The Nature of Immunity

免疫學與藥用植物研究實驗室 楊文欽老師 電話 : 02-27855696 或 02-27899800 轉8101 (實驗室) 電話 : 02-27888340(辦公室) 傳真 : 02-26515120(辦公室) Email : wcyang@gate.sinica.edu.tw Website : www.sinica.edu.tw/~ibswcy 參考書 : Immunology 5e, Kuby 講義 ： ppt slides 上課內容 : 免疫學課程大綱 Introduction to Immunology Outlines • Historical review • Immunology is a branch of biology • Immunity • Composition of the immune system • Immune responses • Immune disorders 自體免疫（autoimmunity） 過敏（hypersensitivity） 免疫不全（immunodeficiency） • Innate vs adaptive • immunity vs humoral • Immune cells • Soluble mediators Historical review • Vaccination/ Variolation • In 1718, Lady Mary Wortley Montagu, dried crusts from smallpox (variola) to be inhaled into the nostrils or inserted into the skin. (variolation) • Improved by Edward Jenner in 1798, he used fluid from a cowpox to be pustuled into people and found that cowpox virus (vaccinia) can prevent people from smallpox infection (vaccination). • Vaccine • ~1880, Louis Pasteur can culture the bacterium, a causative agent for fowl cholera • The attenuated pathogen would immunize and not cause disease, called vaccine Immunology is formed…. • 1881, Pasteur, first vaccinated one group of sheep with heatattenuated Bacillus anthracis • 1885, Pasteur, the first vaccine for human against rabid dog • 1890s, Emil von Behring and Shibasaburo Kitasato, first insight into the mechanism of immunity - serum Immunity Humoral and cellular immunity • Humoral immunity • 1930s, Elvin Kabat, gamma-globulin • The active molecules in immunoglobulin fraction, antibodies, contained in body fluid • Cellular immunity • 1883, Elie Metchnikoff, observe phagocytes • Cell-mediated immunity • 1950s, lymphocytes, the cell responsible for both cellular and humoral immunity Early immunity theories • Selective theory • Interaction between an infectious agent and a cellbound side-chain receptor would result in release of the side chain and would induce the cell to produce and secrete more side-chain receptor with the same specificity • 1950, clonal-selection theory • Instructional theory • Antigen played a central role in determining the specificity of the antibody molecule. The Nature of Immunity - Immunity was originally used to indicate exemption from taxes and this meaning still exits in the term "diplomatic immunity". • 免疫系統保護人體免於受病源體侵入。 • 免疫反應(immune response, immunity)可分為 - 先天性（innate, natural or non-adaptive ） - 應變性（adaptive immune response） • 應變性免疫反應主要特徵: 專一性（specificity）、記憶性（memory）及自我辨 識（self-discrimination）為 Innate immunity – resistance mechanisms are not specific to a particular pathogen Adaptive immunitya high degree of specificity as well as the remarkable memory property • Antigenic specificity • To distinguish subtle difference among antigens • Diveristy • To recognize billions of uniquely different structures on foreign antigens • Immunologic memory • A second encounter with the same antigen induces a heightened state of immune reactivity • Self/nonself recognition • To respond only to foreign antigens Immune System Composition of the immune system I. Immune cells and soluble mediators Immune cells - 專一性及非專一性辨識細胞組成。 • 吞噬細胞 (phagocytes)： • • 單核吞噬細胞 :單核球，mononuclear phagocyte; 進入組織發育成巨噬細胞 （macrophage）。 多形核嗜中性細胞 : 嗜中性白血球 (polymorphonuclear neutrophil);嗜酸性白 血球 (eosinophil) • 淋巴球細胞 (lymphocytes)： • • B細胞（B lymphocyte） • T細胞（T lymphocyte）：T-helper Cell（TH）、T-cytotoxic Cell（TC） • 大顆粒淋巴球（large granular lymphocyte，LGL）：natural killer cell（NK）。 