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1.
Ann Rheum Dis ; 71(6): 1049-54, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22294633

RESUMO

OBJECTIVES: Proteinase-activated receptor 2 (PAR(2)) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functional significance of PAR(2) expression on rheumatoid arthritis (RA)-derived leucocyte subsets. METHODS: Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR(2) on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. RESULTS: Patients with RA had elevated but variable surface expression of PAR(2) on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86-4.10%) vs 0.06% (0.03-0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR(2) expression in patients with RA compared with controls (3.05% (0.36-11.82%) vs 0.08% (0.02-0.28%), p<0.0001). For both subsets, PAR(2) expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR(2) expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR(2) expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR(2) expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR(2) agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05). CONCLUSIONS: These findings are consistent with a pathogenic role for PAR(2) in RA.


Assuntos
Artrite Reumatoide/imunologia , Monócitos/imunologia , Receptor PAR-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/metabolismo , Complexo CD3/metabolismo , Células Cultivadas , Estudos Transversais , Feminino , Citometria de Fluxo , Expressão Gênica/imunologia , Humanos , Interleucina-6/imunologia , Interleucina-6/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Osteoartrite/imunologia , Osteoartrite/metabolismo , Receptor PAR-2/genética , Receptor PAR-2/metabolismo
2.
Ann Rheum Dis ; 68(6): 1059-66, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18635595

RESUMO

BACKGROUND: The relative roles of innate immunity and antigen-specific T cells in rheumatoid arthritis remain controversial. Previous studies demonstrated that T-helper type 1 cells of irrelevant antigen specificity (ovalbumin) induced a transient arthritis in BALB/c mice, which recapitulates many of the pre-articular and articular features of human disease and is associated with the emergence of autoreactive T and B-cell responses to joint-specific antigens. However, the mechanisms underlying this phenomenon were unclear. OBJECTIVES: The aim of this study was to dissect the relative contribution of innate and heterologous antigen-specific pathways to the breach of self-tolerance and pathology observed in this model and how this may result from modified T and B-cell interactions. METHODS: To address this issue, experimental arthritis was elicited either by a non-specific inflammatory stimulus alone, by activation of T cells of an irrelevant specificity or a combination of both. RESULTS: The non-specific inflammatory response generated by lipopolysaccharide led to articular inflammation and cartilage erosion, but did not break tolerance to joint-specific antigens. In contrast, local activation of T cells of an irrelevant specificity produced a similar pathological picture but, in addition, induced T-cell responses to unrelated joint-specific antigens with associated activation of autoreactive B cells. These effects could be further potentiated by the addition of lipopolysaccharide. CONCLUSION: These data demonstrate that non-specific inflammation alone is insufficient to breach self-tolerance. In contrast, T cells of an irrelevant specificity, when triggered locally in an antigen-specific manner, can breach self-tolerance leading to arthritis and autoantibody production, which can then be amplified in a non-specific manner.


Assuntos
Artrite Reumatoide/imunologia , Transferência Adotiva/métodos , Animais , Formação de Anticorpos , Artrite Experimental/imunologia , Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Proliferação de Células , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Imuno-Histoquímica , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Tolerância a Antígenos Próprios/imunologia , Células Th1/imunologia , Células Th2/imunologia
3.
Parasitology ; 131(Pt 2): 169-79, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16149193

RESUMO

Studies using antibodies to immunolocalize the Toxoplasma gondii dense granule protein GRA3, have shown that this protein associates strongly with the parasitophorous vacuole membrane (PVM). However, as there was no predicted membrane-spanning domain this highlighted an unanswered paradox. We demonstrate that the previously published sequence for GRA3 is actually an artificial chimera of 2 proteins. One protein, of molecular weight 65 kDa, shares the C-terminus with published GRA3 and possesses no significant sequence similarity with any protein thus far deposited in Genbank. The second, with a predicted molecular weight of 24 kDa shares the N-terminal region, is recognized by the monoclonal antibody 2H11 known to react with the dense granules of T. gondii and is therefore the authentic GRA3. The corrected GRA3 has an N-terminal secretory signal sequence and a transmembrane domain consistent with its insertion into the PVM. Antibodies to recombinant GRA3 recognize a protein of 24 kDa in T. gondii excretory-secretory antigen preparations. The signal peptide is necessary and sufficient to target GFP to the dense granules and parasitophorous vacuole. A homologue was identified in Neospora caninum. Finally, GRA3 possesses a dilysine 'KKXX' endoplasmic reticulum (ER) retrieval motif that rationalizes its association with PVM and possibly the host cell ER.


