医学分子遗传学——第七讲 免疫系统疾病分子遗传学

免疫系统是人体的主要防御系统。免疫系统由许多来自不同克隆的淋巴细胞所组成。淋巴细胞可分为两种类型:B细胞和T细胞。B细胞是由骨髓产生的,它的主要功能是制造抗体。抗体是在外来抗原作用于B细胞后所产生的,它可以专一性地识别相应的特定抗原。T细胞是由胸腺产生的,它在免疫系统中起细胞介导的作用。T细胞的功能是多方面的,它能产生T细胞受体。T细胞受体是一类蛋白质,它能为由B细胞产生的抗体提供直接的模板。

Is leptin related to systemic inflammatory response in acute pancreatitis?

AIM： To evaluate the relationship between leptin and systemic inflammation in acute pancreatitis. METHODS： Consecutive patients with acute pancreatitis were included. Body mass index and serum samples were obtained at admission. Leptin, TNF-α, IL-6, -8 and -10 levels were determined by ELISA. Severity was defined according to Atlanta criteria. RESULTS： Fifty-two （29 females） patients were studied. Overall body mass index was similar between mild and severe cases, although women with severe pancreatitis had lower body mass index （P = 0.04） and men showed higher body mass index （P = 0.05）. No difference was found in leptin levels regarding the severity of pancreatitis, but higher levels tended to appear in male patients with increased body mass index and severe pancreatitis （P = 0.1）. A multivariate analysis showed no association between leptin levels and severity. The strongest cytokine associated with severity was IL-6. Correlations of leptin with another cytokines only showed a trend for IL-8 （P = 0.058）. CONCLUSION： High body mass index was associated with severity only in males, which may be related to android fat distribution. Serum leptin seems not to play a role on the systemic inflammatory response in acute pancreatitis and its association with severe outcome in males might represent a marker of increased adiposity.

Association between autoimmune pancreatitis and systemic autoimmune diseases

AIM: To investigate the association between autoimmune pancreatitis (AIP) and systemic autoimmune diseases (SAIDs) by measurement of serum immunoglobulin G4 (IgG4). METHODS: The serum level of IgG4 was measured in 61 patients with SAIDs of different types who had not yet participated in glucocorticosteroid treatment. Patients with an elevated IgG4 level were examined by abdominal ultrasonography (US) and, in some cases, by computer tomography (CT). RESULTS: Elevated serum IgG4 levels (919 ± 996 mg/L) were detected in 17 (28%) of the 61 SAID patients. 10 patients had Sj gren's syndrome (SS) (IgG4: 590 ± 232 mg/L), 2 of them in association with Hashimoto's thyroiditis, and 7 patients (IgG4: 1388 ± 985.5 mg/L) had systemic lupus erythematosus (SLE). The IgG4 level in the SLE patients and that in patients with SS were not significantly different from that in AIP patients (783 ± 522 mg/L). Abdominal US and CT did not reveal any characteristic features of AIP among the SAID patients with an elevated IgG4 level. CONCLUSION: The serum IgG4 level may be elevated in SAIDs without the presence of AIP. The determination of serum IgG4 does not seem to be suitable for the differentiation between IgG4-related diseases and SAIDs.

Autoantibody profiles in autoimmune hepatitis and chronic hepatitis C identifies similarities in patients with severe disease

To determine how the auto-antibodies (Abs) profiles overlap in chronic hepatitis C infection (CHC) and autoimmune hepatitis (AIH) and correlate to liver disease.METHODSLevels of antinuclear Ab, smooth muscle antibody (SMA) and liver/kidney microsomal-1 (LKM-1) Ab and markers of liver damage were determined in the sera of 50 patients with CHC infection, 20 AIH patients and 20 healthy controls using enzyme linked immunosorbent assay and other immune assays.RESULTSWe found that AIH patients had more severe liver disease as determined by elevation of total IgG, alkaline phosphatase, total serum bilirubin and serum transaminases and significantly higher prevalence of the three non-organ-specific autoantibodies (auto-Abs) than CHC patients. Antinuclear Ab, SMA and LKM-1 Ab were also present in 36% of CHC patients and related to disease severity. CHC cases positive for auto-Abs were directly comparable to AIH in respect of most markers of liver damage and total IgG. These cases had longer disease duration compared with auto-Ab negative cases, but there was no difference in gender, age or viral load. KLM-1+ Ab CHC cases showed best overlap with AIH.CONCLUSIONAuto-Ab levels in CHC may be important markers of disease severity and positive cases have a disease similar to AIH. Auto-Abs might have a pathogenic role as indicated by elevated markers of liver damage. Future studies will unravel any novel associations between these two diseases, whether genetic or other.

