CMV Causes Rheumatoid Arthritis

T cells specific for CMV are expanded in rheumatoid arthritis and are associated with RA severity, and this is tied to the HLA-DRB1 shared epitope alleles. CD4+CD28- T-cells arise during primary CMV infection, and are found only in CMV-infected persons. Gamma delta T cells, aka effector/memory Vδ2− γδ T cells, present antigen to them. Smokers are more likely to have been infected by CMV, for socioeconomic reasons. The Surgeon General report of 2014 makes no mention at all of CMV in RA, therefore it is a deliberate act of scientific fraud to blame smoking for rheumatoid arthritis.

Correlative studies of rheumatoid factors and anti-viral antibodies in patients with rheumatoid arthritis. AS Ferraro, MM Newkirk. Clin Exp Immunol 1993 Jun;92(3):425-431. 20 random plus 9 selected patients, 17 controls. "When the patients and normal controls were subdivided according to the presence of serum RF, it was found that when RF were present, the frequency of anti-CMV antibodies, but not anti-EBV or anti-VZV antibodies, was significantly higher (P = 0.02) when compared with RF-negative individuals. The titres of anti-CMV but not anti-VZV antibodies were found to increase in the RA patients with disease duration."

Ferraro & Newkirk - . Clin Exp Immunol 1993 full article landing / PubMed Central

CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. D Schmidt, JJ Goronzy, CM Weyand. J Clin Invest 1996 May 1;97(9):2027-2037. 34 patients with rheumatoid arthritis and 34 age-matched controls, plus 13 HLA-DRB1*04 controls. "[S]ubsets of CD4+ CD28- (9.7 vs 1.7, P = 0.00002) and CD4+ CD7- T cells (21.5 vs 12.26, P = 0.018) were increased in RA patients compared with age-matched normal individuals. Despite the lack of CD28 expression, clonally expanded CD4+ T cells were not anergic but proliferated in response to immobilized anti-CD3..."

Schmidt - J Clin Invest 1996 full article / PubMed Central (pdf, 11 pp)

The repertoire of CD4+ CD28- T cells in rheumatoid arthritis. D Schmidt, PB Martens, CM Weyand, JJ Goronzy. Mol Med 1996 Sep;2(5):608-618. 30 RA patients and 30 controls. "The CD4+ CD28- T cell compartment was expanded to more than 2.5% in 70% of the RA patients and 30% of the normal individuals. Compared with the CD4+ CD28+ T cells, the TCR BV gene segment usage among CD4+ CD28- cells was grossly skewed with the dominance of single BV elements. Molecular TCR analysis provided evidence for oligoclonality in 17 of 21 expanded BV elements. In two unrelated RA patients who shared both HLA-DRB1 alleles, the TCR beta-chain sequences of dominant clonotypes were highly conserved."

Schmidt - Mol Med 1996 full article landing / PubMed Central

CD11b+CD28-CD4+ human T cells: activation requirements and association with HLA-DR alleles. A Chapman, SJ Stewart, GT Nepom, WF Green, D Crowe, JW Thomas, GG Miller. J Immunol 1996 Dec 1;157(11):4771-4780. 57 donors; two with rheumatoid arthritis (one DRBI*0401/0408 with 15.8% CDI lb+CD4' T cells, one DR1,2(15) with 0.3% CDl lb+CD4+ T cells), and with type I diabetes (DR1,7 with 1.9% CDllb*CD4+ Tcells). The rest were healthy potential organ donors. "The presence of CD28-CD4+ T cells was verified in peripheral blood, and their frequency ranged from 0% to >22% of CD4+ T cells in different individuals. The percentage of CD28-CD4+ T cells in the peripheral blood of 57 individuals was significantly correlated with specific class II MHC alleles. Persons with HLA-DRB1*0401 and DR1 alleles had significantly higher numbers of CD28- T cells, while individuals with HLA-DR2(15) had significantly fewer CD28-CD4+ T cells than the mean."

Chapman / J Immunol 1996 full article (pdf, 10 pp)

Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. PB Martens, JJ Goronzy, D Schaid, CM Weyand. Arthritis Rheum 1997 Jun;40(6):1106-1114. "Carriers of CD4+ CD28- T cells accumulated in the RA population (64% versus 45%; P = 0.02). The expansion of CD4+ CD28- T cells correlated with extraarticular involvement, but not with disease duration, antirheumatic treatment, or severity of joint destruction. The patient subsets with nodular disease (P = 0.02) and rheumatoid organ disease (P = 0.04) had the highest proportion of CD4+ CD28- T cell carriers. The size of the CD4+ CD28- compartment correlated with extraarticular progression of RA (P = 0.001 in nodular RA, P = 0.003 in rheumatoid organ disease)."

Martens - Arthritis Rheum 1997 abstract / PubMed

Cytomegalovirus seropositivity is associated with the expansion of CD4+CD28- and CD8+CD28- T cells in rheumatoid arthritis. M Hooper, EG Kallas, D Coffin, D Campbell, TG Evans, RJ Looney. J Rheumatol 1999 Jul;26(7):1452-1457. 45 RA patients (36 women). "Previous researchers have found expansion of CD4+CD28- T cells in patients with rheumatoid arthritis (RA) compared to age matched controls, and have identified expanded clones of autoreactive cells within this population.... (CD28 and CD57 are reciprocally related.) CD4+CD28-CD57+ T cells were expanded only in CMV seropositive patients. CONCLUSION: The "carrier" phenotype that has been hypothesized based on a 2 population model for the distribution of CD4+CD28- T cells in RA can be explained by prior infection with CMV."

Hooper - J Rheumatol 1999 abstract / PubMed

Killer cell activating receptors function as costimulatory molecules on CD4+CD28null T cells clonally expanded in rheumatoid arthritis. T Namekawa, MR Snyder, JH Yen, BE Goehring, PJ Leibson, CM Weyand, JJ Goronzy. J Immunol 2000 Jul 15;165(2):1138-1145. "Here, we report that CD4+CD28null, but not CD4+CD28+, T cells express MHC class I-recognizing receptors normally found on NK cells. CD4+CD28null T cells preferentially expressed killer cell activating receptors (KAR), often in the absence of killer cell inhibitory receptors... Aberrant expression of KAR molecules in the absence of inhibitory receptors and in the appropriate HLA setting may lead to the clonal outgrowth of autoreactive CD4+CD28null T cells commonly seen in rheumatoid arthritis."

Namekawa / J Immunol 2000 full article

Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. AN Vallejo, M Schirmer, CM Weyand, JJ Goronzy. J Immunol 2000 Dec 1;165(11):6301-6307. "CD4(+)CD28(null) T cells are oligoclonal lymphocytes rarely found in healthy individuals younger than 40 yr, but are found in high frequencies in elderly individuals and in patients with chronic inflammatory diseases... In this study, we show that CD4(+)CD28(null) T cells are protected from undergoing activation-induced cell death. Whereas CD28(+) T cells underwent Fas-mediated apoptosis upon cross-linking of CD3, CD28(null) T cells were highly resistant. CD28(null) T cells were found to progress through the cell cycle, and cells at all stages of the cell cycle were resistant to apoptosis, unlike their CD28(+) counterparts."

