RESUMO
Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti-PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene-knockout (Pdcd1-/-) mice. Histopathologic analysis showed that Pdcd1-/- mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3+ T cells and only a small proportion of CD19+ B cells. Among infiltrating T cells, the CD4+ Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1-/- mice. Experiments of lymphocyte transfer from Pdcd1-/- into irradiated wild-type mice confirmed that CD4+ T cells from Pdcd1-/- mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4+ Th1 cells.
Assuntos
Doenças Autoimunes/imunologia , Dacriocistite/imunologia , Dacriocistite/metabolismo , Receptor de Morte Celular Programada 1/deficiência , Células Th1/imunologia , Animais , Doenças Autoimunes/metabolismo , Autoimunidade/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/imunologia , Síndrome de Sjogren/imunologiaRESUMO
OBJECTIVES: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. METHODS: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. RESULTS: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. CONCLUSIONS: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.
Assuntos
Autoanticorpos/imunologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Idoso , Anticorpos Antiproteína Citrulinada/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Antinucleares/imunologia , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/imunologia , Doenças da Aorta/diagnóstico , Doenças da Aorta/imunologia , Aortite/diagnóstico , Aortite/imunologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/imunologia , Dacriocistite/diagnóstico , Dacriocistite/imunologia , Diagnóstico Diferencial , Reações Falso-Negativas , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/imunologia , Nefropatias/diagnóstico , Nefropatias/imunologia , Linfoma/diagnóstico , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/imunologia , Pancreatopatias/diagnóstico , Pancreatopatias/imunologia , Pancreatite/diagnóstico , Pancreatite/imunologia , Estudos Retrospectivos , Doenças das Glândulas Salivares/diagnóstico , Doenças das Glândulas Salivares/imunologia , Sarcoidose/diagnóstico , Sarcoidose/imunologia , Sialadenite/diagnóstico , Sialadenite/imunologiaRESUMO
Purpose: To identify the differential expression of microRNAs (miRs) and the related gene networks and signal pathways in lacrimal glands (LGs) of rabbit autoimmune dacryoadenitis. Methods: Autoimmune dacryoadenitis in rabbits was induced by transferring activated peripheral blood lymphocytes (PBLs). The LGs of normal and model group rabbits were collected for small RNA sequencing. The most differentially expressed miRs were validated by quantitative real time-polymerase chain reaction (qRT-PCR). Further, bioinformatics analysis including target gene prediction, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Results: A total of 15 miRs were differentially expressed in the LGs of rabbit autoimmune dacryoadenitis relative to normal controls. GO and KEGG analysis revealed that most target genes of these dysregulated miRs were implicated in MAPK signaling pathway. Conclusion: Our results showed for the first time the differentially expressed miRs and the related pathways involved in the pathogenesis of rabbit autoimmune dacryoadenitis. These results may contribute to elucidating molecular pathogenesis of Sjögren's syndrome (SS) dry eye.
Assuntos
Dacriocistite/genética , Regulação da Expressão Gênica/imunologia , Aparelho Lacrimal/imunologia , MicroRNAs/metabolismo , Síndrome de Sjogren/genética , Animais , Dacriocistite/imunologia , Dacriocistite/patologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Aparelho Lacrimal/patologia , Coelhos , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologiaRESUMO
Mesenchymal stem cells (MSCs) exhibit beneficial effects on autoimmune dacryoadenitis. However, the underlying mechanisms are not fully understood. In this study, we investigated the therapeutic effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on rabbit autoimmune dacryoadenitis, an animal model of Sjögren's syndrome (SS) dry eye, and explored whether the effects of MSCs were related to their modulation on macrophage polarization. We have showed that systemic infusion of hUC-MSCs after disease onset efficiently diminished the chronic inflammation in diseased LGs and improved the clinical symptoms. Further analysis revealed that hUC-MSC treatment significantly inhibited the expression of pro-inflammatory M1 macrophage markers iNOS, TNF-α and IL-6, and promoted the expression of anti-inflammatory M2 macrophage markers Arg1, CD206, IL-10, IL-4 and TGF-ß in LGs. Mechanistically, hUC-MSCs activated AKT pathway in macrophages, resulting in upregulation of M2-associated molecule Arg1, which was partly abolished by PI3K inhibitor, LY294002. Together, our data indicated that hUC-MSCs can skew macrophages into an M2 phenotype via affecting AKT pathway. These data may provide a new insight into the mechanisms of hUC-MSCs in the therapy of SS dry eye.
