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19. CD4+CD25+ immunoregulatory T cells may not be involved in controlling autoimmune arthritis

Author

Bardos, T., Czipri, M., Vermes, C., Finnegan, A., Mikecz, K., and Jian Zhang

Subjects
Mice, Knockout, Mice, Inbred BALB C, autoimmunity, hemic and immune systems, chemical and pharmacologic phenomena, Receptors, Interleukin-2, Mice, SCID, peripheral tolerance, Arthritis, Experimental, regulatory T cells, Autoimmune Diseases, Mice, Inbred C57BL, Mice, arthritis, CD28 Antigens, T-Lymphocyte Subsets, CD4 Antigens, Animals, Female, Proteoglycans, Research Article
Abstract

Accumulating evidence suggests that regulatory T cells play a crucial role in preventing autoimmunity. Recently, a naturally occurring CD4+CD25+ T-cell subset that is anergic and also suppressive has been shown to suppress autoimmunity in several animal models. We used proteoglycan-induced arthritis (PGIA) as a study model to investigate the role of the CD4+CD25+ regulatory T cells in autoimmune arthritis. There was no significant change in the percentage of CD4+CD25+ T cells during the immunization period when proteoglycan- or ovalbumin-immunized BALB/c and C57BL/6 mice were compared. An adoptive transfer study showed that the CD4+CD25+ T cells did not protect severe combined immunodeficient mice from arthritis when they were cotransferred with splenocytes from arthritic animals. Similarly, depletion of the CD4+CD25+ T cells did not enhance the onset of the disease or disease severity in severe combined immunodeficient mice. Moreover, CD28-deficient mice, which have very few CD4+CD25+ T cells, were highly resistant to PGIA. These findings indicate that the CD4+CD25+ regulatory T cells may not play a critical role in controlling PGIA.

Published
2003

20. Proteoglycan Aggrecan Conducting T Cell Activation and Apoptosis in a Murine Model of Rheumatoid Arthritis

Author

Hanyecz, A., Olasz, K., Tarjanyi, O., Nemeth, P., Mikecz, K., Glant, T. T., and Boldizsar, F.

Subjects
Article Subject
Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease and its targeting of the joints indicates the presence of a candidate autoantigen(s) in synovial joints. Patients with RA show immune responses in their peripheral blood to proteoglycan (PG) aggrecan. One of the most relevant animal models of RA appears to be proteoglycan-induced arthritis (PGIA), and CD4+ T cells seem to play a crucial role in the initiation of the disease. In this review, the role of various T cell epitopes of aggrecan in the induction of autoreactive T cell activation and arthritis is discussed. We pay special attention to two critically important arthritogenic epitopes, 5/4E8 and P135H, found in the G1 and G3 domains of PG aggrecan, respectively, in the induction of autoimmune arthritis. Finally, results obtained with the recently developed PG-specific TCR transgenic mice system showed that altered T cell apoptosis, the balance of activation, and apoptosis of autoreactive T cells are critical factors in the development of autoimmunity.

Published
2014
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29. 26 SYNOVIAL FLUID FROM PATIENTS WITH OSTEOARTHRITIS AND MENISCAL INJURY MODULATES THE RESPONSE OF FIBROBLAST-LIKE SYNOVIOCYTES TO TLR-2 AND TLR-4 LIGANDS VIA SOLUBLE CD14

Author

Scanzello, C.R., primary, Nair, A., additional, Kanda, V., additional, Bush-Joseph, C., additional, Verma, N., additional, Chubinskaya, S., additional, Mikecz, K., additional, Malfait, A.-M., additional, Crow, M.K., additional, Spear, G.T., additional, and Finnegan, A., additional

Published
2011
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39. Visualization and in situ analysis of leukocyte trafficking into the ankle joint in a systemic murine model of rheumatoid arthritis.