Vallejo / J Immunol 2000 full article

Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. JH Yen, BE Moore, T Nakajima, D Scholl, DJ Schaid, CM Weyand, JJ Goronzy. J Exp Med 2001 May 21;193(10):1159-1167. "CD4(+)CD28(null) T cell clones isolated from RA patients with vasculitis were found to express killer cell immunoglobulin-like receptors (KIRs) with the stimulatory KIR2DS2 often present in the absence of opposing inhibitory receptors with related specificities... The KIR2DS2 gene was significantly enriched among patients with rheumatoid vasculitis compared with normal individuals (odds ratio 5.56, P = 0.001) and patients with RA but no vasculitis (odds ratio 7.96, P = 0.001). Also, the distribution of human histocompatibility leukocyte antigen (HLA)-C, the putative ligand for KIRs, was significantly different in patients with rheumatoid vasculitis in comparison with the control populations." HLA-C*03 (odds ratio 3.74, P = 0.003), for which 60% of patients were positive; and HLA-C*05 (2.92, P = 0.024) were also significant risk factors.

Yen - J Exp Med 2001 full article / PubMed Central

The expansion of CD4+CD28- T cells in patients with rheumatoid arthritis. A Pawlik, L Ostanek, I Brzosko, M Brzosko, M Masiuk, B Machalinski, B Gawronska-Szklarz. Arthritis Res Ther 2003;5(4):R210-R213. 42 patients with RA and 24 healthy subjects. "Cells of this CD4+CD28- subset have several features differentiating them from classic T helper cells. They do not depend on the B7/CD28 pathway for activation, do not express the CD80 receptor, are incapable of activating B cells, have significant cytolytic activity, and express high levels of IFN-γ and IL-2 [4]. Thus, the presence of significant numbers of CD4+CD28- T cells could shift immune response from B-cell activation and production of immunoglobulins toward activation of type-1 T helper cells and production of IFN-γ and involvement of macrophages releasing matrix-degrading proteases. CD4+CD28- T cells are infrequent in healthy individuals (comprising 0.1–2.5% of T cells), whereas higher levels have been seen in patients with unstable angina, multiple sclerosis, Wegener's granulomatosis, and rheumatoid arthritis with extra-articular manifestations.... The frequency of CD4+CD28- T cells was 4.82% in patients with limited joint manifestations, 7.05% in those with advanced joint involvement, and 10.35% in those with extra-articular manifestations."

Pawlik / Arthritis Res Ther 2003 full article
Pawlik - Arthritis Res Ther 2003 full article / PubMed Central

Expression of activation-induced, T cell-derived, and chemokine-related cytokine/lymphotactin and its functional role in rheumatoid arthritis. S Blaschke, P Middel, BG Dorner, V Blaschke, KM Hummel, RA Kroczek, K Reich, P Benoehr, M Koziolek, GA Muller. Arthritis Rheum 2003 Jul;48(7):1858-1872. 20 RA patients and 15 osteoarthritis controls. "OBJECTIVE: To evaluate the possible role of activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin (Lptn) in the pathogenesis of rheumatoid arthritis (RA)... Levels of ATAC/Lptn were similar in sera and synovial fluids from RA patients (n = 20) and osteoarthritis controls (n = 15). In phorbol myristate acetate/ionomycin-stimulated PBMCs, ATAC/Lptn expression was detected in CD8+ T cells and in a significantly increased proportion of CD4+,CD28- T cells from RA patients as compared with healthy controls. In synovial tissues, ATAC/Lptn was predominantly localized in CD3+ T cells in the sublining layer. Lymphocytes, synovial macrophages, and, unexpectedly, fibroblast-like synoviocytes (FLS) were identified as major target cells for ATAC/Lptn in RA synovium, as determined by analysis of the ATAC/Lptn receptor XCR1. In vitro, ATAC/Lptn stimulation of FLS resulted in a marked down-regulation of matrix metalloproteinase 2 production."

Blaschke - Arthritis Rheum 2003 abstract / PubMed

Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. V Groh, A Bruhl, H El-Gabalawy, JL Nelson, T Spies. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9452-9457. "In rheumatoid arthritis (RA), the severity of autoimmune and inflammatory joint disease correlates with large numbers of CD4+CD28- T cells, which are scarce in healthy individuals.... CD4+CD28- T cells in peripheral blood and synovial tissue of RA patients were found to express NKG2D, a costimulatory receptor that is absent on normal CD4 T cells. NKG2D was induced by tumor necrosis factor alpha and IL-15, which are abundant in inflamed synovia and RA patient sera. RA synoviocytes aberrantly expressed the stress-inducible MIC ligands of NKG2D, which stimulated autologous CD4+CD28- T cell cytokine and proliferative responses. Peripheral blood serum samples of RA patients contained substantial amounts of synoviocyte-derived soluble MICA, which failed to induce down-modulation of NKG2D because of the opposing activity of tumor necrosis factor alpha and IL-15."

Groh / PNAS 2003 full article
Groh - PNAS 2003 full article / PubMed Central

Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MT Vossen, AT Rowshani, PM Wertheim-van Dillen, RA van Lier, IJ ten Berge. J Immunol 2004 Aug 1;173(3):1834-1841. "In this study, we show that in primary CMV infections, CD4(+)CD28(-) T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4(+)CD28(-) T cells. In line with this, we found these cells only in CMV-infected persons [emphasis added]. CD4(+)CD28(-) cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4(+)CD28(-) cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4(+)CD28(-) cells only produced IFN-gamma after stimulation with CMV-Ag, whereas CD4(+)CD28(+) cells also produced IFN-gamma in response to varicella-zoster virus and purified protein derivative. Thus, CD4(+)CD28(-) T cells emerge as a consequence of CMV infection."

van Leeuwen / J Immunol 2004 full article

Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis. X Zhang, T Nakajima, JJ Goronzy, CM Weyand. Arthritis Rheum 2005 Dec;52(12):3839-3849. "CD4+,CD28- T cells resemble both short-lived effector memory cells and long-lived central memory cells, and they find a niche both in inflamed synovium and in lymph nodes. Nonspecific cytokine stimulation, not antigen recognition, triggers the transition from the lymph node to the synovium. By maintaining CCR7 expression, these end-differentiated T cells can home to lymphoid organs, enhance their survival, support clonal expansion, and perpetuate autoreactivity."