輔助細胞（auxiliary cells） • 嗜鹼性白血球（ basophil ） • 肥大細胞（mast cell） • 血小板（platelet） • 組織細胞 (Tissue cell) 抗原呈現細胞 (antigen-presenting cell, APC) Soluble mediators in the immune system • 抗體（antibodies，immunoglobulins） • 調理素（opsonin）進行調理作用 （opsonization） • 細胞激素（cytokines）： •免疫反應進行時，傳遞各細胞間 訊息的一群大分子，稱之。 •為蛋白質、或醣蛋白，如干擾素 （interferons，INFs）、間白素 （interlukins，ILs）、株落刺激 因子（colony stimulating factors， CSFs）、腫瘤壞死因子（tumor necrosis factors，TNF）及轉型生 長因子（transforming growth factor，TGF）。 • 補體蛋白質（complements）： •血清蛋白，調節吞噬作用、控制 發炎反應、與抗體相互作用參與 免疫防禦（專一性防禦）。 Composition of the immune system II. Lymphoid tissues : lymph nodes and lymph ducts Immune system Tonsils Right lymphatic duct Subclavian veins Thymus Spleen Peyer’s patches Appendix Bone marrows Lymphatic vessels Lymph nodes Thymus Immune Responses What happens upon antigen exposure? B lymphocytes T lymphocytes Virgin lymphocyte pool Infection or injection PRIMARY RESPONSE effector cells memory cell pool SECONDARY RESPONSE effector cells memory cell pool Activated T lymphocytes Plasma cells Regulatory T Cytotoxic T Antibodies Summary of the phases of the immune response Time Immediate 0-4hrs Innate Early 4-96hrs Innate (inducible) Late >96hrs Specific Type Key Complement molecul Histamine,etc es Key cells Macrophages Mast cells Neutrophils Complement IL1,TNFalpha, IL12, IFNa/b, MBP, CRP Macrophages Neutrophils NK cells IgM and IgG Abs IL2,IL4,IL12,IFNg Macrophages T cells B cells Where is that stuff? Blood Serum or Plasma Leukocytes, Platelets and RBC Serum Proteins Mononuclear Cells Polymorphonuclea r leukocytes (or Granulocytes) •Immunoglobulins •Complement •Clotting factors •Many others •Lymphocytes (T cells, B cells & NK cells) •Monocytes •Neutrophils •Eosinophils •Basophils Response of immune system • 專一性（specificit）： • 記憶性（memory）： • • 對外來物之間化學性質微小的不 同具有顯著的辨識能力。 專一性（specificity）、記憶性（memory）及自我辨識（self-discrimination） • 受外來物質感染後，能演變出對 外來物特性的記憶，此種特性可 能可以持續一生。 個體受感染後，先後產生免疫反 應稱為primary response及 secondary response，經過此免疫 反應後，個體會產生具有記憶性 的細胞，進而對相同之病源體產 生記憶性之對抗。 • 自我辨識（selfdiscrimination）： • 如器官移植或輸血時產生的排斥 現象。 Biological events of immune system 免疫系統中的事件： recognition of the target pathogen effective defence against the pathogen Recognition unit： 如抗體分子、TCR（T細胞表面受體，T Cell Receptor）。 Defence unit： 如T細胞、mast cell或其他具有抗體受器之免疫 細胞。 形式： Combined recognition and defence unit：僅具有 單一辨識特異性，如T細胞的作用。 Separate recognition and defence unit：具有多種 不同的辨識特異性，如免疫球蛋白的作用。 Immunological recognition 抗原的辨認是所有應變性免疫反應的 基礎。 抗原與少數可以辨認它的細胞結合後， 可誘導細胞迅速增殖，即抗原能選擇 對本身產生專一結合之細胞株落，此 種過程稱之為株落選擇（colonal selection）。 • Antibodies（immunoglobulins）：與抗原 結合之作用。 • 抗原：可以誘導B細胞產生抗體之分子or可被 • 應變性免疫系統中之組成細胞專一性辨識之 分子。 抗原決定部位（epitope）：抗原與抗體結合 之特定部位。 Antibody-dependent cytotoxicity • T lymphocytes • 細胞受感染會將病源體之一小段蛋白表 • 現在細胞表面上，T細胞就能辨認出來。 將抗原片段表現出來的細胞稱之為抗原 呈獻細胞（antigen presenting cell， APC）。 位於抗原呈獻細胞表面，用來呈獻抗原片段的 分子稱為主組織相容復合體（major histocompatibility complex，MHC）。 Immunological defence -Lysis or digestion：the successful elimination of pathogens • • • • 中和作用（neutralization） 吞噬作用（phagocytosis） 毒殺作用（cytotoxic reaction） 細胞自殺作用（apoptosis） Inflammation :紅、熱、腫、痛  受感染部位血流量增加。  微血管通透性增加，使原 無法通過的大分子通過內 皮細胞，使免疫反應之可 溶性物質到達感染部位。  白血球離開微血管進入周 圍組織 – Influx of phagocytes • 趨化作用（chemotaxis）藉由 白血球表面分子(L-selectin)與 活化之內皮細胞(P- and Eselectin)間的交互作用，使細 胞向感染部位移動的作用。 • 細胞遷移作用： margination（selectinmediated，integrin-mediated） and extravasation (diapedesis)。 