RESUMO
It is known that NB-UVB therapy can suppress a broad range of immune cells, but the additional effect of bathing in geothermal seawater still remains unclear. To study the influence of treatment on the expression of circulating immune cells contributing to the pathogenesis of psoriasis, six patients with psoriasis were treated with bathing in geothermal seawater two times daily combined with NB-UVB five times/week for 2 weeks and six patients were treated with NB-UVB therapy three times/week for 8 weeks. Disease severity (Psoriasis Area and Severity Index, PASI), chemokines, inflammatory cytokines, T cells and Toll-like receptors in the blood and skin samples were evaluated on enrolment (W0) and at 1 (W1), 3 (W3) and 8 (W8) weeks. Compared with healthy controls, psoriasis patients with active disease had significantly higher proportion of peripheral CLA+ T cells expressing CCR10 and CD103 and T cells with both Th1/Tc1 (CD4+/CD8+ IFN-γ+ or TNF-α+ cells) and Th17/Tc17 (CD4+CD45R0+IL-23R+, CD4+/CD8+ IL-17A+ or IL-22+ cells) phenotypes. Both treatments gave a significant clinical effect; however, bathing in geothermal seawater combined with NB-UVB therapy was more effective than NB-UVB therapy alone. This clinical improvement was reflected by a reduction in circulating CLA+ peripheral blood T cells and by a decreased Th1/Th17 and Tc1/Tc17 inflammatory response. These findings suggest that the inflammatory response in psoriasis is predominantly driven by both CD4+ and CD8+ skin-homing tissue retaining T cells of the Th17/Tc17 lineages.
Assuntos
Banhos , Fontes Termais , Psoríase/imunologia , Psoríase/terapia , Células Th17/imunologia , Terapia Ultravioleta/métodos , Adulto , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Progressão da Doença , Feminino , Humanos , Cadeias alfa de Integrinas/metabolismo , Interferon gama/sangue , Interleucina-17/sangue , Interleucinas/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Psoríase/radioterapia , Receptores CCR10/metabolismo , Água do Mar , Pele/citologia , Pele/imunologia , Células Th1/imunologia , Receptores Toll-Like/sangue , Interleucina 22RESUMO
Recent studies have highlighted the involvement of the palatine tonsils in the pathogenesis of psoriasis, particularly among patients with recurrent throat infections. However, the underlying immunological mechanism is not well understood. In this study we confirm that psoriasis tonsils are infected more frequently by ß-haemolytic Streptococci, in particular Group C Streptococcus, compared with recurrently infected tonsils from patients without skin disease. Moreover, we show that tonsils from psoriasis patients contained smaller lymphoid follicles that occupied a smaller tissue area, had a lower germinal centre to marginal zone area ratio and contained fewer tingible body macrophages per unit area compared with recurrently infected tonsils from individuals without skin disease. Psoriasis patients' tonsils had a higher frequency of skin-homing [cutaneous lymphocyte-associated antigen (CLA(+) )] CD4(+) and CD8(+) T cells, and this correlated significantly with their frequency of blood CLA(+) T cells. The psoriasis patients also had a higher frequency of tonsil T cells expressing the interleukin (IL)-23 receptor that was expressed preferentially by the CLA(+) T cell population. In contrast, recurrently infected tonsils of individuals without skin disease had a higher frequency of tonsil T cells expressing the activation marker CD69 and a number of chemokine receptors with unknown relevance to psoriasis. These findings suggest that immune responses in the palatine tonsils of psoriasis patients are dysregulated. The elevated expression of CLA and IL-23 receptor by tonsil T cells may promote the egression of effector T cells from tonsils to the epidermis, suggesting that there may be functional changes within the tonsils, which promote triggering or exacerbation of psoriasis.