Author

Gal I, Bajnok E, Szanto S, Sarraj B, Glant TT, and Mikecz K

Abstract

OBJECTIVE: To describe the kinetics of leukocyte migration into a distal joint during the development of chronic inflammation in a murine model of rheumatoid arthritis (RA), to identify leukocyte subpopulations recruited in the synovial vessels, and to test in real time the effects of an antiinflammatory compound on leukocyte-endothelial cell interactions in the arthritic joint. METHODS: We used intravital video microscopy (IVM), which was adapted to the microcirculation of the mouse ankle, to monitor the kinetics of leukocyte-endothelium interactions (rolling and firm adhesion) during the onset and progression of proteoglycan-induced arthritis (PGIA), a chronic autoimmune model of RA. Subpopulations of rolling and adherent leukocytes were identified by in vivo immunostaining. Leukocyte extravasation into the ankle joint was verified histologically. RESULTS: Between the onset of arthritis and the beginning of the destructive phase of PGIA, we found a steady increase in the number of leukocytes that exhibited firm adherence to the endothelium of synovial vessels, which clearly underscores the chronic, self-perpetuating character of joint inflammation in this autoimmune model. We showed, however, that granulocytes, and not T cells, constituted the major cell population that was continuously recruited to the inflamed ankle. Using IVM, we could detect instant changes in leukocyte adhesion behavior in the synovial vessels of the arthritic joint upon administration of a compound that antagonizes leukocyte rolling. CONCLUSION: IVM of the microcirculation of the mouse ankle could become an essential tool for investigating the mechanisms that regulate leukocyte migration to the joint in systemic models of RA as well as for preclinical testing of antiinflammatory therapies. [ABSTRACT FROM AUTHOR]

Published
2005
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40. Genetic control of experimental spondylarthropathy.

Author

Szabó Z, Szántó S, Végvári A, Szekanecz Z, Mikecz K, and Glant TT

Abstract

OBJECTIVE: To characterize experimentally induced spondylarthropathy (SpA) in arthritis-susceptible inbred mice and in their F(1) and F(2) hybrid generations of susceptible and resistant mouse strains. METHODS: SpA was induced in susceptible BALB/c and C3H/HeJCr (C3H) strains of mice, and in their F(1) and F(2) generations derived from intercrosses with arthritis- and/or spondylitis-resistant DBA/2 and DBA/1 parent strains, by systemic immunization with cartilage proteoglycan (PG) aggrecan. The incidence and severity of PG-induced spondylitis (PGIS) were scored histologically, and these scores for spine involvement were correlated with serum antibody and cytokine levels and with in vitro T cell responses to cartilage PG. RESULTS: PGIS was induced by systemic immunization with cartilage PG in adjuvant, and approximately 60-70% of susceptible mouse strains and their F(2) hybrids developed spondylitis either with or without arthritis. Adjuvants, particularly those activating the innate immune system and enforcing the Th1 dominance, had significant effects on the outcome and progression of SpA. The DBA/1 strain appeared to carry genes protecting this strain and its F(1) and F(2) hybrids from spondylitis, whereas the DBA/2 strain, although resistant to PGIS, harbored genes permitting PGIS in its hybrid generations. Arthritis- and/or spondylitis-susceptible BALB/c and C3H parent strains and their F(2) hybrids exhibited the highest incidence and severity of spondylitis. CONCLUSION: PGIS, a murine model of autoimmune spondylitis, shows similarities to ankylosing spondylitis. Segregation of susceptibility to PG-induced arthritis (PGIA) from that to PGIS in different genetic crosses suggests that PGIA and PGIS are separate diseases. Therefore, this model allows for the elucidation of genetic components involved in the etiology of SpA, independent of those controlling the susceptibility to PGIA. [ABSTRACT FROM AUTHOR]

Published
2005
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41. Chondrocyte matrix metalloproteinase-8. Human articular chondrocytes express neutrophil collagenase.

Author

Cole, A A, Chubinskaya, S, Schumacher, B, Huch, K, Szabo, G, Yao, J, Mikecz, K, Hasty, K A, and Kuettner, K E

Abstract

This study confirms that normal human articular chondrocytes express neutrophil collagenase or matrix metalloproteinase-8 (MMP-8), a gene product previously thought to be expressed exclusively by neutrophil leukocytes. Both MMP-8 protein and mRNA were present in articular cartilages collected from normal human donors. Cartilage extracts were assayed by immunoblotting and by analysis of enzymatic activity on gelatin-substrate gels. Latent MMP-8 extracted from cartilage has a molecular mass of 55 kDa; active MMP-8 was identified at 46 and 42 kDa. In the absence of a reducing agent, MMP-8 migrated in a high molecular mass complex above 200 kDa. Northern blotting results demonstrated the expression of MMP-8 in chondrocytes, which could be up-regulated by stimulation with interleukin-1 beta. In addition, reverse transcription-polymerase chain reaction using nested primers and in situ hybridization revealed the presence of MMP-8 mRNA in chondrocytes. The presence of both MMP-8 protein and message in cartilage supports the concept that neutrophil collagenase could be the enzyme described as "aggrecanase".

