老年醫(yī)學(xué)：老年免疫學(xué)

1、老年免疫學(xué),Background,the population of the world age 60 or older will be 2 billion （20億）by 2050. where more than 30% of the population is expected to be age 60 or older in 2050 in china it will of course be necessary to devote more resources to the care and health of the elderly. it will benefit by adop

2、ting programs that aim to diminish behaviors that lead to chronic conditions.,Source Data: United Nations, 2009,Population and Fertility Rate,Chinas total fertility rate fell from around 6 in 1950-1970 to 2 in 1990-1995. The fertility rate was below 2 by 1995. The decline, which was especially rapid

3、 between 1970 and 1980,深入研究老年免疫的特征、與疾病的相關(guān)性，對老年性疾病的診斷、預(yù)防和治療具有重要意義。,老年免疫的特征 典型老年疾病的預(yù)防和治療,Immune system,Immune organs and tissues central: bone marrow, thymus peripheral: lymph node, spleen, mucosal-associated lymphoid tissue Immunocytes innate immunity: M, NK, DC, granulocyte, etc adapted immunity: ly

4、mphocyte Immunological molecules Classified based on structure cytokines/chemokines and their receptors complements and their regulatory molecules differentiation antigens (CD antigen) adhesion molecules products of TCR, BCR, MHC genes Classified based on function molecules in immunocyte differentia

5、tion molecules in inflammation; molecules in antigen-recognition and costimulation molecules in signal transduction for immunocyte activation molecules in apoptosis and cell death,免疫學(xué)基礎(chǔ),識別,活化,效應(yīng),抗原（Ag）雙識別體液免疫 抗原提呈細(xì)胞（APC）雙信號細(xì)胞免疫,Immunity 2006, 24: 677-688,1）免疫調(diào)節(jié)功能（Th1、Th2、Tr） 2）特異性殺傷功能（CTL、Th1、gd T）,

6、T細(xì)胞的功能,CTL對靶細(xì)胞的特異性殺傷,效靶細(xì)胞的結(jié)合 CTL的極化 殺傷靶細(xì)胞,CTL直接殺傷靶細(xì)胞,穿孔素/顆粒酶 Fas/FasL, TNFR/TNF,三大功能： 產(chǎn)生抗體：中和作用，調(diào)理作用 提呈抗原：專職APC，籍BCR結(jié)合可溶性抗原 分泌細(xì)胞因子：參與免疫調(diào)節(jié)，炎癥反應(yīng)，造血過程,B細(xì)胞功能,免疫器官和細(xì)胞的發(fā)育分化有其鮮明特征,胸腺是T細(xì)胞發(fā)育的重要器官,胸腺對衰老敏感,胸腺對衰老很敏感,免疫器官和細(xì)胞的發(fā)育分化有其鮮明特征,CLP,DN,Pre-TCR,DP,TCR,CD4,CD8,CD4SP,TCR,CD4,陽性選擇,陰性選擇,TCR-b rearrangement,TCR

7、-a rearrangement,TCR,CD8,CD8SP,雙陰性,雙陽性,單陽性,基因重排，陽性/陰性選擇,免疫器官和細(xì)胞的發(fā)育分化有其鮮明特征,成熟T細(xì)胞在外周進(jìn)行 進(jìn)一步分化,Innate immunity Adaptive immunity,Memory T cell frequency, pathogen susceptibility and mortality throughout human life,There is an increase in the frequency of memory T cells in the blood (red line) over time

8、. In the whole body, which includes the blood, intestines, lungs, skin, liver, brain and lymphoid tissues, the overall frequency of memory T cells (black line) also increases with age. The increase in memory T cell frequency throughout the body inversely correlates with a decreased susceptibility to

9、 pathogen infection (dashed line),At birth, all T cells in the peripheral blood are naive, and memory T cells develop over time in response to exposure to diverse antigens. A marked increase in the proportion of circulating memory T cells occurs in the first decade of life memory T cells constitute

10、up to 35% of circulating T cells by the end of the second decade of life During this initial memory generation phase, particularly during infancy and early childhood, individuals have the highest susceptibility to pathogens, as measured by infectious disease hospitalization rates,memory homeostasis,

