
`Reactive arthritis
`As arthritis can occur in RA, Crohn's disease,9
`As arthritis can occur in RA, Crohn's disease,'
`sarcoidosis,8 and psoriasis, it
`is particularly
`sarcoidosis,8 and psoriasis, it is particularly
`important to note that the established slow
`important to note that the established slow
`bacterial infections can also be accompanied by
`bacterial infections can also be accompanied by
`this symptom. This is sometimes owing to
`this symptom. This is sometimes owing to
`direct infection of the joint. Most slow bacterial
`direct infection of the joint. Most slow bacterial
`infections, however, can also be accompanied
`infections, however, can also be accompanied
`by a 'reactive arthritis', similar in some ways to
`by a 'reactive arthritis', similar in some ways to
`transiently
`patients
`that
`in
`and
`seen
`that seen in patients transiently and
`superficially infected in the gut or genitour-
`superficially infected in the gut or genitour-
`inary tract by Yersinia, Chlamydia, Shigella,
`inary tract by Yersinia, Chlamydia, Shigella,
`Salmonella, etc. This kind of arthritis can be the
`Salmonella, etc. This kind of arthritis can be the
`presenting symptom in Whipple's disease,"'
`presenting symptom in Whipple's disease,"
`and it can be seen in a tninority of patients with
`and it can be seen in a minority of patients with
`leprosy,13 14 tuberculosis,15-19 M avium infec-
`leprosy,'3 14 tuberculosis,'5-'" M avium infec-
`or after BCG immunotherapy for
`tion,20
`tion," or after BCG immunotherapy for
`cancer.' 22 It is characteristic of reactive
`characteristic
`cancer.2' 22
`of reactive
`is
`It
`arthritis that the genome of the causative
`arthritis that the genome of the causative
`organism is not present within the joints but
`organism is not present within the joints but
`that the joint contains both antigens derived
`that the joint contains both antigens derived
`from the organism, and T cells responding to
`from the organism, and T cells responding to
`antigens.23-2' T cells responding to
`those
`those antigens.'" T cells responding to
`antigens that are confined to the mycobacteria,
`antigens that are confined to the mycobacteria,
`and to a very closely related genus, are also
`and to a very closely related genus, are also
`found in rheumatoid joints (see below).
`found in rheumatoid joints (see below).
`
`Epidemiology
`Epidemiology
`The epidemiology of sarcoidosis and Crohn's
`The epidemiology of sarcoidosis and Crohn's
`disease points to an environmental factor,27-29
`disease points to an environmental factor,27-29
`likely to be an infection, because there is well
`likely to be an infection, because there is well
`documented clustering in space and time, and
`documented clustering in space and time, and
`geographical variation independent of race.
`geographical variation independent of race.
`The epidemiology of RA is
`less obvious,
`The epidemiology of RA is less obvious,
`though studies of fossil evidence suggest that
`though studies of fossil evidence suggest that
`it is a recent disease, which has behaved like an,
`it is a recent disease, which has behaved like an
`epidemic in the West, but has now reached a
`epidemic in the West, but has now reached a
`peak and may even be declining. Meanwhile,
`peak and may even be declining. Meanwhile,
`there is evidence that a similar epidemic has
`there is evidence that a similar epidemic has
`begun in Africa, where incidence in peoples of
`begun in Africa, where incidence in peoples of
`background
`genetic
`depends
`similar
`on
`similar genetic background depends on
`whether they they live
`in urban or rural
`whether they they live in urban or rural
`environments.
`Similarly, twin concordance
`environments. Similarly, twin concordance
`studies show that RA is about 30% genetic, so
`studies show that RA is about 30% genetic, so
`an environmental factor is involved, and in a
`an environmental factor is involved, and in a
`recent review Silman concludes that this factor
`recent review Silman concludes that this factor
`is most likely to be an infection.30
`is most likely to be an infection.30
`
`Serological changes in patients with
`Serological changes in patients with
`Crohn's disease and RA, and in their
`Crohn's disease and RA, and in their
`spouses
`spouses
`The autoantibodies seen in RA clearly do not
`The autoantibodies seen in RA clearly do not
`constitute evidence that the disease is primarily
`constitute evidence that the disease is primarily
`
`due to autoimmunity. These autoantibodies,
`due to autoimmunity. These autoantibodies,
`including rheumatoid factor, are essentially
`including rheumatoid factor, are essentially
`similar to those seen in the accepted slow
`similar to those seen in the accepted slow
`bacterial infections,3'
`particularly when the
`bacterial infections,' particularly when the
`antibody
`prominent,
`is
`in
`antibody response is prominent, as in
`response
`as
`lepromatous leprosy. It is possible that they
`lepromatous leprosy. It is possible that they
`contribute to immunopathology, but it is no
`contribute to immunopathology, but it is no
`more logical to regard them as the primary
`more logical to regard them as the primary
`problem in RA than it would be in the
`problem in RA than it would be in the
`mycobacterial diseases, unless the greater titres
`mycobacterial diseases, unless the greater titres
`or higher affinities, or both, characteristic of
`or higher affinities, or both, characteristic of
`RA cause them to become pathogenic.