Published
1996

42. Age-related changes in protein-related epitopes of human articular-cartilage proteoglycans

Author

Glant, T T, Mikecz, K, Roughley, P J, Buzás, E, and Poole, A R

Abstract

Monoclonal antibodies were prepared that recognize different age-related epitopes on proteoglycan subunits of high buoyant density isolated from human epiphysial and articular cartilages. Antibody EFG-4 (IgG1) recognizes a proteinase-sensitive segment associated with the core protein. Antibody BCD-4 (IgG1) reacts with keratan sulphate bound to core protein. Both epitopes are minimally expressed in foetal cartilage and increase with age after birth to become maximally expressed in adult cartilage by about 30 years of age. In contrast, monoclonal antibody alpha HFPG-846 (IgM) recognizes a core-protein-related epitope that is maximally expressed in young foetal cartilage, declines up to birth and thereafter and is almost absent after about 30 years of age. Antibody alpha HFPG-846 was used to isolate by immuno-affinity chromatography two subpopulations of proteoglycan subunits from a 16-year-old-human cartilage proteoglycan subunit preparation. Only the antibody-unbound population showed a significant reaction with antibodies EGF-4 and BCD-4. The amino acid and carbohydrate compositions of these proteoglycan fractions were different, and one (antibody-bound) resembled those of foetal and the other (antibody-unbound) resembled those of adult proteoglycans isolated from 24-27-week-old-foetal and 52-56-year-old-adult cartilage respectively. These observations demonstrate that human cartilages contain at least two chemically and immunochemically distinct populations of proteoglycans, the proportions and content of which are age-dependent. It is likely that these populations represent the products of different genes, though their heterogeneity may be compounded by the result of different post-translation modifications.

Published
1986
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43. Monoclonal antibodies to different protein-related epitopes of human articular cartilage proteoglycans

Author

Glant, T T, Mikecz, K, and Poole, A R

Abstract

Monoclonal antibodies produced against chondroitinase-treated human adult cartilage proteoglycans were selected for their ability to recognize epitopes on native proteoglycans. Binding analyses revealed that four of these monoclonal antibodies (BCD-4, BCD-7, EFG-4 and KPC-190) each recognized a different epitope on the same proteoglycan molecule which represents a subpopulation of a high buoyant density (D1) fraction of human articular cartilage proteoglycans (10, 30, 50 and 60% in fetal-newborn, 1.5 years old, 15 years old and 52-56 years old cartilages, respectively). Analysis of epitope specificities revealed that BCD-7 and EFG-4 monoclonal antibodies recognized epitopes on proteoglycan monomer which are associated with the protein structure in that they are sensitive to cleavage by Pronase, papain and alkali treatment and do not include keratan sulphate, chondroitin sulphate or oligosaccharides. The BCD-4 and KPC-190 epitopes also proved to be sensitive to Pronase or papain digestion or to alkali treatment, but keratanase or endo-beta-galactosidase also reduced the immunoreactivity of these epitopes. These observations indicate that the BCD-4 and KPC-190 epitopes represent peptides substituted with keratan sulphate or keratan sulphate-like structures. The BCD-4 epitope is, however, absent from a keratan sulphate-rich fragment of human adult proteoglycan, while the other three epitopes were detected in this fragment. None of these four epitopes were detected in the link proteins of human cartilage, in the hyaluronic acid-binding region of human newborn cartilage proteoglycan, in Swarm rat chondrosarcoma proteoglycan, in chicken limb bud proteoglycan monomer and in the small dermatan sulphate-proteoglycan of bovine costal cartilage. EFG-4 and KPC-190 epitopes were not detected in human fetal cartilage proteoglycans, although fetal molecules contained trace amounts of epitopes reactive with BCD-4 and BCD-7 antibodies.

Published
1986
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45. A proteoglycan (aggrecan)-specific T cell hybridoma induces arthritis in BALB/c mice

Author

Buzas, E. I., Brennan, F. R., Mikecz, K., Garzo, M., Gabriela Negroiu, Hollo, K., Cs-Szabo, G., Pintye, E., and Glant, T. T.

Subjects
Extracellular Matrix Proteins, Mice, Inbred BALB C, Hybridomas, Arthritis, T-Lymphocytes, Immunology, Immunization, Passive, Immunophenotyping, Major Histocompatibility Complex, Epitopes, Mice, Immunology and Allergy, Animals, Female, Lectins, C-Type, Proteoglycans, Aggrecans
Abstract

