Ankylosing spondylitis

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Ankylosing spondylitis (AS) is a chronic inflammatory arthritis, characterized by exacerbations and remissions, affecting primarily the axial skeleton and the sacroiliac joints. In 1973 it was demonstrated by two independent groups that the class I major histocompatibility complex (MHC) molecule HLA-B27 was present in over 90% of patients with AS, while its frequency in the general Caucasian population was of the order of 8%. Clearly the HLA-B27 molecule was somehow involved in the development of the disease, but there are many healthy individuals who possess HLA-B27 but do not develop the disease.

Studies using identical twins showed that when one of the twins had AS, the chance or concordance rate of the other twin developing AS was well below 50%. A low concordance rate in identical twin studies clearly suggests the interaction of an environmental factor acting in conjunction with a genetic factor to produce the disease.

Any theory proposed as a solution to the causation of AS must also explain why individuals possessing particular antigens, such as HLA-B27, have a greater chance of developing the disease. Currently two main theories have been proposed to explain the association of HI.A-B27 with AS. The two theories are the receptor theory and the molecular mimicry theory.

The receptor theory states that the HLA-B27 molecule acts as a receptor cavity for some, as yet undefined, external polypeptide, which then somehow increases the susceptibility to develop the disease. No such polypeptide has yet been described. Until such a polypeptide is identified, the validity of the receptor theory will remain untested. The molecular mi mien theory is so far the only theory that has provided a

Figure 1 Comparison of space-filling models. (A) HLA-B27.5 (B*2705) (DREDL) predicted from known crystallography structure; (B) Klebsiella pneumoniae pulD secretion protein (DRDEY); (C) Klebsiella pneumoniae nitrogenase enzyme (DREDE). (Reproduced with permission from Dr M Fielder, PhD thesis (1995). Molecular modeling by Dr C Etteliae.)

Figure 1 Comparison of space-filling models. (A) HLA-B27.5 (B*2705) (DREDL) predicted from known crystallography structure; (B) Klebsiella pneumoniae pulD secretion protein (DRDEY); (C) Klebsiella pneumoniae nitrogenase enzyme (DREDE). (Reproduced with permission from Dr M Fielder, PhD thesis (1995). Molecular modeling by Dr C Etteliae.)

specific etiological agent which may be involved in the causation of AS.

Molecular mimicry and AS

The molecular mimicry theory states that the HLA antigen has a sequence that resembles biochemically and immunologically a similar sequence, located in some environmental agent, such as a bacterium or a virus. The molecular mimicry model was first proposed by Hbringer, in 1976, at the HLA and Disease Congress, which was held in Paris. Sera obtained from rabbits immunized with HLA-B27-positive lymphocytes reacted with a number of gram-negative bacteria, such as Klebsiella, Enterobacter, Salmon ella arid Yersinia. A search for these microbes in fecal samples obtained from AS patients during active phases of the disease revealed that only Klebsiella could be isolated from such patients.

In 1980, Avakian and coworkers reported that allogeneic, anti-HLA-B27 tissue typing sera showed increased binding for Klebsiella antigens using three different techniques: radiobinding assay, radioimmunoassay and hemagglutination. Van Bohemen later showed that an anti-HLA-B27 monoclonal antibody (Ml), produced by Grumet, reacted with Klebsiella, Shigella and Yersinia strains. Kono and coworkers described an anti-Yersinia monoclonal antibody which reacted with 12 out of 12 B27-posi-tive lymphoblastoid cell lines, but with only 4 out of 31 B27-negative ones. However, three out of the four reactive B27-negative cell lines carried HLA-B7, an antigen that crossreacts with HLA-B27. They then went on to show that a second anti-HLA-B27 monoclonal antibody (M2), again produced by Grumet, bound specifically to a 70 kDa component of Klebsiella, while no such reactivity was demonstrated by five other monoclonal antibodies. In 1987, Schwimmbeck, Yu and Oldstone identified a hexamer sequence, Gln-Thr-Asp-Arg-Glu-Arg (QTDRED), which was present in amino acid residues spanning positions 188-193 of the nitrogenase enzyme found in Klebsiella pneumoniae and the same sequence also occurs on the outer lip of the al domain of the main Caucasian HLA-B27 molecule. Furthermore antibodies to this shared sequence were found in the sera of AS patients.

Fielder and coworkers, in 1995, identified a second molecular complex in Klebsiella microorganisms which showed crossreactivity with self tissues. Molecular mimicry was shown to be present between two sequences of Klebsiella pneumoniae: pulD secretion protein (DRDE) with HLA-B27 and pulA (pul-lulanase) enzyme (Gly-X-Pro) with types I, III and IV collagen respectively (Figure 1). Furthermore, antibodies to both pullulanase and types I and IV collagen were observed in AS but not rheumatoid arthritis patients when compared with controls. It is relevant to note that type I collagen is present predominantly in tendons and bone. Antibodies cross-reacting between pulA and type I collagen could explain the deposition of fibrous tissue in the axial skeleton, thereby accounting for the main pathological feature of this disease, namely its spinal manifestations. Type IV collagen has been reported to be present in the basement membrane of uveal tissues but it remains to be determined whether crossreactivity with Klebsiella pulA is involved in the uveitis found in AS patients.

The molecular mimicry between HLA-B27 and

Klebsiella bacteria isolated from AS patients has been defined down to the level of similarity of four amino acids, found in both the suspect bacteria involving two separate molecules and the genetically susceptible population. Thus the term 'molecular mimicry' could not be said to be inappropriate when studying crossreactivity between bacterial antigens and HL.A molecules. Since both the bacteria and antibodies to the bacteria have been demonstrated in AS patients, maybe molecular mimicry could provide a pathogenetic model for the causation of the disease.