Assuntos
Anti-Inflamatórios/metabolismo , Doenças Autoimunes/prevenção & controle , Dacriocistite/prevenção & controle , Macrófagos/imunologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Cordão Umbilical/citologia , Animais , Doenças Autoimunes/imunologia , Western Blotting , Técnicas de Cultura de Células , Dacriocistite/imunologia , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Ativação de Macrófagos , Fenótipo , Coelhos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
A 73-year-old woman with a history of muscular weakness and dyspnoea of unknown etiology was referred to our Ophthalmology Department for dacryocystitis. Lacrimal sac biopsy revealed IgG4 plasma cell infiltration and systemic diagnosis was done based on this, allowing an appropriate treatment to be established. To our knowledge, this is the first reported case of IgG4-related dacryocystitis associated to aortitis.
Assuntos
Aortite/imunologia , Dacriocistite/imunologia , Imunoglobulina G/sangue , Aparelho Lacrimal/patologia , Idoso , Feminino , HumanosRESUMO
Herpes stromal keratitis (HSK) is a chronic immunoinflammatory condition which develops in response to recurrent herpes simplex virus-1 (HSV-1) infection of the cornea. Patients with HSK often demonstrate the concurrence of corneal desiccation and the loss of blink reflex. However, the relationship between severity of HSK, level of basal tears and inflammation of the lacrimal gland is mostly unexplored. In this study, we compared these variables in extraorbital lacrimal gland (EoLG) after corneal HSV-1 infection in the C57BL/6J mouse model. Our results showed a significant reduction in the volume of tears in infected eyes during the development of HSK. Extensive architectural damage to EoLG, presumably caused by a massive influx of interferon-gamma secreting T cells, was observed during clinical disease period of HSK. A positive correlation between the decrease in tear volume, severity of HSK and the damage to EoLG were evident in infected mice. The presence of infectious virus measured in EoLG during pre-clinical, but not clinical disease period of HSK, suggested that viral cytopathic effects are not the major contributors of extensive damage seen in EoLG. Furthermore, topical administration of lacritin peptide delayed but did not prevent the decrease in tears in HSV-1 infected mice, and had no significant effect in either reducing the severity of HSK or T cell infiltration in EoLG of infected mice. Together, our results showed an interplay between the severity of HSK, inflammation of EoLG, and the reduced level of tears after corneal HSV-1 infection.
Assuntos
Substância Própria/patologia , Dacriocistite/fisiopatologia , Modelos Animais de Doenças , Ceratite Herpética/fisiopatologia , Animais , Linfócitos T CD4-Positivos/imunologia , Dacriocistite/tratamento farmacológico , Dacriocistite/imunologia , Dacriocistite/virologia , Feminino , Glicoproteínas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/virologia , Ceratite Herpética/tratamento farmacológico , Ceratite Herpética/imunologia , Ceratite Herpética/virologia , Camundongos , Camundongos Endogâmicos C57BL , Lágrimas/metabolismoRESUMO
Objectives: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is often complicated by allergic disorders. This study was conducted to investigate the mechanism of type 2 helper T-inflammation (Th2-inflammation) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS). Methods: We separated and analyzed the proportion of growth stimulation expressed gene 2 (ST2)+ memory Th2 cells among the peripheral blood mononuclear cells by flow cytometry in cases with IgG4-DS and healthy individuals. Finally, we identified the role of ST2+ memory Th2 cells in the involved tissues. Results: The proportion of circulating ST2+ memory Th2 cells was much higher in the patients with IgG4-DS than in the healthy controls. Abundant infiltration of ST2+ memory Th2 cells was detected in the involved salivary glands and lymph nodes, and these cells produced interleukin-5. Conclusion: We demonstrated that there is an increase of interleukin-5 producing ST2+ memory Th2 cells in the involved tissues in IgG4-DS. This subset of cells is considered to be an important player in inducing the inflammatory Th2 environment characteristic of IgG4-DS.
