Re: NIH Intramural Study

a_weisman_at_yahoo.com
Date: 01/13/05 

Date: 13 Jan 2005 06:15:10 -0800

Lyme relevant excerpts:

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Behar, Samuel M.. Porcelli, Steven A.. Review: Mechanisms of Autoimmune
Disease Induction: The Role of the Immune Response to Microbial
Pathogens. Arthritis & Rheumatism. 38(4):458-476, April 1995. Table of
Contents | Complete Reference (without Full Text) | Full Text

Arthritis & Rheumatism

© 1995, American College of Rheumatology

Volume 38(4) April 1995 pp 458-476

Review: Mechanisms of Autoimmune Disease Induction: The Role of the
Immune Response to Microbial Pathogens
[Special Article]

Behar, Samuel M.; Porcelli, Steven A.

Dr. Behar's work was supported in part by NIH training grant AR-07530.
Dr. Porcelli's work was supported by NIAMS Clinical Investigator Award
AR-01854.
Samuel M. Behar, MD, PhD, Steven A. Porcelli, MD: Brigham and Women's
Hospital and Harvard Medical School, Boston, Massachusetts.
Address reprint requests to Steven A. Porcelli, MD, Department of
Rheumatology and Immunology, Room 508 Seeley G. Mudd Building, 250
Longwood Avenue, Boston, MA 02115.
Submitted for publication August 29, 1994; accepted in revised form
November 15, 1994.

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Outline
Molecular mimicry by microbial antigens: a triggering mechanism for
autoimmune disease?
Persistent antigens and persistent pathogens: the merging of infectious
and autoimmune disease
Bacterial superantigens
Retroviruses and autoimmunity
Conclusions
REFERENCES

Persistent antigens and persistent pathogens: the merging of infectious
and autoimmune disease
The mechanisms discussed above consider the introduction of an
infectious agent and the immune response to its antigens as a trigger
for autoimmune diseases. However, also implicit in this model is the
elimination of the infectious agent in the setting of continuing
inflammatory disease. Thus, in true autoimmune disease, it is believed
that the immune response is actually directed against self components,
and that the continuing recognition of these self antigens accounts for
the chronic phase of these diseases. However, a substantial number of
situations have now been brought to light in which inflammatory disease
believed to be autoimmune in nature may actually be caused by an immune
response directed against nonviable but persistent microbial antigens
present in the target tissues, or even against occult viable infectious
organisms. Such situations blur the distinction between autoimmune and
infectious diseases, and raise the possibility that some syndromes now
classified as autoimmune diseases may be more
correctly viewed as chronic infections.

Persistent microbial antigens. Persistence or repeated deposition of
microbial antigens is a potential mechanism by which pathogenic
organisms could cause chronic inflammatory disease. A possible example
of this mechanism is the joint inflammation that is sometimes observed
following nonarticular infections, and which has traditionally been
classified as either postinfectious or reactive arthritis.
Postinfectious arthritis, which occurs during the acute phase of an
infectious illness, is a noninfectious synovitis believed to be
mediated primarily by deposition of foreign antigens in the form of
immune complexes. Examples include the arthritis associated with acute
hepatitis B ( [25]), and the sterile joint effusions sometimes seen
during acute disseminated infections with meningococci ( [26]) or
gonococci ( [27]). In contrast, reactive arthritis occurs in a subset
of patients several weeks after acute bacterial diarrhea (postenteric
arthritis) ( [28]) or urogenital infection with Chlamydia trachomatis
(sexual
ly acquired arthritis) ( [29,30]). This is generally thought to occur
after the clearance of infectious agents and their products, and is
presumed to arise from an autoimmune mechanism such as molecular
mimicry. However, recent improvements in our ability to detect the
presence of microbes and their products have begun to erode the
traditional distinction between postinfectious and reactive arthritis
by suggesting that the latter may also result from the persistence of
microbial products in the inflamed tissues.