Zhang / Arthritis Rheum 2005 full article

Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MH Heemskerk, IJ ten Berge, RA van Lier. Blood 2006 Nov 1;108(9):3121-3127. "In the acute response, CMV-specific CD4+ T cells are highly activated and proliferating, have a CD45RA+CD45R0+CD28+CD27+ phenotype, and produce IFN after stimulation with CMV antigen in vitro. Late after primary infection, CMV-specific CD4+ T cells have returned to a resting stage, and the percentage of IFN-producing CMV-specific CD4+ T cells is considerably lower than during the acute infection. Moreover, a considerable number of CMV-specific CD4+ T cells have progressed toward a further differentiated phenotype, characterized by the loss of both CD27 and CD28 and the acquisition of cytolytic molecules such as perforin and granzyme B (grB). CD4+CD28– grB+ T cells appear to be characteristic for CMV infection because they emerge after primary CMV infection and can be found only in CMV-seropositive individuals. Consequently, proliferation and cytokine production by CD4+CD28– T cells can be induced by CMV but not by other viral antigens."

van Leeuwen / Blood 2006 full article

Analyses of immunosenescent markers in patients with autoimmune disease. M Thewissen, V Somers, K Venken, L Linsen, P Van Paassen, P Geusens, J Damoiseaux, P Stinissen. Clin Immunol 2007 May;123(2):209-218. "T cell receptor excision circles (TREC) and the percentage of CD4(+)CD28(null) T cells were studied as markers of immunosenescence in 175 patients with chronic autoimmune arthritis, other connective tissue autoimmune diseases, multiple sclerosis and 60 healthy controls. In both the rheumatoid arthritis (RA) and multiple sclerosis patient group, TREC numbers were age-inappropriately declined which points to an accelerated thymic output. Furthermore, enhanced percentages of CD4(+)CD28(null) T cells could be detected in a significant proportion of patients included in this study. These immunosenescent phenomena seemed to be present already early in the disease process. High percentages of CD4(+)CD28(null) T cells were associated with the presence of RA linked HLA DR4 alleles and with plasma reactivity to cytomegalovirus."

Thewissen - Clin Immunol 2007 abstract / PubMed

Surface expression of fractalkine receptor (CX3CR1) on CD4+/CD28 T cells in RA patients and correlation with atherosclerotic damage. E Pingiotti, P Cipriani, A Marrelli, V Liakouli, S Fratini, M Penco, R Giacomelli. Ann N Y Acad Sci 2007 Jun;1107:32-41. 50 early RA patients and 26 healthy controls (HC). "We observed: a higher expansion of CD4+/CD28- subset in RA patients when compared to HC (7.7%, 5.15-9.7 vs. 0.7%, 0.2-1.5, P < 0.01; respectively); this expansion directly correlated with increased IMT (0.91 mm, 0.5-1.3 vs. 0.7 mm, 0.2-1, P < 0.01; RA vs. C, respectively) and inversely correlated with FMV [flow-mediated vasodilation] (3.5%, 1.7-7 vs. 9%, 3.5-11, P < 0.01; RA vs. C, respectively); the large majority of CD4+/CD28-, in RA, coexpressed CX3CR1 (93%, 67-99 vs. 30%, 10-48, P < 0.01; RA vs. C, respectively); this expansion significantly correlated with both the parameters of premature vascular damage and DAS 28."

Pingiotti - Ann N Y Acad Sci 2007 abstract / PubMed

Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. WW Lee, ZZ Yang, G Li, CM Weyand, JJ Goronzy. J Immunol 2007 Aug 15;179(4):2609-2615. "Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4(+)CD28(-) and CD4(+)CD28(+) T cells to discover disease-promoting activities of CD28(-) T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p < 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity."

Lee - J Immunol 2007 abstract / PubMed

Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis. AE Fasth, O Snir, AA Johansson, B Nordmark, A Rahbar, E Af Klint, NK Björkström, AK Ulfgren, RF van Vollenhoven, V Malmström, C Trollmo. Arthritis Res Ther 2007;9(5):R87. "CD4+CD28null T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-Vβ subsets of CD4+CD28null T cells in peripheral blood were often absent in synovial fluid. CD4+CD28null T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease."

Fasth / Arthritis Res Ther 2007 full article

CD4+ CD28 null T cells in coronary artery disease: when helpers become killers. IE Dumitriu, ET Araguás, C Baboonian, JC Kaski. Cardiovasc Res 2009 Jan 1;81(1):11-19. REVIEW. "One of the best characterized autoimmune diseases associated with increased frequencies of CD4+CD28null T cells is rheumatoid arthritis (RA). Studies in patients with RA showed CD4+CD28null T cells to be increased in over one-third of patients. Furthermore, expansion of the CD4+CD28null T cell subset correlated directly with an increased frequency of extra-articular involvement like rheumatoid vasculitis, and the clinical severity of the disease. These results suggest that the expansion of CD4+CD28null T cells does not represent just an epiphenomenon but could have a critical role in the pathogenesis of the disease."

Dumitriu - Cardiovasc Res 2009 abstract / PubMed
Dumitriu / Cardiovasc Res 2009 full article

Cross-recognition of HLA DR4 alloantigen by virus-specific CD8+ T cells: a new paradigm for self-/nonself-recognition. M Rist, C Smith, MJ Bell, SR Burrows, R Khanna. Blood 2009 Sep 10;114(11):2244-53. "Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8(+) T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8(+) T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13(+) clonotypes. More importantly, cross-reactive TRBV13(+) clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype." HLA DR4 cross-reactive, HCMV-specific T cells were found in 3 of 8 HLA Cw*0602 persons. "Of the major subtypes of HLA DR4 tested, DRB*0401 and DRB*0408 were strongly recognized, whereas a lower level of recognition of DRB*0410 was also observed. In contrast, APCs expressing DRB*0402, DRB*0403, DRB*0404, DRB*0406, and DRB*0407 were not recognized. It is interesting to note that DRB*0401 and DRB*0408 show high levels of homology within the peptide binding pocket with a single highly conserved change from lysine to arganine at position 71. However, DRB*0402, DRB*0403, DRB*0404, DRB*0406, and DRB*0407 and DRB*0410 alleles show a series of changes at residues 37 (Y→S), 57 (D→S), 67 (L→I), 70 (Q→D), 71 (K→E), 74 (A→E), and 86 (G→V). Of particular interest are the residues 57 (aspartic acid) and 86 (glycine), which are conserved in DRB*0401 and DRB*0408 alleles, and any change in these residues partially or completely abrogated the cross-recognition by HCMV-specific CD8+ T cells. Although the side chains of amino acids at positions 57 and 86 point into the peptide-binding groove, we cannot rule out the possibility that they may be partially accessible to direct contact with the TCR. Indeed, it would be interesting to resolve the structure of the HLA DR4-peptide complex bound to TRAT-specific TRBV13 TcR to delineate the precise interaction of the relevant residues that play a crucial role in the cross-recognition."

Rist / Blood 2009 full article

Altered T-cell subtypes in spondyloarthritis, rheumatoid arthritis and polymyalgia rheumatica. C Dejaco, C Duftner, A Klauser, M Schirmer. Rheumatol Int 2010 Jan;30(3):297-303. 22 SpA, 15 RA, 38 PMR/GCA patients and 17 healthy controls. "The frequency of CD3(+)CD4(+)CD28(-) memory/effector T-cells was increased in PB of patients with SpA (median 1.1%, range 0.1-69.6), RA (2.5%, 0-42.9) and PMR/GCA (2.7%, 0-49.5) when compared with HC (0.7%, 0-38.0) and tended to be higher in SF of SpA patients (4.5%, 0.2-7.2, P = 0.084)." Naive T-cells were reduced, and memory and activated cells were increased in synovial fluid compared to peripheral blood.