Assuntos
Dacriocistite/sangue , Imunoglobulina G/imunologia , Sialadenite/sangue , Células Th2/imunologia , Idoso , Dacriocistite/imunologia , Feminino , Humanos , Interleucina-5/sangue , Masculino , Sialadenite/imunologiaAssuntos
Dacriocistite/tratamento farmacológico , Glucocorticoides/efeitos adversos , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Prednisolona/efeitos adversos , Sialadenite/tratamento farmacológico , Idoso , Dacriocistite/imunologia , Progressão da Doença , Feminino , Glucocorticoides/uso terapêutico , Humanos , Doença Relacionada a Imunoglobulina G4/imunologia , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Sialadenite/imunologia , Resultado do TratamentoRESUMO
CASE REPORT: The case is presented of a 64-year-old woman with bilateral palpebral swelling and dacryoadenitis, exophthalmos, and a history of chronic rhinitis and asthma. An increase in serum IgG4 was observed, and an incisional biopsy of lacrimal glands was performed, which showed fibrosis and a lymphoplasmacytic infiltrate with IgG4 producing cells. DISCUSSION: Orbital involvement in IgG4-related disease is frequent. Bilateral dacryoadenitis is the most common manifestation. Histopathology is essential for the diagnosis and to exclude malignancy.
Assuntos
Dacriocistite/etiologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doenças Orbitárias/diagnóstico , Asma/complicações , Biópsia , Dacriocistite/imunologia , Dacriocistite/patologia , Diagnóstico Diferencial , Exoftalmia/etiologia , Feminino , Fibrose , Humanos , Doença Relacionada a Imunoglobulina G4/complicações , Doença Relacionada a Imunoglobulina G4/patologia , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/patologia , Pessoa de Meia-Idade , Doenças Orbitárias/complicações , Doenças Orbitárias/imunologia , Doenças Orbitárias/patologia , Neoplasias Orbitárias/diagnóstico , Plasmócitos/patologia , Rinite/complicações , Glândulas Salivares Menores/patologia , Xeroftalmia/complicaçõesRESUMO
CD25 knock-out (CD25KO) mice spontaneously develop Sjögren Syndrome (SS)-like inflammation. We investigated the role of commensal bacteria by comparing CD25KO mice housed in conventional or germ-free conditions. Germ-free CD25KO mice have greater corneal barrier dysfunction, lower goblet cell density, increased total lymphocytic infiltration score, increased expression of IFN-γ, IL-12 and higher a frequency of CD4+IFN-γ+ cells than conventional mice. CD4+ T cells isolated from female germ-free CD25KO mice adoptively transferred to naive immunodeficient RAG1KO recipients caused more severe Sjögren-like disease than CD4+ T cells transferred from conventional CD25KO mice. Fecal transplant in germ-free CD25KO mice reversed the spontaneous dry eye phenotype and decreased the generation of pathogenic CD4+IFN-γ+ cells. Our studies indicate that lack of commensal bacteria accelerates the onset and severity of dacryoadenitis and generates autoreactive CD4+T cells with greater pathogenicity in the CD25KO model, suggesting that the commensal bacteria or their metabolites products have immunoregulatory properties that protect exocrine glands in the CD25KO SS model.
Assuntos
Córnea/imunologia , Dacriocistite/microbiologia , Proteínas de Homeodomínio/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Aparelho Lacrimal/imunologia , Síndrome de Sjogren/microbiologia , Simbiose/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Córnea/patologia , Dacriocistite/genética , Dacriocistite/imunologia , Dacriocistite/patologia , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Vida Livre de Germes , Células Caliciformes/imunologia , Células Caliciformes/patologia , Proteínas de Homeodomínio/genética , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Subunidade alfa de Receptor de Interleucina-2/deficiência , Subunidade alfa de Receptor de Interleucina-2/genética , Aparelho Lacrimal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologiaRESUMO
OBJECTIVES: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution. METHODS: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed. RESULTS: Both serum IL-5 and IFN-α concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group. CONCLUSION: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD.