Aggrecan, the high buoyant density cartilage proteoglycan (PG), has been shown to induce progressive polyarthritis and ankylosing spondylitis in genetically susceptible BALB/c mice. To further characterize the nature of the autopathogenic effector T cells operating in these mice and to determine the region(s) of the PG molecule recognized by these T cells, we generated PG-specific T cell hybridomas from arthritic mice. One of the PG-specific T cell hybridomas (5/4E8), when injected into naive irradiated BALB/c mice, was capable of inducing clinical and histopathologic signs of arthritis. Massive swelling and redness of the paws dominated the clinical picture. A reactive synovial cell proliferation, the accumulation of hybridoma and inflammatory cells in the enlarged joint space, the loss of PG from the superficial layer of the articular cartilage, and the erosion of articular surface were identical histopathologic signs to those found either in primary or adoptive transfer of PG-induced arthritis. The PG-specific and arthritogenic T cell hybridoma (5/4E8) expressed TCR-alpha beta + (V beta 4), CD4+, and CD8- phenotypes and belonged to the Th1 subset, as the cells secreted IL-2 and IFN-gamma, but not IL-4 upon PG stimulation, and the response was MHC class II (I-Ad)-restricted. These observations provide direct evidence that PG-specific Th cells play crucial roles in autoimmune arthritic processes.

46. Critical roles of glycosaminoglycan side chains of cartilage proteoglycan (aggrecan) in antigen recognition and presentation

Author

Glant, T. T., Buzás, E. I., Finnegan, A., Gabriela Negroiu, Cs-Szabó, G., and Mikecz, K.

Subjects
Adult, Cartilage, Articular, Male, Antigen Presentation, Extracellular Matrix Proteins, Mice, Inbred BALB C, Adolescent, Arthritis, Immunology, Molecular Sequence Data, Cross Reactions, Epitopes, Mice, Fetus, Carbohydrate Sequence, Immunology and Allergy, Animals, Humans, Cattle, Female, Lectins, C-Type, Proteoglycans, Aggrecans, Amino Acid Sequence, Glycosaminoglycans
Abstract

Systemic immunization of BALB/c mice with proteoglycan (aggrecan) from fetal human cartilage induces progressive polyarthritis, an experimental disease similar to human rheumatoid arthritis. The development of the disease in this genetically susceptible murine strain is based on cross-reactive immune responses between the immunizing fetal human and mouse self-proteoglycans. One of the cross-reactive and arthritogenic T cell epitopes (92GR/QVRVNSA/IY) is localized in the G1 domain of human/murine proteoglycan. Susceptible BALB/c mice, however, develop arthritis only if both the chondroitin sulfate (CS) and keratan sulfate (KS) side chains of the arthritogenic human proteoglycans are removed. The function of these two glycosaminoglycan side chains is opposite. The presence of a KS side chain in adult proteoglycan inhibits the recognition of arthritogenic T cell epitopes, prevents the development of T cell response, and protects animals from autoimmune arthritis. In contrast, the depletion of the CS side chain generates clusters of CS stubs and provokes a strong B cell response. These carbohydrate-specific B cells are the most important proteoglycan APC. Taken together, proteoglycan-induced progressive polyarthritis is dictated by three major components: genetic background of the BALB/c strain, highly specific T cell response to epitope(s) masked by a KS chain in aging tissue, and the presence of proteoglycan (CS stub)-specific B cells required for sufficient Ag presentation.

50. Age-related changes in arthritis susceptibility and severity in a murine model of rheumatoid arthritis

Author

Nemeth Peter, Mikecz Katalin, Boldizsar Ferenc, Tarjanyi Oktavia, and Glant Tibor T

Subjects
Immunologic diseases. Allergy, RC581-607, Geriatrics, RC952-954.6
Abstract

Abstract Background Rheumatoid arthritis (RA) most often begins in females in the fourth-fifth decade of their life, suggesting that the aging of the immune system (immunosenescence) has a major role in this disease. Therefore, in the present study, we sought to investigate the effect of age on arthritis susceptibility in BALB/c mice using the proteoglycan (PG)-induced arthritis (PGIA) model of RA. Results We have found that young, 1-month-old female BALB/c mice are resistant to the induction of PGIA, but with aging they become susceptible. PG-induced T cell responses decline with age, whereas there is a shift toward Th1 cytokines. An age-dependent decrease in T cell number is associated with an increased ratio of the memory phenotype, and lower CD28 expression. Antigen-presenting cells shifted from macrophages and myeloid dendritic cells in young mice toward B cells in older mice. The regulatory/activated T cell ratio decreases in older mice after PG injections indicating impaired regulation of the immune response. Conclusion We conclude that immunosenescence could alter arthritis susceptibility in a very complex manner including both adaptive and innate immunities, and it cannot be determined by a single trait. Cumulative alterations in immunoregulatory functions closely resemble human disease, which makes this systemic autoimmune arthritis model of RA even more valuable.

Published
2009
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