Dejaco - Rheumatol Int 2010 abstract / PubMed

Activating NK cell receptors co-stimulate CD4+CD28- T cells in patients with rheumatoid arthritis. AE Fasth, NK Björkström, M Anthoni, KJ Malmberg, V Malmström. Eur J Immunol 2010 Feb;40(2):378-387. "Pair-wise ligations of 2B4 with DNAM-1 and/or NKG2D lead to increased effector functions of primary CD4(+)CD28(-) T cells to suboptimal levels of anti-CD3 stimulation. Using multi-parameter flow cytometry, we demonstrate that such co-ligation lead to an increased magnitude in overall responsiveness without changing qualitative aspects of the response."

Fasth - Eur J Immunol 2010 abstract / PubMed

Decreased circulating CD28-negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response. M Scarsi, T Ziglioli, P Airò. J Rheumatol 2010 May;37(5):911-916. "After 48 weeks of treatment, the proportion and the absolute number of circulating CD8+CD28- T cells decreased (p = 0.008, p = 0.055, respectively, compared with baseline), as well as the proportion of the CD8+CD45RA+CCR7- cells, thought to represent terminally differentiated effector T cells (p = 0.03). Reductions of percentages of circulating CD4+CD28- and CD8+CD28- T cells, and (CCR7-) CD8+ total effector T cells were directly correlated with the reduction of Disease Activity Score 28 C-reactive protein (r = 0.58, p = 0.014; r = 0.47, p = 0.059; r = 0.59, p = 0.012, respectively)."

Scarsi - J Rheumatol 2010 abstract / PubMed

Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15. D Herndler-Brandstetter, S Brunner, D Weiskopf, R van Rijn, K Landgraf, C Dejaco, C Duftner, M Schirmer, F Kloss, R Gassner, G Lepperdinger, B Grubeck-Loebenstein. Hum Immunol 2011 Aug;72(8):627-631. "We here demonstrate that post-thymic human T-cell differentiation was associated with the downregulation, but not loss, of the inhibitory molecule CD5. The sensitivity of human CD8(+) and CD4(+) memory T cells to interleukin (IL)-15 was inversely associated with the level of CD5 expression. CD5 expression was downregulated by IL-15-mediated signaling in vitro and CD5(lo) memory T cells accumulated in the bone marrow. Persistent antigenic stimulation, as in the case of cytomegalovirus infection and rheumatoid arthritis (RA), was also associated with an increased number of CD5(lo) memory T cells. In conclusion, CD5 may be a useful marker to identify memory T-cell subsets with distinct responsiveness to the homeostatic cytokine IL-15."

Herndler-Brandstetter - Hum Immunol 2011 full article / PubMed Central

IL-15 preferentially enhances functional properties and antigen-specific responses of CD4+CD28(null) compared to CD4+CD28+ T cells. R Alonso-Arias, MA Moro-García, JR Vidal-Castiñeira, JJ Solano-Jaurrieta, FM Suárez-García, E Coto, C López-Larrea. Aging Cell 2011 Oct;10(5):844-852. We found that treatment with IL-15 increased the frequency of elderly CD4+CD28(null) T cells by the preferential proliferation of these cells compared to CD4+CD28+ T cells. IL-15 induced an activated phenotype in CD4+CD28(null) T cells. Although the surface expression of IL-15R α-chain was not increased, the transcription factor STAT-5 was preferentially activated. IL-15 augmented the cytotoxic properties of CD4+CD28(null) T cells by increasing both the mRNA transcription and storage of granzyme B and perforin for the cytolytic effector functions. Moreover, pretreatment of CD4+CD28(null) T cells with IL-15 displayed a synergistic effect on the IFN-γ production in CMV-specific responses, which was not observed in CD4+CD28+ T cells. IL-15 could play a role enhancing the effector response of CD4+CD28(null) T cells against their specific chronic antigens."

Alonso-Arias - Aging Cell 2011 abstract / PubMed

A profile of immune response to herpesvirus is associated with radiographic damage in rheumatoid arthritis. JM Davis 3rd, KL Knutson, JA Skinner, MA Strausbauch, CS Crowson, TM Therneau, PJ Wettstein, EL Matteson, SE Gabriel. Arthritis Res Ther 2012 Jan 31;14(1):R24. 58 patients with RA and 15 healthy controls. "The immune response profile for cytomegalovirus (CMV) / Epstein-Barr virus (EBV) stimulation was correlated with both the SHS total and erosion scores (r = 0.31, p = 0.018 and r = 0.33, p = 0.011, respectively). After adjusting for age, sex, disease duration, autoantibody status, CMV/EBV serological status, current disease activity, disability, and treatments, the correlation of the CMV/EBV immune response and the SHS erosion score became stronger (r = 0.43, p < 0.003). The CMV/EBV immune response correlated with CMV IgG (r = 0.44, p < 0.001), but not with EBV IgG. The most important cytokines for the CMV/EBV immune response profile were IFN-gamma, IL-2, IL-4, IL-5, IL-13 and IL-17A, all of which are associated with T-cell immunity. Both the summary immune response score and the individual responses of IFN-gamma and IL-13 to CMV/EBV stimulation were associated with greater joint damage."

Davis - Arthritis Res Ther 2012 abstract / PubMed

T-cell autoreactivity to citrullinated autoantigenic peptides in rheumatoid arthritis patients carrying HLA-DRB1 shared epitope alleles. SC Law, S Street, CH Yu, C Capini, S Ramnoruth, HJ Nel, E van Gorp, C Hyde, K Lau, H Pahau, AW Purcell, R Thomas. Arthritis Res Ther 2012 May 17;14(3):R118. 6 SE+ healthy controls and 21 RA patients. "In healthy controls, CD28- cells comprised only a small proportion of the CD4+ T cells, and cytokine-secreting cells were exclusively CD4+CD28+. CD28- cells were more abundant among CD4+ PB T cells in some, but not all, RA patients. Where CD4+CD28- T cells were present, IL-6 and IFNγ were secreted by both CD28- and CD28+CD4+ T cells in response to citrullinated peptides. We noted high background cytokine secretion in these cultures, as we had observed earlier in analysis of supernatants (Figures ​(Figures 2A and ​6A)."

