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The role of Chlamydia in connective tissue diseases
ANTIMICROBICS AND INFECTIOUS DISEASES NEWSLETTER The Role of Chlamydiu in Connective Tissue Diseases Charles W. Stratton, MD AssociateProfessor of Medicine and Pathology Vanderbilt University School of Medicine Nadwilk, iW 37232 Introduction
Chlamydiae are unique intracellular pathogens that are separated from other eubacteria and represent one of the kingdom-level branches of the phylogenie tree. Chlamydia species are widely distributed in nature, infecting mammals and birds as well as humans. Chtizmydia species have a very complex life cycle in which a number of distinctive forms are seen. The first is a metabolically inactive spore-like form called an elementary body (EB). Only this inert spore-like EB is infectious and able to spread Chlamydia infection from one host/host cell to another. EBs have heparan sulfate receptors and are able to attach to target cells. EBs can then invade the host eukaryotic cell and transform into a reticulate body (RB). RBs are obligate intracellular parasites that are metabolically active and able to replicate by binary fission. During replication, some RBs condense back into EBs that then can be released from the cell to initiate a new cycle of infection. During acute infection, replication produces inclusions that often become quite large; infected cells then lyse and release many EBs. In contrast, persistent chlamydial infections involve the cryptic form. This cryptic form of Chlamydia species seems to be RBs that are able to metabolize, but do not replicate nor differentiate into EBs to any degree. Cryptic forms of Chlamydiu species cannot be cultured due to
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the relative lack of infectious EBs. Among chronic illnesses that Chiumydia species have been associated with are connective tissue diseases. Connective tissue diseases are &fined as those involving joints and related structures of the skeleton. ‘Ihis brief review will address this association and discuss the diagnostic and therapeutic implications.
Inflammatory Connective Tissue Diseasesin Humans Joints and related structures of the human skeleton are considered the principal connective tissues and vary widely in structure and function as well as in predisposition to disease. Joints and related structures that are nearly rigid such as the calvarial sutures almost never are involved in disease. Much more disease, including inflammatory processes, is seen in articulating diarthrodial joints in which the ends of the bones are capped by articular cartilage and the joint space is lined by synovial membrane except in the cartilaginous, weight-bearing areas. Synovial surface membranes normally contain two types of synoviocytes. The type A synovial cell is more common and is closely related to macrophages. As such, type A synovial cells have phagocytic functions and remove particulate matter from the synovial fluid. In addition, these cells can produce degradative enzymes, mostly collagenases. The type B synovial cells are of mesenchymal origin and have a fibroblastic appearance. These cells syntbesize and secrete a number of substances including mutinous hyaluronic acid, glycosaminoglycans, collagenase, fibronectin, and lubrican. Qpe A and B syn-
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ovial lining cells are dispersed evenly as a single cell layer without an underlying basement membrane. This allows these cells close contact with a thin layer of connective tissue matrix which contains mononuclear cells, interdigitating dendritic cells, blood vessels, lymphatics, and nerve filaments. The articular cartilage itself is a unique type of connective tissue that serves as an elastic shock absorber and wear-resistant surface. Articular cartilage is metabolically active with chondrocytes that synthesize the cartilaginous matrix. These cells also have the ability to synthesize collagenases and other proteinases. Many connective tissue diseases in humans involve inflammation. The most common is rheumatoid arthritis @A). RA is a chronic connective tissue disease of unknown etiology which has been considered by some to be the result of an chronic inflammatory synovial response to an unrecognized antigen such as that from an infectious agent. Distinctive and dramatic changes occur in the synovial membrane in RA. The histopathologic findings seen early in RA are hyperplasia of the synovial lining and disruption of endothelial cell that is accompanied by rapid vascular proliferation consisting of new capillaries with relatively little change in larger vessels. This acute process is followed
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by an intense infiltration of this hyperplastic synovia with macrophages, lymphocytes, and plasma cells. As the rheumatoid disease progresses, the hyperplastic synovia becomes a multilayered proliferative and fibrous mass of granulation tissue is known as “pannus” that invades surrounding bone, cartilage, tendons, and ligaments via villous processes. Within the pannus, synoviocytes are activated and secrete metaloproteinases that degrade surrounding bone and cartilage. Villi from this pannus protrude into the joint space as well. The joint fluid becomes turbid. There are often focal areas of inflammation in tendons, muscles, and periarticuar connective tissue with infiltration of macrophages, lymphocytes, and plasma cells. Another connective tissue disease that involves inflammation is reactive arthritis (ReA). The clinical association between ReA and certain venereal infections has been well established over the years. Currently, the venereal infection is thought be responsible for the arthritis. Because microorganisms have rarely been isolated from affected joints in these patients, ReA has been thought to be due to an immunological response either to antigen deposited in the joint or to self-connective tissue caused by molecular mimicry. Reactive arthritis, thus, is considered an inflammatory arthritis that occurs as a consequence of infection elsewhere in the body. Undifferentiated oligoarthritis is yet anther inflammatory connective tissue disease that has a clinical and pathological pattern that is very similar to ReA, except that there is no clear evidence of an antecedent triggering infection, ReA is a well-known component of Reiter’s syndrome, the other two in this triad being urethritis and conjunctivitis. In Reiter’s syndrome, the synovial membrane is characterized by the plug-
ging of capillaries and venules with platelets and polymorphonuclear cells; these findings can be experimentally produced by the local injection of bacterial endotoxins such as lipopolysaccharide (LPS). Indeed, considerable evidence has accumulated supporting bacterial antigens, such as LPS, in the pathogenesis of this synovial inflammatory process. The exact role of the microorganism remains a subject of controversy. The issue in question is whether joint infection per se causes the inflammation or whether an immunological reaction to an infection elsewhere is responsible for the pathological changes in affected joints.
Important pathogenic Issues Concerning Chlamydial Infection There are a number of pathogenic issues concerning chlamydial infection that strongly suggest that Chlamydiu may play an important role in inflammatory diseases of connective tissue. Each of these issues will be briefly discussed. ctdamydlal
lnfeetloll of
monocytedmacrophages Infection of connective tissues by Chlamydia species may be facilitated by the ability of these pathogens to infect and replicate within monocytes and macrophages. Relatively few other microorganisms are able to survive inside monocytes and macrophages, due to the abundance of acidic phagocytic vacuoles and hydrolytic enzymes. Following EB entry and subsequent infection of the host macrophage, Chlamydia species may escape from the initial site of infection via lymphatic channels and blood vessels and disseminate. For example, Koehler et al. have been able to produce persistent infection of cultured human peripheral blood mononuclear cells with C. trachomutis in which the organism was viable and metabolically active, but could not be cultured. Infection of peripheral blood
mononuclear cells clearly would allow Chlamydia species to reach connective tissues and possibly infect type A synovial cells, which are closely related to macrophages. Persistent chhmydial infection Chlamydial infections are persistent. Persistence is defined as a long-term association between the pathogens and their host cells in which these microorganisms remain in a viable but culture-negative state. Chlamydia species are able to persist due to their ability to enter a quiescent cryptic state that involves alterations in antigen expression, altered morphology, and loss of infectivity. Once the stimulus for persistence has been removed, these cryptic forms may revert to the replicating form that can be cultured. The decline in recoverable infectivity of these cryptic forms would make cell cultures relatively insensitive as a means of detecting persistent chlamydial infection. Although not replicating, these cryptic forms are thought to play an important role in the chlamydial disease pathogenesis due to their production of heat shock proteins (HSPs). Chlamydld persistence and heat shock proteins Both eurkaryotic and prokaryotic cells respond to harmful environmental stress with a highly conserved cellular response known as the stress response. Part of this stress response includes the increased production of HSPs that normally are constitutively synthesized at low levels, but are synthesized at high levels when a cell is subjected to stress. Examples of stressful cellular events include a sudden increase in temperature, viral infection, exposure to superoxides, anoxia, or glucose starvation. HSPs chaperone the folding, unfolding, and translation of other proteins as well as in the assembly and disassembly of protein complexes in the endoplasmic reticulum and mitochondria. The
NOTE: No responsibility is assumed by the Pnblishet for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material her&. No suggested test or procedure should be carried out unless, in the reader’s judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verification of diagnoses and dmg doses should be made. Discussions. views. and recommendations as to medical procedures, choice of drugs, and dmg dosages are the responsibility of the authors. Antimirmbics and InfMious Diseases Newsletter @SSN 1069-417X) is issued monthly in one indexed vohutx per year by Elsevier Science Inc., 655 Avenue of the Americas, New York, NY 10010. For customer service, phone (212) 633-3950; TOLLFREE for customers in the U.S.A. and Canada: I-888-4~INFO (l-888-437-4636) or fax: (212) 633-3680. Subscriptions are available on a calendar yeat basis or as a rolling (anytime-start) subscription. Subscription price per year: for institutional subscribers in Europe, The CIS, and Japan: NLG 668; for iastitwional subscribers in all other counties: USS 339. For personal subscribers io Europe, The CIS. and Japan: NLG 390; for personal subscribers in all other countries: USS 198. Periodical postage paid at New York, NY and at additional mailing offices. Postmaster: Send address changes to Antimicmbics and infectiousDiseases Newsletter. Elxvier Science inc., 655 Avenue of the Atnecicas. New York, NY 10010.