Assuntos
Tonsila Palatina/patologia , Faringite/diagnóstico , Psoríase/diagnóstico , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Regulação para Cima/imunologia , Ensaios Clínicos como Assunto/tendências , Comorbidade , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Tonsila Palatina/imunologia , Faringite/complicações , Faringite/patologia , Psoríase/complicações , Psoríase/patologia , Recidiva , Pele/patologia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/patologia , Subpopulações de Linfócitos T/patologiaRESUMO
Psoriasis is a common chronic skin disease with strong genetic associations and environmental triggers. Patients with psoriasis develop sore throats much more frequently than nonpsoriatic individuals and it is well documented that streptococcal throat infections can trigger the onset of psoriasis, and such infections cause exacerbation of chronic psoriasis. It is now generally accepted that psoriatic lesions are caused by abnormal reactivity of specific T lymphocytes in the skin. However, it has been shown in recent years that activation of specific immunity is always preceded by activation of nonspecific innate immune mechanisms, and that abnormalities in the innate immune system can cause dysregulation in specific immune responses. Here we explore the possible immune mechanisms that are involved in the link between infection of the tonsils and this inflammatory skin disease. Moreover, we survey the literature and discuss the suitability of tonsillectomy as a treatment for psoriasis.
Assuntos
Imunidade Inata/fisiologia , Tonsila Palatina/imunologia , Psoríase/imunologia , Humanos , Psoríase/cirurgia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes , Tonsilectomia , Tonsilite/imunologiaRESUMO
The interaction between two species of gadoid and a shrimp stock was studied in a 40 km long two-armed fjord in north-west Iceland. On the basis of acoustic and trawl surveys in 2005 and 2006, immature cod Gadus morhua and haddock Melanogrammus aeglefinus were found to migrate to the inner part of the fjord in late summer, concurrent with rising temperatures. At the same time, the local northern shrimp Pandalus borealis stock retreated into the north-east arm of the fjord. Vertical distribution of acoustic targets indicated that a significant and temporally variable fraction of the gadoids was inaccessible to the trawl. Shrimp was a significant part of the diet of immature G. morhua, except in June 2006 when euphausiids comprised most of the diet of both G. morhua and M. aeglefinus. Shrimp was only a minor part of the diet of M. aeglefinus. An on-off relationship was observed in the catches of gadoids and shrimp. In hauls with large catches of gadoids, few shrimp were found and vice versa, indicating avoidance reaction at this spatial scale. The cooling in winter may have driven the gadoids to the outer parts of the fjord, which in turn may have aided in the dispersal of the shrimp stock in the following months.
Assuntos
Migração Animal/fisiologia , Gadiformes/fisiologia , Gadus morhua/fisiologia , Pandalidae/fisiologia , Comportamento Predatório/fisiologia , Estações do Ano , Animais , Demografia , DietaRESUMO
OBJECTIVES: Psoriasis and psoriatic arthritis (PsA) are associated with nail changes. Recent reports suggest that nail changes may be a part of the enthesitis of PsA and that they predict the onset of arthritis among patients with psoriasis, but they have not reported on subclasses of nail changes. However, earlier reports suggested that onycholysis is the nail change most strongly associated with PsA. If nail changes in PsA are a sign of enthesitis, they might be associated with small joint disease in general and the objective of this study was to test this hypothesis. METHODS: A total of 154 patients recruited through the Reykjavik Psoriatic Arthritis Study had a joint, skin, and nail evaluation. Associations with small joint disease were tested using univariate analysis, and confirmed in a multivariate model. RESULTS: Onycholysis had a strong association with small joint involvement [odds ratio (OR) 3.42, 95% confidence interval (CI) 1.41-8.92], while other types of nail changes did not. The number of swollen joints and shorter disease duration were also associated with small joint disease. CONCLUSIONS: Onycholysis is associated with small joint disease in PsA. Future studies of PsA should report the subtypes of nail changes. Longitudinal studies are needed to determine whether onycholysis predicts PsA.