`RA cause them to become pathogenic.
`Interestingly, some of the serological changes
`Interestingly, some of the serological changes
`seen in RA and Crohn's disease provide rather
`seen in RA and Crohn's disease provide rather
`strong evidence for an infectious component.
`strong evidence for an infectious component.
`Lymphocytotoxic activity,
`detected in
`the
`Lymphocytotoxic activity, detected in the
`serum of patients with Crohn's disease, was
`serum of patients with Crohn's disease, was
`also present in the serum of their spouses.32 In
`also present in the serum of their spouses.' In
`addition spouses of patients with RA, like the
`addition spouses of patients with RA, like the
`themselves, have raised
`patients
`levels of
`patients themselves, have raised levels of
`agalactosyl IgG (Gal(0)),33 (discussed further
`agalactosyl IgG (Gal(0)),33 (discussed further
`below), the PR4 idiotype,34 and an apparent
`below), the PR4 idiotype,34 and an apparent
`change in the
`activity of a DNA repair
`change in the activity of a DNA repair
`enzyme.35
`observations
`These
`all
`enzyme.' These observations are all
`are
`compatible with a transmissible agent. Indeed
`compatible with a transmissible agent. Indeed
`they are difficult to explain in any other way.
`they are difficult to explain in any other way.
`
`HLA, sex differences, and spouses
`HLA, sex differences, and spouses
`The findings reviewed in the previous section
`The findings reviewed in the previous section
`imply at first sight that the spouses of patients
`imply at first sight that the spouses of patients
`with RA ought to develop the disease. In fact
`with RA ought to develop the disease. In fact
`there is no reason why this should happen, and
`there is no reason why this should happen, and
`we must distinguish between transmission of
`we must distinguish between transmission of
`an infection and development of the disease.
`an infection and development of the disease.
`Disease is merely one possible outcome of the
`Disease is merely one possible outcome of the
`host/microbe
`relation.
`there
`fact
`In
`host/microbe relation. In fact there are
`are
`numerous reports of Crohn's disease devel-
`numerous reports of Crohn's disease devel-
`oping in spouses, and even sarcoidosis has
`oping in spouses, and even sarcoidosis has
`appeared simultaneously in spouses.36 In RA
`appeared simultaneously in spouses." In RA
`this may not occur because of the HIA
`this may not occur because of the HLA
`associations and sex differences. The spouse
`associations and sex differences. The spouse
`tends to be male and is not necessarily
`tends to be male and is not necessarily
`genetically
`instance, DR4
`(for
`susceptible
`genetically susceptible (for instance, DR4
`positive). Thus even if the agent is transmitted
`positive). Thus even if the agent is transmitted
`to the spouse it need not cause disease.
`to the spouse it need not cause disease.
`Transmission of mycobacterial disease within
`Transmission of mycobacterial disease within
`families can parallel this situation for similar
`families can parallel this situation for similar
`reasons. HLA associations
`also
`occur in
`reasons. HLA associations also occur in
`leprosy (though the relevant haplotypes are
`leprosy (though the relevant haplotypes are
`different),37 and sex differences (F>M) in RA
`different)," and sex differences (F>M) in RA
`are mirrored by the reverse sex difference in
`are mirrored by the reverse sex difference in
`tuberculosis, which is markedly commoner in
`tuberculosis, which is markedly commoner in
`men.
`men.
`
`T cell mediated autoimmunity in RA,
`T cell mediated autoimmunity in RA,
`inflammatory bowel diseases, and
`inflammatory bowel diseases, and
`sarcoidosis
`sarcoidosis
`If neither the arthritis nor the autoantibodies
`If neither the arthritis nor the autoantibodies
`necessarily point to an autoimmune aetiology,
`necessarily point to an autoimmune aetiology,
`can we deduce anything from the T cell
`can we deduce anything from the T cell
`responses in these diseases? There have been
`responses in these diseases? There have been
`extensive searches for autoreactive T cells.
`extensive searches for autoreactive T cells.