Spleen:A new role ffoorr an old player?

The spleen could be considered a neglected organ.To date,it has been deemed an ancillary organ in portal hypertension or an organ localization in lymphoproliferative diseases,even though it has had significant attention in infectious diseases for some time.Now,it is thought to be central in regulating the immune system,a metabolic asset and involved in endocrine function with regard to nonalcoholic fatty liver disease.The main mechanisms involved in this complex network will be critically discussed in this article.

Application of geographical information system technology to epidemiological surveillance and prevention and cure decision-making for SARS

Objective:To expound geographical information system (GIS) technology is a very important tool when it was employed to assist to present the distribution by time and place and the model of transmission of infectious disease. Methods: We illustrated the assistant decision-making support function of GIS with an example of the spatial decision support system for SARS controlling in Shaanxi province of China which was developed by us. Results: The spatial decision support system established by applying GIS technology fulfilled the needs of real-time collection and management and dissemination SARS information and of surveillance and analysis the epidemic situation of SARS. Conclusion: Occurrence and epidemic of diseases, implement prevention and intervention measures and collocation hygienic resources are all with the characteristic of the variation of time and space, therefore, GIS technology has become a powerful tool for identifying risk factors of diseases, providing clues of causation of diseases , evaluating the effects of intervention measures and drawing a health management plan.

Human endogenous retroviruses and cancer:Causality and therapeutic possibilities

A substantial part of the human genome is derived from transposable elements;remnants of ancient retroviral infections.Conservative estimates set the percentage of human endogenous retroviruses(HERVs) in the genome at 8%.For the most part,the interplay between mutations,epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic cells.We first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and therapy.It has been shown that at least in some cases,tumor cells expressing HERV open reading frames(ORFs) thus gain tumor-promoting functions.However,since these proteins are not expressed in healthy tissues,they become prime target structures.Of potential pharmacological interest are the prevention of HERV transposition,the inhibition of HERV-encoded protein expression and the interference with these proteins' activities.Evidence from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity boundaries.The development of new tumor(immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side effects.Finally,we postulate on main future research streams in order to stimulate discussion on this hot topic.

Anal metastasis from recurrent breast lobular carcinoma:A case report

We report a case of isolated gastrointestinal metastasis from breast Iobular carcinoma, which mimicked primary anal cancer. In July 2000, an 88-year-old woman presented with infiltrating Iobular cancer （pT1/G2/N2）. The patient received postoperative radiotherapy and hormonal therapy. Four years later, she presented with an anal polypoid lesion. The mass was removed for biopsy. Immunohistochemical staining suggested a breast origin. Radiotherapy was chosen for this patient, which resulted in complete regression of the lesion. The patient died 3 years after the first manifestation of gastrointestinal metastasis. According to the current literature, we consider the immunohistochemistry features that are essential to support the suspicion of gastrointestinal breast metastasis, and since we consider the gastrointestinal involvement as a sign of systemic disease, the therapy should be less aggressive and systemic.

