Prognostic value of soluble interleukin 2 receptor levels in Langerhans cell histiocytosis

We investigated the prognostic significance of soluble interleukin 2 receptor (sIL-2r) levels in the pre- and post-treatment serum of paediatric patients with Langerhans cell histiocytosis (LCH). Serum levels of sIL-2r from 32 LCH patients and 14 healthy controls were determined using enzyme-linked immunosorbent assay. The LCH patients were classified, evaluated and treated according to the Histiocyte Society's protocols. The following clinical stages were considered: single-system disease (A) divided into single-site (A1; n=4), multiple-site (A2; n=9), and multisystem disease (B) without organ dysfunction (B1; n=5) and with organ dysfunction (B2; n=14). Pretreatment concentrations of sIL-2r were markedly increased at diagnosis in LCH patients compared with controls [in pg/ml, median (range) 9200 (1124-40000) versus 610 (343-800)], P < 0.0001. Levels differed significantly between stages A [3250 (1124-11000)] and B [22750 (3400-40000)], P < 0.05, and between substages A2 and B2, P < 0.05. There was a significant correlation between clinical stages and sIL-2r serum levels, r=0.7996 (P < 0.0001). Patients with > or = 17500 pg/ml of sIL-2r had a 30-month survival of 0.417 (SEM: 0.142) compared with those with levels < 17500 pg/ml, who presented a 30-month survival of 0.848 (SEM: 0.100) (log-rank, P < 0.0001). In multivariate analysis, sIL-2r levels > or = 17500 pg/ml were found to have greater predictive strength than other well-known prognostic factors.     

Adult Langerhans cell histiocytosis and immunomodulatory drugs: Review and analysis of thirty-four case reports

Langerhans cell histiocytosis (LCH) is a rare neoplastic disease in dendritic cells. LCH is classified as either a single-system (SS) or multisystem (MS) disease. There is not a standard first-line treatment for LCH in adults. We analyzed the efficacy and safety of immunomodulatory drugs (IMiDs) by searching PubMed/MEDLINE for case reports previously published. The clinical response (nonactive disease or active disease that regressed) was 94% in SS and 53% in MS. IMiDs should only be considered for adults with cutaneous SS involvement; in MS, they should be used only for patients not eligible for more aggressive treatments.     

Cytokine imbalance in hyper-IgE syndrome: reduced expression of transforming growth factor beta and interferon gamma genes in circulating activated T cells

Hyper-IgE syndrome (HIES) is a primary immunodeficiency disease characterized by recurrent infections and marked immunoglobulin (Ig)E elevation. To assess the proper T-cell defects of HIES, the cytokine profile of naturally activated T cells was compared between HIES, atopic dermatitis and chronic granulomatous disease (CGD). Intracellular flow cytometric analysis after in vitro stimulation showed no difference in the proportion of interferon (IFN)gamma- or interleukin 4 (IL-4)-producing T cells among these diseases. Quantitative polymerase chain reaction (PCR) for the cytokine genes was performed using circulating highly fractionated HLA-DR+ and HLA-DR- T cells. The IFNgamma/IL-4 or IFNgamma/IL-10 ratios were lower in HLA-DR+ T cells of HIES than in CGD (P = 0.0106, 0.0445), but did not differ between HIES and atopy. The transforming growth factor-beta (TGFbeta)/IL-4 ratio in HLA-DR+ T cells of HIES was lower than that of atopy (0.0106) or CGD (0.0062). The TGFbeta/IL-4 ratio in HLA-DR- T cells of HIES was also lower than that of atopy (0.0285). Stepwise logistic regression analysis identified TGFbeta/IL-4 ratios in HLA-DR+ (0.0001) or HLA-DR- (0.0086) T cells as the most powerful parameters to distinguish HIES from atopy and/or CGD. Serum IgE levels negatively correlated with IFNgamma/IL-4 (0.0108), IFNgamma/IL-10 (0.0254), or TGFbeta/IL-4 (0.0163) ratios in HLA-DR+, but not HLA-DR-, T cells. These results suggested that the in vivo activated T cells of HIES did not sufficiently express the IFNgamma and TGFbeta genes, which could affect IL-4-dependent IgE production. The reduced TGFbeta expression may involve the indigenous T-cell defects of HIES.     