Assuntos
Artrite Psoriásica/complicações , Articulações dos Dedos/imunologia , Inflamação/imunologia , Onicólise/complicações , Articulação do Dedo do Pé/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Psoriásica/imunologia , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Onicólise/imunologia , Seleção de Pacientes , Análise de Regressão , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The effects of non-steroidal anti-inflammatory drugs (NSAIDs) on acute inflammation have been thoroughly investigated. NSAIDs are, however, also prescribed for patients with chronic inflammation, such as rheumatoid arthritis (RA), and objective improvement suggestive of anti-inflammatory action from NSAIDs has not been convincingly shown in chronic RA. An antigen-induced arthritis (AIA) model was used to investigate the effects of piroxicam on chronic inflammation. METHODS: AIA was induced by injecting methylated bovine serum albumin (mBSA) into the knee joints of previously immunized rats that were treated orally with the NSAID piroxicam or with saline. This treatment was started either before AIA was induced or after it had reached a chronic phase. The findings were recorded by clinical and histological assessment of the joints. RESULTS: The piroxicam group developed significantly less acute and subsequent chronic knee joint inflammation but this was only evident if the drug was administered prior to the intra-articular mBSA injections. Piroxicam treatment that was initiated during the chronic inflammation did not have any clinical effect, whereas short-term corticosteroid treatment abolished the chronic inflammation. Moreover, histological analysis of the chronic inflammation revealed significantly more inflammatory changes in the piroxicam group compared with the control group. CONCLUSIONS: Piroxicam treatment had no beneficial effects on the chronic stable inflammation in this model and might even delay histological resolution. As the anti-inflammatory effect of piroxicam is restricted to acute inflammation, the use of NSAIDs during periods of chronic stable arthritis in humans, such as in RA, may need to be investigated.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Inflamação/tratamento farmacológico , Piroxicam/uso terapêutico , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Feminino , Membro Posterior/patologia , Inflamação/etiologia , Inflamação/patologia , Articulações/patologia , Ratos , Ratos Endogâmicos LewRESUMO
BACKGROUND: Obesity is a significant risk factor for psoriasis and body mass index (BMI) correlates with disease severity. Objectives To investigate the relationship between obesity and psoriasis, focusing on the role of adipokines such as leptin and resistin. PATIENTS/METHODS: Patients with psoriasis (n = 30) were recruited and their BMI, waist circumference and disease severity [Psoriasis Area and Severity Index (PASI)] were recorded. Fasting serum samples were obtained on enrolment and after a course of ultraviolet (UV) B treatment. Age-, sex- and BMI-matched healthy controls were also recruited. RESULTS: On enrolment, serum leptin and soluble leptin receptor levels were not raised compared with the controls. However, resistin, interleukin (IL)-1beta, IL-6, and chemokines CCL2, CXCL8 and CXCL9 were all significantly elevated in the patient group and serum resistin correlated with disease severity (r = 0.372, P = 0.043). Improvement after UVB treatment was accompanied by decreased serum CXCL8. In vitro, both leptin and resistin could induce CXCL8 and tumour necrosis factor-alpha production by blood monocytes, and leptin could additionally induce IL-1beta and IL-1 receptor antagonist production. Leptin also dose dependently increased secretion of the growth factor amphiregulin by ex vivo-cultured lesional psoriasis skin. CONCLUSIONS: These data support the view that leptin and resistin may be involved in the pathogenesis of psoriasis in overweight individuals, possibly by augmenting the cytokine expression by the inflammatory infiltrate.
Assuntos
Mediadores da Inflamação/sangue , Leptina/sangue , Obesidade/complicações , Psoríase/etiologia , Resistina/sangue , Adipocinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfirregulina , Constituição Corporal , Índice de Massa Corporal , Doença Crônica , Citocinas/biossíntese , Citocinas/sangue , Regulação para Baixo , Família de Proteínas EGF , Feminino , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Leptina/farmacologia , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Psoríase/metabolismo , Psoríase/radioterapia , Receptores para Leptina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/metabolismo , Técnicas de Cultura de Tecidos , Terapia UltravioletaRESUMO
Deficiency of both mannan-binding lectin (MBL) and complement components C4 and C2 has been associated with increased risk of systemic lupus erythematosus (SLE). MBL can activate the complement system either through C4 and C2 or directly through C3. Circulating immune complexes (CICs) are believed to play a pathogenic role in SLE and MBL has been shown to bind certain forms of immunoglobulins, including IgM, IgG and IgA. Thus, MBL might promote CIC clearance. In order to evaluate this, six individuals with non-functional classical pathway due to the rare homozygous C2 deficiency were chosen, as the classical pathway is known to have a fundamental role in CIC clearance. Four of the six C2-deficient individuals had SLE, two of whom also had MBL deficiency. MBL serum levels and genotypes were compared with the serum levels of CICs, as measured by their content of kappa, lambda, IgM, IgA, IgG and C3 opsonization. The C2-deficient individuals had higher serum levels of CICs than 16 healthy controls (P < 0.0001). Furthermore, an inverse association was observed between MBL and CIC levels in the C2-deficient individuals, which was strongest for IgM-CICs (r = - 0.84, P = 0.037). Moreover, C3 opsonization of the CICs correlated positively with MBL levels in the C2-deficient individuals (r = 0.89, P = 0.017). In conclusion, individuals with C2 deficiency have increased levels of CICs and MBL may facilitate their clearance. Defective CIC clearance might partly explain the increased risk of SLE associated with low MBL.