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importance of these proteins can be appreciated by the fact that the structure of HSPs is highly conserved during evolution and is similar in bacteria, yeasts, plants, and animals. HSPs produced by microbial pathogens have been found to be major antigens. The immune response to HSPs may be a major factor in many diseases. Both CD4 and CD8 T cells are activated by HSP and can recognize and Iyse macrophages that are producing HSP due to stress such as heat, gammainterferon, or intracellular pathogens. This immune response would contribute to the removal of injured cells or infected cells. HSPs thus are thought to contribute to the development of autoimmune disease. Patients with RA are known to have specific T lymphocyte reactivity to HSP Pancreatic islet beta-cells express HSP which is the target of T lympho-
cytes in insulin-depen&nt
diabetes.
Chlamydia species produce HSPs of which the 57-kDa HSP is the second most abundant protein in chlamydial whole cell lysates. This HSP is found in both EBs and BBS and is loosely associated with the cell surface. Chlamydial HSPs are highly conserved. For example, the 57-kDa HSP of C. trachomatis has a 95% amino acid similarity with the 57-kDa HSP of C. pneunwniae. For humans infected with C. trachomatis, the cdl-mediated immune response to the chlamydial57kDa HSP is one of delayed hypersensitivity with lymphocytic proliferation. This hypersensitivity is thought to be an important aspect of the pathogenesis of trachoma, chronic salpingitis, tubal infertility, and immune-mediated pregnancy loss. Cell-mediated
immunity and
cblamydia Cell mediated immunity is crucial in host defenses against intracellular pathogens such as Chlamydia. There is increasing evidence that cell-mediated immunity to Chlamydia may be responsible for either recovery from infection or immunopathology. Both CD4 and CD8 T cells are needed for efficient protection against Chlamydia infection in mice. The CD4 T cells are essentially for protection and are activated by chlamydial antigens derived from vacuolar contents bound to the HLA class II molecules exposed on host cells such as macmphages, dendrites, and endo-
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thelial cells; recognition of antigen results in secretion of cytokines. The cytokines then activate macrophages as well as stimulate B cells to produce antibodies. The CD8 T cells require gamma-interferon to be fully effective and have potential for a more comprehensive antigen response because they recognize cytoplasmic antigenic peptides bound to HLAclass 1 molecules which are expressed an aI1 micleated cells. CD8 T cells when activated by antigen may respond in several ways which include the production of gammainterferon, cytolytic activity, or suppression of the immune response. The outcome of the immune response to Chlumydia can be protection or immunopathology and seems to be determined by the antigen that dominantly stimulates T cell activation. The major outer membrane protein (MOMP) of Chlamydia appears to provide protection while HSP seems to stimulate pathological events leading to tissue destruction associated with chlamydial infection. Cytokines are major factors in the regulation of the immune response to Chlamydia species and, in part, determine the outcome. An efficient cellmediated immune response as well as macrophage activation are associated with gamma-interferon, interleukin-2 (IL.-2), and IL-12 by Thl cells whereas humoral immunity and antibudy production are related to IL-4, IL-5 and IL-10 secretion by Th2 cells; the latter suppress macrophage functions. There is considerable published data for Chlamydia infections that suggest gamma-interferon and Th 1 activation play a substantial role in chlarnydial immunity. The significance of gammainterferon in chlamydial immunity is suggested by the fact that activation of the Th2 cells with a resultant too low amount of gamma-interferon leads to the development of inapparent and persistent infection with non-infectious but viable Chfamydia. Another marker for activation of the Th2 type of cell is increased levels of IgA antibodies, which is mediated by IL-lo.
Chkizmydiu Species and Connective Tissue Diseases in Animals Chlamydia species causing mammalian diseases have been studied extensively in common farm animals due to the obvious economic importance. Young
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animals we especially prone to infection with C. psittaci, which is the chlamydial species that most often causes infection in animals. For example, lambs, calves, foals, and piglets are recognized as having polyarthritis and polyserositis after initial intestinal infections. In these animals, C. psittaci spreads systemically from the initial intestinal infection and subsequently reaches, infects, and replicates in synovid tissue ceIIs. Chlamydial polyarthritis of lambs, also called “stiff lamb disease,” is the best studied of the chlamydial inflammatory diseases of animals. This is a disease that occurs in epizootic proportions in the major sheep-raising regions of the United States. It is caused by C. psittaci, which infects most of the synovial tissues of the diarthrodial joints of the limbs, leading to inflammation, stiffness, and lameness. Affected lambs have varying degrees of stiffness and lameness, and also exhibit anorexia and conjunctivitis. Moreover, these lambs become gaunt, depressed, and are reluctant to move, stand, or bear weight on one or more limbs, hence lingering behind the rest of the flock. In naturally occurring cases of polyarthritis in lambs, C. psittaci has been isolated from affected joints as well as from different organs and body fluids including lungs, liver, spleen, lymph nodes, brain, cerehrospind tluid, and blood. These findings suggest that a blood-borne phase with infectious chlamydial EBs occurs and leads to the infection of the joint tissues. An identical polyarthritis can readily be repraduced experimentally by inoculating lambs via the oral, subcutaneous, intramuscular, intravenous, or intraarticular routes. In both naturally occurring and experimentally induced chlamydial polyarthritis of lambs, the most striking tissue pathology is found in articular and periarticular tissues. Larger, freely movable, weight-bearing joints contain excessive, grayish-yellow, turbid synovial fluid. In joints with advanced lesions, fibrin flakes and plaques of different sizes and shapes are seen. These fibrin plaques often adhere to the synovial membranes. The joint capsules of affected joints are thickened. Tendon sheaths are often distended and contained creamy, grayishyellow exudate. Surrounding muscles
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are hyperemic, edematous, and have petechiae in their associated fascial planes. The histopathological findings begin with an early serous reaction, move to a librinopurulent inflammatory phase, and finally end with fibroplasia and accumulations of lymphoid cells. Mononuclear cells accumulate in perivascular areas. Advanced lesions in joint capsules and tendon sheaths show marked fibrotic thickening. Advanced lesions are accompanied by an extensive inflammatory response that consist primarily of plasma cells, monocytes, lymphocytes, macrophages, and neutrophils. The viable synoviocytes become swollen and hyperplastic with a pseudostriated appearance; fibroblasts in these infected tissues are large, plump, and round. In such infected tissues, chlamydial inclusions are found in synovial cells as well as in flbroblasts, monocytes, and endothelial cells. Changes in adjacent muscles are periarticular and associated with tendinous insertions. These changes are best characterized as myositis due to their infiltration with inflammatory cells, accumulation of edema fluid, and fibroblastic proliferation. Similar findings have been describe in polyarthritis of calves. Chlomydiu trachomutis and Connective Tissue Diseases in HlmUUiS C. trachomatis is a frequent pathogen of the urogenital tract and is the most common sexually-transmitted disease reported to the U.S. Centers for Disease Control and Prevention. Thus, it is not surprising that C. trachomatis has emerged as a major cause of reactive arthritis. Chtamydia-induced arthritis is characterized by aseptic synovitis of the peripheral or sacroiliac joints. Despite the difficulty in isolating C. trachomatis from joint fluid in patients with ReA, chlamydial antigens, nucleic acids, and non-cultivable Chlamydia-like particles in affected joints have been demonstrated by numerous investigators. In addition to evidence for the presence of C. trachomatis in affected joints in patients with ReA, a recent report by Gerard and colleagues suggests that viable, metabolically active C. trachomatis reside in the synovial tissue of patients with this disease. C. trachomatis not only are present in the joint tis-