Elevated interleukin-4 and interleukin-13 production by T cell lines from patients with Churg-Strauss syndrome

OBJECTIVE: To investigate cytokine production patterns of T cell lines (TCL) from patients with Churg-Strauss syndrome (CSS). METHODS: Short-term polyclonal TCL were generated from peripheral blood of patients with CSS or Wegener's granulomatosis (WG) and healthy controls (HC). TCL were established in the presence of interleukin-2 (IL-2) and phytohemagglutinin and were phenotypically characterized by flow cytometry. Th1/ Th2 cytokine production by stimulated TCL (72 hours) was analyzed by enzyme-linked immunosorbent assay. RESULTS: TCL that represented the progeny of in vivo-activated T cells from CSS patients displayed a heterogeneous immunophenotype, with a predominance of CD4+ T cells when compared with WG TCL, which were predominantly CD8+. All CSS TCL shared the ability to produce large amounts of interferon-gamma (IFNgamma), IL-4, and IL-13 compared with HC (P = 0.014 for all 3). Production of IL-4 and IL-13 was higher in CSS TCL than in WG TCL (P = 0.014 for both). IL-5 production was up-regulated in WG TCL compared with CSS TCL (P = 0.014). Compared with HC, WG TCL showed increased production of IFNgamma (P = 0.021), IL-5 (P = 0.043), and IL-13 (P = 0.021). CONCLUSION: Our results indicate that, while there is evidence for both a type 1 and a type 2 response in CSS, type 2 cytokine production pattern appears to predominate in this disease when compared with WG and HC.     

Evans syndrome in a patient with Langerhans cell histiocytosis: possible pathogenesis of autoimmunity in LCH

We report a 1-year-old girl with Evans syndrome coexisting with histologically confirmed Langerhans cell histiocytosis (LCH) affecting the cervical lymph nodes, liver, and spleen. Anti-cardiolipin antibody, anti-SS-A antibody, and anti-SS-B antibody as well as a direct antiglobulin test and platelet-associated IgG were all positive at the onset, and these autoantibodies became negative with the resolution of LCH by chemotherapy. Serum T-helper-2 (Th2) cytokine levels such as those of interleukin (IL)-6 and IL-10 were high whereas those of Th1 cytokines such as IL-2 and interferon-gamma were low at the onset, and this cytokine imbalance was normalized during the resolution of LCH. These results suggest that cytokine imbalance due to LCH led to multiple autoimmune phenomena in the present patient.     

Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3

AIM: To investigate the association between cytokine gene polymorphism and disease status in chronic hepatitis C genotype 3 by liver biopsy, ALT, HCV RNA levels and response to treatment. METHODS: Patients with chronic hepatitis C genotype 3 were analyzed for single nucleotide polymorphisms of interleukin (IL)-10, IL-1 beta, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) by polymerase chain reaction using sequence-specific oligonucleotide primers. Liver biopsies were assessed by modified histological activity index (HAI) scoring system using a scale of 0-18 for grading the necro-inflammatory activity and 0-6 for staging the fibrosis. HCV RNA levels were determined by bDNA assay. The patients were treated with interferon alpha and ribavirin for 6 mo. Sustained virological response was assessed 6 mo after the completion of the treatment. RESULTS: Out of the 40 patients analyzed, 26 were males. Mean age was 40.5±12.5 years (range 18-65 years). The frequencies of different dimorphic polymorphisms based on single nucleotide substitution were as follows: IL-10-1082 G/A 85%, A/A 12.5%, G/ G 2.5%; IL-10-819 A/C 87.5%, C/C 10%, A/A 2.5%; IL-10-592 C/A 72.5%, C/C 27.5%; IL-1 C 90%, U 10%; IFN-874 T/A 50%, T/T 27.5%, A/A 22.5%; TNF-308 A/G 95%, GIG 5%; TGF-10 T/C 52.5%, C/C 35%, T/T 12.5%. The mean grades of necro-inflammatory activity of different genotypes of IL-10 at promoter site -1082 were A/A = 3.6, A/G = 5.0, and G/G = 10.0 and the difference was significant (P = 0.029). The difference in the stage of disease at a scale of 0-6 was A/A 0.8, A/G 2.3, and G/G 4.0 (P = 0.079). The difference in the HAI seemed to be related to the presence of allele -1082G. For IL-10 -819 genotypes, mean scores of fibrosis were A/A = 6.0, A/C = 2.2, and C/C = 1.0 (P = 0.020) though the inflammatory activity was not much different. No significant differences in HAI were noted among polymorphisms of other cytokines. Moreover, ALT and HCV RNA levels were not significantly different among different cvtokine polymorphisms. There was a significant correlation of HAI and HCV RNA levels with the duration of disease. TGFBBB -10 genotype CC patients had a better end of treatment response than those with other genotypes (P = 0.020). Sustained virological response to the treatment was not influenced by the cytokine polymorphism. No effect of other factors like viral load, degree of fibrosis, gender, steatosis, was observed on sustained virological response in this population infected with genotype 3. CONCLUSION: There is no significant correlation between cytokine polymorphisms and HAI except for the polymorphisms of anti-inflammatory cytokine IL-10, which may influence hepatic inflammatory activity and fibrosis in patients with chronic hepatitis C genotype 3. Sustained virological response in this genotype does not seem to be influenced by cytokine gene polymorphisms.     