Assuntos
Proteínas de Membrana/química , Proteínas de Protozoários/química , Toxoplasma/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sequência de Bases , Chlorocebus aethiops , Dipeptídeos/química , Retículo Endoplasmático/química , Proteínas de Membrana/fisiologia , Dados de Sequência Molecular , Neospora/química , Sinais Direcionadores de Proteínas , Proteínas de Protozoários/fisiologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/fisiologia , Vacúolos/parasitologia , Células Vero
4.
Parasite Immunol ; 26(2): 75-82, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15225294

RESUMO

The role of interleukin-4 (IL-4) during the course of Toxoplasma gondii infection was studied using IL-4-/- mice and their wild-type (WT) counterparts on a C57BL/6 background. Following oral infection with T. gondii tissue cysts an exacerbative role for IL-4 was demonstrated and IL-4-/- mice were found to be more resistant to infection than WT mice as measured by significantly reduced mortality. Furthermore pathology in the small intestine was less severe in IL-4-/- mice although conversely liver pathology was greater than in wild-type mice. Significantly, plasma IL-12 and IFN-gamma levels, which peaked at days 6 and 8, respectively, were higher in IL-4-/- mice. The exacerbatory role of IL-4 in the intestine was found by competitive RT-PCR not to be associated with increased parasite burdens but was related to comparative expression of IL-10.


Assuntos
Interleucina-4/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/patologia , Toxoplasma/crescimento & desenvolvimento , Toxoplasmose Animal/patologia , Doença Aguda , Animais , Citocinas/metabolismo , Feminino , Interleucina-4/genética , Intestino Delgado/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th2/imunologia , Toxoplasmose Animal/imunologia , Toxoplasmose Animal/mortalidade , Toxoplasmose Animal/parasitologia
5.
Infect Immun ; 69(2): 1044-52, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11160001

RESUMO

The role of interleukin-5 (IL-5) during Toxoplasma gondii infection was investigated by comparing disease progression in IL-5 gene deficient (IL-5-/-) mice and their wild-type (WT) counterparts on a C57BL/6 background. IL-5-/- mice infected orally with T. gondii were less susceptible to infection than WT mice as demonstrated by reduced mortality rates. Consistent with this data, orally infected IL-5-/- mice had less severe pathological changes in their small intestines than WT mice at 8 days postinfection. At this time, splenocytes and mesenteric lymph node cells derived from IL-5-/- mice produced levels of IL-12, interferon-gamma (IFN-gamma), IL-4, IL-10, and nitric oxide (measured as nitrite) similar to those derived from WT mice when stimulated with Toxoplasma lysate antigen. However, peak serum IL-12 and IFN-gamma levels (at days 6 and 8, respectively) were significantly higher in IL-5-/- mice than in WT mice. In addition, WT mice but not IL-5-/- mice had raised levels of eosinophils in their peripheral blood between days 5 and 8 following infection. Oral administration of N omega-nitro-L-arginine methyl (from day 4 postinfection) increased mortality rates in both IL-5-/- and WT mice, indicating a protective role for nitric oxide during the early stages of oral T. gondii infection. In comparison with oral infection, no difference in mortality was observed between IL-5-/- and WT mice following intraperitoneal infection with T. gondii, with all mice surviving until 35 days postinfection. Similarly, no significant differences were observed in the severity of the meningitis, perivascular cuffing, or number of microglial nodules or parasites in the brains of intraperitoneally infected mice. Together, these results demonstrate a detrimental role for IL-5 during the early stage of oral infection with T. gondii which is associated with increased small-intestine pathology, eosinophilia, and reduced plasma IL-12 and IFN-gamma levels.


Assuntos
Interleucina-5/fisiologia , Toxoplasmose Animal/imunologia , Doença Aguda , Animais , Eosinófilos/fisiologia , Interleucina-10/sangue , Interleucina-12/sangue , Linfonodos/imunologia , Ativação Linfocitária , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Toxoplasmose Animal/mortalidade , Toxoplasmose Animal/patologia , Fator de Necrose Tumoral alfa/biossíntese
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