RESUMO
Lower extremity arteriosclerosis obliterans (LEASO) is a vascular disease that may result in adult limb loss worldwide. CD4+T cell-mediated immunity plays a significant role in LEASO. The T cell immunoglobulin and mucin domain 3 (Tim-3) and inhibitory receptor programmed cell death-1 (PD-1) are well-known immune checkpoints that play crucial roles in regulating CD4+T cell activation or tolerance. In this study, blood mononuclear cells were isolated from the blood samples of healthy controls and patients who were diagnosed with LEASO for the first time [stage III or IV according to the Fontaine classification system and had not received drugs (except for heparin) or surgery treatment]. We concluded the higher proportion of Tim-3+PD-1+CD4+T cells in human higher stage LEASO, and oxidized low-density lipoprotein increased Tim-3 and PD-1 co-expression by activating CD4+T cells in a dose- dependent manner. Tim-3+PD-1+CD4+T cells displayed a more active status and produced more anti-atherogenic cytokines compared to Tim-3-PD-1-CD4+T cells. Apart from the increased frequency, the altered function of Tim-3+PD-1+CD4+T cells was also observed in LEASO compared to those from healthy controls. These in vitro results indicated that Tim-3 and PD-1 might be promising early warning targets of higher stage LEASO. In addition, the blockade of Tim-3 and PD-1 signaling pathways aggravated the pro-atherogenic Th1 responses in LEASO, further suggesting that the cardiovascular safety must be a criterion considered in using immune checkpoint inhibitors to reverse T cell exhaustion during tumors and chronic viral infections.
Assuntos
Arteriosclerose Obliterante , Linfócitos T CD4-Positivos , Receptor Celular 2 do Vírus da Hepatite A , Receptor de Morte Celular Programada 1 , Adulto , Arteriosclerose Obliterante/imunologia , Linfócitos T CD4-Positivos/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Extremidade Inferior , Receptor de Morte Celular Programada 1/imunologiaRESUMO
BACKGROUND: Immunoglobulin (Ig) G4-related disease has recently been recognized to occur in the cardiovascular system in the aorta and main branching arteries, often manifesting as aneurysms and arteritis/periarteritis. Peripheral arteries (the femoral and popliteal arteries) are frequent sites of arteriosclerosis obliterans (ASO) and occasionally show aneurysms or arteritis. This study re-examined peripheral arterial lesions from the standpoint of IgG4-related disease. METHODS: The study comprised 104 patients who underwent surgical treatment of peripheral arterial lesions, including 30 patients with peripheral arterial aneurysms (PAAs) and 74 with ASO. IgG4-related disease was identified on the basis of diffuse infiltration of numerous IgG4-positive plasmacytes as revealed by immunohistochemical examination. Clinicopathologic features were compared between IgG4-related and IgG4-unrelated lesions. RESULTS: IgG4-related disease was found in four of the 30 patients with PAAs (13.3%; two in the deep femoral artery, two in the popliteal artery) but not in any patients with ASO. IgG4-related PAA displayed clinicopathologic features resembling those of other IgG4-related diseases and a characteristic saccular appearance (P = .002). CONCLUSIONS: IgG4-related disease was detected in PAA patients but not in ASO patients. IgG4-related disease thus represents one potential etiology of aneurysm in the peripheral arteries.
Assuntos
Aneurisma/patologia , Arteriosclerose Obliterante/patologia , Arterite/patologia , Artéria Femoral/patologia , Imunoglobulina G/análise , Artéria Poplítea/patologia , Idoso , Idoso de 80 Anos ou mais , Aneurisma/sangue , Aneurisma/imunologia , Aneurisma/cirurgia , Arteriosclerose Obliterante/sangue , Arteriosclerose Obliterante/imunologia , Arteriosclerose Obliterante/cirurgia , Arterite/sangue , Arterite/imunologia , Arterite/cirurgia , Biomarcadores/análise , Distribuição de Qui-Quadrado , Feminino , Artéria Femoral/imunologia , Artéria Femoral/cirurgia , Fibrose , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/patologia , Artéria Poplítea/imunologia , Artéria Poplítea/cirurgia , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: In systemic lupus erythematosus (SLE) patients, the prevalence of arteriosclerosis obliterans (ASO) is high despite a lack of common risk factors for ASO. The main objective of this study was to investigate a possible direct role of anti-phospholipid antibodies (aPLs), which are frequently detected in SLE patients, in the pathogenesis of ASO. MATERIALS AND METHODS: We examined tissue factor (TF) expression on the monocyte surface by flow cytometric analysis in 89 SLE patients with or without ASO and/or aPLs and studied the in vitro effect of purified IgG fractions from plasma of SLE patients or normal healthy volunteers (aPLs(+) IgG, n=8; aPLs(-) IgG, n=6; Normal IgG, n=6) on the expression of TF and production of TNF-α and IL-1ß in healthy peripheral blood mononuclear cells (PBMCs) or isolated monocytes. RESULTS: We confirmed that high expression of monocyte TF was strongly associated with the prevalence of ASO and the presence of aPLs. Treatments of PBMCs with aPLs(-) IgG or normal IgG did not significantly increase expression of TF, TNF-α, and IL-1ß messenger RNA (mRNA) and the production of TNF-α and IL-1ß. However, stimulation of PBMCs with aPLs(+) IgG caused significant increase in expression of TF, TNF-α, and IL-1ß mRNA. Moreover, aPLs(+) IgG stimulated PBMCs and significantly enhanced the production of TNF-α and IL-1ß. CONCLUSION: These results suggest that IgG-aPLs cause persistently high TF expression and inflammatory cytokine production by interacting with peripheral blood monocytes and lymphocytes, which may be an important mechanism in the pathogenesis of ASO peculiar to SLE patients.
