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Submitter: Dennis McGonagle | d.g.mcgonagle@leeds.ac.uk

Department of Rheumatology, The University of Leeds, 36 Clarendon Road, LS2 9NZ

Published October 19, 2001

Dear Editor,
I would like to comment on the mechanisms whereby infectious agents are thought to induce autoimmunity as outlined by Wucherpfennig (1). As Wucherpfennig's article illustrates, much of the present understanding of autoimmunity comes from animal models which provide some insights but, nevertheless, may be poor surrogates for human disease. It has long been recognised that a better understanding of autoimmune disease in man will come from studies in reactive arthritis (ReA) and ankylosing spondylitis (AS) because major host genetic factors (HLA-B27) and environmental factors (triggering bacteria) have been well defined (2).
Wucherpfennig rightly gives both AS and ReA coverage in his review of infection in the induction of autoimmunity, but he portrays a rather simplified model of bacterial associated autoimmunity directed against a synovial antigen as perpetuating these diseases (1). This is a long held belief that lacks proof and is certainly not supported by emerging experimental data. With the advent of PCR methods it has now been shown that there is equal evidence for bacterial products in the synovium in rheumatoid arthritis-- and indeed osteoarthritis-- as there is in ReA (3). Therefore, the idea of persistent bacterial products in the synovium in some way perpetuating ReA no longer seems tenable and, in any event, this theory has never been squared with the reality that ReA and AS have a predilection for the spine-- a site that is largely devoid of synovium.
Indeed, the primary abnormality in AS and ReA (4) does not reside in the synovium but at tendon and ligament insertional points and in the adjacent bone (5). This may be true for synovial joint disease too (4)(5). All of the sites of disease in AS including the insertion points and adjacent bone and the extraskeletal sites of disease including the aortic root and eye are sites of abnormal mechanical stress with tissue microtrauma; the importance of this is now appreciated by investigators in this field (6). It is now evident how these biomechanical factors could contribute to immune activation since Matzinger's group have shown how mechanical stress may act as a 'danger signal' or non-specific immune stimulus (7). Of course, bacterial products including lipopolysaccharides and bacterial DNA are amongst the best-recognised danger signals and have been shown in animal models (8) and in human AS and ReA.
In order for autoimmunity to develop, tolerance needs to be broken (1). This occurs when dendritic cell receive co-stimulation or 'danger signals' during the course of peptide presentation. Neither the mechanical stress danger signal alone nor the bacterial danger signal may be of sufficient magnitude to stimulate an immune response at sites of stress in AS and ReA (9). However, the additive danger signals from the biomechanically stressed environment combined with bacterial products could provide sufficient co-stimulation to break immune tolerance (9). It is also worth pointing out that microbial and biomechanical factors converge on the the nuclear factor kappa B (NF-kB)transcriptional pathway- thus providing a molecular link between mechanics,microbes and immune activation in AS and ReA (9) These factors explains why subjects with ReA and AS get disease at characteristic sites following breach of mucosal barriers. Whilst evidence for persistent viral infection at sites of autoimmunity has been furnished (reviewed in 1) evidence is lacking for persistent microbes at sites of disease in AS and ReA (4). The additive model of microbial interactions and mechanical stress does not require the presence of viable microbes- just the presence of bacterial molecules with adjuvant properties at sites of mechanical stress and is in keeping with the known microbiological data from ReA and AS.
In support of biomechanical stress related factors in AS and ReA, we have recently shown that the HLA-B27 gene determines the severity of the osteitis in the bone at sites of increased mechanical stress adjacent to insertions points (10). To date no association between HLA-B27 and synovitis in AS or ReA has been shown.
This additive danger signal or multi-hit model of autoimmunity explains all of the known features of ReA and AS-the diseases where microbial factors are best understood. Furthermore, and importantly, this model does not require an intrinsically dysregulated immune system for human autoimmune disease to occur. Continued access of bacterial products to sites of mechanical stress could provide an ongoing environment that favors persistence of the inflammatory response. Finally, this model for autoimmunity is not just relevant to arthritis, but also offers an explanation for the poorly defined relationship between bacterial infection and the propensity towards atherosclerosis, where mechanical stress and microbes are also important and where autoimmunity is thought to play a role (11). The relationship between infection and autoimmune disease could therefore relate to subtle changes in the delicate balance of organ homeostasis with microbial products such as lipopolysaccharides contributing to inflammation without the parent viable replicating organism being present.
1. Kai W. Wucherpfennig. Mechanisms for the induction of autoimmunity by infectious agents. J. Clin. Invest. 2001; 108: 1097-1104.
2. Calin A, Taurog JD: The Spondylarthritides. Second edition. Oxford, Oxford University Press, 1998.
3. van der Heijden IM, Wilbrink B, Tchetverikov I, Schrijver IA, Schouls LM, Hazenberg MP et al. Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides. Arthritis Rheum 2000 Mar;43(3):593-8
4. Sieper J, Kingsley GH, Braun J, Report on the Fourth International Workshop on Reactive Arthritis. Arthritis Rheum 2000;43:720-34.
5. Mc Gonagle D, Gibbon W, O'Connor P, Green M, Pease C, Emery P: Characteristic MRI entheseal changes of knee synovitis in Spondyloarthropathy. Arthritis Rheum 1998;41:694-700.
6. Edwards JC, Bowness P, Archer JR. Jekyll and Hyde: the transformation of HLA-B27. Immunol Today 2000 Jun;21(6):256-60.
7. Gallucci S, Lolkema M, Matzinger P Natural adjuvants: endogenous activators of dendritic cells. Nat Med 1999 Nov;5(11):1249-55.
8. Deng GM, Nilsson IM, Verdrengh M, Collins LV, Tarkowski, A. Intra- articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med 1998;5:702-705.
9. McGonagle D, Stockwin L, Isaacs JD, Emery P. An Enthesitis Based Model for the Pathogenesis of SpA. Additive Effects of Microbial Adjuvant and Biomechanical Factors at Disease Sites. J Rheumatol 2001;28:10,2155-9.
10. McGonagle D, Marzo-Ortega H, O'Connor P, Pease C, Reece RJ, Emery P. The role of biomechanical factors and HLA-B27 on MRI determined bone changes in plantar fascia enthesopathy. Arthritis & Rheum (In press).
11. Ross R: Atherosclerosis--an inflammatory disease. NEJM 1999; 340:115- 126
Dennis McGonagle,
Senior Lecturer/MRC Clinical Scientist, The University of Leeds, 36 Clarendon Road, LS2 9NZ