Gene polymorphisms of 22 cytokines in macedonian children with atopic dermatitis

Atopic dermatitis (AD) is a common chronically relapsing skin disease associated with abnormal cytokine production, and activation of T-helper 2 cells. The aim if this study was to determine whether cytokine gene polymorphisms might influence the development of AD. Single nucleotide polymorphisms in the genes for I-L1alpha, IL-1beta, IL-1R, IL-2, IL-4, IL-6, IL-10, IL-12, TGF beta, TNF and IFNgamma were investigated by PCR and sequence specific primers in Macedonian patients with AD (67 children, age of 6 months to 5 years) and 301 normal unrelated individuals. Susceptible cytokine polymorphisms for AD for eleven genotypes (IL-4 -33/T:T IL-4 -1098/G:G, TGFbeta cdn25C:G, IL-4 -1098/T:T, IL-1alpha -889/C:T, IL-2 +166/T:T, IL-1beta -511/C:T, IL-12 -1188/C:T, IL-10 -1082/A:G, IL-1beta +3962/C:T, IFNgamma +874/A:T), five diplotypes, six haplotypes, and for alleles were found. Protective cytokine polymorphisms for AD for seven cytokine genotypes (IL-4 -1098/G:T, TGFbeta cdn25/G:G, IL-4 -33/C:C, IL-1alpha -889/C:C, IFNgamma +874/A:A, IL-10 -1082/A:A, IL-1beta -511/C:C), one cytokine diplotypes, two cytokine haplotypes, and four cytokine alleles were also found. We concluded that several cytokine polymorphisms are protective, or susceptible associated with AD in population of Macedonians.     

Telomere length shortening in Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a clonal, proliferative disorder of phenotypically immature CD1a⁺ Langerhans cells (LC). The aetiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as promoting chromosomal instability. To determine whether LCH LC have altered telomere lengths, we used dual detection of CD1a expression by immunofluorescence and telomere length by fluorescence in situ hybridization of LCH LC and lymphocytes in local, multisystem and systemic LCH and compared these with telomere lengths of LC and lymphocytes in reactive lymph nodes. LCH LC showed significantly shorter telomere lengths than LC from reactive lymph nodes or unaffected skin. Lymphocyte telomere lengths showed similar profiles among the different samples. These data show a significant telomere shortening in LCH LC in all stages of disease involvement compared with LC from reactive lymph nodes, suggesting that LCH may share mechanisms of telomere shortening and survival with clonal preneoplastic disorders and cancer, although an initiating infectious or immune event is still possible.     

Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis: abundant expression of cytokines relevant to disease and treatment

The pathogenesis of Langerhans cell histiocytosis (LCH) remains poorly understood. To further elucidate LCH pathogenesis, we analyzed the expression of 10 cytokines relevant to cellular recruitment and activation at the protein level in 14 patients and identified the lesional cells responsible for cytokine production in situ by immunohistochemistry. The cytokines investigated included the hematopoietic growth factors interleukin-3 (IL-3), IL-7, and granulocyte-macrophage colony-stimulating factor (GM-CSF); the lymphocyte regulatory cytokines IL-2, IL-4, and IL-10; the inflammatory regulators IL-1alpha and tumor necrosis factor-alpha (TNF-alpha); and the effector cell-activating cytokines IL-5 and interferon-gamma (IFN-gamma). In all specimens, CD1a(+) histiocytes (LCH cells) and CD3(+) T cells produced large amounts of cytokines, creating a true cytokine storm. IL-2, IL-4, IL-5, and TNF-alpha were produced exclusively by T cells, whereas only IL-1alpha was produced by LCH cells. Equal numbers of LCH cells, T cells, and macrophages produced GM-CSF and IFN-gamma. Equal numbers of LCH cells and macrophages produced IL-10, whereas IL-3 was produced by T cells and macrophages. IL-7 was only produced by macrophages. Eosinophils, present in some specimens, were partially responsible for the production of IL-5, IFN-gamma, GM-CSF, IL-10, IL-3, and IL-7. Expression of all cytokines, abundant in most biopsies, was irrespective of age, gender, or site of biopsy. These findings emphasize the role of T cells in LCH. The juxtaposition of T cells and LCH cells suggests that both cells interact in a cytokine amplification cascade, resulting from stimulation of autocrine and paracrine stimulatory loops. This cascade can be linked directly to the development of LCH through recruitment, maturation, and proliferation of LCH cells. The cytokines studied are known to be involved in the development of other characteristic features of LCH, such as fibrosis, necrosis, and osteolysis.     

Relapses of multisystem/multifocal bone Langerhans cell histiocytosis in paediatric patients: Data analysis from the JLSG-96/02 study

We assessed relapse patterns in paediatric patients with relapsed Langerhans cell histiocytosis (LCH) who were initially treated with the JLSG-96/02 protocol. We analysed 187 relapse events in 101 relapsed LCH patients [31 with multifocal bone (MFB) and 70 with multisystem (MS) at LCH diagnosis] among a total 317 patients enrolled in JLSG-96/-02 studies. Relapse of LCH was defined as an exacerbation of the non-active disease (NAD) condition. Of the 317 patients, 101 (31.9%) had the first relapse at 1.5 years after initiation of therapy. The first relapse and subsequent relapses did not differ between patients with MFB and MS disease. Of the 187 relapse events, relapse occurred as a single-system disease (n = 159; 85%), in which isolated bone relapse (n = 104; 55%) was the most common. Relapse at MS disease with the risk of organ involvement is extremely rare. After relapse(s), most patients underwent chemotherapy (122/187; 65%) and 87% of them achieved NAD status again. The incidence of permanent consequences was significantly higher in patients with relapses than in those without relapses. In the JLSG cohort, bone relapse most occurred in both MFB and MS patients. Most relapses could be effectively controlled by repeated administration of the initial chemotherapy.     

Adult Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a proliferative histiocytic disorder of unknown cause originating from dendritic cells. The clinical presentation of LCH is highly variable. Although the features of this disease have been well described in children, they remain poorly defined in adults. Here, we review the current knowledge about adult LCH, focussing on clinical presentation, diagnosis, treatment, and prognosis.     

Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation

Proinflammatory cytokines including interferon-gamma (IFNgamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) are implicated in the pathogenesis of acute graft-versus-host disease (aGVHD). Cytokine gene polymorphism is associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. Polymorphism in the IFNgammaIntron1 microsatellite (CA)n repeat has been linked with in vitro IFNgamma production and renal transplant rejection. The IL-6(-174)(G/C) single nucleotide polymorphism has been linked to in vitro and in vivo IL-6 production, juvenile chronic arthritis, and renal transplant rejection. This study examined the potential association of GVHD with IFNgamma and IL-6 polymorphisms in 80 sibling bone marrow transplant (BMT) donor/recipient pairs. Patients homozygous for the IFNgammaIntron1 allele 3 had more severe (grade III-IV) aGVHD. Patients possessing the IL-6(-174)G allele had a trend toward higher grades of aGVHD, and those homozygous for the IL-6(-174)G allele were more likely to develop chronic GVHD (cGVHD). The associations of previously identified aGVHD severity-associated cytokine gene polymorphisms (TNFd and IL-10(-1064)) with severe aGVHD were reconfirmed. Logistic regression analysis confirmed the association of severe aGVHD with recipient genotype at IFNgammaIntron1 (odds ratio [OR] 3.92; P =.02), IL-10(-1064) (OR 4.61; P =.026) and TNFd (OR 3.29; P =.039), and that of cGVHD with recipient IL-6(-174) genotype (OR 4.25; P =.007), in addition to age, gender mismatch, and underlying disease. Assessment of cytokine genotype may potentially allow more accurate prediction of GVHD and appropriate adjustment of GVHD prophylaxis, as well as indicating novel areas for future studies of GVHD pathogenesis.     

Association of cytokine gene polymorphisms with bronchial asthma in Macedonians

Bronchial asthma is a multifactorial disease whereby both environmental and genetic factors contribute to its aetiology and/or clinical severity. The aim of this study was to examine the association of 22 cytokine gene polymorphism in the Macedonian population with bronchial asthma (BA). The sample of the population comprised of 301 normal unrelated individuals and 74 patients with BA. Cytokine genotyping was performed by PCR. Susceptible cytokine polymorphisms for BA for ten genotypes (IL-4 -1098/T:T, TNF-alpha -238/A:G, IL-4 -590/C:C, IL-2 +166/T:T, IL-2 -330/T:T, IL-10 -1082/G:G, IFNgamma utr5644/T:T, IL-10 -1082/A:A, IL-1beta +3962/T:T, IL-6 -174/G:G), six diplotypes, four haplotypes, and two alleles were found. Protective cytokine polymorphisms for BA for seven cytokine genotypes (IL-4 -1098/G:T, TNF- alpha -238/G:G, IL-2 -330/G:T, IL-4 -590/C:T, IFNgamma utr5644/A:T, IL-1beta +3962/C:T, IL-10 -1082/A:G), six cytokine diplotypes, four cytokine haplotypes, and four cytokine alleles were found. We concluded that several cytokine polymorphisms are protective, or susceptible associated with BA in population of Macedonians.     

CD27+ memory and CD27- effector CD8+ T cells are responsible for a decreased production of proinflammatory cytokines in HLA B27-positive subjects

BACKGROUND AND OBJECTIVE: AS and other spondyloarthritides (SpA) are mostly chronic inflammatory rheumatic diseases characterised by a strong association with HLA B27. Recent data from our group have suggested that AS patients have a diminished secretion capacity of inflammatory cytokines, possibly associated with HLA B27. The aim of this study was to identify CD4+ and CD8+ T cell subsets responsible for the observed lower cytokine secretion capacity in HLA B27-positives. METHODS: Highly purified (> 98%) CD4+ and CD8+ T cells of HLA B27-positive AS patients (n = 13), healthy HLA B27-positive (n = 7) and -negative controls (n = 9) were stimulated for 6h with PMA/ Ionomycin and, after fixation, stained for surface markers CD45RA and CD27 and cytokines TNFalpha, IFNgamma, IL-4 and IL-10. RESULTS: CD27+ CD45RA- memory CD8+ T cells of HLA B27-positive subjects showed a significantly lower percentage of TNFalpha (median 71.4%) and IFNgamma production (median 69.7%) than HLA B27-negative controls (TNFalpha 85.1%; p < or = 0.027; IFNgamma 82.7%, p < or = 0.026). A similar result was also detected in CD27- CD45RA+ effector CD8+ T cells of which 43.2% produced TNFalpha and 66.3% IFNgamma in HLA B27-positive subjects, respectively, compared to 75.6% TNFalpha and 84.4% IFNgamma producing T cells in HLA B27-negatives (p < or = 0.045 and p < or = 0.062, respectively). For all CD4+ T cell subsets no significant differences between HLA B27-positive and HLA B27-negative donors were observed, regarding neither the frequency of IFNgamma, TNFalpha, IL-4 or IL-10 producers nor the coexpression of IFNgamma and IL-4 in memory subsets. CONCLUSIONS: HLA B27-positive subjects are characterized by a low proinflammatory cytokine production in CD8+ effector and memory T cell subsets. This suggests an influence of HLA B27 on cytokine production in antigen-experienced CD8+ T cells.     