Assuntos
Complexo Antígeno-Anticorpo/sangue , Complemento C2/deficiência , Lúpus Eritematoso Sistêmico/imunologia , Lectina de Ligação a Manose/sangue , Via Clássica do Complemento , Ensaio de Imunoadsorção Enzimática/métodos , Genótipo , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lúpus Eritematoso Sistêmico/genéticaRESUMO
OBJECTIVE: To study the effect of tobacco smoking and rheumatoid factor (RF) isotypes on disease activity and joint damage in early rheumatoid arthritis (RA). METHODS: One hundred early RA patients were followed prospectively for 2 yr. They were evaluated at recruitment and at 6 and 24 months. Sociodemographic information included smoking history, and radiographs of hands and feet were obtained. RF was monitored by IgM- and IgA-specific RF enzyme-linked immunosorbent assay and by agglutination, and serial measurements were also obtained for C-reactive protein. The influence of tobacco smoking and RF positivity on disease outcome was evaluated using multivariate analysis. Covariates for the regression analysis included sex, age, coffee consumption and IgA-RF positivity. RESULTS: A gradient of increase in disease activity was observed from never smokers to former smokers to current smokers during the 2 yr of observation, defined by number of swollen joints (SJC), tender joints (TJC) and visual analogue scale for pain (P<0.001, P=0.02 and P=0.005, respectively), but smoking status did not influence radiological progression. Ever smokers were more often IgA RF positive (P<0.05). IgA RF-positive patients had more active disease (SJC P=0.002, TJC P=0.01) and showed more radiological progression (P<0.0001) compared with IgA RF-negative patients. Of the RF-positive patients 22% had elevated IgM RF without IgA RF and these patients showed similar disease activity and radiological joint progression to the RF-negative patients. None of these associations were explained by possible confounders. CONCLUSION: Tobacco smoking has an adverse effect on patients with early RA and this is possibly immunologically mediated. IgM RF does not predict poorer prognosis in RA unless it is associated with a concomitant elevation of IgA RF.
Assuntos
Artrite Reumatoide/patologia , Fator Reumatoide/sangue , Fumar/efeitos adversos , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Progressão da Doença , Métodos Epidemiológicos , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Medição da Dor , Prognóstico , Radiografia , Fator Reumatoide/imunologia , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To determine whether low mannan-binding lectin (MBL) and C4A null alleles (C4AQ0) are associated with systemic lupus erythematosus (SLE) in multicase families with SLE. METHODS: Low MBL level was determined by measuring serum levels and by genotyping for mutant structural (B/C/D, designated as 0) and promoter (LX) alleles (by real-time polymerase chain reaction). C4AQ0 was detected by protein electrophoresis and corroborated with haplotype and genotype analysis. In nine Icelandic families, 24 patients with SLE were compared with 83 first-degree and 23 second-degree relatives without SLE. Twenty four unrelated family members and a population group of 330 Icelanders served as controls. RESULTS: Overall, the frequency of low MBL genotypes (0/0, LX/0 and wild-type/0) tended to be higher in patients with SLE than in their first-degree and second-degree relatives (p = 0.06), but the frequency was similar in the families and in the controls (p = 0.6). The frequency of C4AQ0 was, however, increased in patients and their relatives compared with that in the controls (p = 0.04). The combination of low MBL genotypes and C4AQ0 was found more often in the patients than in their relatives (p = 0.03) and controls (p = 0.02). However, low MBL level was observed only in patients and first-degree relatives in five of the nine multicase families. In these five families, patients with SLE had low MBL genotypes more often (64%) than their first-degree (38%) and second-degree (0%) relatives (p = 0.001), and the patients with SLE also had, accordingly, lower MBL levels than their relatives (p = 0.001). CONCLUSIONS: These findings indicate that low MBL levels can predispose people to SLE and highlight the genetic heterogeneity of this disease.