11、 begins in the third decade of life, when circulating memory T cell frequencies reach a plateau and remain stable throughout adulthood Thymic output gradually decreases during this phase and T cell numbers are mostly maintained through homeostatic cell turnover Individuals in these middle years of l

12、ife are less susceptible to pathogens, as shown by the low hospitalization rate of infectious diseases,After decades of stable memory T cell frequencies, the proportion and the functionality of memory T cells becomes altered during immunosenescence, starting at 6570 years of age Immunosenescence（免疫衰

13、老） also marks an increased susceptibility to pathogens that is partly caused by age-associated immune dysregulation and non-immune-related physiological decline,老年免疫的特征 典型老年疾病的預(yù)防和治療 老年帶狀皰疹的預(yù)防性疫苗與免疫治療 老年癡呆癥的免疫學(xué)治療 老年心血管疾病的治療,Immune therapy for age-relateddiseases,three of the most important diseases o

14、f aging: shingles, Alzheimers disease and atherosclerotic cardiovascular disease. all of these diseases have significant immunological components in either their etiology（病因?qū)W） and/or progression, suggesting that appropriate immune intervention could be used in their prevention or treatment,帶狀皰疹的預(yù)防,針

15、對老年三大疾病之一的帶狀皰疹疾病的預(yù)防性疫苗-帶狀皰疹疫苗于2006 年在美國上市，并被推薦用于大于60 歲免疫力健全的老年人，通過隨機(jī)對照及長期隨訪，證實(shí)了該帶狀皰疹疫苗的短期和長期安全性。,Development of a VZV vaccine for shingles,Shingles is manifested by a painful, vesicular skin eruption usually limited to the distribution of a single sensory nerve arising from its dorsal ganglion（背側(cè)神經(jīng)節(jié)

16、）. The lifetime risk of shingles is 33%, with the disease most often affecting persons over 60 years of age. Up to 20% of patients with shingles develop debilitating（衰弱）, postherpetic neuralgia（帶狀皰疹后神經(jīng)痛） (PHN), and the risk of this complication increases with age over 60. The pain of PHN occurs in t

17、he same distribution as the rash of shingles but can persist for months or even years after the rash of shingles has disappeared.,both laboratory and clinical observations have proven that shingles（帶狀皰疹） and chickenpox（水痘） are caused by the same virus, now termed the VZV（水痘帶狀皰疹病毒）. the relationship

18、between increasing age and the increasing incidence of shingles with 1 child in 1000 under 5 years old developing shingles. Between 5 and 20 years of age, the incidence of shingles doubles and remains at this level until 50 years of age. there is a linear increase in the incidence of zoster from 2 p

19、er 1000 at 50 years of age to 10 per 1000 at 90 years of age.,The frequency of VZV-responding T cells within the peripheral blood mononuclear cells (PBMCs) in 60- to 87-year old individuals is lower than in younger individuals. it was subsequently shown that an age associated decline in VZV-specific

20、 T cells (Figure 1a) and not the level of VZV-specific antibodies correlated with the increasing incidence of shingles.,VZV-specific T-cell proliferation, production of interferon g (IFN-g), or generation of major histocompatibility complex (MHC) class I restricted VZV cytotoxic T cells, was lower i

21、n older than in young people,their frequency remained higher for 6 years than their preimmunization frequency,VZV responsive PBMC frequency in elderly recipients immunized with live attenuated Oka strain varicella vaccine. Vaccination results in prolonged elevation of VZV specific PBMCs above preimm

22、unization levelsThe level of VZV responding T cells in immunized elderly individuals was 85% of the level of VZV-responding T cells in young adults.,A study examining nearly 40 000 aged adults raised the hope that the risk of shingles and PHN could be reduced after immunization Vaccination significa

23、ntly reduced the burden of illness by 61% in the total population studied. There was also a significant reduction of 51% in the incidence of shingles, and the incidence of PHN was reduced by 60%. There was no evidence that shingles in vaccinated subjects was caused by the attenuated VZV in the vacci

