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The infectious etiology of rheumatoid arthritis.

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53 I
FUTURE RESEARCH DIRECTIONS
THE INFECTIOUS ETIOLOGY OF
RHEUMATOID ARTHRITIS
NEW CONSIDERATIONS
J. CLAUDE BENNETT
Several possible mechanisms of chronic inflammatory arthritis that might be initiated by infectious agents
are discussed. Some recent information on mycoplasma
infections, long-term virus infections, and shed bacterial
components provides the bases for new experimental approaches. Currently, evidence of involvement of mycoplasma or viral agents in rheumatoid arthritis is tenuous.
Chronic peptidoglycan-immunecomplex formation is a
consideration that has been discussed, but only recently
pursued in depth. It may well be that experimental studies
on the infectious etiology of rheumatoid arthritis will be
revitalized through an appreciation of the bacterial antigen load in the gastrointestinal tract. The experimental
vehicles for testing this possibility are available and should
be directly applicable at the clinical level.
Throughout the history of rheumatic diseases no
possible basis for pathogenesis has been more discussed
or pursued, and proved more disappointing, than that of
infection. Work in the fields of bacteriology, virology,
From the University of Alabama in Birmingham.
Presented at the New England Rheumatism Society Meeting,
Hanover, New Hampshire, October 7-8, 1977.
J. Claude Bennett, M.D.: Professor of Medicine, Director,
Division of Clinical lmmunology and Rheumatology, Chairman, D e
partment of Microbiology, University of Alabama in Birmingham.
Address reprint requests to J. Claude Bennett, M.D., University of Alabama in Birmingham, University Station, Birmingham AL
35294.
Arthritis and Rheumatism, Vol. 21, No. 5 (June 1978)
and immunology has contributed in an extraordinary
way to our understanding of inflammatory disease and
host responses. Nevertheless, the burning issue of the
events responsible for the initiation of a chronic, sustained arthritis of the rheumatoid type, which waxes and
wanes over many years and may cause generalized systemic reactions, remains to be solved.
Although much has been said about the possible
infectious basis of Reiter’s syndrome and certain other
reactive arthritides (see Ward and Atcheson, reference
1 ), the scope of this discussion will be limited primarily
to rheumatoid arthritis. Other diseases, however, will
occasionally be cited for illustrative purposes.
The literature dealing with the etiology of rheumatoid arthritis reads like a twentieth century microbestiary with descriptions of such diverse microorganisms as the streptococcus and its various subcategories;
mycoplasma, including M fermentans, arthritidis, hyorhinis, and hominis; clostridia; diphtheroids; and viruses (2). Some degree of categorization is needed to
gain a perspective in how various infectious agents
might be involved in the pathogenesis of arthritis. Table
1 depicts four general ways in which arthritis associated
with infections might be classified. In the first there is
multiplication of an agent within a joint space, classic
examples comprising pyogenic bacteria, mycobacteria,
certain fungi, and certain viruses such as smallpox. The
second is that in which the infectious agent localizes in
BENNETT
532
Table 1. Four General Mechanisms by Which Infeciious Agents Can
Initiate Synovitis
~~
~
~~
~
Classification of Arthritis Associated with Infections
I Multiplicationof the agent within a joint space
11 Infectious agent or its derived antigens localize in the joint
space and initiate an immune response
I11 Infectious agent or its derived antigens at a distant site, but
the associated immune response causes arthritis
IV Infectious agents produce “arthritogenictoxins”
the joint space and initiates an immune response. This
includes Mycoplasma hyorhinis in swine (3), herpes simplex in rabbits and guinea pigs, rubella in human beings
(4), and organisms within immune complexes such as
hepatitis B virus ( 5 ) and, perhaps, the meningococcus
(6). The third category includes infections in which the
agent is at a distant site, but the associated immune
response causes arthritis. Major examples include rheumatic fever, in which crossreacting streptococcal antigens initiate an autoimmune process, and certain disorders in which there is often antecedent infection. This
latter group is exemplified by Reiter’s syndrome (7)
following Shigella or Salmonella infections of the gastrointestinal system, and the reactive arthritis associated
with Yersinia enterocolitica (8). Arthritis caused by toxins makes up the fourth category. Examples include the
epidemic forms of arbovirus infections due to chiku-
ngunya, dengue, and other members of the togaviridae
family (9). Clearly, there is a broad spectrum of infectious agents which may bring about arthritis through
differing mechanisms.