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sue, but also are actively expressing HSP. This study challenges the established dogma in the field of rheumatology and will need to be confinned. The implications of the study by Gerard et al. are important. First of all, the expression of chlamydial HSP by viable C. trachomatis in the synovial cells of affected joints may be inducing the chronic inflammation seen with ReA. Of interest here is that a number of other groups including Campbell et al., Sieper et al., as well as Gaston et al. have demonstrated that sexually-acquired ReA synovial T cells respond to C. truchomads antigens, including the 57-kD HSP Simon has demonstrated that these patients have a cytokine profile that suggests the predominance of the Th 1 subset. Moreover, if there is active infection in the joints, the use of corticosteroids in arthritis therapy must be reevaluated. Finally, it is possible that
some current antimicrobial agents may not be effective in eradicating Chlamydiu that are not actively replicating. In fact, antibiotics are known to produce persistent chlamydial infections in cell culture. Chlamydiu pneumoniue and Connective Tissue Diseases in Humans The association of C. pneumoniae with arthritis syndromes has been reported by Braun et al., Gran et al., Moling et al., and by Saario and Toivanen. Clearly, the potential for this association is strong as many more people are infected by C. pneumoniae than by C. trachomatis. The emerging understanding of the pathogenic nature of C. pneumoniae infections strongly suggests that this pathogen reaches and infects synovial tissue. However, the exact role of C. pneumoniae in specific arthritis syndromes such as RA remains to be determined. Chkamydia species and Rheumatoid Arthritis The histopathology of RA is consistent with an acute infectious process leading to a chronic infection with delayed hypersensitivity: infection with Chlamydia species could easily produce such a response. Of note, moreover, is the longstanding observation that antimicrobial agents not only are effective against ReA, but also have some success in
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RA. Indeed, the greatest success has been with minocycline, which is active against Chlamydia species. Methotrexate, another agent commonly used in the therapy of RA, is known to have antimicrobial activity against Chlamydia species. Penicillamine, an effective drug less commonly used in RA, is a sullhydryl-containing reducing agent which, as such, would be active against the disulfide bonds of chlamydial MOMF! Thiols have been noted to activate chlamydial ATP synthase; were this to happen in the extracellular milieu, the result might be detrimental to the organism. Other antimicrobial agents that have been tried with varying degrees of success for the therapy of RA include rifampin, isoniazid, and metronidazole. At least one of these, rifampin, is known to be active against Chlamydia. Summary In summary, Chlamydia species have been shown to infect synovial tissues. The synovial infection produced can be persistent and can cause a cell-mediated inflammatory response directed at chlamydial HSPs. Antimicrobial therapies of arthritis syndromes to date have demonstrated some success despite not being optimized for persistent chlamydial infection. Clearly, additional work is both needed and warranted to firmly establish the role of Chlamydia species in connective tissue diseases. Included in this is the need to optimize antimicrobial therapy against persistent infections caused by Chlamydia. Suggested Readings Allen JE, Locksley RM, StephensRS: 1991. A single peptide form the major outer membrane protein of Chlumydia trachonaaris elicits T cell help for the production of antibodies to protective determinants.J Immunol 147:674-679. Bas S, Griffais R, Kvien TK, GlennasA, Melby K, Visher TL: 1995. Amplification of plasmid and chromosome Chlamydia DNA in synovial fluid of patients with reactive arthritis and undifferentiated seronegativeoligoarthropathies.Arthritis Rheum 38: 10051013. Bavoil P,Ohlin A, SchachterJ: 1984. Role of disulftde bonding in outer membrane structureand permeability in Chlamydia rrachomatis. Infect Immun 44:479-485. Beatty RP,StephensRS: 1994. CDS+ T lymphocyte-mediated lysis of
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Chlumydiu-infected L cells using an endogenous antigen pathway. J Immunol 153:4588-4595. Beatty WL, Byrne GI, Morrison RP: 1993. Morphologic and antigenic characterization of interferon gamma-mediated persistent Chlamydia trachomatis infection in vitro. Proc Nat1Acad Sci USA 90:3998-4002 Beatty WL, Byrne GI, Morrison RP: 1994. Repeated and persistent infection with Chlamydiu and the development of chronic inflammation and disease. Trends Microbial 2:94-98. Beatty WL, Morrison RP, Byrne GI: 1994. Persistentchlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microbiological Rev 58:686-699. Beatty WL, Morrison RP, Byrne GI: 1995. Reactivation of persistentChlamydia trachomatis infection in cell culture. Infect Immun 63: 199-205. Branigan PJ, Gerard HC, Saaibi D et al.: 1995. PCR screeningof synovial tissue vs. fluid from patients with Reiter’s syndrome and other spondyloarthropathies for Chkamydia trachomutis. Arthritis Rheum 38(Suppl9):5348. Braun J, Laitko S, Treharne J et al.: 1994. Chlamydia pneumoniae - a new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 53:100-105. Braun J, Tuszewski M, Ehlers S et al: 1997. Nested polymerasechain reaction strategy simultaneously targeting DNA sequencesof multiple bacterial speciesin inflammatory joint diseases.II. Examination of sacroiliacand knee joint biopsiesof patientswith spondyloarthropathies and other arthritides. J Rheumatol 24ZllOl-1105. Briere F, Bridon JM, Chevet D et al.: 1994. Interleukin 10 induces B lymphocytes from IgA-deficient patients to secrete IgA. J Clin Invest 94:97- 104. Browmidge E, Wyrick P: 1979. Interaction of Chlamydia psittaci reticulate bodies with mouse peritoneal macrophages. Infect Immun 24697-700. Brunham RC, Maclean IW, Binns B, Peeling RW 1985. Chlamydia trachomaris: its role in tubal infertility. J Infect Dis 152:1275-1282. Brunham RC, Peeling RW 1994. Chlamydia truchomatis antigens: role in immunity and pathogenesis.Infect Agents Dis 3:218-233. Bushel1AC, Hobson D: 1978. Effect of cortisol on the growth of Chlamydia trachomatis in McCoy cells.Infect Immun 21:946-953. Byrne GE, SchobertCS, Williams DM, Krueger DA: 1989. Characterization of gamma interferon-mediated cytotoxicity
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to chlamydia-infected fibroblasts. Infect Immun 57:870-874. Campbell R, Birkelund S, Ward MS, Panayi GS. Kingsley GH: 1996. Sexually acquiredreactive arthritis synovialT cells respond to Chlamydia trachomatis 57 kD heat shock protein but not the major outer membrane protein. Arthritis Rheum 39(Suppl9):S184. Campbell LA, Patton DL, Moore DE, Cappuccio AL, Mueller BA, Wang S-P: 1993. Detection of Chkzmydia trachomatis deoxyribonucleic acid in women with tubal infertility. Fertility Sterility 59:45-50. Coles AM, ReynoldsDJ, Harper A, Devitt A, PearceJH: 1993. Low-nutrient induction of abnormal chlamydial development: a novel component of chlamydial pathogenesis?FEMS Microbial Letters 106:193-200. Coxgrove PA, PattonDL, Tahija S, Campbell L, Kuo C-C, Cappuccio AL: 1992. In situ DNA hybridization detection of C. trachomatis in chronic ocular infections. Invest Gphthal Vis Sci 33:848-856. Craig E: 1985. The heat shockresponse. Crit Rev Biochem 18:239-280. Cutlip RC, Ramsey FK: 1973. Ovine chlamydial polyarthritis: sequential development of articular lesionsin lambs after intraarticular exposure.Am J Vet Res 34:71-75. Domeika K, Brade L, Mardh PA, Brade H, Witkin SS,Domeika M: 1997. Characteristics of serum antibody responseto chlamydia in patients with sexually acquired reactive arthritis. FEMS Immunol Med Microbial 19:191-202. Domeika M, Domeika K, PaavonenJ, Mardh P-A, Witkin SS: 1998. Humoral immune responseto conservedepitopes of Chlamydia trachomatis and human 60-kDa heat-shockprotein in women with pelvic inflammatory disease. J Infect Dis 177:714-719. EugsterAK, StorzJ: 1971. Pathogenic events in intestinal chlamydial infections leading to polyarthtitis in calves.J Infect Dis 123:41-50. FassbenderHG: 1983. Histomorphological basisof articular cartilage destruction in rheumatoid arthritis. Co11Relat Res 3:141-155. Ford DK, Da RD, SchulzerM: 1985. Lymphocytes from the site of disease but not blood lymphocytes indicate the causeof arthritis. Ann Rheumatic Dis 44:701-710. Ford DK, Reid GD, Magge S, Schumacher HR: 1988. Synovial lymphocyte responseto chlamydial stimulation associated with intrasynovial chlamydial antigen in a patient with “rheumatoid arthritis.“Arthtitis Rheum 31:914-917. Gabriel SE, COM DL, Luthra H: 1990.