Molecular mimicry and pathology of AS

The identification of a shared tetramer sequence between HLA-B27 and Klebsiella has confirmed the molecular mimicry model.

If there is crossreactivity between HLA antigens and bacteria, then infection by such microorganisms will lead to the production of antibodies, which will have both antimicrobial as well as anti-self or autoimmune activity. Only a small proportion of the subset of the antimicrobial antibodies will also have anti-self or autoimmune activity. Those bacterial antigens carrying the shared sequences will be immunogenic, especially around the edges of the shared sequence, because it is at these sites that the immune system will not recognize that it is dealing with a self antigen.

If, for example, the bacterial shared sequence is spanning residues 188-193 of the nitrogenase molecule, then the edge antigenic pentamer 187-188-189-190-191 will not be recognized as a self antigen because of the haptenic effect of the nonself amino acid at position 187, and yet the antibody produced may well bind to HLA-B27.

When present in sufficient quantities, such antibodies might activate the complement cascade and cause cytotoxic death with consequent stimulation of the inflammatory cascades, which will eventually result in localized tissue damage. There is thus no breakdown of tolerance and the evocation of bacterial antibodies having also anti-self or autoimmune activity is part of the normal immune response when encountering partially crossreacting antigens.

A classical example of this process, where one haptenic amino acid can cause autoimmune disease, is shown by autoimmune hemolytic anemia, which occurs in hypertensive patients treated with u-methyldopa. Yet the process is not self-sustaining, because once the drug is withdrawn the autoimmune hemolytic anemia subsides. A similar mechanism may be considered to occur in AS and the pathogenetic process can be illustrated as follows:

1. infection occurs in the ileum and ascending

Figure 2 Comparison of space-filling models. (A) ESRRAL sequence of Proteus mirabilis hemolysin predicted from known crystallography structure; (B) EQRRAA sequence within DRB1*0101 (HLA-DR1), predicted from known crystallographic structure; (C) EDERAA sequence of DRB1*0402 (HLA-DR4/Dw10); (D) predicted LRREI sequence of n2(XI) collagen; (E) predicted IRRET sequence of Proteus mirabilis urease. (Reproduced with permission from Wilson eta! (1995). Molecular modelling by Dr C Ettelaie.)

Figure 2 Comparison of space-filling models. (A) ESRRAL sequence of Proteus mirabilis hemolysin predicted from known crystallography structure; (B) EQRRAA sequence within DRB1*0101 (HLA-DR1), predicted from known crystallographic structure; (C) EDERAA sequence of DRB1*0402 (HLA-DR4/Dw10); (D) predicted LRREI sequence of n2(XI) collagen; (E) predicted IRRET sequence of Proteus mirabilis urease. (Reproduced with permission from Wilson eta! (1995). Molecular modelling by Dr C Ettelaie.)

colon, where the bactcria replicate; their quantity will depend on the dietary intake of the patient. Elegant ileocolonoscopic studies by Mie-lants have shown that over 50% of active AS patients have histological evidence of gut inflammation. This infection is at a different site from the eventual location of the arthritic lesions in AS.

2. Antibody against Klebsiella is produced in the lymph nodes draining the lower ileum and colon; the nodes are located in the mesentery which is attached to the anterior aspect of the lumbar spine and sacroiliac joints. Elevated levels of antibodies to Klebsiella and to no other bacteria were first reported by Trull and coworkers and subsequently confirmed by other groups. Thus a high concentration of anti-Klebsiella antibodies is being produced by lymph nodes that are anatomically or geographically located near the main pathological sites in AS, namely the lumbar spine and sacroiliac joints. A subset of these antibodies will bind to cells carrying HLA-B27.

3. Inflammation will be triggered by those anti-Klebsiella antibodies binding to HLA-B27 molecules and, because of complement activation, cell death and tissue damage will occur. The end-result of inflammation is fibrosis and this is the main pathological lesion of AS.

4. Chronic disease will supervene because repeated cycles of infection will produce recurrent waves of anti-Klebsiella antibodies, which will cause tissue damage. Eventually this will manifest itself as a generalized fibrosis around the lumbar spine and we call this disease 'ankylosing spondylitis'.

Is there any evidence which suggests that the pathological processes in AS occur through such a molecular mimicry mechanism? In 1989, Husby and coworkers showed that rat antisera raised against Klebsiella nitrogenase enzyme antigens containing the shared QTDRED hexamer reacted with 13 out of 14 synovial biopsies obtained from HLA-B27-positive AS patients but with none out of seven biopsies obtained from HLA-B27-negative individuals suffering from either rheumatoid arthritis or osteoarthritis.

The following year, Baines and coworkers showed that rabbit anti-Klebsiella sera bound to a greater extent to lymphocytes obtained from 30 B27-positive AS patients and 21 B27-positive healthy controls compared with the binding by lymphocytes from 37 B27-negative healthy controls. Finally, Ewing and coworkers demonstrated, using synthetic peptides, that higher antibody activity was found around the edges of the shared hexamer sequence.

Since anti-Klebsiella antibodies are found in AS patients and since xenogeneic anti-Klebsiella antibodies bind preferentially to HLA-B27-positive cells, it is not too speculative to suggest that in the presence of high antibody titers the characteristic lesions of AS may arise. One obvious way of testing this theory is to eliminate the antibacterial antibodies and determine whether further pathological damage can be stopped.

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Responses

  • brogan moore
    Is there any increased immune response to ankylosing spondylitis?
    7 months ago

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