Law - Arthritis Res Ther 2012 full article / PubMed Central

Association of anticytomegalovirus seropositivity with more severe joint destruction and more frequent joint surgery in rheumatoid arthritis. M Pierer, K Rothe, D Quandt, A Schulz, M Rossol, R Scholz, C Baerwald, U Wagner. Arthritis Rheum 2012 Jun;64(6):1740-1749. 202 RA patients and in 272 healthy controls. "Overall, no significant difference in the frequency of anti-CMV seropositivity between RA patients and healthy controls was observed. Among individuals older than age 55 years, however, anti-CMV IgG antibodies were significantly more frequent in RA patients than controls (65.3% and 54.7%, respectively; P = 0.05). Anti-CMV seropositivity in RA patients was associated with an increased frequency of CD4+CD28(null) T cells and increased serum concentrations of MCP-1. The frequency of anti-CMV-specific CD4+ T cells producing IFNγ was increased in RA patients compared to controls. Most importantly, anti-CMV-seropositive RA patients showed radiographic evidence of more advanced joint destruction and had increased frequencies of joint-related surgical procedures, indicating more severe joint disease."

Pierer - Arthritis Rheum 2012 abstract / PubMed

Disease activity in patients with long‑lasting rheumatoid arthritis is associated with changes in peripheral blood lymphocyte subpopulations. Z Smoleńska, J Pawłowska, A Daca, M Soroczyńska-Cybula, J Witkowski, EM Bryl. Pol Arch Med Wewn 2012 Dec 21;122(12):591-598. 60 patients with RA and 19 healthy volunteers. "The percentage of CD3+CD4+, NKT, CD4+CD28-, CD8+CD28-, CD4+CD69+, CD4+CD25+, and CD4+HLA‑DR+ was significantly higher in RA compared with the control group. A higher proportion of CD4+CD28- was associated with more active disease, while an inverse correlation was observed for B cells. The proportion of CD4+CD28- was not associated with disease activity."

Smoleńska / Pol Arch Med Wewn 2012 full article (pdf, 8 pp)

Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity. JM Davis, KL Knutson, MA Strausbauch, AB Green, CS Crowson, TM Therneau, EL Matteson, SE Gabriel. Arthritis Res Ther 2013 Nov 25;15(6):R199. 71 patients. "At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-gamma (P = 0.039) and IL-4 (P = 0.027)... the findings of this study point to an interaction of rheumatoid disease specifically with CMV immunity. The significant correlation with CMV IgG suggests that the CMV-induced T-cell immune response signature is mediated by memory T cells."

Davis / Arthritis Res Ther 2013 full article landing page

Peripheral and site-specific CD4+ CD28null T cells from Rheumatoid Arthritis patients show distinct characteristics. J Pieper, S Johansson, O Snir, L Linton, M Rieck, JH Buckner, O Winqvist, R van Vollenhoven, V Malmström. Scand J Immunol 2014 Feb;79(2):149-155. 44 RA patients. "Circulating CD4+ CD28null T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4+ CD28+ T cells and produced higher levels of both IFN-γ and TNF after TCR crosslinking. CD4+ CD28null T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4+ CD28null cells from the blood, a significant production was observed in CD4+ CD28null T cells from synovial fluid. CD4+ CD28null T cells were not only found to differ from conventional CD4+ CD28+ T cells in the circulation, but we could also demonstrate that synovial CD4+ CD28null T cells showed additional effector functions (IL-17 co-production) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28null population."

Pieper - Scand J Immunol 2014 abstract / PubMed

Latent CMV infection in rheumatoid arthritis increases frequencies of cytolytic LIR-1+ CD8+ T cells. K Rothe, D Quandt, K Schubert, M Rossol, M Klingner, S Jasinski-Bergner, R Scholz, B Seliger, M Pierer, C Baerwald, U Wagner. Arthritis Rheumatol 2016 Feb;68(2):337-346. "Here, we report increased frequencies of CD8+ T cells with CMVpp65 specific T cell receptors in CMV+ RA patients compared to CMV+ healthy controls. CMV specific CD8+ T cells in those patients are preferentially LIR-1 positive and exhibit a terminally differentiated polyfunctional phenotype. LIR-1+CD8+ T cells increase with age and disease activity, and show high reactivity towards CMV antigens. Ligation of LIR-1 with soluble HLA-G molecules in vitro confirmed an inhibitory role of the molecule when expressed on CD8+ T cells in RA... The known deficiency of sHLA-G in RA and the observed association of LIR-1expression with disease activity suggest, however, that LIR-1+T cells are insufficiently controlled in RA and are still likely involved in the pathogenesis of the disease."

Rothe - Arthritis Rheumatol 2016 abstract / PubMed

Senescent profile of angiogenic T cells from systemic lupus erythematosus patients. P López, J Rodríguez-Carrio, A Martínez-Zapico, L Caminal-Montero, A Suarez. J Leukoc Biol 2016 Mar;99(3):405-412. 84 lupus patients and 46 healthy controls, plus 48 rheumatoid arthritis patients and 72 "with traditional cardiovascular risk factors" as disease controls. "CD4+CD28null cells were notably increased in the systemic lupus erythematosus patients and disease controls compared with healthy controls. In contrast, angiogenic T cells were only reduced in the disease controls (those with rheumatoid arthritis or traditional cardiovascular risk factors). Nevertheless, an anomalous presence of CD28null-angiogenic T cells, with cytotoxic and senescent characteristics, was noted in systemic lupus erythematosus patients in association with anti-dsDNA titer, anti-SSA/Ro antibodies and circulating TNF-α, IL-8, IFN-α, and B lymphocyte stimulator amounts. This subset was also detected in those with traditional cardiovascular risk factors but not in the rheumatoid arthritis patients. In contrast, CD28+-angiogenic T cells were reduced in the systemic lupus erythematosus patients with cardiovascular disorders. In conclusion, CD28 expression must be used to redefine the angiogenic T cell population, because in pathologic conditions, a senescent CD28null-angiogenic T cell subset with inflammatory, rather than protective, effects could be present."

López - J Leukoc Biol 2016 abstract / PubMed

Significant IFNγ responses of CD8+ T cells in CMV-seropositive individuals with autoimmune arthritis. G Almanzar, M Schmalzing, R Trippen, K Höfner, B Weißbrich, E Geissinger, T Meyer, J Liese, HP Tony, M Prelog. J Clin Virol 2016 Apr;77:77-84. Number of subjects not given in abstract. "CMVpp65-specific IFNγ production with expansion of CD28-CD8+ T-cells suggests an efficient control of latent CMV regardless of immunosuppressive therapy or in vitro blockade of TNFα or IL-6 in CMV-seropositive arthritis patients. Increased IgG-anti-CMV antibody concentrations and increased proportions of intracellular IFNγ-producing CMVpp65-specific CD8+ T-cells in long-term cultures propose a possibly role of endogenous CMV reactivations boosting antibody levels and a higher possibly CMV-driven IFNγ-mediated inflammatory potential of CD8+ T-cells in arthritis patients."