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Rifampin therapy in rheumatoid arthritis. J Rheumatol 17:163-166. Gaston JSH, Keane KHO, JecockRM, PearceJH: 1996. Identification of two Chlamydiu trachomatis antigens recognized by synovial fluid T cells from patients with Chkzmydia-inducedreactive arthritis. J Rheumatol23:130-136. Gerard HC, Branigan PJ, SchumacherHR Jr, Hudson Ap: 1998. Synovial Chlamydia trachomatis in patients with reactivearthritis/Reiter’s syndrome are viable but show aberrant gene expression. J Rheumatol25:734-742. Gordon FB, Quart AL, Steinman TI, Philip RN: 1973. Chlamydial isolatesfrom Reiter’s syndrome. Br J Vener Dis 49:376-380. Gran JT, Hjetland R, AndreassenAH: 1993. Pneumonia, myocarditis and reactive arthritis due to Chlamydia pneumoniae. Stand J Rheumatol22:43-44. HackstadtT, Todd WJ, Caldwell HD: 1985. Disulfide-mediated interactions of the chlamydial major outer membrane protein: role in the differentiation of chlamydiae? J Bacterial 161:25-31. Halme S, SurcelH-M: 1997. Cell mediated immunity to Chlamydia pneumoniae. Stand J Infect Dis 104(Suppl):18-21. Hammer M, Nettelnbreker E, Hopf S, SchmitzE, PorschkeK, Zeidler H: 1992. Chlamydial rRNA in the joints of patients with Chfamydia-induced arthritis and undifferentiated arthritis. Clin Exp Rheumatol l&63-66. Hanna L, Merigan TC, Jawetz F: 1966. Inhibition of TRIC agents by virus induced interferon. Proc Sot Exp Biol Med 122:417-421. Harris ED: 1990. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322:1277-1289. Hatch TP,Allen I, PearceJH: 1984. Structural and polypeptide differences between envelopesof infective and reproductive life cycle forms of Chlamydia spp. J Bacterial 157:13-20. Hatch Tp: 1996. Disulfide cross-linked envelope proteins: the functional equivalent of peptidoglycan in chlamydiae? J Bacterial 178:1-5. Hatch TP, Miceli M, Sublett JE: 1986. Synthesisof disulfide-bonded outer membrane proteins during the developmental cycle of Chiamydia psittuci. J Bacterial 165:379-385. Heinemann M, SusaM, SimnacherU, Marre R, EssigA: 1996. Growth of Chlamydia pneumoniae induces cytokine production and expressionof CD14 in a human monocytic cell line. Infect Immun 6414872-4875. Holland SM, Hudson AP, Bobo L, et al.: 1992. Demonstration of chlamydial
RNA and DNA during a culture-negative state. Infect Immun 602040-2047. Holoshitz J, Klajman A, Drucker I et al.: 1986. T lymphocytes of rheumatoid arthritis patients show augmented reactivity to a fraction of mycobacteria cross-reactivewith cartilage. Lancet ii:305309. Hudson AP, McEntee CM, Reacher M, Whitum Husdon JA, Taylor HR: 1992. Inapparent ocular infection by Chlamydia trachomatis in experimental human trachoma. Curr Eye Res 11:279-283. Hughes RA, Keat AC: 1994. Reiter’s syndrome and reactive atthritis: a current view. Stand Arthritis Rheum 24: 190-210. JonesDB, Coulson AWF, Duff GV: 1993. Sequencehomologies between hsp 60 and autoantigens. Immunol Today 14115118. Kaufmann SHE: 1990. Heat shock protein and the immune response.Immunol Today 11:129-136. Kaufmann SHE: 1995. Immunity to intracellular microbial pathogens. Immunol Today 16:338-342. Kaukoranta-Tolvanen SS,Teppo AM, Laitinen K, Saikku P,Linnavuori K, Leinonen M: 1996. Growth of Chlamydia pneumoniae in cultured human peripheral blood mononuclear cells and induction of a cytokine response.Microb Path0121:215-221. Keat A, Thomas B, Hughes R, TaylorRobinson D: 1989. Chlamydia trachomatis in reactive arthritis. Rheumatol Int 9:197-200. Kelso A: 1995. Thl and Th2 subsets:paradigm lost? Immunol Today 16374-379. Kingsley G, Sieper J: 1993. Current perspectivein reactive arthritis. Immunol Today 14387-391. Kinne RW, Palombo-Kinne E, Emmrich R: 1995. Activation of synovial flbroblasts in rheumatiod arthritis. Ann Rheum Dis 54:501. Kloppenburg M, Breedveld FC, Terwiel JP, Mallee C, Dijkmans BA: 1994. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum 37626-636. Kohler L, Netteinbreker E, HudsonAP et al.: 1997. Ultrastructural and molecular analyses of the persistenceof Chfamydia trachomatis (serovar K) in human monocytes. Microb Pathogen 22: 133-142. Koga T, Wand-WurtenbergerA, DeBruyn J et al.: 1989. T cells against a bacterial heat shock protein recognized stressed macrophages.Science245: 1112-1115. Kvien TK, GlennasA, Melby K et al.: 1994. Reactive arthritis: incidence, triggering agents and clinical presentation.J Rheumatol21:115-122. Lamb JR, Bal V, Mendez-Samperio Pet al:
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1989. Stressproteins may provide a link between the immune responseto infection and autoimmunity. Int Immunol 1:191-196. Magee DM, Williams DM, Smith JG et al.: 1995. Role of CD8 cells in primary Chlamydia infection. Infect Immun 63:516-521. Malinverni R, Kuo C-C, Campbell LA, Grayston JT: 1995. Reactivation of Chlamydia pneumoniae lung infection in mice by cortisone. J Infect Dis 172:593594. Malinvemi R: 1996.The role of cytokines in chlamydia infection. Cut-rOpinion Infect Dis 9:150-156. Manor E, SarovI: 1986. Fate of Chlamydia trachomatis in human monocytes and monocyte-derived macrophages.Infect Immun 54:90-95. McCafferty MC, Maley SW,Entrican G, Buxton D: 1994. The importance of interferon-gamma in an early infection of Chlumydia psittaci in mice. Immunology 8163 l-636. McClarity G: 1994. Chlamydiae and the biochemistry of intracellular parasitism. Microbiology 2: 157-164. Mehta SJ,Miller RD, RamirezJA, SummersgillJT: 1998. Inhibition of Chlamydia pneumoniae in Hep-2 cells by interferon-gamma: role of tryptophan catabolism.J Infect Dis 177:1326-1331. Meyer KF, Eddie B: 1933. Latent psittacosis infection in shell parakeets.Proc Sot Exp Biol Med 30:483-488. Moazed TC, Kuo C-C, Grayston JT, Campbell LA: 1998. Evidence of systemic dissemination ofchlamydia pneumoniae via macrophagesin the mouse.J Infect Dis 177:1322-1325. Moling 0, Pegoretti S, Rielli M et al.: 1996. Chlamydia pneumoniae-reactivearthritis and persistentinfection. Br J Rheumatol 35:1189-1190. Morrison RP,Belland RJ, Lyng K, Caldwell HD: 1989. Chlamydial diseasepathogenesis:the 57-kD chlamydial hypersensitivity protein is a stressresponse protein. J Exp Med 170:1271-1283. Morrisson RP, Lyng K, Caldwell HD: 1989. Chlamydial diseasepathogenesis:ocular hypersensitivityelicited by a genus specific 57 kD protein. J Exp Med 169:663675.