Assuntos
Dacriocistite , Imunoglobulina G/sangue , Interferon-alfa/sangue , Interleucina-5/sangue , Sialadenite , Idoso , Dacriocistite/sangue , Dacriocistite/classificação , Dacriocistite/diagnóstico , Dacriocistite/imunologia , Feminino , Humanos , Testes Imunológicos/métodos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Administração dos Cuidados ao Paciente/métodos , Prognóstico , Glândulas Salivares/imunologia , Sialadenite/sangue , Sialadenite/diagnóstico , Sialadenite/imunologia , Sialadenite/terapia , Fator de Necrose Tumoral alfa/sangueRESUMO
Dry eye disease (DED) is a common, multifactorial ocular condition with major impact on vision and quality of life. It is now well recognized that the pathophysiology of chronic DED can include a cycle of inflammation involving both innate and adaptive immune responses. Recently, in vitro/in vivo models have been used to obtain a better understanding of DED-related inflammatory processes at molecular/cellular levels although they do not truly reproduce the complex and chronic hallmarks of human DED. In clinical DED research, advanced techniques such as impression cytology, conjunctival biopsy, in vivo confocal microscopy and multiplex tear analyses have allowed an improved assessment of inflammation in DED patients. This was supported by the identification of reliable inflammatory markers including matrix metalloproteinase-9, human leucocyte antigen-DR or intercellular adhesion molecule-1 in tears and impression cytology samples. One of the current therapeutic strategies focuses on breaking the inflammatory cycle perpetuating the ocular surface disease, and preclinical/clinical research has led to the development of promising anti-inflammatory compounds. For instance, cyclosporine, already approved in the United States, has recently been authorized in Europe to treat DED associated with severe keratitis. In addition, other agents such as corticosteroids, doxycycline and essential fatty acids, through their anti-inflammatory properties, show encouraging results. We now have a clearer understanding of the inflammatory processes involved in DED, and there is hope that the still emerging preclinical/clinical findings will be translated into new and highly effective therapies for patients in the near future.
Assuntos
Síndromes do Olho Seco/fisiopatologia , Inflamação/fisiopatologia , Animais , Biomarcadores/metabolismo , Congressos como Assunto , Conjuntivite/imunologia , Conjuntivite/fisiopatologia , Dacriocistite/imunologia , Dacriocistite/fisiopatologia , Síndromes do Olho Seco/imunologia , Humanos , Inflamação/imunologia , Ceratite/imunologia , Ceratite/fisiopatologiaRESUMO
PURPOSE OF REVIEW: IgG4-related disease is a multi-organ fibro-inflammatory disease with characteristic histopathology showing lymphoplasmacytic infiltration, increased IgG4+ plasma cells and elevated IgG4/IgG ratios (>40%). The lacrimal gland is the most common ocular site of involvement. Scleritis and intraocular involvement in IgG4-related ophthalmic disease (IgG4-ROD) have recently been reported. The purpose of this review is to describe orbital and intraocular IgG4-ROD with a focus on publications since 2016. RECENT FINDINGS: Case reports of scleritis and uveitis in IgG4-ROD have been described since 2012. Systemic prednisone is recommended as the first-line treatment, but immunosuppressive therapy may be required for steroid-sparing or in steroid-resistant cases. High rates of systemic IgG4-RD involvement exist in patients with bilateral IgG4-ROD or if the lacrimal gland is involved. Rituximab is the most specific immune targeted therapy available with high rates of remission. SUMMARY: IgG4-ROD is an emerging cause of scleritis and uveitis and should be considered in any patient with multisystem inflammatory disease. New targeted immune therapies may improve outcomes and lead to clinical remission.
Assuntos
Oftalmopatias/imunologia , Imunoglobulina G , Paraproteinemias/imunologia , Dacriocistite/diagnóstico , Dacriocistite/tratamento farmacológico , Dacriocistite/imunologia , Oftalmopatias/diagnóstico , Oftalmopatias/tratamento farmacológico , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G/imunologia , Imunossupressores/uso terapêutico , Pseudotumor Orbitário/diagnóstico , Pseudotumor Orbitário/tratamento farmacológico , Pseudotumor Orbitário/imunologia , Paraproteinemias/diagnóstico , Paraproteinemias/tratamento farmacológico , Esclerite/diagnóstico , Esclerite/tratamento farmacológico , Esclerite/imunologia , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Uveíte/imunologiaRESUMO
IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1hi circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.