Almanzar - J Clin Virol 2016 abstract / PubMed

Senescent T-Cells Promote Bone Loss in Rheumatoid Arthritis. J Fessler, R Husic, V Schwetz, E Lerchbaum, F Aberer, P Fasching, A Ficjan, B Obermayer-Pietsch, C Duftner, W Graninger, MH Stradner, C Dejaco. Front Immunol 2018 Feb 1;9:95. 107 patients with RA, 75 with primary osteopenia/-porosis, 38 healthy individuals. "Patients with osteopenia/-porosis yielded a higher prevalence of senescent CD4+CD28- T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4+CD28- T-cells as compared to CD28+ T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28- T-cells. CD4+CD28- T-cells induced osteoclastogenesis more efficiently than CD28+ T-cells."

Fessler - Front Immunol 2018 abstract / PubMed

P. gingivalis, alpha-Enolase and Rheumatoid Arthritis

Porphyromonas gingivalis is a gram-negative bacterium that causes periodontitis, an inflammation of the gums which leads to tooth loss. RA is 4 times more common in patients with periodontitis than without it. Poorer people are more to be infected by it, so smokers as generally poorer people are more likely to have it.

Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis. A Kinloch, V Tatzer, R Wait, D Peston, K Lundberg, P Donatien, D Moyes, PC Taylor, PJ Venables. Arthritis Res Ther 2005;7(6):R1421-1429. In an initial screen, a protein identified as citrullinated alpha-enolase reacted with the sera from four RA patients, but not with the control serum. Subsequently, with 52 patients and 40 conrols, "Twenty-four sera from patients with RA (46%) reacted with citrullinated alpha-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. Alpha-enolase was detected in the RA joint, where it co-localised with citrullinated proteins." In osteoarthritis sections, α-enolase staining was predominantly localised in vascular endothelial cells.

Kinloch - Arthritis Res Ther 2005 full article / PubMed Central
Kinloch / Arthritis Res Ther 2005 full article

Interaction between smoking, the shared epitope, and anti–cyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts. HS Lee, P Irigoyen, M Kern, A Lee, F Batliwalla, H Khalili, F Wolfe, RF Lum, E Massarotti, M Weisman, C Bombardier, EW Karlson, LA Criswell, R Vlietinck, PK Gregersen. Arthritis Rheum 2007 Jun;56(6):1745-1753. 2,476 white patients with RA from three cohorts. "Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti-CCP positivity. Weak evidence of gene-environment interaction between smoking and shared epitope alleles for anti-CCP formation was found only in the NARAC."

Lee - Arthritis Rheum 2007 abstract / PubMed

Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. A Kinloch, K Lundberg, R Wait, N Wegner, NH Lim, AJ Zendman, T Saxne, V Malmström, PJ Venables. Arthritis Rheum 2008 Aug;58(8):2287-2295. 20 patients with RA, 20 patients with spondylarthritides (SpA), and 20 patients with osteoarthritis (OA). "Citrullinated polypeptides were detected in the synovial fluid from patients with RA and patients with SpA, but not in OA samples. Alpha-enolase was detected in all of the samples, with mean levels of 6.4 ng/microl in RA samples, 4.3 ng/microl in SpA samples, and <0.9 ng/microl in OA samples. Two-dimensional electrophoresis provided evidence that the alpha-enolase was citrullinated in RA synovial fluid. The citrullinating enzyme PAD-4 was detected in samples from all 3 disease groups. PAD-2 was detected in 18 of the RA samples, in 16 of the SpA samples, and in none of the OA samples. Antibodies to CEP-1 were found in 12 of the RA samples (60%), in none of the SpA samples, and in 1 OA sample."

Kinloch / Arthritis Rheum 2008 full article

Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. K Lundberg, A Kinloch, BA Fisher, N Wegner, R Wait, P Charles, TR Mikuls, PJ Venables. Arthritis Rheum 2008 Oct;58(10):3009-3019. Antibodies to citrullinated alpha-enolase peptide 1 were found in 37-62% of sera from patients with RA, 3% of sera from disease control subjects, and 2% of sera from healthy controls. "The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated alpha-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2=0.803, P<0.0001)." And, "the sequence of 9 amino acids spanning the immunodominant epitope on CEP-1 was 100% identical to that encoded by P gingivalis." Venables, Lundberg and Kinloch filed patents as coinventors of of the discovery of citrullinated α-enolase peptide 1 (CEP-1) and other sequences from citrullinated α-enolase. [Yet they blamed smoking for a supposed "gene-environment interaction between HLA SE alleles... in anti-CCP antibody–positive patients but not in anti-CCP antibody–negative patients," based on studies that ignored the role of CMV. They claimed that "to date, no single organism has survived as a compelling candidate for the etiology of the disease," while citing only four studies, which were of Staph B, parvovirus B19, and EBV!] This study was funded by the Arthritis Research Campaign and the Medical Research Council UK, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Lundberg / Arthritis Rheum 2008 full article

Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. TR Mikuls, JB Payne, RA Reinhardt, GM Thiele, E Maziarz, AC Cannella, VM Holers, KA Kuhn, JR O'Dell. Int Immunopharmacol 2009 Jan;9(1):38-42. 78 RA patients, 39 periodontitis patients, 40 controls. "Antibody titers to P. gingivalis were highest in PD, lowest in controls, and intermediate in RA (p=0.0003). Elevations in P. gingivalis (titer> or =800) were more common in RA and PD (67% and 77%, respectively) than in controls (40%) (p=0.002). In RA, there were significant correlations with P. gingivalis titer with CRP, anti-CCP-IgM, and -IgG-2. CRP (p=0.006), anti-CCP-IgM (p=0.01) and -IgG2 (p=0.04) concentrations were higher in RA cases with P. gingivalis titers > or =800 compared to cases with titers <800."

Mikuls - Int Immunopharmacol 2009 full article / PubMed Central

Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. O Snir, M Widhe, C von Spee, J Lindberg, L Padyukov, K Lundberg, A Engström, PJ Venables, J Lundeberg, R Holmdahl, L Klareskog, V Malmström. Ann Rheum Dis 2009 May;68(5):736-743. 291 patients with established RA and 100 healthy controls. "72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients' sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1(III). These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles."

Snir - Ann Rheum Dis 2009 abstract / PubMed

Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. TR Mikuls, GM Thiele, KD Deane, JB Payne, JR O'Dell, F Yu, H Sayles, MH Weisman, PK Gregersen, JH Buckner, RM Keating, LA Derber, WH Robinson, VM Holers, JM Norris. Arthritis Rheum 2012 Nov;64(11):3522-3530. Relatives of RA patients, 113 with ≥1 RA-related autoantibody, 38 with ACPA or ≥2 assays for RF, 171 autoantibody-negative controls. "Anti-P gingivalis concentrations were higher in high-risk (P = 0.011) and autoantibody positive group (P = 0.010) than in the autoantibody negative group. There were no group differences in anti-P intermedia or anti-F nucleatum concentrations. After multivariable adjustment, anti-P gingivalis concentrations (but not anti-P intermedia or anti-F nucleatum) were significantly associated with autoantibody-positive and high-risk status (P < 0.05)."