In order t o appreciate the importance of host
response factors in initiating a given rheumatic disease,
one must be aware of known relationships between disease susceptibility and genetically controlled cell surface
molecules. These cell surface markers include those
coded by the major histocompatibility complex (MHC).
Certain rheumatic diseases seem to have a high degree of
association with specific markers (Figure 1). The genes
coding these glycoprotein surface markers are on the
sixth chromosome. The association of HLA-B27 with
ankylosing spondylitis and with diseases related to it
(Reiter’s, “reactive” arthritides, some cases of juvenile
rheumatoid arthritis) is exceptionally strong (lo), and
there is also a good correlation of B5 with Behcet’s
disease (11). In the A region, hemochromatosis with
arthritis has an association with A3 (12). SjGgren’s syndrome and chronic active hepatitis relate with Dw3 (l3),
and rheumatoid arthritis with Dw4. Systemic lupus erythematosus (SLE) often occurs in patients found to
have complement component deficiences (see Schaller et
al., reference 14, for discussion), particularly C2, whose
gene seems to map just outside the MHC. The most
marked association of histocompatibility antigens with
disease involves the B and D loci. The D region markers
currently are detected primarily by nonserologic methods, that is, cell-cell interactions, and they may provide
better tools for definition of specific host response pat-
MHC ASSOCIATED RHEUMATIC DISEASES
?
I
C2 deficiency
WE)
Sjogren‘s
CAH
Dw4
RA
I
?
I
AS
Reiter’s
Reactive
arthritis
JRA
Anterior uveitis
85
Behcets
Figure 1. Diagrammaiic representation of the approximate order of H L A markers on ihe 6ih chromosome. Rheumatic syndromes which
have a signifcani association with any of ihe various markers are listed. Modified from: McDeviti and Engleman. Arihritis Rheum.
20:S9-18, 1977.
FUTURE RESEARCH DIRECTIONS
terns. The current hypothesis (13) is that HLA-D will be
found in conjunction with, or in fact be, an immune
response (Ir) gene. It should be emphasized that even in
the case of the strongest associations, ankylosing
spondylitis and B27, all patients with the disease are not
B27 positive. It is also obvious that all individuals who
have B27 do not have ankylosing spondylitis. Therefore,
the marker itself does not cause the disease, but rather
alerts us t o look for further factors or determinants
(such as Ir gene products) on cell surfaces that may be
more directly causative of the disease response.
Several reasons for the association of HLA
markers and disease have been expounded (15). These
include the possibility that HLA itself is a receptor for a
virus or toxin. HLA may assume a sort of molecular
mimicry of viral or bacterial antigens, or in some way
act as a “new” antigen by virtue of association with a
microbial component. Finally, the association might reflect a situation in which the marker is in linkage disequilibrium with an immune response-like (Ir) gene, yet
to be discovered. At any rate, these correlations are not
likely to provide the ultimate answer to disease causation. We must aim our efforts toward the identification
and isolation of the putative inciting agents.
In order to provide an awareness of the various
patterns of reaction that take place against infectious
agents and an understanding of the intricate, yet highly
specific host responses, possible pathogenetic situations
will now be examined. Emphasis will be given to three
areas:
1. New pathophysiologic information on mycoplasmas
2. Viral infections, the way in which slow viruses
cause disease, and viral mimicry of surface
components
3. Peptidoglycan molecules and other bacterial
debris that might initiate a chronic inflammatory response
MYCOPLASMA
Recent investigations into the mode of pathogenicity of mycoplasma infections have revealed some unusual capabilities of these organisms to become attached
to the surfaces of inflammatory cells. This relationship is
so intimate that by electron photomicrography apparent
bridging can be visualized between the mycoplasma and
the surface of the host lymphoid cells (16). The importance of this intimacy resides in additional observations
made recently by Wise, Acton, and Cassell (17). These
investigators have found that mycoplasma can adsorb
533
onto their surface shed antigens from mammalian host
cells; that is, the histocompatibility markers of the mammalian cell become a part of the cell membrane of the
mycoplasma. This should not be an unexpected observation, since the mycoplasma itself has no cell wall, but
only a membrane, which is similar in structure to the
external lipid bilayer of the eukaryotic cell. Hence, the
organism has the capability of interacting with cells in
almost the same way as liposomes and as such has the
ability to take up shed molecules, presumably through
hydrophobic components. Good biochemical models
are now available to study this phenomenon in greater
molecular detail (18). These studies have provided new
clues for understanding the way in which chronic mycoplasma infections might persist, that is, by camouflaging
themselves in their host’s own histocompatibility antigens.