Assuntos
Complemento C4a/genética , Lúpus Eritematoso Sistêmico/genética , Lectina de Ligação a Manose/genética , Adulto , Complemento C4a/análise , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Lectina de Ligação a Manose/sangue , Pessoa de Meia-IdadeRESUMO
Respiratory tract infections, allergies and otitis media are common problems in early childhood. Our aim was to evaluate in a longitudinal community-based cohort study the association between maturation of immunoglobulin (Ig) and mannan-binding lectin (MBL) responses and disease manifestations in the first 4 years of life. Sustained low levels of IgA proved the strongest single indicator of susceptibility for recurrent otitis media (P = 0.008) and respiratory tract infections (P = 0.02), and this condition was also associated with low production of IgG subclasses. About 7% of the cohort had sustained low levels of MBL (<0.4 mg/l). Low MBL did not predispose to any ailments studied, but children with low IgA and recurrent otitis media had relatively low MBL at birth, which failed to increase during the study period and was significantly reduced at the age of 4 years (P = 0.04). MBL levels increased from birth to 2 years (P < 0.0001) and were higher in children than in adults (P = 0.001). The increase was 1.9-fold in children with no recorded clinical events and 1.7-fold in children with asthma or infections, but significantly lower, 1.2-fold, in children with recurrent otitis media. Low levels of IgA within the normal range may reveal disease susceptibility not detected by conventional criteria. Slow maturation of Ig appears to be the main factor of susceptibility during childhood, but a strong corollary role for MBL is indicated by the high levels produced during childhood as well as the precipitation of disease in children with low levels of MBL and Ig.
Assuntos
Hipersensibilidade/imunologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Lectina de Ligação a Manose/sangue , Otite Média/sangue , Infecções Respiratórias/sangue , Adulto , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/patologia , Imunoglobulina G/imunologia , Lactente , Masculino , Otite Média/patologia , Recidiva , Infecções Respiratórias/patologiaRESUMO
BACKGROUND: We have previously reported an association between low IgA and allergic manifestations in early childhood (0-2 years) and have now followed our cohort for an additional 2 years. OBJECTIVE: To evaluate in a longitudinal community-based cohort study the association between maturation of Ig production and allergic manifestations in the first 4 years of life. METHODS: A cohort of 161 randomly selected children was followed from birth to the age of 42-48 months and evaluated at 18-23 months (EV1; n = 179) and again at the age of 42-48 months (EV2; n = 161). Diagnoses were made with the help of a clinical questionnaire, physical examination and skin prick tests (SPTs) to 10 common allergens. Serum immunoglobulins were measured at EV1 and EV2, and salivary IgA (sal-IgA) at EV2. RESULTS: Serum IgA, IgE, IgG1, IgG2 and IgG4 increased from 2 to 4 years of age (P < 0.001) and their levels showed close correlations (P < or = 0.01 for most comparisons). Children with one or more positive SPTs had lower serum IgA (P = 0.004) and IgG4 (P = 0.05) at EV2 than those who did not respond, and children who developed allergic rhinitis between EV1 and EV2 had low sal-IgA (P = 0.006) and IgG3 (P < 0.05) at EV2. Atopic eczema was associated with low sal-IgA at EV2, and children who developed eczema between EV1 and EV2 had significantly lower sal-IgA than those who recovered after EV1 (P = 0.02). CONCLUSION: Allergic manifestations in predisposed children may be influenced by the rate of maturation of immunological components that counteract sensitization or inhibit effector mechanisms of allergy.
