Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus

Objective

To observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients.

Methods

Peripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5⁺PD1⁺/CD4⁺ T cells (Tfh), CD4⁺CCR6⁺ T cells (Th17-like) and CD19⁺CD138⁺ plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours.

Results

Compared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013).

Conclusions

We demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.     

Acute Renal Failure in Systemic Lupus Erythematosus

Acute anuric renal failure complicating systemic lupus erythematosus does not usually respond to treatment with corticosteroids and immunosuppressive agents. We describe four cases treated by dialysis, corticosteroids, and heparin in anticoagulant doses in which there was remarkable improvement in renal function after prolonged anuria. One patient died later from a gastric haemorrhage. The other three were alive and well 55, 54, and 30 months from the onset of anuria. In two cases a second renal biopsy showed a striking improvement in the lesions. Large doses of corticosteroid and heparin may be the best treatment in acute anuric lupus nephritis.     

ANCA与SLE临床表现的相关性及其意义

目的:探讨系统性红斑狼疮(Systemic Lupus Erythematosus,SLE)患者抗中性粒细胞胞浆抗体(Anti-neutrophil Cytoplasmic Antibodies,ANCA)与肾炎及其他临床表现和实验室检查的相关性及其意义.方法:采用前瞻性研究收集77例系统性红斑狼疮患者,用间接免疫荧光法(IIF)检测患者血清ANCA、ELISA法检测ANCA抗原,检测其他免疫学指标如抗核抗体、抗dsDNA抗体等.结果:77例SLE患者中ANCA阳性28(36.4%)例,ANCA阳性组浆膜炎、肾损害、神经精神症状、皮肤血管炎、抗dsDNA抗体阳性、抗Sm抗体阳性、补体下降以及血清IgG升高的发生率明显高于阴性组(P＜0.05).52例LN患者中,25例(48.1%)ANCA阳性,其中P-ANCA阳性者22例(88%).3例(12%)为a-ANCA均出现在RPGN,无一例出现c-ANCA.非LN组25例患者中,仅3例(12%)p-ANCA阳性,且均为抗-MPO.正常对照组无一例ANCA阳性.77例SLE患者中,14例(18.2%)为抗-MPO;13例(16.9%)为抗LF,且只见于DPGN、FPGN和RPGN伴有新月体形成者;10例(13%)为抗-CG,但在非狼疮肾炎患者未检测到抗-LF及抗-CG.在各种临床表现中,抗-MPO与肾脏和皮肤表现有关;而抗-LF与肾脏、关节炎及浆膜炎有关;抗-CG可见于各种临床表现.结论:ANCA可作为评价SLE疾病及鉴别血管炎和狼疮肾炎的一个重要指标.     

Animal Models of Human Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a human autoimmune disease of unknown etiology. Clinical, serologic, immunologic, and pathologic findings are highly variable in different patients and at different times in the same patient. Murine and canine animal models of SLE have been found with clinicopathologic abnormalities resembling those observed in humans. Each animal model has unique characteristics; taken together they reflect the spectrum of disease in human SLE.Investigations in the animals have suggested that genetic, hormonal, immunologic, viral, and other environmental factors contribute to and modify the expression of disease. Where analogous studies are available for humans, the same factors have been found to modify disease expression in a similar fashion. Together, these studies have helped to clarify the multifactorial basis for SLE.The best characterized abnormalities are immunologic. These include excessive B cell function with the formation of large amounts of autoantibodies, and T cell abnormalities which include defects in T cell regulatory function as well as certain T cell effector functions.The animal models of SLE also serve as convenient test subjects for newer therapeutic modalities. It is hoped that further study of the animal models will provide a more rational approach to therapeutic modulation of disease in humans with SLE.     

BLyS与系统性红斑狼疮

淋巴细胞刺激因子BLys是肿瘤坏死因子家族的新成员,对于B细胞的发育增殖具有重要的作用。狼疮小鼠及系统性狼疮患体内BLys水平增高,阻断BLys的作用可以使使狼疮小鼠的病情缓解,存活时间延长。因此,BLys拮抗剂可能对系统性红斑狼疮患具有治疗作用。     

Glycation end-products specific auto-antibodies in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease, which is highly inflammatory. Compared to a healthy control group, SLE patients exhibit a higher concentration of advanced glycation end products (AGEs) and a lower concentration of receptors for AGEs (RAGE) in serum, however, the exact aetiology is still unclear. In the present study, non-enzymatic glycation induced modification of human serum albumin (HSA) has been studied by biophysical techniques. Glycated HSA (G-HSA) was used as an antigen, and serum autoantibody levels were estimated in SLE and normal humans (NH) against it, using direct binding ELISA and competitive inhibition ELISA. Compared to N-HSA, remarkable structural modifications were observed in G-HSA. Modified HSA also showed increased pentosidine fluorescence (213.7 ± 13.4 AU). Glycation of HSA induced a conversion of α-helix and random coil to β-sheet and β-turns. Serum immuno assays results exhibited significantly (p < 0.001) higher binding of G-HSA with serum autoantibodies from SLE patients when compared with native HSA (N-HSA). Furthermore, competitive ELISA results showed significantly (p < 0.001) high percent inhibition of serum IgG from SLE patients with modified antigen. Chronic inflammation with excessive oxidative stress in SLE patients could be a possible reason for structural alterations in blood proteins, generating highly immunogenic unique new-epitopes. These in turn induce the generation of specific autoantibodies against G-HSA that may serve as a potential biomarker for SLE pathogenesis.     

Systemic Lupus Erythematosus associated with Haemobartonella-like Organisms

SYSTEMIC lupus erythematosus (SLE) is a severe disease affecting thousands of human beings each year in the United States¹. Its aetiology is not known, although infections and autoimmune processes have been suggested. Immunological mechanisms have been associated with the pathogenesis of anaemia in certain haemotropic infections of domestic animals² caused by the haemobartonella group. This communication describes the possible association between a haemo-bartonella-like agent and SLE.     

Systemic Lupus Erythematosus Syndrome Induced by Practolol

Three patients with angina pectoris treated with practolol in varying doses developed a syndrome of arthralgia, particularly of the small joints of the hands, rash, fever, a raised E.S.R., and positive tests for lupus erythematosus (L.E.) cells and antinuclear antibody. The syndrome responded partly to withdrawal of the drug, but steroids were required to produce adequate symptomatic improvement. These disease features suggest that this is an example of drug-induced systemic lupus erythematosus (S.L.E.). The impaired ability of lymphocytes from these patients to transform in vitro indicates a testable hypothesis for the pathogenesis of the syndrome.