Assuntos
Anticorpos Antifosfolipídeos/imunologia , Arteriosclerose Obliterante/etiologia , Arteriosclerose Obliterante/imunologia , Citocinas/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Tromboplastina/genética , Adolescente , Adulto , Idoso , Arteriosclerose Obliterante/genética , Criança , Citocinas/genética , Feminino , Regulação da Expressão Gênica , Humanos , Imunoglobulina G/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Tromboplastina/análise , Tromboplastina/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Adulto JovemRESUMO
Atherosclerosis obliterance and critical lower limb ischemia lead to immunodeficiency and disbalance of T- and B- components of immune system. Surgical treatment doesn't eliminate but in a number of cases aggravates immune disorders. Immunocorrection stimulates anti-infectious protection. Indications to different variants of immunocorrection are formulated.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Arteriosclerose Obliterante , Imunidade Celular/imunologia , Terapia de Imunossupressão/métodos , Plasmaferese , Terapia Ultravioleta/métodos , Procedimentos Cirúrgicos Vasculares/métodos , Arteriosclerose Obliterante/tratamento farmacológico , Arteriosclerose Obliterante/imunologia , Arteriosclerose Obliterante/cirurgia , Transfusão de Sangue Autóloga/métodos , Seguimentos , Humanos , Linfócitos T/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Patients with haptoglobin deficiency associated with haptoglobin IgG antibodies, who experienced severe nonhemolytic transfusion reactions (NHTRs), have been identified in Japan. Haptoglobin deficiency therefore might be a risk factor for NHTRs. STUDY DESIGN AND METHODS: A total of 4138 cases of voluntarily reported NHTRs in Japan, including 367 cases of immediate-onset anaphylactic NHTRs, were examined to identify haptoglobin deficiency. Serum haptoglobin IgG and IgE antibodies were determined in haptoglobin-deficient patients to elucidate the mechanism underlying the transfusion reactions. RESULTS: Seven patients with haptoglobin deficiency were identified. Six of them experienced severe and acute NHTRs. Six of them were identified to be homozygous for the Hpdel allele of the haptoglobin gene. Both haptoglobin IgG and IgE antibodies were detected in serum samples of all the patients. The stimulative effects of blood transfusion on the production of hap- toglobin antibodies in the patients and the relation- ship between the presence of the antibodies and the occurrence of the transfusion reactions were observed. CONCLUSION: Anaphylactic NHTRs in these patients with haptoglobin deficiency associated with serum haptoglobin antibodies were suggested to be prevalent in Japan. In addition to IgG antibodies, IgE haptoglobin antibodies detected in the sera of such patients were suggested to play a role in the occurrence of the reactions.
Assuntos
Anafilaxia/etiologia , Haptoglobinas/deficiência , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Isoanticorpos/imunologia , Reação Transfusional , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Anafilaxia/epidemiologia , Anafilaxia/imunologia , Especificidade de Anticorpos , Arteriosclerose Obliterante/imunologia , Arteriosclerose Obliterante/terapia , Basófilos/imunologia , Basófilos/metabolismo , Western Blotting , Criança , Pré-Escolar , Comorbidade , Ensaio de Imunoadsorção Enzimática , Feminino , Deleção de Genes , Genótipo , Haptoglobinas/genética , Humanos , Hipersensibilidade Imediata/etiologia , Hipersensibilidade Imediata/imunologia , Imunização , Imunodifusão , Lactente , Recém-Nascido , Japão/epidemiologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/terapia , Masculino , Programas de Rastreamento , Mastócitos/imunologia , Mastócitos/metabolismo , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/terapia , Gravidez , Complicações na Gravidez/imunologia , Prevalência , Receptores de IgE/imunologia , Sistema de Registros , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapiaAssuntos
Doenças da Aorta/imunologia , Arteriosclerose Obliterante/imunologia , Doenças Autoimunes/etiologia , Fibrose Retroperitoneal/etiologia , Aorta Abdominal , Aneurisma Aórtico/complicações , Autoanticorpos , Humanos , Masculino , Pessoa de Meia-Idade , Fibrose Retroperitoneal/imunologia , Fibrose Retroperitoneal/patologiaRESUMO
Using a NIH standard lymphocytotoxicity test, a possible Japanese specific HLA antigen, HLA-BJW 22.2 was identified in 17 out of 48 patients with thromboangiitis obliterans (35.4 per cent), in 5 out of 15 patients with Takayasu's arteritis (33.3 per cent) and in 11 out of 113 normal controls (9.7 per cent). On the other hand, HLA-CWl was found in 4 out of 47 patients with arteriosclerosis obliterans (8.5 per cent) and in 41 out of 113 normal controls (36.3 per cent).