24、ne. Finally, a substudy from this trial demonstrated that vaccination boosted VZV-specific antibody and cell-mediated immune responses (as measured by IFN-g). These responses persisted during a 3-year follow-up and the immunological response paralleled the clinical effects of the vaccine,Anti-amyloi

25、d b peptide therapy for AD,In 1907, Alois Alzheimer reported cerebral pathology characterized by microscopic circular lesions, plaques（斑塊）, in the brain of a patient with dementia（癡呆） the disease is the most common cause of dementia and affects 5 million persons in the United States. 1% of 65 year o

26、lds have AD, and this percentage increases to nearly 50% in persons over 85 years of age. the accumulation of A b in the brain is caused by an impaired capacity to clear A b from the brain.,The gene coding for the amyloid peptide (A b) is located on the 21st human chromosome. the DNA sequence that c

27、odes for the A b peptide is a small portion of a much larger gene that encodes a transmembrane amyloid precursor protein(APP). APP is cleaved by two enzyme complexes, b and g secretases, to release the A b peptide. A causal link between A b and AD was first suggested by finding that patients with ea

28、rly onset AD had either an extra copy of an unmutated APP gene (trisomy 21) or mutations in either the APP or presenilin genes. The presenilin genes encode components of the enzyme complex that cleave A b from APP. introducing a mutant human APP gene from a patient with hereditary AD into the murine

29、 genome (APP-transgenic mouse) led to the appearance of cerebral A b plaques and cognitive decline(認(rèn)知下降）,Anti-A b peptide immunotherapy of AD: studies in vitroand in vivo,Active immunization of APP-transgenic mice with A b peptide in complete Freunds adjuvant was shown to prevent or reverse cerebral

30、 amyloid plaque deposition in young or middle-aged AP passive immunization of APP-transgenic mice with anti-A b peptide antibodies was shown to clear cerebral amyloid deposits within a month.,Figure 2. Peripherally administered antibodies against amyloid b (A b)-peptide can cross the bloodbrain barr

31、ier and decrease brain A b deposits in an Alzheimers disease model of mice. Quantification of diffuse amyloid and small plaques shows a 60% reduction between 3- and 35-day treatment groups (n = 10/group,In a phase I study of active immunization of 80 AD patients with Ab peptide, no significant toxic

32、ity was observed, although 60% of the patients developed a significant anti-A b antibody response. A subsequent phase II study of active immunization with A b peptide in 300 AD patients had to be interrupted because encephalitis was diagnosed and eventually affected 6% of A b peptideimmunized patien

33、ts. Brains from some of those patients were studied at autopsy and found to have perivascular infiltration of T cells. This suggested that a T-cell epitope expressed on the A b peptide had stimulated a T cellmediated form of encephalitis（腦形成）.,Immunological approaches to the treatment of atheroscler

34、osis,Atherosclerosis is an immune disease, this age-associated disease is caused, in part, by an inflammatory thickening of arterial walls, leading to their narrowing and ultimately obstruction causing heart attacks and strokes. A key antigen, OxLDL（氧化型低密度脂蛋白）, stimulates immune and inflammatory rea

35、ctions within arterial walls The severity of atherosclerosis reflects a balance between protective auto-antibodies, such as anti-OxLDL antibodies, produced by B lymphocytes and pathogenic inflammatory cytokines produced by T cells and monocytes within the vessel wall,Figure 4. Splenectomy （脾切除術(shù)）(Sx)

36、 increases atherosclerotic lesion size in Apo-E knockout mice. Adoptive transfer of whole spleen cells or purified B cells protects against atherosclerosis by reducing lesion size, whereas adoptive transfer of T cells alone is equivalent to sham thymectomized Apo-E knockout mice. B cells therefore account for the atherosclerosis protective effects of splenocytes, probably because of the production of anti-OxLDL (oxidized low-density lipoprotein) antibodi,Figure 5. Immunization with phosphorylcholine (PtdCho) conjugated to the antigen Keyhole limpet hemocyanin (KLH) reduces atheroscleroti