Morrisson RP: 1998. PersistentChlamydia trachomatis infection: in vitro phenomenon or in vivo trigger of reactivearthritis? J Rheumatol25:610-612. Moulder JW,Levy NJ, SchulmanRP: 1980. Persistentinfection of mouse tlbroblasts (L cells) with Chlamydia psittaci: evidence for a cryptic chlamydial form. Infect Immun 20:874-883. Mygind P,ChristiansenG, PerssonK,
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Birkelund S: 1998. Analysis of the humoral immune responseto Chlamydia outer membrane protein 2. Clin Diagn Lab Immunol5:313-318. Nanagara R, Li F, Beutler A, Hudson A, SchumancherHR Jr: 1995. Alteration of Chlamydia trachomatis biological behavior in synovial membranes. Suppressionof surfaceantigen production in reactive and Reiter’s syndrome. Arthritis Rheum 38:1410-1417. Newall WJ: 1987. Biosynthesisand disulfide cross-linkingof outer membrane components during the growth cycle of Chlamydia trachomatis. Infect Immun 55:162-168. Nikkari S, PuolakkainenM, Yli-Kerttula R, Luukkainen R, Lehtonen OP,Toivanen P: 1997. Ligase chain reaction in detection of Chlamydia DNA in synovial fluid cells. Br J Rheumatol36:763-765. Norton WL, Lewis D, Ziff M: 1966. Light and electron microscopicobservation on the synovitis of Reiter’s syndrome. Arthritis Rheum 9:747-757. Norton WL, Storz J: 1967. Observationson sheepwith polyarthritis produced by and agent of the psittacosis-lymphogranuloma venereum-trachomagroup. Arthritis Rheum lO:l-12. O’Dell JR, Haire CE, Palmer W, Drymalski S et al: 1997. Treatment of early rheumatoid arthritis with minocyclineor placebo: resultsof a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 122:81-89. Gng G, Thomas BJ, Mansfield AO, Davidson BR, Taylor-Robinson: 1996. Detection and widespreaddistribution of Chlamydia pneumoniae in the vascular systemand its possibleimplications. J Clin Path0149:102-106. Patton DL, SweeneyYT, Kuo C-C: 1994. Demonstration of delayed hypersensitivity in Chlamydia trachomatis salpingitis in monkeys: a pathogenic mechanism of tubal damage. J Infect Dis 169:680-683. Peeling RW, Bailey RL, Conway DJ et al.: 1998. Antibody responseto the 60-kDa chlamydial heat-shockprotein is associated with scarringtrachoma. J Infect Dis 177:256-259. Peeling RW, Brunham RC: 1996. Chlamydiae as pathogens: new speciesand new issues.Emerg Infect Dis 2:1061-1065. Peeling RW, Peeling J, Brunham RC: 1989. High-resolution 3 1Pnuclear magnetic resonancestudy of Chlumydia trachomatis: induction of ATPaseactivity in elementary bodies. Infect Immun 57:3338-3344.
Perez-MarinesJA, Storz J: 1985. Persistent infection of L cells with an ovine abortion strain of Chlamydia psittaci. Infect Immun 50:453-458.
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Ramsey KH, Rank RG: 1991. Resolution of chlamydial genital infection with antigen-specific T-lymphocyte lines. Infect Immun 59:925-931. RasmussenSJ,lhnrns P, Beatty R, Stephens RS: 1996. Cytotoxic-T-lymphocytemediated cytolysis of L cells persistently infected with Ch/umy& species.Infect Immun 64:1944-1949. Rahman MU, Cantwell R, Johnson CC, Hodinka RL, SchumacherR, Hudson Ap: 1992. Inapparent genital infection with Chlamydia trachomatis and its potential role in the genesisof Reiter’s syndrome. DNACell Biol 11:215-219. Raham MU, Cheema MA, SchumacherHR, Hudson AP: 1992. Molecular evidence for the presenceof Chlamydia in the synovium of patients with Reiter’s syndrome. Arthritis Rheum 35521-529. Rahman MU, Hudson AP, SchumacherHR: 1992. Chlamydia and Reiter’s syndrome (reactive arthritis). Rheum Dis Clin North Am 18:67-79. Saario R, Toivanen A: 1993. Chktmydia pneumoniae as a causeof reactive atthritis. Br J Rheumato132: 1112-l 118. SchachterJ, Barnes MG, JonesJp, Engleman EP,Myer KF: 1966. Isolation of bedsoniae from the joints of patients with Reiter’s syndrome. Proc Sot Exp Biol Med 122:283-285. SchachterJ: 1988. The intracellular life of Chlamydia. Curr Top Microbial Immunol 138:109-130. Schmitz E, Nettelnbreker E, Zeidler H, Hammer M, Manor E, Wollenhaupt J: 1993. Intracellular persistenceof chlamydial major outer membrane protein, lipopolysaccharide and ribosomal RNA after non-productive infection of human monocytes with Chlamydia trachomutis serovar K. J Med Microbial 38:278-285. SchumacherHR Jr, Magge S, Chemian PV et al.: 1994. Light and electron microscopic studieson the synovial membrane in Reiter’s syndrome; immunocytochemical identification of Chlamydia antigen in patients with early disease.Arthritis Rheum 37:710-717. Sewell KL, Trentham DE: 1993. Pathogenesis of rheumatoid arthritis. Lancet 341:283-286. SieperJ, Kingsly G, Palacois-BoixA et al.: 1991. Synovial T lymphocyte-specific immune responsein Chlamydia trachomutis in Reiter’s disease.Arthritis Rheum 34588-598. Sieper J, Kingsley G: 1996. Recent advancesin the pathogenesisof reactive arthritis. Immunol Today 17:16-163. Simon AK, Seipelt E, Wu P, WenzelB, Braun J, SieperJ: 1993. Analysis of cytokine profiles in synovialT cell
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clones from chlamydial reactive arthritis patients: predominanceof the Thl subset. Clin Exp Immunol94:122-126. Skinner M, Cathcart ES, Mills JA, Pinals RS: 1971. Tetracyclinein the treatment of rheumatic arthritis: a double blind controlled study. Arthritis Rheum 14:727-732. Stagg AJ, ElsleyWAJ, Pickett MA, Ward ME, Knight SC: 1993. Primary human T-cell responseto the major outer membrane protein of Chlamydia trachomatis. Immunology 79: l-9. StephensRS, Chen W-J, Kuo C-C: 1982. Effects of corticosteroidsand cyclophosphamide on a mouse model of Chlamydia trachomatis pneumonitis. Infect Immun 35:680-684. StephensRS, Kalman, Lammel C et al.: 1998. Genome sequenceof an obligate intracelhtlar pathogen of humans: Chlamydia trachomatis. Science 282:754-759. Stan J, Marriott ME, Smart RA, Davis RV: 1966. Polyarthritis of calves: isolation of psittacosisagentsform affected joints. Am J Vet Res 27:633-641. StorzJ. Overviewof animal diseasesinduced by chlamydial infections. Ch. 9, p. 16% 172. In: Microbiology of Chlamydia. Barron AL (ed.), CRC Press,Boca Raton. FL 1988. Storz J: 1966. Polyarthrltis of calves: isolation of psittacosisagents from affected joints. Am J Vet Res 27:633-641. Storz J, Shupe JL, Marriott ME, Thornley WR: 1965.Polyarthritisof lambs induced experimentally by a psittacosisagent. J Infect Dis 1159-15. Storz J, Shupe JL, Smart RA, Thornley RW 1966. Polyarthritis of calves: experimental induction by a psittacosisagent. Am J Vet Res 27:987-992. Stratton CW, Mitchell WM: 1996. The pathogenesisof Chlamydia species. Antimicrobics Infect Dis Newslett 15:83-88. Theijls H, GnarpeJG, Lundkvist 0, Heimer G, Larrson C, Victor A: 1991. Diagnosis and prevalenceof persistentchlamydia infection in infertile women: tissueculture, direct antigen detection, and serology. Fertility Sterility 55:104-310. Tilley BC, Alarcon GS, Heyse SP et al.: 1995. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebocontrolled trial. MIRA Trial Group. Ann Intern Med 122:81-89. Trentham DE, Dynesius-TrenthamRA: 1995.Antibiotic therapy for rheumatoid arthritis. Scientific and anecdotal appraisals.Rhematic Dis Clin NA 21:817-834. Toye B, Lafetriere C, Claman P,JessamineP, Peeling R: 1993. Associationbetween
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antibody to the chlamydial heat-shock protein and tubal infertility. J Infect Dis 168:1236-1240. Tsumura N, Emre U, Roblin P, Hammers&lag MR: 1996. Effect of hydrocortisone succinateon growth of Chlumydia pneumoniae in vitro. J Clin Microbial 342379-2381. Wang LL, Henson E, McClarty G: 1994. Characterization of trimethoprim- and sulphisoxazoleresistant C-y&r rruchomatis. Molecular Microbial 14271-281. Ward ME: 1995. The immunology and immunopathology of chlamydial infections. APMIS 103:769-796. Weinblatt ME, Coblyn JS, Fox DA: 1985. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312:818-822. Williams DM, Grubbs BG, SchachterJ, Magee DM: 1993. Gamma interferon levels during Chlamydia trachomatis pneumonia in mice. Infect Immun 61:3556-3558. Witkin SS,JeremiasJ, Toth M, Ledger WJ: 1993. Cell-mediated immune responseto the recombinant 57-kDa heat-shockprotein of Chkzmydiatrachomatis in women with salpingitis. J Infect Dis 167:13791383. Witkin SS,Torh M, JeremiasJ, Ledger WJ: 1991. Increasedinducibility of inflammatory mediators from peripheral blood mononuclear cells of women with salp ingitis.Am J ObstetGynecol165:719-723. Wyrick PB, Browmidge EA: 1978. Growth of Chkmydia psittaci in macrophages. Infect Immun 19: 1054-1060. Yang Y-S, Kuo C-C, Chen W-J: 1983. Reactivation of Chlamydia trachomatis lung infection in mice by cortisone. Infect Immun 39:658-665. Yang Z-P,Kuo C-C, Grayston JT: 1993. A mouse model of Chkznydia pneumoniae strain TWAR pneumonitis. Infect Immun 61:2037-2040. Yang Z, Kuo C, Grayston JT: 1995. Systemicdisseminationof Chlamydia pneumoniae following intranasalinoculation in mice. J Infect Dis 171:736-738. Young RA, Elliot TJ: 1989. Stressproteins, infection and immune surveillance.Cell 59:5-8. Young RA: 1990. Stressproteins and immunology. Ann Rev Immunol 8401-420. Zvillich M, Sarov I: 1989. The persistence of Chlamydia trachomatis elementary body cell walls in human polymorphonuclear leukocytes and induction of a chemihuninescent response.J Gen Microbial 135:95-104.
