Gut-mediated Autoimmune Arthritis Treated with Antibiotics

Alan Ebringer


Abstract and Introduction


Bacterial infection is known to trigger a number of autoimmune disorders, an observation that indicates a potentially important role for antibiotics in treating these diseases. Indeed, results from an experimental model of autoimmune arthritis in mice suggest that antibiotics can prevent the onset of disease.


The role of antibiotics in the treatment of autoimmune diseases has been controversial; however, reduction in the incidence of rheumatic fever by treating upper respiratory tract infections with antibiotics[1] implies a similar approach might work for other rheumatic conditions. accordingly, a study by wu et al.[2] suggests that antibiotics might be beneficial in treating gut-mediated autoimmune arthritis.

Experimental autoimmune arthritis in K/BxN mice—which develop symptoms similar to those observed in rheumatoid arthritis (RA)—is known to be strongly attenuated when the animals are housed in germ-free conditions.[3] wu et al. found that serum titers of autoantibody against glucose-6-phosphate isomerase (GPI) decreased in the mice in germ-free conditions, as did the numbers of splenic T helper 17 cells, in comparison to mice housed in a specific-pathogen-free facility.[2] GPI is an enzyme of the glycolytic pathway in many animal and bacterial species. Interestingly, in a separate study, synthetic peptides of human GPI (corresponding to amino acids 325–339) were found to induce polyarthritis in DBA/1 mice.[4]

In the K/BxN mice, interleukin (IL)-17 was found to be necessary for the efficient formation of germinal centers and the promotion of autoantibody production.[2] The use of an anti-IL-17 monoclonal antibody blocked the development of arthritis. Furthermore, this disease attenuation could be reversed through exposure of the mice to the segmented filamentous bacteria Candidatus arthromitus, which provoked the rapid onset of arthritis as measured by ankle-thickening.[2]

Interestingly, the treatment of the K/BxN mice from birth with ampicillin and vancomycin strongly inhibited the onset of arthritis; a weaker inhibition was associated with metronidazole but neomycin treatment actually exacerbated the arthritis.[2] The mechanism by which the arthritic disorder was produced was not investigated, although Wu et al. suggest it to be a nonspecific activity of antigen–antibody complexes.[2] the contribution of molecular mimicry between joint collagens and GPI to the development of arthritis in these mice remains unclear.

At the Symposium on Autoantibodies held in Dresden, Germany, in September 2009, Professor Yehuda Shoenfeld from Tel Aviv University proposed that "all auto immune diseases are caused by external agents (drugs, viruses, bacteria, parasites)." This conjecture implies that sensu stricto there are no 'autoimmune' diseases; rather, these conditions are caused by molecular mimicry or crossreactivity between external agents and self molecules which may even involve a single 'self ' amino acid such as tyrosine. Indeed, autoantibodies against red blood cells have been demonstrated in patients who have been prescribed α-methyldopa, a derivative of tyrosine, for the treatment of hypertension.[5] Norepinephrine is derived from tyrosine and α-methyldopa competes with this agent for norepinephrine receptors but does not activate them, thereby producing its hypotensive effect. In this study, the presence of autoantibodies against red blood cells was dependent on the dose of the drug taken and could lead to autoimmune hemolytic anemia. Removal of the drug was associated with attenuation of autoimmune hemolytic anemia and a loss of anti-red-blood-cell autoantibodies without further complications.[5]

The class I MHC molecule HLA-B27 protein is found in 96% of patients with ankylosing spondylitis (AS), as opposed to about 8% of the general population.[6] Clearly, this disparity might have something to do with the origin of this disease. Molecular mimicry between a DRED amino acid sequence in HLA-B27 protein and the DRDE sequence found in the pullulanase enzyme of Klebsiella pneumoniae might be an etiologic factor in AS.[7] Indeed, antibodies to K. pneumoniae have been found in patients with AS from 16 different countries. In addition, >90% of patients with RA express either the HLA-DR4 molecule or the equivalent HLA-DR1 molecule, but the frequency of these antigens in the general population is about 35%.[8] The hexameric sequence EQR(K)RAA at amino acids 69–74 of these proteins is a powerful antigenic determinant, owing to the charged amino acids, and forms the basis of the 'shared epitope' found in these patients. This sequence shows molecular mimicry with the ESRRAL sequence found in the hemolysin protein of Proteus mirabilis; antibodies to this microbe have been found in patients from 14 different countries and have cytopathic properties.[9]

The findings of Wu et al.[2] lead to the question of which human autoimmune arthritic disorders these results could apply to. Tetracycline is useful in the treatment of some patients with RA;[10] however, this condition is not associated with the elevated levels of serum IgA antibodies that are characteristic of a disease caused by an agent acting across a gut mucosal surface. this caveat suggests that RA is not a gut-mediated autoimmune disorder but that it is more likely to be associated with an upper urinary tract infection in which the microbe is acting across a ureteric surface.[9] in addition, since urinary tract infections are common in women (particularly elderly women), this etiology might account for the greater prevalence of RA in women than in men. Elevated levels of serum IgA are, however, found in patients with AS, and this observation suggests that the Wu et al.[2] model might apply to the treatment of this condition.

The demonstration by Wu et al.[2] that experimental autoimmune arthritis in mice responds favorably to antibiotics is an important and timely finding that might apply to other rheumatic conditions such as RA. Furthermore, this result suggests that it is time for relevant therapies for P. mirabilis infection to be assessed together with other existing successful modalities, such as inhibitors of tumor necrosis factor, in the management of RA.


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