`Occasional T cell clones responsive to type II
`Occasional T cell clones responsive to type II
`collagen can be detected in some rheumatoid
`collagen can be detected in some rheumatoid
`synovial
`fluid T cell
`populations.38 Such
`synovial fluid T cell populations.' Such
`reactivity is not present in all patients, however,
`reactivity is not present in all patients, however,
`and can be found in the peripheral blood of
`and can be found in the peripheral blood of
`normal donors.39 Moreover, there is now some
`normal donors." Moreover, there is now some
`
`

`

`S32 (cid:9)
`S32
`
`Rook, Lydyard, Stanford
`Rook, Lydyard, Stanford
`
`doubt about the validity of at least some work
`doubt about the validity of at least some work
`on T cell reactivity to collagen because the
`on T cell reactivity to collagen because the
`pepsin used to prepare it is a potent T cell
`pepsin used to prepare it is a potent T cell
`stimulus and has been shown to account for
`stimulus and has been shown to account for
`much of the apparent reactivity in both murine
`much of the apparent reactivity in both murine
`and human studies.40
`and human studies."
`The possibility that there is autoreactivity to
`The possibility that there is autoreactivity to
`heat shock proteins (hsps) is more difficult to
`heat shock proteins (hsps) is more difficult to
`analyse. There is concrete proof that sequences
`analyse. There is concrete proof that sequences
`derived from the mycobacterial 65 kilodalton
`derived from the mycobacterial 65 kilodalton
`hsp are relevant to most, perhaps all, the
`hsp are relevant to most, perhaps all, the
`rodent models of arthritis,4'-44 so it was logical
`rodent models of arthritis,41-" so it was logical
`to seek evidence for responses to this protein
`to seek evidence for responses to this protein
`in human disease. The data on this point are
`in human disease. The data on this point are
`conflicting, as discussed later, but most authors
`conflicting, as discussed later, but most authors
`agree that there are at least some T cells
`agree that there are at least some T cells
`mycobacterial
`responding
`hsp65
`in
`to
`responding to mycobacterial hsp65 in
`rheumatoid joints. Do any of these T cells also
`rheumatoid joints. Do any of these T cells also
`recognise the human homologue, which is the
`recognise the human homologue, which is the
`60 kilodalton mitochondrial hsp? There are
`60 kilodalton mitochondrial hsp? There are
`reports that some T cells from reactive arthritis
`reports that some T cells from reactive arthritis
`and from juvenile chronic arthritis do indeed
`and from juvenile chronic arthritis do indeed
`have this property, though the frequency of
`have this property, though the frequency of
`such cells is not clear.45 When the epitopes
`such cells is not clear." When the epitopes
`recognised by other clones responding to the
`recognised by other clones responding to the
`mycobacterial hsp65 were studied they turned
`mycobacterial hsp65 were studied they turned
`only
`with
`be
`limited
`sequences
`out
`to
`out to be sequences with only limited
`homology to the human protein.46 These
`homology to the human protein." These
`the corresponding
`clones will respond to
`clones will respond to the corresponding
`human sequence, but only when this is present
`human sequence, but only when this is present
`at high concentrations. At first sight this seems
`at high concentrations. At first sight this seems
`to imply that this cross reactivity is irrelevant,
`to imply that this cross reactivity is irrelevant,
`but recent findings in a quite different model
`but recent findings in a quite different model
`suggest that this conclusion may be premature.
`suggest that this conclusion may be premature.
`A study of the sequence from myelin basic
`A study of the sequence from myelin basic
`protein, which is involved in the pathogenesis
`protein, which is involved in the pathogenesis
`of experimental autoallergic encephalitis in
`of experimental autoallergic encephalitis in
`mice, has shown that the peptide causing
`mice, has shown that the peptide causing
`disease has a remarkably low affinity for the
`disease has a remarkably low affinity for the
`major histocompatibility complex (MHC).
`major histocompatibility complex (MHC).
`Changes to the sequence which increase the
`Changes to the sequence which increase the
`binding to the MHC while conserving the
`binding to the MHC while conserving the
`moieties involved in the interaction with T cells
`moieties involved in the interaction with T cells
`allow the same T cells to recognise a much
`allow the same T cells to recognise a much
`lower concentration of the peptide. However,
`lower concentration of the peptide. However,
`such a peptide, instead of inducing the disease
`such a peptide, instead of inducing the disease
`actually
`readily,
`blocks
`disease
`more readily, actually blocks disease
`more
`induction.47 Presumably this peptide leads to
`induction.' Presumably this peptide leads to
`suppression, inactivation, or elimination of the
`suppression, inactivation, or elimination of the
`it, whereas the
`T cells which recognise
`T cells which recognise it, whereas the
`response to the original peptide, with its low
`response to the original peptide, with its low
`affinity binding to the MHC, escapes the
`affinity binding to the MHC, escapes the
`regulatory
`mechanism.
`relevant
`The
`relevant regulatory mechanism. The
`implications for the hsp60 story are clear. We
`implications for the hsp60 story are clear. We
`cannot dismiss it yet.
`cannot dismiss it yet.
