Marion1

He will cover the immune system. Today’s lecture introduces the way it functions, originates, is organized, and provides background so that you can read and learn on your own. He will post on blackboard his notes. Much of lecture will be drawn on the blackboard in the room.
What is system for?
1. major function is to protect against pathogens(protection from infection)- sometimes must kill cells of self to eliminate virus.
2. surveillance to eliminate tumorigenic cells
3. tolerance to self (protects against autoimmunity)
4. self- control (protects against over-inflammation, over-multiplication of immune cells)
To protect against infection, must recognize potential pathogens. (See slide with graph of number of bacteria vs. time)
There is innate recognition and acquired recognition. Receptors allow the cell to know there is a pathogen around. Our health depends on both. Without innate immunity, the mouse (or a person) is completely susceptible to infection without ability to get rid of it. With innate but without acquired immunity, you can deal for a while, but eventually get overwhelmed (bubble boy).
Normal function- organism grows for a bit, but we get rid of it eventually.
How do the 2 systems work?
Tomorrow- innate immune function.
Way innate works- see paper. Pathogens are detected as a class. Recognition based on expression of molecules necessary to pathogen’s function, mostly on surface. Example in viruses, dsRNA. This response is fast. Receptors are all encoded in germ line and expressed on every immune cell of a particular type. Germ line receptors do not involve somatic manipulation. Non-clonotypic- every phagocyte has same types of receptors and same ability to respond. This response is quick. Innate response initiates adaptive immune response and maintains immune tolerance.
Disadvantage of innate response:
not efficient enough at clearing an infection. Adaptive immunity can focus the response initiated by innate immune response.
limited specific recognition because receptors are not designed for specifics- designed for pattern recognition. Microorganisms change over time. (limited diversity)
What does adaptive immunity have that innate does not? immunological memory. This is most important difference. Why important? secondary response. Enables us to eliminate diseases with vaccines.
Adaptive immunity- major functional difference from innate immunity- how receptors are generated. Innate encoded in germ line. Adaptive are somatically derived from same genetic information everyone inherits- used differently in each cell making receptors, resulting in incredible diversity. Receptors are highly specific to target a single epitope within a molecule. Also clonotypic- any given immune cell has only one type of receptor, and all its derivatives will be specific for one specific determinant.
Adaptive immunity focuses innnate immune response.
Has memory to maintain protective immunity.
Ablity to generate response to any antigen includes determinants that are self. Immune system culls cells specific to self.
Disadvantages of adaptive immunity:
autoimmunity
time (slow- takes time to clone cell)
memory is specific, so if pathogen changes, you don’t remember it (flu)
How and where immune cells and tissues develop:
1. hematopoiesis:
He will post diagram on blackboard. Schematic of hematopoeisis:
in neonate, hematopoiesis in liver. Embryo- in yolk sac in blood islands in chicken. This pattern exists in mammals. In embryo, develop in fetal liver. Then shifts to bone marrow at birth.
Precursor: HSC- hematopoietic stem cell. It divided to generate precursors and another of itself. 2 forms: long term HSC (used to reconstitute immunodeficient individual through bone marrow transplant- gives rise to short-term. Usually quiescent. Signals only partially understood – at surface of bone marrow stromal cells and cytokines push differentiation) and short term HSC. CLP- common lymphoid progenitor. Short-term HSC differentiates into common lymphoid or common myeloid progenitor.
CLP can diff into B lymphocyte, T lymphocyte, or NK (natural killer). Lymphocytes are responsible for adaptive immunity.
B lymphocyte produces antibody.
T lymphocyte can differentiate to cytotoxic T cell (kills virus-infected cells), helper T cells ( 2 types: helper T cell and inflammatory T cell.Differ in induced response).
NK cell- innate immune cells. No clonotypic receptors. receptors recognize self molecule on cells and are triggered by decreased expression or absence of self molecules.