郎格汉斯组织细胞增多症的消化系表现、诊断及治疗

郎格汉斯组织细胞增多症是一种少见的全身多系统受侵犯的组织细胞异常增生性疾病,常见受累部位为骨、皮肤、肺脏、骨髓、淋巴结等,除此之外,尚可侵犯肝脏、胆道及胃肠道等消化器官,临床表现与其他消化系统疾病相比缺乏特异性,故诊断难度较大,一旦郎格汉斯组织细胞增多症患者明确诊断消化系统受累,则需要系统性治疗,甚至是肝脏移植.本文综述郎格汉斯组织细胞增多症的消化系统表现,从而对其早期诊断及治疗提供帮助.     

Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans cell histocytosis. AIEOP-Istiocitosi Group

The aetiopathogenesis of Langerhans cell histiocytosis (LCH) is still undefined. Constitutional abnormalities in LCH have rarely been reported. One study showed chromosomal instability in lesional cells from three patients. No chromosomal studies are available on peripheral blood lymphocytes. Peripheral blood lymphocytes were analysed for the presence of chromatid and/or chromosomal breaks and structural rearrangements. A fluorescence in situ hybridization (FISH) painting technique was also applied in two cases. Sixteen patients with multisystem (MS, n = 11) or single system (SS, n = 5) LCH were studied, either at the diagnosis (n = 8), during treatment (n = 2) or during follow‐up, when asymptomatic (n = 6). Thirteen patients had chromosomal abnormalities. Eleven patients (69%) had chromatid and chromosomal breaks in 7–45% of cells. Overall, chromosome and chromatid breaks were significantly more frequent in the 11 patients with MS disease than in the five patients with SS disease: the mean percentage of cells showing chromosome and chromatid breaks was 13·4% in MS patients vs. 6·2% in SS patients (P = 0·003). Chromosomal abnormalities may be found in phytohaemagglutinin (PHA)‐stimulated peripheral blood lymphocytes of LCH patients at diagnosis, during the disease course and even during long‐term follow‐up, more frequently in MS disease. Chromosome instability may be considered as either a basic genetic instability or as a landmark of reaction to an environmental agent (viral?) that, through genome alteration, may play a role in histiocyte proliferation and, in some cases, also in the increased risk of malignancy.     

同种异体反应中分泌细胞因子T淋巴细胞的测定及其临床初探

目的　测定同种异体反应中分泌细胞因子的T淋巴细胞水平并初步探讨其临床意义。方法　利用细胞因子分泌检测方法 (CKSA)从单细胞水平定量测定人混合淋巴细胞反应中分泌γ干扰素 (IFNγ) ,白细胞介素 4 (IL 4 )和IL 10的T细胞 ;分析 2例患者外周血分泌IFNγ的T细胞和急性移植物抗宿主病 (aGVHD)的关系。结果　经同种异体外周血单个核细胞 (PBMNC)刺激后分泌IFNγ的T细胞水平 (1 12± 0 13) %明显高于对照组 (0 2 3± 0 0 7) % ,P <0 0 1。而分泌IL 4和IL 10的T淋巴细胞则无升高 ,分别为 (0 12± 0 0 3) %、(0 10± 0 0 3) % ,P >0 0 5。 2例患者外周血分泌IFNγ的T细胞水平和aGVHD有一定的相关性。结论　利用CKSA测定同种异体PBMNC刺激后分泌IFNγ的T细胞水平显著升高 ,提示具有临床应用价值     

Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine

Langerhans cell histiocytosis (LCH) is a disorder characterized by proliferation of activated Langerhans cells. Immune dysregulation is believed to be part of the pathogenesis. Although current therapies are very effective at inducing remission, multiple recurrences and long-term sequelae are common for patients with low-risk disease, and a significant proportion of young patients die of their disease. More effective therapies based on the pathogenesis of LCH are needed. We investigated the use of 2-chloro-deoxyadenosine (2-CdA), a purine analogue with an antiproliferative effect on histiocytes and lymphocytes, in patients with recurrent or high-risk LCH. Six patients with recurrent LCH received 2-CdA (5-7 mg/m(2)/day for 5 days, repeated every 21-28 days). All patients achieved remission. With a median follow-up of 15 months (range, 3-25 months), 5 patients remain in remission. A patient with multisystem disease who recurred after 13 months, achieved a second remission with 2-CdA. Hematologic toxicity was minimal, and no infectious complications were documented. 2-CdA is among the most effective drugs for the treatment of LCH, and this is probably due to both its anti-proliferative and immunomodulatory effects. 2-CdA needs to be considered for the treatment of recurrent LCH. However, its incorporation into front-line treatment of patients with multi-system LCH needs further study.     

郎格罕组织细胞增生症五例临床分析

目的 提高对郎格罕组织细胞增生症（LCH）的认识。方法 回顾分析我院近10年来确诊的5例LCH成年患者的临床、影像和病理资料。结果 男3例,女2例,平均年龄36．8岁。所有病例均表现有肺、骨骼、中枢神经系统、皮肤、肝、脾、淋巴结等多器官病变。LCH肺部病变的典型放射影像学表现为双肺弥漫结节影,间质纤维化伴多发囊疱形成。有3例患者行骨X线检查,可低密度骨质破坏灶。全部患者的活检标本均可见异常的郎格汉斯细胞浸润。对5例患者均予反复全身化疗（激素＋蒽环类细胞毒药物）,化疗对肝、脾、淋巴结、皮肤病变的疗效较好,而对肺部病变、中枢性尿崩症、骨损害的疗效较差。结论 LCH可在任何年龄发病,对有尿崩症、特征性骨质破坏和肺部病变的患者应警惕此病,并及时行病灶部位的病理学检查,确诊后予放疗、全身化疗治疗。     

Cytokine genotypes correlate with pain and radiologically defined joint damage in patients with juvenile rheumatoid arthritis

OBJECTIVES: Single nucleotide polymorphisms (SNPs) in cytokine genes have been associated with risk of a number of autoimmune diseases. Moreover, some SNPs are associated with variations in rates of in vitro gene expression, and it is therefore possible that these functional polymorphisms may differentially affect inflammatory processes and disease outcome. This project's objective was to determine whether cytokine genotypes correlate with disease outcomes in patients with juvenile rheumatoid arthritis (JRA). METHODS: Genotypes of SNPs of pro-inflammatory cytokines, tumour necrosis factor-alpha -308G -->A, interleukin-6 (IL-6) -174G -->C and interferon-gamma +874G -->A, and anti-inflammatory, immunosuppressive cytokines, interleukin-10 -1082G -->A, -819C -->T and -592A -->C and transforming growth factor-beta1 (TGF-beta1) codon 10T -->C and codon 25G -->C, were determined for patients with JRA who previously participated in a long-term outcome study. Cytokine genotypes and clinical variables showing significant correlations with clinical outcomes at the alpha = 0.100 level in univariate analyses were entered in multivariate tests. RESULTS: In multivariate tests, the IL-6 genotype -174G/G was positively correlated with pain [regression coefficient B = 0.899, 95% confidence intervals (CI) 0.185, 1.612, P = 0.014]. The homozygous TGF-beta1 codon 25G/G genotype showed a protective effect against joint space narrowing on radiographs taken within 2 yr of disease onset, but confidence intervals were wide [odds ratio (OR) 0.176, 95% CI 0.037, 0.837 P = 0.029]. CONCLUSIONS: The correlation of IL-6 genotype with pain and the possible association of the TGF-beta1 codon 25 genotype with short-term radiographic damage (G/C with greater risk and G/G with decreased risk) suggests that both these polymorphisms may be useful early prognostic indicators. Further studies of the relation between cytokine genotypes and outcomes in patients with all forms of juvenile idiopathic arthritis (JIA) are warranted.