Assuntos
Asma/imunologia , Hipersensibilidade/sangue , Imunoglobulina A/análise , Saliva/imunologia , Pré-Escolar , Dermatite Atópica/imunologia , Seguimentos , Humanos , Imunoglobulina A/sangue , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Recém-Nascido , Rinite Alérgica Sazonal/imunologia , Testes Cutâneos , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The association of psoriasis with Streptococcus pyogenes throat infections suggests a potential antigenic target for the T cells that are known to infiltrate psoriatic skin. Streptococcal M protein share an extensive sequence homology with the human epidermal keratins. Keratin 17 (K17), while being mostly absent from uninvolved skin, is up-regulated in psoriatic lesions. Consequentially, M-protein-primed T cells may recognize up-regulated keratin epitopes via molecular mimicry. Using in vitro lymphocyte culture and cytokine flow cytometry we demonstrate that HLA-Cw*0602(+) psoriasis patients had significant CD8(+) T cell interferon (IFN)-gamma responses to peptides from the K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. These responses were about 10 times more frequent in the skin-homing cutaneous lymphocyte-associated antigen-expressing (CLA(+)) subset of CD8(+) T cells. CD4(+) T cells showed only borderline responses. CLA(+) CD8(+) T cells from Cw6(+) non-psoriatic individuals responded to some M6 peptides but rarely to K17 peptides. Cw6(-) psoriasis patients showed a response that was intermediate between Cw6(+) patients and controls. These findings indicate that psoriatic individuals have CD8(+) T cells that recognize keratin self-antigens and that epitopes shared by streptococcal M proteins and human keratins may be targets for the CD8(+) T cells that infiltrate psoriatic skin lesions.
Assuntos
Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/imunologia , Queratinas/imunologia , Psoríase/imunologia , Pele/imunologia , Antígenos de Diferenciação de Linfócitos T , Antígenos de Neoplasias , Linfócitos T CD4-Positivos/imunologia , Feminino , Antígenos HLA-C/imunologia , Humanos , Interferon gama/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Peptídeos/imunologia , Receptores de Retorno de Linfócitos/imunologia , Homologia de Sequência de Aminoácidos , Streptococcus pyogenes/imunologiaRESUMO
Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It recognizes certain sugar residues arranged in a pattern that enables MBL to bind with sufficient strength. Such sugar patterns are common on the surface of many microorganisms, and MBL has therefore been considered to be an agent that can discriminate between self and nonself. There is, however, increasing evidence supporting that MBL, like many membrane-bound C-type lectin-like receptors, also helps to dispose of various outworn or abnormal body components. Most self-components are protected with sialic acid or galactose that disrupt the pattern of the sugars that MBL can bind, but MBL may be significantly involved in the elimination of self-components that have lost these protective terminal residues. The role of MBL in the clearance of invading pathogens has previously been thoroughly reviewed. Here, we review some findings that support the notion that MBL may contribute to noninflammatory removal of immune complexes and abnormal cells by the reticuloendothelial system. Defects in this clearance mechanism may cause an accumulation of potentially dangerous self-components, thereby increasing the likelihood of chronic inflammation and autoimmunity.
Assuntos
Complexo Antígeno-Anticorpo/imunologia , Lectina de Ligação a Manose da Via do Complemento/imunologia , Lectina de Ligação a Manose/imunologia , Animais , Autoantígenos/imunologia , Carboidratos/imunologia , HumanosRESUMO
OBJECTIVE: A functional deficiency of complement has been implicated but not conclusively demonstrated in the pathogenesis of systemic lupus erythematosus (SLE). To test this, we studied several aspects of complement in 44 patients with SLE, 46 patients with rheumatoid arthritis and 102 blood donors. METHODS: Prevention of immune precipitation (PIP) was measured by an enzyme immunoassay, levels of C1q, C4 and C3 by rocket immunoelectrophoresis, C4A, C4B and C3d by enzyme-linked immunosorbent assay (ELISA), complement haemolysis (CH50) by standard methods and C4 allotypes by high-voltage agarose electrophoresis and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS: PIP was significantly reduced in SLE (P<0.001); the defect was revealed by a sensitive assay measuring this function of complement but not by the other tests employed. The patients were clinically well at the time of study, and levels of C3d, which have been shown to correlate with disease activity, were normal. The defect was more common in patients with early disease (P = 0.009), supporting a role in aetiology or early pathophysiology. PIP was positively correlated with levels of C4 (P = 3 x 10(-5)) and in particular the C4A isotype (P = 9 x 10(-10)) whereas C4B was redundant. CONCLUSIONS: Our results reveal a defect in prevention of immune precipitation in SLE that is apparent at an early stage in the disease and correlates with low levels of C4A. These results indicate that subtle deficiencies of complement may predispose to SLE.