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Chlamydiae are unique intracellular pathogens that are separated from other eubacteria and represent one of the kingdom-level branches of the phylogenie tree. Chlamydia species are widely distributed in nature, infecting mammals and birds as well as humans. Chtizmydia species have a very complex life cycle in which a number of distinctive forms are seen. The first is a metabolically inactive spore-like form called an elementary body (EB). Only this inert spore-like EB is infectious and able to spread Chlamydia infection from one host/host cell to another. EBs have heparan sulfate receptors and are able to attach to target cells. EBs can then invade the host eukaryotic cell and transform into a reticulate body (RB). RBs are obligate intracellular parasites that are metabolically active and able to replicate by binary fission. During replication, some RBs condense back into EBs that then can be released from the cell to initiate a new cycle of infection. During acute infection, replication produces inclusions that often become quite large; infected cells then lyse and release many EBs. In contrast, persistent chlamydial infections involve the cryptic form. This cryptic form of Chlamydia species seems to be RBs that are able to metabolize, but do not replicate nor differentiate into EBs to any degree. Cryptic forms of Chlamydiu species cannot be cultured due to
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the relative lack of infectious EBs. Among chronic illnesses that Chiumydia species have been associated with are connective tissue diseases. Connective tissue diseases are &fined as those involving joints and related structures of the skeleton. ‘Ihis brief review will address this association and discuss the diagnostic and therapeutic implications.
Inflammatory Connective Tissue Diseasesin Humans Joints and related structures of the human skeleton are considered the principal connective tissues and vary widely in structure and function as well as in predisposition to disease. Joints and related structures that are nearly rigid such as the calvarial sutures almost never are involved in disease. Much more disease, including inflammatory processes, is seen in articulating diarthrodial joints in which the ends of the bones are capped by articular cartilage and the joint space is lined by synovial membrane except in the cartilaginous, weight-bearing areas. Synovial surface membranes normally contain two types of synoviocytes. The type A synovial cell is more common and is closely related to macrophages. As such, type A synovial cells have phagocytic functions and remove particulate matter from the synovial fluid. In addition, these cells can produce degradative enzymes, mostly collagenases. The type B synovial cells are of mesenchymal origin and have a fibroblastic appearance. These cells syntbesize and secrete a number of substances including mutinous hyaluronic acid, glycosaminoglycans, collagenase, fibronectin, and lubrican. Qpe A and B syn-
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ovial lining cells are dispersed evenly as a single cell layer without an underlying basement membrane. This allows these cells close contact with a thin layer of connective tissue matrix which contains mononuclear cells, interdigitating dendritic cells, blood vessels, lymphatics, and nerve filaments. The articular cartilage itself is a unique type of connective tissue that serves as an elastic shock absorber and wear-resistant surface. Articular cartilage is metabolically active with chondrocytes that synthesize the cartilaginous matrix. These cells also have the ability to synthesize collagenases and other proteinases. Many connective tissue diseases in humans involve inflammation. The most common is rheumatoid arthritis @A). RA is a chronic connective tissue disease of unknown etiology which has been considered by some to be the result of an chronic inflammatory synovial response to an unrecognized antigen such as that from an infectious agent. Distinctive and dramatic changes occur in the synovial membrane in RA. The histopathologic findings seen early in RA are hyperplasia of the synovial lining and disruption of endothelial cell that is accompanied by rapid vascular proliferation consisting of new capillaries with relatively little change in larger vessels. This acute process is followed
In This Issue The Role of Chkizmydia in
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by an intense infiltration of this hyperplastic synovia with macrophages, lymphocytes, and plasma cells. As the rheumatoid disease progresses, the hyperplastic synovia becomes a multilayered proliferative and fibrous mass of granulation tissue is known as “pannus” that invades surrounding bone, cartilage, tendons, and ligaments via villous processes. Within the pannus, synoviocytes are activated and secrete metaloproteinases that degrade surrounding bone and cartilage. Villi from this pannus protrude into the joint space as well. The joint fluid becomes turbid. There are often focal areas of inflammation in tendons, muscles, and periarticuar connective tissue with infiltration of macrophages, lymphocytes, and plasma cells. Another connective tissue disease that involves inflammation is reactive arthritis (ReA). The clinical association between ReA and certain venereal infections has been well established over the years. Currently, the venereal infection is thought be responsible for the arthritis. Because microorganisms have rarely been isolated from affected joints in these patients, ReA has been thought to be due to an immunological response either to antigen deposited in the joint or to self-connective tissue caused by molecular mimicry. Reactive arthritis, thus, is considered an inflammatory arthritis that occurs as a consequence of infection elsewhere in the body. Undifferentiated oligoarthritis is yet anther inflammatory connective tissue disease that has a clinical and pathological pattern that is very similar to ReA, except that there is no clear evidence of an antecedent triggering infection, ReA is a well-known component of Reiter’s syndrome, the other two in this triad being urethritis and conjunctivitis. In Reiter’s syndrome, the synovial membrane is characterized by the plug-
ging of capillaries and venules with platelets and polymorphonuclear cells; these findings can be experimentally produced by the local injection of bacterial endotoxins such as lipopolysaccharide (LPS). Indeed, considerable evidence has accumulated supporting bacterial antigens, such as LPS, in the pathogenesis of this synovial inflammatory process. The exact role of the microorganism remains a subject of controversy. The issue in question is whether joint infection per se causes the inflammation or whether an immunological reaction to an infection elsewhere is responsible for the pathological changes in affected joints.