Mikuls - Arthritis Rheum 2012 abstract / PubMed

Rheumatoid arthritis is an autoimmune disease caused by periodontal pathogens. M Ogrendik. Int J Gen Med 2013 May 24;6:383-386. Review.

Ogrendik - Int J Gen Med 2013 full article / PubMed Central

Porphyromonas gingivalis and the pathogenesis of rheumatoid arthritis: analysis of various compartments including the synovial tissue. MC Totaro, P Cattani, F Ria, B Tolusso, E Gremese, AL Fedele, S D'Onghia, S Marchetti, G Di Sante, S Canestri, G Ferraccioli. Arthritis Res Ther 2013 Jun 18;15(3):R66. 69 patients with active knee arthritis (32 with RA and 37 with other arthritides, of which 14 with undifferentiated peripheral inflammatory arthritis. "Full PB samples showed a higher positivity for Pg DNA than plasma samples (11.8% vs. 1.5%, p=0.04). Patients with RA showed a higher positivity for Pg DNA in the synovial tissue compared to controls (33.3% vs. 5.9%, p<0.01). UPIA and RA patients carrying the HLA DRB1*04 allele showed a higher positivity for Pg DNA in the synovial tissue compared to patients negative for the allele (57.1% vs. 16.7%, p=0.04)."

Totaro - Arthritis Res Ther 2013 abstract / PubMed

Clinical correlations with Porphyromonas gingivalis antibody responses in patients with early rheumatoid arthritis. SL Arvikar, DS Collier, MC Fisher, S Unizony, GL Cohen, G McHugh, T Kawai, K Strle, AC Steere. Arthritis Res Ther 2013 Sep 9;15(5):R109. 50 DMARD-naive RA patients; controls were 43 patients with late RA, 17 patients with lupus, 10 with Sjogren’s syndrome, 4 with scleroderma, 3 with mixed connective tissue disease, and 19 age-similar healthy hospital personnel, plus blood bank donors. "RA patients had significantly higher Pg antibody responses than healthy hospital personnel and blood bank donors (P<0.0001)... Compared with Pg antibody-negative patients, early RA patients with positive Pg responses more often had anti-CCP antibody reactivity, their anti-CCP levels were significantly higher (P=0.03), and the levels of anti-Pg antibodies correlated directly with anti-CCP levels (P<0.01)."

Arvikar / Arthritis Res Ther 2013 full article landing

Porphyromonas gingivalis Facilitates the Development and Progression of Destructive Arthritis through Its Unique Bacterial Peptidylarginine Deiminase (PAD). KJ Maresz, A Hellvard, Sroka A, K Adamowicz, E Bielecka, J Koziel, K Gawron, D Mizgalska, KA Marcinska, M Benedyk, K Pyrc, AM Quirke, R Jonsson, S Alzabin, PJ Venables, KA Nguyen, P Mydel, J Potempa. PLoS Pathog 2013 Sep;9(9):e1003627. Collagen-induced arthritis in mice. "The ability of P. gingivalis to augment CIA was dependent on the expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), which converts arginine residues in proteins to citrulline. Infection with wild type P. gingivalis was responsible for significantly increased levels of autoantibodies to collagen type II and citrullinated epitopes as a PPAD-null mutant did not elicit similar host response. High level of citrullinated proteins was also detected at the site of infection with wild-type P. gingivalis."

Maresz - PLoS Pathog 2013 full article / PubMed Central
Maresz / PLoS Pathog 2013 full article

Periodontal Treatment Decreases Levels of Antibodies to Porphyromonas Gingivalis and Citrulline in Patients With Rheumatoid Arthritis and Periodontitis. M Okada, T Kobayashi, S Ito, T Yokoyama, A Abe, A Murasawa, H Yoshie. J Periodontol 2013 Dec;84(12):e74-84. 55 RA patients randomly assigned to scaling (n = 26) or no scaling (n = 29). "The treatment group exhibited a significantly greater decrease in disease activity score including 28 joints using C-reactive protein (DAS28-CRP) (P = 0.02), serum levels of IgG to P. gingivalis hemin binding protein 35 (HBP35) (P = 0.04) and citrulline (P = 0.02) than the control group. Serum levels of IgG to P. gingivalis HBP35 were significantly correlated positively with those of anti-CCP antibodies (P = 0.0002). The same correlation was obtained between serum levels of IgG to P. gingivalis sonicated extracts and those of rheumatoid factor (P = 0.02)."

Okada - J Periodontol 2013 abstract / PubMed

Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. AM Quirke, EB Lugli, N Wegner, BC Hamilton, P Charles, M Chowdhury, AJ Ytterberg, RA Zubarev, J Potempa, S Culshaw, Y Guo, BA Fisher, G Thiele, TR Mikuls, PJ Venables. Ann Rheum Dis 2014;73(1):263-269. 80 patients with RA, 44 with periodontal disease, 82 controls. Antibodies to a citrullinating enzyme (PPAD), but not to another P gingivalis protein (RgpB), "were elevated in the RA sera (median 122 U/ml) compared with controls (median 70 U/ml; p<0.05) and PD (median 60 U/ml; p<0.01)... The elevated antibody response to PPAD was abolished in RA sera if the C351A mutant was used on ELISA." They note that "P gingivalis is apparently unique among periodontal pathogens in possessing a citrullinating enzyme, peptidylarginine deiminase (PPAD) with the potential to generate antigens driving the autoimmune response."

Quirke / Ann Rheum Dis 2014 full article

A116: increased antibody responses to porphyromonas gingivalis in children with anticyclic citrullinated Peptide antibody-positive juvenile idiopathic arthritis. L Lange, GM Thiele, M Pichavant, G Wang, L Ponder, KR Stevens, ST Angeles-Han, C Kennedy, LB Vogler, TR Mikuls, S Prahalad. Arthritis Rheumatol 2014 Mar;66 Suppl 11:S153. 207 children with JIA, 77 positive and 130 negative for anti-cyclic citrullinated peptide antibodies. "Anti-P. gingivalis IgG antibody titers were significantly higher in the CCP+JIA cohort than in the CCP-JIA cohort (9.04 vs. 5.69; p < 0.003). Anti-P. intermedia IgG and anti-F. nucleatum IgG antibody titers were not different between the two groups. There was no association between CCP+JIA and smoke exposure in the prenatal period or in the 6 months prior to JIA symptom onset."

Lange - Rheumatol 2014 abstract / PubMed

Autoantibodies from single circulating plasmablasts react with citrullinated antigens and Porphyromonas gingivalis in rheumatoid arthritis. S Li, Y Yu, Y Yue, H Liao, W Xie, J Thai, TR Mikuls, GM Thiele, MJ Duryee, H Sayles, JB Payne, LW Klassen, JR O'Dell, Z Zhang, K Su. Arthritis Rheumatol 2016 Mar;68(3):614-626. "19.5% of plasmablast-derived antibodies from CCP-positive RA patients, but none from the CCP-negative RA patient or healthy controls, specifically recognized citrullinated antigens. The immunoglobulin genes encoding these ACPAs were highly mutated with increased replacement/silent mutation ratios, suggesting the involvement of active antigen selection in ACPA generation. Interestingly, 63% of the ACPAs cross-reacted with OMAs and/or citrullinated enolase from P. gingivalis. The reactivity of ACPAs against citrullinated proteins from P. gingivalis was confirmed by immuno blot and mass spectrometry. Furthermore, germ-line reversions of some ACPAs completely eliminated their reactivity to citrullinated human antigens but retained their reactivity to P. gingivalis."