`Another aspect of the hsp60 story is also
`Another aspect of the hsp60 story is also
`suggestive. Several groups have noted that
`suggestive. Several groups have noted that
`murine or human T cell clones or lines
`murine or human T cell clones or lines
`responsive to the human or bacterial hsp may
`responsive to the human or bacterial hsp may
`recognise stressed autologous cells and can
`recognise stressed autologous cells and can
`indeed kill them.48-51 This implies that the
`indeed kill them."' This implies that the
`mitochondrial hsp60 can be processed and that
`mitochondrial hsp60 can be processed and that
`cross reactive peptides can be presented. This
`cross reactive peptides can be presented. This
`may well be a physiological mechanism with
`may well be a physiological mechanism with
`some as yet obscure regulatory role. At present
`some as yet obscure regulatory role. At present
`we are unaware of any studies aimed at finding
`we are unaware of any studies aimed at finding
`out whether hsp65 reactive T cells from
`out whether hsp65 reactive T cells from
`patients with tuberculosis or leprosy are also
`patients with tuberculosis or leprosy are also
`able to recognise such stressed cells in the
`able to recognise such stressed cells in the
`absence of external antigen. If, as we predict,
`absence of external antigen. If, as we predict,
`
`they can do so, it will be difficult to claim that
`they can do so, it will be difficult to claim that
`this mechanism is specific for RA, or a primary
`this mechanism is specific for RA, or a primary
`event in its pathogenesis.
`event in its pathogenesis.
`The complexity of the hsp60 story has been
`The complexity of the hsp60 story has been
`further increased by a series of publications
`further increased by a series of publications
`claiming that cells can express not just MHC
`claiming that cells can express not just MHC
`bound peptides derived from the hsp60 but
`bound peptides derived from the hsp60 but
`even macromolecular forms detectable with a
`even macromolecular forms detectable with a
`variety
`polyclonal
`of
`monoclonal
`and
`variety of polyclonal and monoclonal
`the
`antibodies
`mycobacterial52
`antibodies to the mycobacterial" or
`to
`or
`mammalian homologues.53 54 Whereas this
`mammalian homologues." 54 Whereas this
`work certainly suggests that something cross
`work certainly suggests that something cross
`reactive with this family of hsps can appear on
`reactive with this family of hsps can appear on
`mammalian cell membranes, there
`is no
`mammalian cell membranes, there is no
`evidence that this is in fact the hsp60. Indeed
`evidence that this is in fact the hsp60. Indeed
`the monoclonal antibody ML30 used in some
`the monoclonal antibody ML30 used in some
`of these studies binds to numerous mammalian
`of these studies binds to numerous mammalian
`constituents. Nevertheless, a cross reactive
`constituents. Nevertheless, a cross reactive
`molecule may be relevant, and its identification
`molecule may be relevant, and its identification
`is awaited with interest.
`is awaited with interest.
`Thus although there are several 'loose ends',
`Thus although there are several 'loose ends',
`particularly in relation to the role of hsps as
`particularly in relation to the role of hsps as
`autoantigens, there is no evidence that there
`autoantigens, there is no evidence that there
`are autoimmune manifestations in RA which
`are autoimmune manifestations in RA which
`are not routinely
`in slow bacterial
`are not routinely seen in slow bacterial
`seen
`infections, with perhaps the exception ofhigher
`infections, with perhaps the exception of higher
`affinity self reactive antibodies.
`affinity self reactive antibodies.
`
`Second signals and autoreactive T cells
`Second signals and autoreactive T cells
`An unresolved theoretical issue is relevant
`An unresolved theoretical issue is relevant
`here. It is not clear that autoreactive T cells can
`here. It is not clear that autoreactive T cells can
`function in the absence of a 'second signal'.55
`function in the absence of a 'second signor."
`This second signal may be provided by those
`This second signal may be provided by those
`microbial components which are recognised
`microbial components which are recognised
`independently of the receptors on T cells and
`independently of the receptors on T cells and
`B cells. These components include glycolipids,
`B cells. These components include glycolipids,
`polyanions, peptidoglycans, formyl peptides,
`polyanions, peptidoglycans, formyl peptides,
`mannans, glucans, etc, and constitute the
`mannans, glucans, etc, and constitute the
`'adjuvant' components without which most
``adjuvant' components without which most
`animal models of autoreactivity cannot be
`animal models of autoreactivity cannot be
`elicited. This requirement for a second signal
`elicited. This requirement for a second signal
`ensures that potentially autoreactive responses
`ensures that potentially autoreactive responses
`are activated only when an infectious agent is
`are activated only when an infectious agent is
`present, and may even allow the immune
`present, and may even allow the immune
`elementary
`perform
`response to perform some elementary
`some
`response
`to
`'taxonomy', and so activate the mechanism
``taxonomy', and so activate the mechanism
`appropriate for the organism in question.56
`appropriate for the organism in question."
`Does sustained T cell autoreactivity occur
`Does sustained T cell autoreactivity occur
`without the continuing presence of mic