Assuntos
Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Dacriocistite/imunologia , Imunoglobulina G/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Glândula Submandibular/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Movimento Celular , Células Cultivadas , Feminino , Humanos , Imunoglobulina G/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-IdadeRESUMO
The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo.
Assuntos
Tolerância Central/imunologia , Quimiocina CCL21/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Tolerância Central/genética , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Dacriocistite/genética , Dacriocistite/imunologia , Dacriocistite/metabolismo , Citometria de Fluxo , Expressão Gênica/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Camundongos Transgênicos , Microscopia Confocal , Receptores CCR7/imunologia , Receptores CCR7/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tolerância a Antígenos Próprios/genética , Linfócitos T/metabolismo , Timócitos/imunologia , Timócitos/metabolismo , Timo/imunologia , Timo/metabolismoRESUMO
Autoimmune dacryoadenitis, such as Sjögren syndrome, comprises multifactorial and complex diseases. Inflammation of the lacrimal gland plays a key role in the pathogenesis of diseases. Unfortunately, current treatment strategies, including artificial tears, anti-inflammatory drugs, punctual occlusion, and immunosuppressive drugs, are only palliative, and long-term administration of these strategies is associated with adverse effects that limit their utility. Hence, an effective and safe treatment for autoimmune dacryoadenitis is urgently needed. Mesenchymal stem cells (MSCs) have emerged as a promising tool for treating autoimmune dacryoadenitis, owing to their immunosuppressive properties, tissue repair functions, and powerful differentiation capabilities. A large number of studies have focused on the effect of MSCs on autoimmune diseases, such as autoimmune uveitis, inflammatory bowel disease, and collagen-induced arthritis, but few studies have, to date, unequivocally established the efficacy of MSCs for treating autoimmune dacryoadenitis. In this review, we discuss recent advances in MSC treatment for autoimmune dacryoadenitis.
Assuntos
Doenças Autoimunes/terapia , Dacriocistite/terapia , Imunomodulação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Animais , Doenças Autoimunes/imunologia , Diferenciação Celular , Dacriocistite/imunologia , Modelos Animais de Doenças , Cães , Humanos , Terapia de Imunossupressão , Células-Tronco Mesenquimais/citologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/terapiaRESUMO
IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder, characterized by elevated serum IgG4 levels as well as abundant infiltration of IgG4-positive plasmacytes and fibrosis in various organs, including the head and neck region. In particular, the salivary glands, orbit, and thyroid are common sites of disease involvement. IgG4-RD is diagnosed based on various clinical, serological, and histopathological findings, none of which are pathognomonic. Hence, various differential diagnoses, which exhibit elevated serum IgG4 levels and infiltration of IgG4-postive cells into tissues, need to be excluded, especially malignant diseases and mimicking disorders. Systemic corticosteroids are generally effective in inducing IgG4-RD remission; however, recurrent or refractory cases are common. In addition, although the pathogenic mechanisms of IgG4-RD remain unclear, an antigen-driven inflammatory condition is believed to be involved. Recent studies have indicated the important pathogenic role of B cell/T cell collaboration and innate immunity in this disease. Nevertheless, additional research and discussions are needed to resolve many remaining questions. In this review, we provide an overview of the recent insights on the history, clinical features, diagnosis, and treatment of IgG4-RD in the head and neck region. Furthermore, we have also addressed the pathogenesis of this disease.