Assuntos
Complexo Antígeno-Anticorpo/sangue , Doenças Autoimunes/imunologia , Proteínas do Sistema Complemento/análise , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/imunologia , Complemento C4a/deficiência , Ensaio de Atividade Hemolítica de Complemento , Proteínas do Sistema Complemento/imunologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Mannose-binding lectin (MBL) is an important component of innate immunity that can bind to certain sugar residues on the surface of many types of pathogenic micro-organisms. On binding, MBL generates opsonic activity mainly through activation of the complement system. Genetically determined MBL deficiency is very common and can be associated with increased susceptibility to a variety of infections, especially in children and immunosuppressed individuals. The potential benefits of MBL reconstitution therapy therefore need to be evaluated. We have carried out a phase I safety and pharmacokinetic study on 20 MBL-deficient healthy adult volunteers. The MBL was prepared from plasma of nonremunerated, voluntary Danish donors tested and found negative for hepatitis B surface antigen, antibodies to human immunodeficiency virus (HIV) and hepatitis C virus. Each volunteer received a total of 18 mg of MBL in three 6 mg doses given intravenously, once weekly over a period of 3 weeks. The volunteers were closely monitored at the University Hospital in Reykjavik for 8 h after each infusion and daily thereafter for 5 days after each infusion. No adverse clinical or laboratory changes were observed in any of the 20 participants, and frequent measurements did not reveal any signs of infusion-associated complement activation. No antibodies to MBL, HIV or hepatitis viruses were observed 24 weeks after the last infusion. Serum MBL levels increased up to normal levels (1200-4500 ng/ml) immediately after each infusion, but the half-life of the infused MBL was highly variable, ranging from 18 to 115 h (mean 69.6). It is concluded that infusion of purified MBL as prepared by Statens Serum Institut (SSI) is safe. However, adults have to be given at least 6 mg twice or thrice weekly for maintaining protective MBL levels assumed to be about 1000 ng/ml.
Assuntos
Síndromes de Imunodeficiência/terapia , Lectina de Ligação a Manose/farmacologia , Adolescente , Adulto , Humanos , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/deficiência , Pessoa de Meia-IdadeRESUMO
Psoriasis is a common autoimmune skin disease characterized by T cell-mediated hyperproliferation of keratinocytes. The disease has a strong but complex genetic background with a concordance of approximately 60% in monozygotic twins, and recent linkage and high resolution association studies indicate that HLA-Cw*0602 is itself a major susceptibility allele for psoriasis. Patients carrying this allele have been shown to have different clinical features and earlier age of disease onset, and patients homozygous for this allele have about 2.5 times higher disease risk than heterozygotes. Published data indicate that CD8+ T cells may play a major effector role in psoriasis. Epidermal infiltration of predominantly oligoclonal CD8+ T cells, and probably also of CD4+ T cells in the dermis, is a striking feature of chronic psoriasis lesions, indicating that these cells are responding to specific antigens. We argue that CD4+ T cells are essential for initiating and maintaining the pathogenic process of psoriasis but that cross-primed CD8+ T cells are the main effector cells responding to antigens in the HLA-Cw*0602 binding pocket of keratinocytes. It is further proposed that CD8+ T cells are involved in the control of the Th1 polarization, which is observed in psoriasis lesions, through a complex interplay between CD4+, CD8+ T cells and cross-presenting dendritic cells. It is also suggested that spontaneous remissions or fluctuations in disease activity may be determined by a balance within the lesions between effector and suppressor CD4+ and CD8+ T cells.