Immunopathology 自體免疫（autoimmunity） 過敏（hypersensitivity） 免疫不全（immunodeficiency） Evolution of the immune system • The most ancient immune defenses lie within the innate immune system Drosophila spp. Have well developed innate immune system The first defense molecules in evolutionary terms were probably antimicrobial peptides, produced by plants and animals • • Evolution of the immune system • • Adaptive immunity appeared abruptly in the cartilagenous fish It’s been known for 50 years that all jawed fish can mount an adaptive immune response hagfish and lampreys lack all signs of an adaptive immune system; no organized lymphoid tissue, no immunological memory • Evolution of the immune system in fish Primary lymphoid organs in fish • Hagfish does have T cells. Pronephros may be equivalent to thymus and bone marrow in fetus. In adults, nephrostomes may be the equivalent to the thymus. Central mass and/or spleen are the equivalent to bone marrow for erythropoiesis, macrophage and plasma cells. • Fish don’t have bone marrow. Therefore, hematopoiesis and lymphopoiesis occurs in different organs of fish. • Fish except for cytclostomes (hagfish and lamprey) do have a thymus. Secondary lymphoid organs in fish • The secondary lymphoid organs in fish are mainly spleen (It appears for the 1st time in amphibians) and GALT (It appears for the 1st time in agnatha). • Fish do not have lymph nodes (LN appears fro the first time in birds ) and lymph ducts (they appear for the first tiem in amphobians). • Ag can be captured from gill, skin, gut, spleen, kidney lateral lines and melanomacrophage centers (MMC, located in kidney, liver, spleen and so on). Bone marrow equivalent in fish Agnathostomate/cyclostomes fish : central mass or spleen Immune system in zebrafish Swim bladder pancreas liver Swim bladder pancreas liver Immune cells : T, B, granulocytes, thrombocytes, erythrocytes and melanomacrophage (monocyte/macrophages), NK Soluble mediators : antibody (IgM, IgD), CRP, complement, cytokines Lymphoid organs : Thymus : T cell development Pronephros : hematopoiesis and B cell development (= BM in mice) Pancreas : has similar role in B cell differentiation as fetal liver and spleen Of neonatal mice. Spleen : erythropoiesis GALT : few fishes may have peicular GALT, different from the equivalent in mammals . Jaw hypothesis. Location of lymphocytes and phagocytes 1. T cells can be detected in the thymus (~80%) and intestine (~55%) and fewer cells in the spleen (~7%), head kidney (~6%) and peripheral blood (~3%) in sea bass. 2. B cells are detected in the head kidney (~33%), spleen (~30%) and peripheral blood leukocytes (~21%) and fewer positive cells in the intestine (~3%) and thymus (~2%) in sea bass. 3.Fishes do not have specialized lymph nodes. Spleen, intestine and pancreas are related to the function of LNs in fish. Thymus and pronephros are lymphoid organs for T and B cell development in fishes. Pancreas is for the development of early B cell development. 4. Phagocytic cells are present in the endothelial lining of the atrium of the heart and in the gill lamella. There are no phagocytic cells (Kupffer cells) in the liver. Melanomacrophage centers are present in the liver, kidney and spleen. Comparison of the immune system between teleosts and mammals Fish mammals T cell development Thymus (+) Thymus (+) B cell development Pronephros(+) B1 and B2(+) - (spleen, instestine and pancreas contain T and B cells ) Imcomplete (+/-) Bone marrow (+) + + Lymph nodes GALT(gut-associated lymphoid tissues) Mucosal immunity Immune cells : + Poorly developed T, B, granulocytes, thrombocytes, erythrocytes, melanomacrophage, NK antibody (IgM, IgD), CRP, cytokines Strong complement activity Both are located in different chromosome Well developed + (kupffer cells in liver) Soluble mediators : Better Ig switch (IgM,D,A,G,E), affinity maturation memory Both are located in the same chromosome MHC I and II