title: Are intestinal bacteria involved in the etiology of rheumatoid arthritis? Review article.
abstract: Observations in bowel-related joint diseases give support to this hypothesis. In Crohn's disease and ulcerative colitis, the bowel wall inflammation is complicated in about 20% of the patients by joint inflammation. Bowel infection by Salmonella, Shigella and Yersinia can provoke joint inflammation and supports an etiological link between bowel bacteria and arthritis. The arthropathic properties of the most abundant group of intestinal bacteria, i.e. the obligate anaerobic bacteria, were studied in an animal model. Cell wall fragments (CWF), with peptidoglycan as the major component, from some Eubacterium and Bifidobacterium species induced a severe chronic polyarthritis in Lewis rats after a single intraperitoneal injection. Eubacterium was found in numbers of 10(8)-10(9) per gram in stools of healthy subjects and rheumatoid arthritis (RA) patients. CWF of isolated strains of E. aerofaciens were arthropathic. Soluble peptidoglycan polysaccharide complexes (PG-PS) originating from the obligate anaerobic flora were purified from human intestinal contents. PG-PS from ileostomy fluid that proved to be less processed by intestinal enzymes induced chronic arthritis in rats after a single administration in oil in the base of the tail. It was concluded that the human intestinal bowel contains soluble bacterial cell wall products that are arthropathic in an animal model. Peptidoglycan (PG) or its subunits was reported to be present in mammalian tissues. Immunohistochemical studies from our group showed the presence of intestinal PG-PS in sections of normal rat spleen. Bacterial cell wall or PG-induced joint inflammation in rats is proven to be absolutely dependent on functional T cells. T-cell lines were isolated from the lymph nodes of rats with an E. aerofaciens CWF arthritis. A helper T-cell line B13 was in vivo arthritogenic in knee or ankle joints upon intravenous injection in rats and proliferated in vitro on syngeneic spleen cells alone, but was additionally stimulated by intestinal PG-PS and E. aerofaciens CWF. It was postulated that the arthritogenic T cells that seem to be autoreactive are, in fact, recognizing bacterial PG-PS on antigen-presenting cells (APC). It is generally accepted that RA is a T-cell-dependent process and that therefore the reaction is directed at small peptides bound by the major histocompatibility complex of APC. The only peptides present in arthritis inducing intestinal PG-PS and in CWF are PG peptides interlinking the sugar chains. We feel that the immunoreaction against PG peptides plays a pivotal role in experimental and human arthritis of an unknown etiology.
authors.affiliation: Department of Immunology, Erasmus University Rotterdam, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Hazenberg
authors.forename: I S
authors.initials: IS
authors.lastname: Klasen
authors.forename: J
authors.initials: J
authors.lastname: Kool
authors.forename: J G
authors.initials: JG
authors.lastname: Ruseler-van Embden
authors.forename: A J
authors.initials: AJ
authors.lastname: Severijnen
mesh_terms: D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology / Q000382:microbiology; D002240:Carbohydrate Sequence; D002473:Cell Wall / Q000276:immunology; D005243:Feces / Q000382:microbiology; D006801:Humans; D007422:Intestines / Q000382:microbiology; D008969:Molecular Sequence Data; D010457:Peptidoglycan / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D010457:Peptidoglycan