Even though these observations may provide a
basis for understanding chronicity and may stimulate
new research approaches, the clinical evidence for cultivatable mycoplasma organisms in rheumatoid athritis is
very slim (see Taylor-Robinson and Taylor for discussion in reference 19). The fact that mycoplasmas
cannot be isolated reproducibly may indicate the need
for new approaches to cultivation, new approaches to
antigen detection, and new searches for the presence of
mycoplasma genomes. Examination of animal models
of mycoplasma induced chronic arthritis must be continued (20). At the molecular level fertile areas for study
will be 1) the intimate mycoplasma host cell association,
2 ) the immune response of the host, and 3) mycoplasmal
evasion of immune defenses.
VIRAL INFECTIONS
Represented in Figure 2 are the several ways that
viruses cause disease ranging from acute, short-lived
infections to those that last a lifetime and progress with
age. Recent descriptions of the ability of slow viruses to
produce disease may foretell a complete revolution of
our understanding of chronic infection. We are only
beginning t o develop methods for study of many diseases which in the past have been considered metabolic
or degenerative.
Of particular interest in this regard are studies of
type C oncornaviruses. Although they have been most
vigorously pursued in animal models, they may have
some relevance in human disease, particularly SLE (see
August and Strand for discussion 21). For example, the
GIx marker found on the surface of certain murine
lymphoblastoid cells was described initially as a distinct,
BENNETT
5 34
TIME COURSE OF VIRUS INFECTIONS
Acute i n f e c t i o n ( Sma 1 1 pox)
Acute i n f e c t i o n , e a r l y complication (inmiune complex)
(Rubella)
(Measiis-SSPE)
Acute i n f e c t i o n . l a t ecomplication
_ _ _ _ _ _ _ _ _ _ _ _- -- - - - - - - - - -
Ii
Latent infectioli ( v a r i c e l l a
-
zoster)
I
Chronic I n f e c t i o n (LCM)
and Hammerman (25) has alerted us to differences that
exist between normal and rheumatoid synovial cells relative t o susceptibility to viral infectivity and patterns of
macromolecular synthesis. From time to time reports on
transmissible agents from rheumatoid tissues appear
(26,27), but are seldom reproduced in other laboratories. Taken in perspective, the evidence at present for a
direct viral infection as causative in SLE or rheumatoid
arthritis is very slim. This absence of proof does not
reflect on the diligence and perseverance of many investigators. It may mean simply that the problem is quite
complex and will require new and better methods to
prove or disprove a viral association. The striking discoveries of the role of slow viruses in chronic disease of
the central nervous system (28) offer hope for parallel
work in rheumatoid arthritis.
Shedding
Ctronic i n f e c t i o n ; l a t e disease (Leukemia:Aleutian Disease)
Slow
i n f e c t i o n (Kuru)
TIME (Vears)
Figure 2. Diagrammatic representation of the occurrence of symptoms
during uarious virus infections viewed on a time scale. In each case. the
darkened blocks represent the manifestation of symptomatic illness.
Modifiedfrom: Fenner F. McAwlan BR. Mims C A , Sambrook J, White
DO: The Biology of Animal Viruses. Second Edition. New York, Academic Press, 1974.
genetically determined antigen. Although this marker is
present on certain cell lines in the absence of the virus
production, there has been an unambiguous demonstration that in the mouse this molecule (GIx)is identical to
the gp 69/70 viral coat protein of the type C oncornaviruses (22). By some mechanism, as yet unknown, the
viral coat protein is expressed on the surface of cells that
presumably contain the viral genome, even though no
virion production takes place. Similar situations might
be expected to exist in human beings, and evidence has
been published to suggest that this may be the case in
SLE,but involving a different viral protein (23). On the
other hand, the identification of new cell surface components in SLE, whether or not related to murine and
other mammalian oncornavirus proteins, has been inconsistent at best (24).