Assuntos
Psoríase/imunologia , Subpopulações de Linfócitos T/imunologia , Doenças Autoimunes/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Citocinas/imunologia , Antígenos HLA-C/imunologia , Humanos , Células Th1/imunologiaRESUMO
BACKGROUND: Guttate psoriasis has a well-known association with streptococcal throat infections but the effects of these infections in patients with chronic psoriasis remains to be evaluated in a prospective study. OBJECTIVES: To determine whether streptococcal throat infections are more common in and can cause exacerbation in patients with chronic psoriasis. METHODS: Two hundred and eight patients with chronic plaque psoriasis and 116 unrelated age-matched household controls were followed for 1 year. At recruitment all patients were examined, their disease severity scored and throat swabs taken. Patients and corresponding controls were then re-examined and tested for streptococcal colonization whenever they reported sore throat or exacerbation of their psoriasis during the study period. RESULTS: The psoriasis patients reported sore throat significantly more often than controls (61 of 208 vs. three of 116, P < 0.0001), and beta-haemolytic streptococci of Lancefield groups A, C and G (M protein-positive streptococci) were more often cultured from the patients than the controls (19 of 208 vs. one of 116, P = 0.003). A significant exacerbation of psoriasis (P = 0.004) was observed only if streptococci were isolated and the patients were assessed 4 days or later after the onset of sore throat. No difference was observed between groups A, C or G streptococci in this respect. CONCLUSIONS: This study confirms anecdotal and retrospective reports that streptococcal throat infections can cause exacerbation of chronic plaque psoriasis. It is concluded that psoriasis patients should be encouraged to report sore throat to their physician and that early treatment of streptococcal throat infections might be beneficial in psoriasis. A controlled trial for assessing potential benefits of tonsillectomy in patients with severe psoriasis should also be considered.
Assuntos
Faringite/microbiologia , Psoríase/microbiologia , Infecções Estreptocócicas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Doença Crônica , Humanos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Our first experience of mannan-binding lectin (MBL)-replacement therapy was with a patient experiencing recurrent erythema multiforme associated with reactivation of herpes simplex virus; his erythematous eruptions could be controlled with infusions of fresh frozen plasma containing MBL, but not with plasma lacking MBL. Some years later, we treated a young girl with recurrent, debilitating infections with purified MBL; this was also followed by a dramatic clinical improvement. We have now carried out a phase I clinical trial on 20 MBL-deficient, but healthy, adult volunteers. The MBL was prepared by the State Serum Institute in Copenhagen, Denmark, from blood donor plasma. Each volunteer received a total of 18 mg of MBL in three 6-mg doses given intravenously once a week over 3 weeks. The volunteers were monitored closely after each infusion and no adverse clinical or laboratory effects were observed. Laboratory parameters included C-reactive protein, various complement components, and antibodies to MBL, HIV and hepatitis viruses. C3a (the anaphylotoxin derived from complement component C3) was monitored for signs of complement activation, but no significant infusion-associated fluctuations were observed. Serum levels of MBL after each 6-mg infusion ranged between 1200 and 2500 ng/ml. The half-life of the infused MBL was about 70 h, or 3 days. It was concluded that infusion of purified MBL manufactured by the Danish State Serum Institute is a safe procedure. However, adults may have to be given 6 mg or more at least twice weekly to maintain protective plasma MBL levels in MBL-deficient individuals.
Assuntos
Lectina de Ligação a Manose/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Lectina de Ligação a Manose/efeitos adversos , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/deficiênciaRESUMO
BACKGROUND: T lymphocytes are believed to play a role in the pathogenesis of psoriasis; > 80% of T lymphocytes that infiltrate psoriatic lesions express the surface glycoprotein cutaneous lymphocyte-associated antigen (CLA), compared with < 20% in the blood. Exposure to ultraviolet (UV) B is an effective treatment for psoriasis. OBJECTIVES: To compare the effects of UVB treatment of psoriasis on the expression of CLA and several other surface markers expressed by circulating T lymphocytes. METHODS: Peripheral blood mononuclear cells from psoriatic patients were stained for adhesion molecules and stimulated with streptococcal antigens before and once weekly during 3 weeks of UVB treatment. RESULTS: A marked and progressive decrease was observed during the treatment in expression of the CLA and the very late antigen-4alpha by T cells; this decrease correlated closely with clinical improvement (Psoriasis Area and Severity Index). T-cell expression of intercellular adhesion molecule-1 was not significantly affected during the treatment and no change was observed in the activation markers CD25 and CD69 or lymphocyte proliferation after stimulation with streptococcal antigens or superantigens. CONCLUSIONS: UVB treatment is associated with a marked reduction in the expression of skin-homing molecules by circulating T cells. This may be relevant to the therapeutic effect of UVB in psoriasis.