Characteristics of Thyroid Hormones in Hypertensive Hispanic Population

The aim was to characterize thyroid function in Hispanic hypertensive population. Retrospective study of 1,023 individuals was performed, in which 68.23% had hypertension （74.21% women） and 37.25% had thyroid pathology. Age, weight, blood pressure, biochemical measurements were recorded, mean age： 53.02 ± 14.80 yr, mean weight： 83.05 ±16.95 kg, thyrotropin-stimulating hormone （TSH） hypertensive patients： 5.55±1.63 μUI/mL and without hypertension： 3,72 ± 1.60 μUI/mL. TSH range concentration distributed by sex indicates： 1.50-2.49 μUI/mL men, 2.50-5.01 μUI/mL women. TSH categories vs. age were positively associated （r = ＋ 0.114, P = 0.044） and hypertension by age was also correlated （r = ＋ 0.178, P = 0.0001）. Significant positive association we found between TSH and diastolic blood pressure （r = ＋ 0.197, P = 0.008）. Systolic and diastolic blood pressure vs. age were positively increasing （r = ＋ 0.410,p = 0.0001; r = ＋0.285, P = 0.0001, respectively）. Prevalence of thyroid pathology in hypertensive subjects are hyperthyroidism 5.87%; hypothyroidism 20.34% （5.73% subclinic） and autoimmune disease 6.25%. High percentage of hypertensive population has concomitant thyroid diseases, more common in women （50-70 years）. Systematic surveillance for occult thyroid dysfunction in patients with hypertension could prevent future cardiovascular disease.

The role of iron homeostasis in remodeling immune function and regulating inflammatory disease

The essential trace element iron regulates a wide range of biological processes in virtually all living organisms.Because both iron deficiency and iron overload can lead to various pathological conditions,iron homeostasis is tightly regulated,and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease.In recent years,significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system.Here,we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease,processes in which both the host and the pathogen compete for iron.We also discuss the evidence and implications that immune cells such as macrophages,T cells,and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions,in which iron serves as a co-factor in toll-like receptor 4(TLR4)signaling,mitochondrial respiration,posttranslational regulation,and epigenetic modification.In addition,we discuss the therapeutic implications of targeting ferroptosis,iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection,controlling inflammation,and improving the efficacy of immunotherapy.

Immunosenescence and age-related viral diseases

Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing.Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly.Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process.Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity.However,it is unclear which of these defects are critical for impaired immune defense against infection.This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing.

Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells

Multiple sclerosis(MS) is an autoimmune disease of the central nervous system(CNS), with focal T lymphocytic infiltration and damage of myelin and axons. The underlying mechanism of pathogenesis remains unclear and there are currently no effective treatments. The development of neural stem cell(NSC) transplantation provides a promising strategy to treat neurodegenerative disease. However, the limited availability of NSCs prevents their application in neural disease therapy. In this study, we generated NSCs from induced pluripotent stem cells(iPSCs) and transplanted these cells into mice with experimental autoimmune encephalomyelitis(EAE), a model of MS. The results showed that transplantation of iPSC-derived NSCs dramatically reduced T cell infiltration and ameliorated white matter damage in the treated EAE mice. Correspondingly, the disease symptom score was greatly decreased, and motor ability was dramatically rescued in the iPSC-NSC-treated EAE mice, indicating the effectiveness of using iPSC-NSCs to treat MS. Our study provides pre-clinical evidence to support the feasibility of treating MS by transplantation of iPSC-derived NSCs.

IL-18 maintains the homeostasis of mucosal immune system via inflammasome-independent but microbiota-dependent manner

Inflammasomes and their product interleukin 18(IL-18)play important roles in gut microbiota monitoring and homeostasis,and their loss of function could lead to microbiota dysbiosis and accelerate disease progression.However,the impacts of the resulting microbiota dysbiosis on the mucosal immune system are largely unknown.Here,we show that dysbiotic microbiota from Il18^(-/-)mice induced immune cell loss in the small intestine(SI)in an inflammasome-independent manner.Cohousing experiments revealed that the immunotoxic phenotype of these microbiota was transferable to wild type(WT)mice and induced immune cell death through the receptor-interacting protein kinase 3(RIP3)-mixed lineage kinase domain like pseudokinase(MLKL)pathway.Analysis of microbiota composition identified two types of bacteria at the genus level,Ureaplasma and Parasutterella,that accumulated in Il18^(-/-)mice and negatively mediated changes in immune cells in the SI.Furthermore,dysbiosis in Il18^(-/-)mice also contributed to increased susceptibility to Listeria infection.Collectively,our results demonstrate that IL-18 is essential to microbiota homeostasis and that dysbiotic microbiota could significantly shape the landscape of the immune system.