Serum Antibodies to Oral Anaerobic Bacteria in Patients With Rheumatoid Arthritis

Mesut Ogrendik, MD; Siranus Kokino, MD; Ferda Ozdemir, MD; Philip S. Bird, BSc, MSc, PhD; Stephen Hamlet, BSc, MSc

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Discussion

P gingivalis has arginine- and lysine-specific proteinases and T forsythensis (formerly B forsythus ) has arginine-specific proteinase.[11]

Stastny[12] stated the relationship between the RA and HLA-DR4 in 1978. If we consider that RA-related HLA DR molecules bind with 1 of the P gingivalis or B forsythus virulence factors, when the bacteria is linked to the amino acid codon in the third hypervariable region, then the arginine (R) and lysine (K) amino acids will be selectively and specifically denatured by arginine-specific and lysine-specific proteinase and the different codon will be observed. This codon will be considered alien by the organism, and an immune response will be generated against it, or a T-cell response will be generated against all appropriate molecules presented by this major histocompatibility complex class II molecule.

RFs have been identified as autoantibodies that react to the IgG molecule in the Fc region, and these antibodies may be of the IgM, A, G, or E epitopes.[13] P gingivalis proteinase is responsible for the epitope development in the RF Fc region. Bonagura and colleagues identified the lysine, histidine, arginine amino acid sequences for the Fc region of the IgG molecule.[14] Because P gingivalis specifically decomposes lysine and arginine; the IgG3 CH2 and CH3 domains processed by P gingivalis proteinase become powerful targets for the RF produced by rheumatoid cells.[15]

In patients with RA, loss of galactose residues on IgG has been observed as a glucosylation defect of Fc and this finding leads to a worse prognosis in patients who have agalactosyl IgG.[13] P melaninogenica as a saccharolytic bacteria disintegrates galactose. Consequently, P melaninogenica infection in these patients who have agalactosyl causes this condition by binding to the Fc region of the IgG molecule and metabolizing galactose with its enzymes.

Gioannini and colleagues[16] investigated the expression of the interleukin-8 (IL-8) inherent in the human umbilical vein endothelial cell (HUVEC) by using as agents the lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) of the lipooligosaccharides (LOS) obtained from Neisseria meningitidis serotype B. According to this study, LOS:sCD14 complex does not require LBP to activate HUVEC. P gingivalis lipopolysaccharides show lower affinity to LBP than E coli lipopolysaccharides.[17] Lactoferrin is a lipid-a binding protein, and P gingivalis degrades it.[18,19]P gingivalis also degrades albumin and hemalbumin.[20] Thus it may be argued that the real molecule that acts as an agent for the transport of P gingivalis endotoxin is the sCD14. The 57- to 64-amino acid range in the sCD14 molecules are specific to the lipopolysaccharide binding.[21] In a study performed by McGinley and associates in 1995, it was shown that the 57- to 65-amino acid range of sCD14 protects itself from enzyme disintegration using Asp-N as an endoprotease.[22] Also, a series of alanine substitution mutants of the sCD14 molecule were obtained. Therefore, the principal antigenic peptide presented to T cells by antigen-presenting cells is the amino acid sequence 57-64 within the sCD14 molecule. This is probably the same principal peptide presented in RA.

Some T-cell receptor (TCR) Vb genes are present more frequently in patients with RA than in control subjects.[23,24,25] Similarly, Leung and Torres showed that P intermedia specifically stimulates the expression of Vbeta 8, Vbeta 12, and Vbeta 17 genes in CD4(+) T cells.[26] In 1995, Mathur and colleagues determined that P gingivalis and P intermedia increase the expression of Vbeta 5, Vbeta 6, Vbeta 8, and Vbeta 12.[27] As a result, specific T-cell genes are inherent in RA, and P gingivalis and P intermedia induce T-cell clones specific to them in an almost specific superantigen character.

P gingivalis has a 60-kDa heat shock protein (hsp.GroEL). Due to the similarity of the P gingivalis hsp 60 molecule to the human hsp 60 molecule, it is a key molecule for GroEL homolog autoimmune reactions.[28] In another study conducted in Japan, approximately 70-kDa P melaninogenica and P intermedia hsp proteins have been determined in periodontal disease processes.[29] Ueki and associates determined that P gingivalis GroEL and human hsp60 antibodies are found increasingly more often in periodontal patients compared to those without disease.[30] Hsp 70 antibodies have been detected in the synovial tissue of RA patients, and when the hsp 70 expression is induced with certain stress stimulating factors, proinflammatory cytokines (tumor necrosis factor-alpha, IL-1, IL-6) develop in the RA synovium.[31]

Citrullination or deamination of arginine residues in autoantigenic proteins (profilaggrin/filaggrin, fibrinogen/fibrin, keratin, and vimentin) creates epitopes that are targeted by rheumatoid autoantibodies.[32] As can be clearly seen, arginine is the most important amino acid that allows proteins to gain an autoantigenic character, and P gingivalis has arginine-specific proteinases.

The presence of autoantibodies against collagen II (CII) -- the main component of hyaline cartilage -- has been found previously in RA patients.[33,34] P gingivalis has collagenase activity, and it degrades all collagen molecules except for CII.[35] Within CII 263-270, lysines at 270 can be hydroxylated and further glycosylated with mono- or disaccharides, ie, with a beta-D-galactopyranosyl or an alpha-glucopyranosyl-(1-2)-beta-galactopyranosyl residue. Backlund and coworkers, using transgenic mice expressing human DR4 (DRB1*0401) and human CD, showed that the T cell produced by the postmutation glycosylation of CII influenced the tolerance level of the nominee cartilage-specific antigen and the predominant nature of these T cells specific to the CII epitope (263-270) in humanized transgenic mice and in RA patients.[36] Extracellular proteolysis and other posttranslational modifications of antigenic peptides may be critical in the establishment and perpetuation of autoimmune processes, and lysine hydroxylation is critical for T-cell activation.[37]

P gingivalis, P intermedia, P melaninogenica , and B forsythus produce gingival tissue destruction and autoimmune responses in periodontitis patients. Heat shock proteins are remarkably immunogenic. T-cell and antibody responses in periodontitis confirm the infiltration of reactive T-cell clones into periodontitis lesions. These lesions demonstrate higher proliferative responses of peripheral blood mononuclear cells, cytokines (gamma-interferon, IL-4), and T-cell clonality. Immune responses to microbial heat shock proteins hsp60 are thought to initiate chronic inflammatory diseases; modulation of autoimmune responses may be a method to control pathogenesis.

Higher levels of IgG and IgA antibodies against B forsythus and P intermedia were found in synovial fluid samples from patients with RA.[38] These findings indicate the presence of an active antibody response in synovial tissue and illustrate a potential connection between periodontal and inflammatory joint diseases.

Gingival tissue infections should be considered in RA pathogenesis. Periodontal infections should be treated and prevented from becoming chronic. If successful results are observed against periodontal infections in clinical, radiologic, and laboratory data of the RA patients, the essential role of these bacteria in the etiology of RA can be proven.

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