The role of persistent microbial antigens in reactive arthritis has
been extensively studied in a well-defined population of patients who
developed articular symptoms following enteric infection by Yersinia
enterocolitica ( [31,32]). In two-thirds of these patients, Yersinia
antigens are detected in 1-10% of synovial fluid (SF) cells (mostly
neutrophils and some mononuclear cells) by immunofluorescence staining
using a Yersinia-specific rabbit antiserum or a monoclonal antibody
specific for a polysaccharide antigen of Yersinia, and these results
are further supported by Western blot analysis ( [31]). These studies
have been confirmed by a second group of investigators who, using
immunofluorescence, detected particles that were thought to represent
Yersinia-derived antigens in the synovial membrane of 4 HLA-B27+
patients with Yersinia-triggered reactive arthritis ( [32]). The
antigens appear to be localized in the cytoplasm of large mononuclear
cells, although the precise cell type has not been identified. Som e of
the biopsy specimens used in these studies were obtained long after the
onset of arthritis (5 months to 17 years), indicating that these
bacterial antigens can persist for extended periods of time ( [31,32]).
Although less well studied, similar findings have been reported in
patients with reactive arthritis associated with other infectious
agents. For example, Salmonella antigens have been detected in 10-50%
of the SF cells from 8 HLA-B27+ patients with Salmonella- triggered
reactive arthritis, in studies using rabbit antisera specific for
Salmonella species and monoclonal antibodies specific for
Salmonella lipopolysaccharide ( [33]). Chlamydia antigens have also
been detected in the SF and synovial tissue of patients with sexually
acquired reactive arthritis and negative culture findings ( [34,35]).

The detection of persistent Yersinia antigens in the synovium of
patients with Yersinia-triggered reactive arthritis weeks, months, or
even years after the sentinel enteric infection raises the possibility
that a chronic infection by this organism has been established in the
inflamed joints. This issue has been addressed in many of the above
studies by performing cultures of SF or tissues, the results of which
have proven to be uniformly negative. Furthermore, in studies using the
polymerase chain reaction (PCR), bacterial DNA has been sought in SF
and tissue as a surrogate marker for the presence of viable organisms.
Although this method is exceedingly sensitive (DNA from as few as 10
bacteria per 105 cells can be detected), no Yersinia DNA has been found
in samples of SF or tissue, even when simultaneously performed
immunofluorescence studies demonstrated Yersinia antigens in 1% of the
SF cells ( [36,37]). Similarly, despite the identification of
immunoreactive antigens and particles thought to represent Ch
lamydia, PCR failed to detect chlamydial DNA in the SF of patients with
sexually acquired reactive arthritis ( [38]). Negative findings can
never be viewed as conclusive, but the results of these experiments,
together with the inability to culture the organisms, indicate that
there may be persistent bacterial antigens within the joint in the
absence of viable organisms.

The relevance of the detection of bacterial antigens in the joint to
the development of chronic arthritis is unproven at this time. For
example, it is not known if patients who recover from bacterial
enteritis without developing arthritis also have bacterial antigens in
their joints, or if the antigens that have been detected are present in
a form that is recognized by the immune system. However, the possible
significance of these findings has been highlighted recently by the
isolation of T cell clones specific for Yersinia from the SF and tissue
of patients with reactive arthritis. T cell clones from 1 patient
recognized antigens from Y enterocolitica and Yersinia
pseudotuberculosis, but not other bacterial species ( [39]). Such T
cells presumably arose in vivo as a consequence of persistent
stimulation by antigen in the joint. Interestingly, although the
patient was HLA-B27+, these Yersinia-reactive T cells were CD4+ and
restricted by HLA-DR4. More recently, CD8+ T cell clones have been
derived from SF of s
everal patients with Yersinia-triggered reactive arthritis. These T
cells are restricted by HLA-B27 and lyse Yersinia-infected cells, but
not cells that have been exposed to killed Yersinia organisms ( [40]).
This implies that active intracellular infection, and not simply
phagocytosis of bacterial antigens, may be required for antigen
presentation to HLA-B27-restricted T cells, as appears to be the case
in general for T cells that recognize bacterial antigens in the context
of class I MHC molecules ( [41]).

Based on these preliminary findings, it can be speculated that HLA-B27
and other class I MHC molecules may be involved in the presentation of
bacterial antigens to class I-restricted (i.e., predominantly CD8+) T
cells during the initiation of reactive arthritis, when viable
organisms are present within macrophages and possibly other types of
cells. In contrast, during the chronic and relapsing phases of
arthritis, which appear to be characterized by the presence of
persistent bacterial antigens but no viable organisms, antigen
presentation may be predominantly by class II MHC molecules with
activation of CD4+ T cells. A true test of the validity of such a model
awaits the detailed analysis of T cell clones isolated from the
synovium of reactive arthritis patients at various times after the
onset of their illness. This area of research could lead to new
therapeutic strategies based on the elimination of either intracellular
infections or persistent antigens, depending upon the stage of the
disease ( [42]). In
this regard, differentiation between persistent antigens and chronic
infections may be critical.