Much of the previous work on the association of
viruses with tissues obtained from patients with arthritis
has been discussed by Marmion (2). The work of Smith
PEPTIDOGLYCANS IN CHRONIC
INFLAMMATION
In most bacteria, peptidoglycans are found
within the capsule and outer membrane (Figure 3).
These molecules are interesting in that there is an extraordinary degree of similarity among the peptidoglycans found across the entire spectrum of bacteria. This
degree of similarity is not found among surface antigenic components, such as those used for serologic identification of various types of bacteria. The ubiquity of
similar peptidoglycan structures in diverse species of
bacteria suggests a mechanism that could result in the
same inflammatory response from a wide variety of
microbial stimuli.
Capsule
Outer Membrane
Pept idogly c an
Inner Membrane
Figure 3. Diagrammatic representation of the cell envelope of bacteria
to show the relative location of peptidoglycan molecules. Modifiedfrom:
Liideritz 0: Microbiology-I 977, Washington, D.C.. The American
Society of Microbiology, 1977.
FUTURE RESEARCH DIRECTIONS
535
o\
H
NHAc
ti-
6-CHJ
1
1
L - Ala
1
D-GIu-
co
L-Lys
--
1
D-AlalV
1
( 0 - Ala)
(NH2)
Gly5
-
3
L-Ala2-3
0 - Ala
1
L-Lvs
i y
D-Glu
t
L-Ala
-
INH2)
t
- G - M-GFigure 4. Structural representation of the peptidoglycan molecule. The
basic unit consists of an alternaring N-acetyl glucosamine and N-acetyl
muramic acid, to which the peptide side-chain is attached. Polymerization occurs at the time of incorporation into the cell wall. In some
~ (Ala)2-lare inserted between
bacteria. spacer linkages, such a ( G I Y )or
polymeric units.
T o understand how peptidoglycans might operate to produce chronic arthritis, one must first examine
their chemistry (29). The peptidoglycan (Figure 4) can
be viewed as an alternating chain of N-acetylglucosamine and N-acetylmuramic acid. Attached t o the
lactic acid ether chain of the muramic acid is a tetrapepA fifth residue, D-Ala,
tide L-Ala-D-Glu-L-Lys-D-Ala.
is present o n precursor molecules before they are polymerized and assembled into the bacterial cell wall. In
some cases these units are coupled directly through the
L-Ala of one to the L-Lys of an adjacent unit, etc. In
other cases there is a spacer linkage, such as (Gly), or
(Ala)2-3.
Growing evidence indicates that the arthritogenic
properties of bacterial adjuvants reside within the peptidoglycan dimers (30). How might these molecules relate
t o rheumatoid arthritis? Bokisch et al. (31) have reported that occasionally animals immunized with
streptococci develop rheumatoid factors that recognize
both the peptidoglycan of the bacteria and the Fc component of IgG; that is, a relationship of the peptidoglycan to the Fc region was noted. Additional observations
in patients with rheumatic fever and juvenile rheumatoid arthritis (32) and with rheumatoid arthritis (33)
indicate that antibodies which cross react with peptidoglycans may be present. Clinical studies in patients
with bacterial endocarditis (34) reinforce the importance
of bacterial antigens in initiating an immune response,
chronic inflammation, and occasionally antiglobulins.
Investigators in Munich (29) have been studying
the interrelationships of various types of peptidoglycans, particularly as related to their linkage sequences.
They have been able to show extraordinary degrees of
cross reactivity among certain groups of bacteria by
coupling these synthetic amino acid polymers to a carrier protein, such as ribonuclease. These reactions may
be categorized in such a way as to show specificity for
either (Gly), or (Ala)2-s. Similar immunochemical studies have been directed toward the precursor pentapeptide (35). The implication of these studies is that
the peptide portions of peptidoglycans, that is, the
penta- or tetrapeptide or the linkage group between two
units, are strongly immunogenic. Perhaps these small
peptides behave as univalent (haptenic) antigens, introducing the possibility of immune complexes existing
as 7s components (IgG 2 small univalent peptides). If
the peptidoglycan should indeed be the immunodominant antigen, there would be no reason to expect
larger molecular weight complexes, such as 9S, 1 lS, 13S,
15S, etc. Therefore, a search for the presence of new
antigens within the 7.9 immunoglobulin fraction might
be fruitful.