Important pathogenic Issues Concerning Chlamydial Infection There are a number of pathogenic issues concerning chlamydial infection that strongly suggest that Chlamydiu may play an important role in inflammatory diseases of connective tissue. Each of these issues will be briefly discussed. ctdamydlal
lnfeetloll of
monocytedmacrophages Infection of connective tissues by Chlamydia species may be facilitated by the ability of these pathogens to infect and replicate within monocytes and macrophages. Relatively few other microorganisms are able to survive inside monocytes and macrophages, due to the abundance of acidic phagocytic vacuoles and hydrolytic enzymes. Following EB entry and subsequent infection of the host macrophage, Chlamydia species may escape from the initial site of infection via lymphatic channels and blood vessels and disseminate. For example, Koehler et al. have been able to produce persistent infection of cultured human peripheral blood mononuclear cells with C. trachomutis in which the organism was viable and metabolically active, but could not be cultured. Infection of peripheral blood
mononuclear cells clearly would allow Chlamydia species to reach connective tissues and possibly infect type A synovial cells, which are closely related to macrophages. Persistent chhmydial infection Chlamydial infections are persistent. Persistence is defined as a long-term association between the pathogens and their host cells in which these microorganisms remain in a viable but culture-negative state. Chlamydia species are able to persist due to their ability to enter a quiescent cryptic state that involves alterations in antigen expression, altered morphology, and loss of infectivity. Once the stimulus for persistence has been removed, these cryptic forms may revert to the replicating form that can be cultured. The decline in recoverable infectivity of these cryptic forms would make cell cultures relatively insensitive as a means of detecting persistent chlamydial infection. Although not replicating, these cryptic forms are thought to play an important role in the chlamydial disease pathogenesis due to their production of heat shock proteins (HSPs). Chlamydld persistence and heat shock proteins Both eurkaryotic and prokaryotic cells respond to harmful environmental stress with a highly conserved cellular response known as the stress response. Part of this stress response includes the increased production of HSPs that normally are constitutively synthesized at low levels, but are synthesized at high levels when a cell is subjected to stress. Examples of stressful cellular events include a sudden increase in temperature, viral infection, exposure to superoxides, anoxia, or glucose starvation. HSPs chaperone the folding, unfolding, and translation of other proteins as well as in the assembly and disassembly of protein complexes in the endoplasmic reticulum and mitochondria. The
NOTE: No responsibility is assumed by the Pnblishet for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material her&. No suggested test or procedure should be carried out unless, in the reader’s judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verification of diagnoses and dmg doses should be made. Discussions. views. and recommendations as to medical procedures, choice of drugs, and dmg dosages are the responsibility of the authors. Antimirmbics and InfMious Diseases Newsletter @SSN 1069-417X) is issued monthly in one indexed vohutx per year by Elsevier Science Inc., 655 Avenue of the Americas, New York, NY 10010. For customer service, phone (212) 633-3950; TOLLFREE for customers in the U.S.A. and Canada: I-888-4~INFO (l-888-437-4636) or fax: (212) 633-3680. Subscriptions are available on a calendar yeat basis or as a rolling (anytime-start) subscription. Subscription price per year: for institutional subscribers in Europe, The CIS, and Japan: NLG 668; for iastitwional subscribers in all other counties: USS 339. For personal subscribers io Europe, The CIS. and Japan: NLG 390; for personal subscribers in all other countries: USS 198. Periodical postage paid at New York, NY and at additional mailing offices. Postmaster: Send address changes to Antimicmbics and infectiousDiseases Newsletter. Elxvier Science inc., 655 Avenue of the Atnecicas. New York, NY 10010.
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importance of these proteins can be appreciated by the fact that the structure of HSPs is highly conserved during evolution and is similar in bacteria, yeasts, plants, and animals. HSPs produced by microbial pathogens have been found to be major antigens. The immune response to HSPs may be a major factor in many diseases. Both CD4 and CD8 T cells are activated by HSP and can recognize and Iyse macrophages that are producing HSP due to stress such as heat, gammainterferon, or intracellular pathogens. This immune response would contribute to the removal of injured cells or infected cells. HSPs thus are thought to contribute to the development of autoimmune disease. Patients with RA are known to have specific T lymphocyte reactivity to HSP Pancreatic islet beta-cells express HSP which is the target of T lympho-
cytes in insulin-depen&nt
diabetes.
Chlamydia species produce HSPs of which the 57-kDa HSP is the second most abundant protein in chlamydial whole cell lysates. This HSP is found in both EBs and BBS and is loosely associated with the cell surface. Chlamydial HSPs are highly conserved. For example, the 57-kDa HSP of C. trachomatis has a 95% amino acid similarity with the 57-kDa HSP of C. pneunwniae. For humans infected with C. trachomatis, the cdl-mediated immune response to the chlamydial57kDa HSP is one of delayed hypersensitivity with lymphocytic proliferation. This hypersensitivity is thought to be an important aspect of the pathogenesis of trachoma, chronic salpingitis, tubal infertility, and immune-mediated pregnancy loss. Cell-mediated
immunity and
cblamydia Cell mediated immunity is crucial in host defenses against intracellular pathogens such as Chlamydia. There is increasing evidence that cell-mediated immunity to Chlamydia may be responsible for either recovery from infection or immunopathology. Both CD4 and CD8 T cells are needed for efficient protection against Chlamydia infection in mice. The CD4 T cells are essentially for protection and are activated by chlamydial antigens derived from vacuolar contents bound to the HLA class II molecules exposed on host cells such as macmphages, dendrites, and endo-
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thelial cells; recognition of antigen results in secretion of cytokines. The cytokines then activate macrophages as well as stimulate B cells to produce antibodies. The CD8 T cells require gamma-interferon to be fully effective and have potential for a more comprehensive antigen response because they recognize cytoplasmic antigenic peptides bound to HLAclass 1 molecules which are expressed an aI1 micleated cells. CD8 T cells when activated by antigen may respond in several ways which include the production of gammainterferon, cytolytic activity, or suppression of the immune response. The outcome of the immune response to Chlumydia can be protection or immunopathology and seems to be determined by the antigen that dominantly stimulates T cell activation. The major outer membrane protein (MOMP) of Chlamydia appears to provide protection while HSP seems to stimulate pathological events leading to tissue destruction associated with chlamydial infection. Cytokines are major factors in the regulation of the immune response to Chlamydia species and, in part, determine the outcome. An efficient cellmediated immune response as well as macrophage activation are associated with gamma-interferon, interleukin-2 (IL.-2), and IL-12 by Thl cells whereas humoral immunity and antibudy production are related to IL-4, IL-5 and IL-10 secretion by Th2 cells; the latter suppress macrophage functions. There is considerable published data for Chlamydia infections that suggest gamma-interferon and Th 1 activation play a substantial role in chlarnydial immunity. The significance of gammainterferon in chlamydial immunity is suggested by the fact that activation of the Th2 cells with a resultant too low amount of gamma-interferon leads to the development of inapparent and persistent infection with non-infectious but viable Chfamydia. Another marker for activation of the Th2 type of cell is increased levels of IgA antibodies, which is mediated by IL-lo.