Li - Arthritis Rheumatol 2016 abstract / PubMed

Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. L Johansson, N Sherina, N Kharlamova, B Potempa, B Larsson, L Israelsson, J Potempa, S Rantapää-Dahlqvist, K Lundberg. Arthritis Res Ther 2016 Sep 7;18:201. 251 cases, 198 controls. "Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean ± SEM; 152.7 ± 14.8 AU/ml) and in RA patients (114.4 ± 16.9 AU/ml), compared with controls (p < 0.001). Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 ± 0.59 and 9.29 ± 1.81 AU/ml, respectively) compared with controls (p < 0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time..."

Johansson - Arthritis Res Ther 2016 full article / PubMed Central
Johansson / Arthritis Res Ther 2016 full article

A Role For Epstein-Barr Virus

In ACPA-positive RA patients, antibodies to EBNA35-58Cit, a citrullinated peptide from the Epstein-Barr nuclear antigen-1, strongly cross-react with the peptide β60-74Cit which bears the immunodominant epitope of citrullinated fibrin. M Cornillet, E Verrouil, A Cantagrel, G Serre, L Nogueira. Immunol Res 2015 Feb;61(1-2):117-125. "Here, using a large cohort of RA patients and controls, we showed that for a diagnostic specificity of 98.5 %, 47 % of the AhFibA-positive patients were anti-EBNA35-58Cit-positive and that almost all (98.5 %) the anti-EBNA35-58Cit-positive were AhFibA-positive, whereas 86 % were anti-β60-74Cit-positive and only 43 % anti-α36-50Cit-positive. AhFibA, anti-EBNA35-58Cit- and anti-β60-74Cit-antibody titres were significantly correlated. Competition assays showed that anti-EBNA35-58Cit antibodies are highly cross-reactive with the β60-74Cit peptide. The demonstration that a citrullinated peptide derived from the EBNA-1 protein of EBV presents a molecular mimicry with human citrullinated fibrin constitutes an additional argument for a possible role of EBV in RA aetiopathogeny."

Cornillet - Immunol Res 2015 abstract / PubMed

Isotypes of epstein-barr virus antibodies in rheumatoid arthritis: association with rheumatoid factors and citrulline-dependent antibodies. MW Westergaard, AH Draborg, L Troelsen, S Jacobsen, G Houen. Biomed Res Int 2015;2015:472174. 77 RA patients, 28 patients with systemic lupus erythematosus (SLE), and 28 healthy controls. "Increased percentages of positives and concentrations of IgG/IgA/IgM antibodies against the latent EBV nuclear antigen-1 (EBNA-1) were observed in RA patients compared to SLE patients and HCs. Increased concentrations and percentages of positives of IgG/IgA/IgM against the early lytic EBV antigen diffuse (EAD) were also found in RA patients compared to HCs but were highest in SLE patients. Furthermore, associations between the elevated EBNA-1 IgA and EBNA-1 IgM levels and the presence of IgM and IgA rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPAs, IgG) and between elevated IgA concentrations against EAD and the presence of RFs and ACPAs in RA patients were found. Thus, RA patients had elevated antibodies of all isotypes characteristic of latent EBV infection (whereas SLE patients had elevated antibodies characteristic of lytic EBV infection)."

Westergaard - Biomed Res Int 2015 full article / PubMed Central
Westergaard / Biomed Res Int 2015 full article

The MHC (major histocompatibility complex) and RA

Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. S Raychaudhuri, C Sandor, EA Stahl, J Freudenberg, HS Lee, X Jia, L Alfredsson, L Padyukov, L Klareskog, J Worthington, KA Siminovitch, SC Bae, RM Plenge, PK Gregersen, PI de Bakker. Nat Genet 2012 Jan 29;44(3):291-296. Genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis and 14,974 unaffected controls. "Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk... These variants account for 12.7% of the phenotypic variance, whereas common validated alleles outside the MHC explain ~4%." They noted that "the WTCCC samples have the sparsest SNP coverage across the MHC and that these accuracies probably represent a lower bound." "Of all amino acids tested in HLA-DRβ1, the strongest associations mapped to amino acid positions 11 (p=6.1×10−36) and 13 (p=3.1×10−36), with statistically indistinguishable effects (p>0.08). Thus, amino acids 11 and 13 in DRβ1 are the strongest associations in two different continental populations." "In fact, individual disease risk predicted by a full model where each classical DRB1 allele confers its own unique risk, and a simpler model where risk is defined by amino acid positions 11, 71 and 74, are nearly perfectly correlated (r=0.994)." Primary risk alleles are DRB1*0408, HLA-DRB1*0401, DRB1*0404, DRB1*1001, DRB1*0405, DRB1*0403, and DRB1*0101, with smaller additive effects for HLA-B and HLA-DPβ1, Fig. 5.

Raychaudhuri - Nat Genet 2012 full article / PubMed Central

The United States Government Funds More Scientific Fraud

They claimed to have found puny little odds ratios of 1.45 for smoking, which are routinely generated from residual confounded by true, causal factors, such as CMV and P. gingivalis. This confounding is NOT eliminated by adjustment for surrogates such as socioeconomic status. (Associations of cigarette smoking with rheumatoid arthritis in African Americans. TR Mikuls, H Sayles, F Yu, T LeVan, KA Gould, GM Thiele, DL Conn, BL Jonas, LF Callahan, E Smith, R Brasington, LW Moreland, RJ Reynolds, SL Bridges Jr. Arthritis & Rheumatism 2010 Dec;62(12)3560-3568.) "The African-American disease registry is supported by the National Institutes of Health, and the University of Alabama at Birmingham. Mikuls' work also was supported by the Nebraska Arthritis Outcomes Research Center, the Arthritis Foundation, and the Veterans Affairs Office of Research and Development." (Smoking Among Blacks Linked to RA. By Nancy Walsh. Medpage Today, Nov. 29, 2010.)

Mikuls / Arthritis & Rheumatism 2010 abstract
Smoking Among Blacks Linked to RA / Medpage Today

They are guilty of scientific fraud for ignoring the evidence that cytomegalovirus is solidly implicated in rheumatoid arthritis, and that black people and smokers are more likely to have been exposed to this virus, for socioeconomic reasons. For the government to promote fraud, whose intent is to deprive us of our liberties, is inherently a violation of our right to the equal protection of the laws, and is no different in nature from the government purposely throwing innocent people in prison.

See Also

CMV & other infections cause heart disease
CMV and Immunity
Parvovirus B19 and other illness


cast 02-24-18