If bacterial peptidoglycan should be found in 7s
immunoglobulin fractions in rheumatoid arthritis, we
might have 1) a clue t o the inciting agent and 2) a
means for explaining the production of anti-globulin
based on conformational change in the Fc or haptenic
association. These possibilities exist whether o r not one
introduces the concept of persistent, nonbiodegradable
antigens (36). Recent elegant work, showing chronic
+
Table 2
Arthropathies Associated with Gastrointestinal Disease
Associated with Infection
Salmonella
Shigella
Y ersinia
Amoebiasis
Giardia
Bypass surgery for morbid obesity
Probable Infection
Whipple’s disease
Other
Ulcerative colitis
Crohn’s disease
Idiopathic steatorrhea
BENNETT
536
arthritis in rats after a single injection of bacterial cell
walls (37), would seem to indicate persistent antigen.
However, because of the similarities among all of the
bacterial peptidoglycans, these experiments should be
repeated in germ-free animals to rule out other sources
of continued antigenic supply.
If we now consider the possibility of peptidoglycans, and perhaps other bacterial debris, as being causative in rheumatoid disease, where should we search for
the bacterial reservoir? The area that seems to have the
strongest attraction is the gastrointestinal tract. Situations in which arthritis is frequently found in association
with gastrointestinal diseases are listed in Table 2. For
:
the sake of emphasis the intestinal bypass procedure for
morbid obesity is included with the diseases associated
with infection. In this situation immune complexes apparently do exist with arthritis (38), and reanastomosis
to establish normal gut relationships reverses the situation. The association of arthropathies with bacterial
stasis in the intestine, or a damaged intestinal barrier, is
striking. Additionally, low levels of IgA in patients with
arthritis, particularly in JRA (39), have been found with
sufficient frequency to make one wonder about defective
host resistance to mucosal surface bacteria (40).
From these considerations an hypothesis emerges
(Figure 5 ) . Bacteria, normally present in the gastrointes-
SELF
:ASSOCIATI&
I
I
I
LGGREGATE
I
I
I
MOLECULAR
-:
I
I
CLINICAL
PICTURE
OF R.A.
I
I
I
piiE?
I
I
--
GLVCAN
ANTIGEN!
IMMUNE
:OMPLEXES
uto Ab to Fc
I
I
I
I
I
-
I
IMMUNOGENIC
UNTI-PEPTIU
I
!
Ab
UNIVALENT'
SMALL
ANTffiENS
"UNIVALENT
SMALL
ANTIGENS
PEPTIDO GLVCAN
ANTIGENS
ANTIGEN OVERLOAD AS CAUSE OF MYUNE COMPLEX ARTHRlflS
Figure 5. The possible pathways by which antigen overload from the gastrointestinal tract might result in complex formation and
the initiation of the clinical picture of rheumatoid arthritis. The molecular adsorptive pathway results in the adsorption of
peptidoglycan antigens onto the Fc portion of immunoglobulins, causing anti-Fc antibody formation, as well as self-aggregation.
The immunogenic pathway results in anti-peptidoglycan molecules, which may persist as small (7s) complexes.
FUTURE RESEARCH DIRECTIONS
tinal tract, release debris (including peptidoglycan)
which traverses the gut-blood barrier and stimulates the
immune system (immunogenic pathway). Resultant
antibodies, when bound to small peptidoglycan antigens
via their Fab binding sites, result in 7s immune complexes. Alternatively, the peptidoglycan might become
associated with Fc regions of normal IgG (molecular
adsorptive pathway) and thereby form a new antigenic
site, which initiates an anti-globulin (rheumatoid factor)
response or causes self-association. These reactions
would be expected to result in the presence of several
forms of complexes, some of which are known to occur
in sera and joint fluids of patients with rheumatoid
arthritis. Direct analyses of circulating complexes for
the presence of (D) amino acids and muramic acid are
needed. Methodologies of amino acid and carbohydrate
biochemistry are available to provide detection of these
components at picomole (lO-l2M)levels. Such biochemical analysis, together with obvious immunochemical
probes, should provide tests of the hypothesis. At the
very least we should achieve better insight into the possible pathogenic roles that bacterial products might play
in rheumatoid arthritis and other chronic inflammatory.
processes.
ACKNOWLEDGMENTS
Many thanks are due to Gene V. Ball, M.D., for his
critical reading of this manuscript, and to Charlene Cicero,
Judy Brough, Wanda Kincaid, and Carol Allen for help in its
preparation.
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