Chkizmydiu Species and Connective Tissue Diseases in Animals Chlamydia species causing mammalian diseases have been studied extensively in common farm animals due to the obvious economic importance. Young
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animals we especially prone to infection with C. psittaci, which is the chlamydial species that most often causes infection in animals. For example, lambs, calves, foals, and piglets are recognized as having polyarthritis and polyserositis after initial intestinal infections. In these animals, C. psittaci spreads systemically from the initial intestinal infection and subsequently reaches, infects, and replicates in synovid tissue ceIIs. Chlamydial polyarthritis of lambs, also called “stiff lamb disease,” is the best studied of the chlamydial inflammatory diseases of animals. This is a disease that occurs in epizootic proportions in the major sheep-raising regions of the United States. It is caused by C. psittaci, which infects most of the synovial tissues of the diarthrodial joints of the limbs, leading to inflammation, stiffness, and lameness. Affected lambs have varying degrees of stiffness and lameness, and also exhibit anorexia and conjunctivitis. Moreover, these lambs become gaunt, depressed, and are reluctant to move, stand, or bear weight on one or more limbs, hence lingering behind the rest of the flock. In naturally occurring cases of polyarthritis in lambs, C. psittaci has been isolated from affected joints as well as from different organs and body fluids including lungs, liver, spleen, lymph nodes, brain, cerehrospind tluid, and blood. These findings suggest that a blood-borne phase with infectious chlamydial EBs occurs and leads to the infection of the joint tissues. An identical polyarthritis can readily be repraduced experimentally by inoculating lambs via the oral, subcutaneous, intramuscular, intravenous, or intraarticular routes. In both naturally occurring and experimentally induced chlamydial polyarthritis of lambs, the most striking tissue pathology is found in articular and periarticular tissues. Larger, freely movable, weight-bearing joints contain excessive, grayish-yellow, turbid synovial fluid. In joints with advanced lesions, fibrin flakes and plaques of different sizes and shapes are seen. These fibrin plaques often adhere to the synovial membranes. The joint capsules of affected joints are thickened. Tendon sheaths are often distended and contained creamy, grayishyellow exudate. Surrounding muscles
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are hyperemic, edematous, and have petechiae in their associated fascial planes. The histopathological findings begin with an early serous reaction, move to a librinopurulent inflammatory phase, and finally end with fibroplasia and accumulations of lymphoid cells. Mononuclear cells accumulate in perivascular areas. Advanced lesions in joint capsules and tendon sheaths show marked fibrotic thickening. Advanced lesions are accompanied by an extensive inflammatory response that consist primarily of plasma cells, monocytes, lymphocytes, macrophages, and neutrophils. The viable synoviocytes become swollen and hyperplastic with a pseudostriated appearance; fibroblasts in these infected tissues are large, plump, and round. In such infected tissues, chlamydial inclusions are found in synovial cells as well as in flbroblasts, monocytes, and endothelial cells. Changes in adjacent muscles are periarticular and associated with tendinous insertions. These changes are best characterized as myositis due to their infiltration with inflammatory cells, accumulation of edema fluid, and fibroblastic proliferation. Similar findings have been describe in polyarthritis of calves. Chlomydiu trachomutis and Connective Tissue Diseases in HlmUUiS C. trachomatis is a frequent pathogen of the urogenital tract and is the most common sexually-transmitted disease reported to the U.S. Centers for Disease Control and Prevention. Thus, it is not surprising that C. trachomatis has emerged as a major cause of reactive arthritis. Chtamydia-induced arthritis is characterized by aseptic synovitis of the peripheral or sacroiliac joints. Despite the difficulty in isolating C. trachomatis from joint fluid in patients with ReA, chlamydial antigens, nucleic acids, and non-cultivable Chlamydia-like particles in affected joints have been demonstrated by numerous investigators. In addition to evidence for the presence of C. trachomatis in affected joints in patients with ReA, a recent report by Gerard and colleagues suggests that viable, metabolically active C. trachomatis reside in the synovial tissue of patients with this disease. C. trachomatis not only are present in the joint tis-
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sue, but also are actively expressing HSP. This study challenges the established dogma in the field of rheumatology and will need to be confinned. The implications of the study by Gerard et al. are important. First of all, the expression of chlamydial HSP by viable C. trachomatis in the synovial cells of affected joints may be inducing the chronic inflammation seen with ReA. Of interest here is that a number of other groups including Campbell et al., Sieper et al., as well as Gaston et al. have demonstrated that sexually-acquired ReA synovial T cells respond to C. truchomads antigens, including the 57-kD HSP Simon has demonstrated that these patients have a cytokine profile that suggests the predominance of the Th 1 subset. Moreover, if there is active infection in the joints, the use of corticosteroids in arthritis therapy must be reevaluated. Finally, it is possible that
some current antimicrobial agents may not be effective in eradicating Chlamydiu that are not actively replicating. In fact, antibiotics are known to produce persistent chlamydial infections in cell culture. Chlamydiu pneumoniue and Connective Tissue Diseases in Humans The association of C. pneumoniae with arthritis syndromes has been reported by Braun et al., Gran et al., Moling et al., and by Saario and Toivanen. Clearly, the potential for this association is strong as many more people are infected by C. pneumoniae than by C. trachomatis. The emerging understanding of the pathogenic nature of C. pneumoniae infections strongly suggests that this pathogen reaches and infects synovial tissue. However, the exact role of C. pneumoniae in specific arthritis syndromes such as RA remains to be determined. Chkamydia species and Rheumatoid Arthritis The histopathology of RA is consistent with an acute infectious process leading to a chronic infection with delayed hypersensitivity: infection with Chlamydia species could easily produce such a response. Of note, moreover, is the longstanding observation that antimicrobial agents not only are effective against ReA, but also have some success in
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RA. Indeed, the greatest success has been with minocycline, which is active against Chlamydia species. Methotrexate, another agent commonly used in the therapy of RA, is known to have antimicrobial activity against Chlamydia species. Penicillamine, an effective drug less commonly used in RA, is a sullhydryl-containing reducing agent which, as such, would be active against the disulfide bonds of chlamydial MOMF! Thiols have been noted to activate chlamydial ATP synthase; were this to happen in the extracellular milieu, the result might be detrimental to the organism. Other antimicrobial agents that have been tried with varying degrees of success for the therapy of RA include rifampin, isoniazid, and metronidazole. At least one of these, rifampin, is known to be active against Chlamydia. Summary In summary, Chlamydia species have been shown to infect synovial tissues. The synovial infection produced can be persistent and can cause a cell-mediated inflammatory response directed at chlamydial HSPs. Antimicrobial therapies of arthritis syndromes to date have demonstrated some success despite not being optimized for persistent chlamydial infection. Clearly, additional work is both needed and warranted to firmly establish the role of Chlamydia species in connective tissue diseases. Included in this is the need to optimize antimicrobial therapy against persistent infections caused by Chlamydia. Suggested Readings Allen JE, Locksley RM, StephensRS: 1991. A single peptide form the major outer membrane protein of Chlumydia trachonaaris elicits T cell help for the production of antibodies to protective determinants.J Immunol 147:674-679. Bas S, Griffais R, Kvien TK, GlennasA, Melby K, Visher TL: 1995. Amplification of plasmid and chromosome Chlamydia DNA in synovial fluid of patients with reactive arthritis and undifferentiated seronegativeoligoarthropathies.Arthritis Rheum 38: 10051013. Bavoil P,Ohlin A, SchachterJ: 1984. Role of disulftde bonding in outer membrane structureand permeability in Chlamydia rrachomatis. Infect Immun 44:479-485. Beatty RP,StephensRS: 1994. CDS+ T lymphocyte-mediated lysis of
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Chlumydiu-infected L cells using an endogenous antigen pathway. J Immunol 153:4588-4595. Beatty WL, Byrne GI, Morrison RP: 1993. Morphologic and antigenic characterization of interferon gamma-mediated persistent Chlamydia trachomatis infection in vitro. Proc Nat1Acad Sci USA 90:3998-4002 Beatty WL, Byrne GI, Morrison RP: 1994. Repeated and persistent infection with Chlamydiu and the development of chronic inflammation and disease. Trends Microbial 2:94-98. Beatty WL, Morrison RP, Byrne GI: 1994. Persistentchlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microbiological Rev 58:686-699. Beatty WL, Morrison RP, Byrne GI: 1995. Reactivation of persistentChlamydia trachomatis infection in cell culture. Infect Immun 63: 199-205. Branigan PJ, Gerard HC, Saaibi D et al.: 1995. PCR screeningof synovial tissue vs. fluid from patients with Reiter’s syndrome and other spondyloarthropathies for Chkamydia trachomutis. Arthritis Rheum 38(Suppl9):5348. Braun J, Laitko S, Treharne J et al.: 1994. Chlamydia pneumoniae - a new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 53:100-105. Braun J, Tuszewski M, Ehlers S et al: 1997. Nested polymerasechain reaction strategy simultaneously targeting DNA sequencesof multiple bacterial speciesin inflammatory joint diseases.II. Examination of sacroiliacand knee joint biopsiesof patientswith spondyloarthropathies and other arthritides. J Rheumatol 24ZllOl-1105. Briere F, Bridon JM, Chevet D et al.: 1994. Interleukin 10 induces B lymphocytes from IgA-deficient patients to secrete IgA. J Clin Invest 94:97- 104. Browmidge E, Wyrick P: 1979. Interaction of Chlamydia psittaci reticulate bodies with mouse peritoneal macrophages. Infect Immun 24697-700. Brunham RC, Maclean IW, Binns B, Peeling RW 1985. Chlamydia trachomaris: its role in tubal infertility. J Infect Dis 152:1275-1282. Brunham RC, Peeling RW 1994. Chlamydia truchomatis antigens: role in immunity and pathogenesis.Infect Agents Dis 3:218-233. Bushel1AC, Hobson D: 1978. Effect of cortisol on the growth of Chlamydia trachomatis in McCoy cells.Infect Immun 21:946-953. Byrne GE, SchobertCS, Williams DM, Krueger DA: 1989. Characterization of gamma interferon-mediated cytotoxicity
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