Assuntos
Doenças Autoimunes/imunologia , Dacriocistite/imunologia , Imunoglobulina G/imunologia , Rinite/imunologia , Sialadenite/imunologia , Sinusite/imunologia , Tireoidite Autoimune/imunologia , Corticosteroides/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Hipofisite Autoimune/tratamento farmacológico , Hipofisite Autoimune/imunologia , Dacriocistite/tratamento farmacológico , Humanos , Linfadenite/tratamento farmacológico , Linfadenite/imunologia , Mastoidite/tratamento farmacológico , Mastoidite/imunologia , Neurite (Inflamação)/tratamento farmacológico , Neurite (Inflamação)/imunologia , Otite/tratamento farmacológico , Otite/imunologia , Rinite/tratamento farmacológico , Sialadenite/tratamento farmacológico , Sinusite/tratamento farmacológico , Tireoidite Autoimune/tratamento farmacológicoRESUMO
OBJECTIVES: IgG4-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown aetiology. We have recently described clonally expanded circulating CD4+ cytotoxic T lymphocytes (CTLs) in IgG4-RD that infiltrate affected tissues where they secrete interleukin (IL)-1ß and transforming growth factor -ß1 (TGF-ß1). In this study, we sought to examine the role of CD4+ CTLs in the pathogenesis of IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and to determine whether these cells secrete interferon-gamma (IFN-γ) at lesional sites. METHODS: Salivary glands of 25 patients with IgG4-DS, 22 patients with Sjögren's syndrome (SS), 12 patients with chronic sialoadenitis (CS) and 12 healthy controls were analysed in this study. Gene expression analysis was performed on submandibular glands (SMGs) from five patients with IgG4-DS, three with CS and three healthy controls. Infiltrating CD4+ CTLs were examined by quantitative multicolour imaging in tissue samples from 20 patients with IgG4-DS, 22 patients with SS, 9 patients with CS and 9 healthy controls. RESULTS: In IgG4-DS tissues, nine genes associated with CD4+ CTLs were overexpressed. The expression of granzyme A (GZMA) mRNA was significantly higher in samples from patients with IgG4-RD compared with corresponding tissues from SS and healthy controls. Quantitative imaging showed that infiltrating CD4+ GZMA+ CTLs were more abundant in patients with IgG4-DS than in the other groups. The ratio of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS correlated with serum IgG4 concentrations and the number of affected organs. A large fraction of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS secreted IFN-γ. CONCLUSIONS: The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4+GZMA+ CTLs that secrete IFN-γ.
Assuntos
Doenças Autoimunes/imunologia , Antígenos CD4/imunologia , Dacriocistite/imunologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , RNA Mensageiro/metabolismo , Sialadenite/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Quimiocina CCL4/genética , Quimiocina CCL5/genética , Dacriocistite/genética , Dacriocistite/metabolismo , Feminino , Imunofluorescência , Perfilação da Expressão Gênica , Granzimas/genética , Humanos , Interferon gama/genética , Masculino , Pessoa de Meia-Idade , Perforina/genética , Sialadenite/genética , Sialadenite/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Glândula Submandibular/metabolismo , Proteínas com Domínio T/genética , Fator de Crescimento Transformador beta1/genética , Fator de Necrose Tumoral alfa/genética , Adulto JovemRESUMO
PURPOSE: To investigate the immunoregulatory roles of adipose-derived mesenchymal stem cells (ADSCs) in autoimmune dacryoadenitis. METHODS: Rabbits were treated with ADSCs or phosphate-buffered solution on days 1, 3, 5, 7, and 9 after injection of activated peripheral blood lymphocytes, and clinical scores were determined by assessing tear production, break-up time, and fluorescein and hematoxylin and eosin staining. Inflammatory response was determined by measuring the expression of different mediators of inflammation in the lacrimal glands. The Th1/Th17-mediated autoreactive responses were evaluated by determining the proliferative response and the expression of cytokine genes and the lineage-determining transcription factors. The frequency of regulatory T cells (Tregs) was also examined. RESULTS: The ADSC-treated rabbits showed decreased autoimmune responses, and the secretory function of their lacrimal gland was restored significantly. Treatment with ADSCs downregulated the Th1 and Th17 responses but enhanced Tregs function. In addition, ADSC treatment noticeably suppressed the expression of matrix metalloproteinase (MMP)-9, MPP-2, IL-1ß, and IL-6, whereas it enhanced the expression of the anti-inflammatory cytokine IL-10. CONCLUSIONS: Our results demonstrated that ADSC administration efficiently ameliorates autoimmune dacryoadenitis mainly via modulating Th1/Th17 responses.