Persistent Pathogens: lessons from Lyme disease. Lyme arthritis
provides an excellent example of how inflammatory arthritis with
features suggesting an autoimmune pathogenesis can in fact be caused by
an occult microbial pathogen. Many of the initial cases of Lyme disease
were mistaken for juvenile rheumatoid arthritis before a series of
landmark epidemiologic and laboratory investigations determined that
the disease results from infection with the spirochete Borrelia
burgdorferi, which is transmitted by the bite of the deer tick Ixodes
dammini (for review, see [43]). The many studies that have followed
from this discovery have made Lyme disease perhaps the best example of
a chronic arthritis with a known etiology. Arthritis occurs in
approximately 60% of patients with untreated Lyme disease, and becomes
chronic in 10% of cases, with erosions of cartilage and bone and
synovial histopathologic features similar in many ways to those of RA (
[44,45]).

In contrast to reactive arthritis, Lyme arthritis may be the result of
an immune response in tissues that are persistently infected by viable,
replicating microorganisms. Strong indirect evidence for this view is
provided by the observation that treatment with antibiotics cures many
cases of established Lyme arthritis, and prevents the development of
this condition if given early after infection. More direct evidence for
this hypothesis comes from silver staining of synovium from affected
joints, which has revealed the presence of intact spirochetes ( [46]).
Antigens specific for B burgdorferi also have been detected in the
synovium. In one report, synovial biopsy samples from 12 patients with
chronic Lyme arthritis were investigated by immunohistochemistry (
[45]). Monoclonal antibodies specific for the B burgdorferi 31-kd outer
membrane polypeptide and the 41-kd flagellar antigen detected
spirochetes and globular antigen deposits in and around blood vessels
in areas of lymphocytic infiltration in 50% of bio
psy specimens. Nevertheless, it has proven difficult to culture the
organisms from synovial specimens, and relatively few instances of
successful isolation of B burgdorferi have been reported ( [47-49]).

Recent application of detection methods based on PCR now provides
strong additional support for the presence of intact viable B
burgdorferi in the joints during chronic Lyme arthritis. Using a nested
PCR technique with which DNA can be detected from as few as 10
spirochetes in 1 ml of fluid ( [50-53]), B burgdorferi DNA has been
detected in most synovial specimens. In one of the largest reported
series, PCR was performed on 92 SF samples from 88 patients with Lyme
arthritis and 64 controls with other articular diseases, using primers
specific for the plasmidencoded Osp A gene and the genomic 16S
ribosomal RNA gene of B burgdorferi ( [52]). Seventy-five of the
patients with Lyme arthritis had a positive PCR result, whereas all of
the controls had negative results. Of the 73 patients who had not been
treated or had received only short courses of oral antibiotics, 96% had
a positive PCR reaction. In contrast, only 37% of the 19 patients who
had received appropriate antispirochetal antibiotic treatment had a
posi tive PCR reaction. Remarkably, DNA from B burgdorferi was detected
by PCR in 12 untreated patients up to 7 years after the onset of
arthritis.

The detection of pathogen-specific DNA sequences at the site of
inflammation in chronic Lyme arthritis stands in marked contrast to the
results reported for patients with reactive arthritis associated with
Yersinia and Chlamydia species, as described above. Although it may be
an immune response to bacterial antigens that gives rise to chronic
inflammation in all of these diseases, it appears that in the case of
Lyme arthritis this process is usually sustained by the persistence of
living microorganisms, and not by the failure to clear nonviable
antigenic material from the synovium. However, it may also be that both
of these mechanisms are operating in some cases. For example, of 10
patients who had chronic Lyme arthritis despite multiple courses of
antibiotics, 7 had no B burgdorferi DNA detected by PCR in
posttreatment synovial samples ( [52]), indicating that chronic
arthritis may continue even after the eradication of viable
spirochetes. An immunogenetic basis for this is likely, since certain
class II MHC
alleles (HLA-DR2 or HLA-DR4) are found with increased frequency in
patients with chronic Lyme arthritis compared with patients with Lyme
arthritis of short duration ( [54]). However, it is not yet known if
these patients harbor persistent B burgdorferi antigens in their joints
in the absence of viable spirochetes.

These studies of Lyme disease have increased the need to consider
persistent infection by slow-growing or fastidious bacterial pathogens
as an etiology for idiopathic diseases with autoimmune features. A
variety of other conditions have already been suggested to belong in
this category, although in few of these is the evidence for a bacterial
etiology anywhere near as convincing as for Lyme disease ( [55-61]).
Nonetheless, this concept has obvious clinical importance since, if
correct, it would mandate that treatment strategies shift away from the
use of immunosuppressive agents and toward the development of long-term
antibiotic treatments, vaccines, and immunotherapy,

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