Generation of these occurs in bone marrow. B cells in mammals come out of bone marrow fully mature. T cells come out as pre-T cells which must migrate to thymus to undergo differentiation and selection. Bone marrow and thymus are central lymphoid organs. Function is to generate functional lymphoid cells. Derivation of term T cells and B cells is from early studies of development in chickens. Discovered in 1940s. B cells mature in bursa of fabricius (outpocket of cloaca) in chickens. T cells mature in thymus.
B cells produce antibody (Ab).
Common myeloid progenitor yields MEP(megakaryocyte/erythrocyte progenitor) and GMP(granulocyte/ monocyte progenitor).
Granulocytes are PMNs. Monocytes become macrophages in tissues. Eosinophils, basophils , and maybe mast cells come from GMP. These are innate immune cells. All carry innate immune receptors and have potential to eliminate pathogens. Neutrophils,Monocytes, Eosinophild are phagocytic "to eat cells"- they engulf pathogens by opsonization.
Basophils- function still obscure. Mast cells live in tissues and make you miserable. Mediate inflammation through histamine. Important to mobilize innate and adaptive cells to deal with pathogen.
Inflammation is an innate immune response that mobilizes innate and adaptive immune cells. When innate cells encounter an infection, they cause leaky vessels, microclots, accumulation immune cells and fluid, flushes into afferent lymphatics to push into peripheral lymphoid organs to see if need to mount an immune response.
Another term
cytokine- soluble protein secreted by innate and adaptive immune cells to alter function of other cells. Cell-to cell communication about response.
interleukin or IL are a kind of cytokine. Mostly between lymphocytes, though monocytes use them, too.
CD antigen- means cluster of differentiation. They are cell surface proteins used as markers to ID a particular kind of cell.
CD34,CD45, ckit markers identify HSC.
C19, CD20, CD40, Ig identify B cells.
CD34, CD45, CD2, CD25, CD3, CD4, CD8, CD128, CD154 can identify T cell or T cell precursor.
CD11, CD80, CD86 ID monocyte macrophage or dendritic cells (from GMP- not effector cells for destruction- they stimulate adaptive immune response)
What happens to cells after they are produced?
Thymus is located just over heart in chest cavity. T cells differentiate there and enter peripheral lymphoid system.
Peripheral system: spleen, lymph nodes (sample fluid from Afferent lymphatics(open fluid-collecting vessels)) Lymphoid cells are exposed to potential antigens in lymph nodes. Maximizes exposure of lymph cells to antigen.
Why is immune system designed so the antigen is delivered to lymphocytes in lymph node? Why not deal with it at the site of infection? Site of memory cells is lymph node. The process would be more destructive with more imflammation if handled at site of infection. Activated cells leave lymph node via efferent vessels which coalesce at thoracic duct to reenter circulation. Effector cells can go into infected tissue via circulation.
First time cells enter lymph nodes- enter via high endothelial venule. (HEV)- receptors for non-activated cells.Activated- lose receptors on surface and leave. Lymph nodes filter body fluid (lymph). New ones come in an artery, then HEV, then go to specific areas. T cells go to paracortex. B cells go to cortex and form follicles. T cells migrate in and out. B cells stuck until activated, then migrate out to bone marrow as plasma cell and produce antibody for long periods of time.T cells recirculate.
Dendritic cells display antigens from pathogens to T cells in paracortical area of lymph node. B cells sample fluid and are activated with help of T cells.
Spleen similar- blood filter. Few lymphatics here, but filters blood instead of lymph. Blood in through arterioles into marginal sinus and red pulp. Pools into venous sinuses in spleen. Leaves spleen through venous circulation. Lymphocytes are organized around arteriole and there is region called PALS (Periarteriolar lymphoid sheath-T cell zone)-adjacent are follicles with B cells, then surrounded by marginal sinus or marginal zone with macrophages and dendritic cells to sample fluid. Most lymphocyte migration is within white pulp. Activated T cells can enter circulation. Only B cells leaving would be activated ones. See paper and slides for details. There are some details on blackboard as well.