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97 Cards in this Set
- Front
- Back
- 3rd side (hint)
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What are the features of the innate immune system?
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A PRIMITIVE SYSTEM CONSERVED THROUGH EVOLUTION
Inborne, not learned RAPID RESPONSE- MINUTES TO HOURS USES PRODUCTS OF GERM-LINE GENES NOT SPECIFICALLY DIRECTED AGAINST THE INVADING PATHOGEN – LOW SPECIFICITY – RECOGNIZES PATTERNS (potential for collateral damage) c.f. Adaptive immunity: exquisite specificity minimizing collateral damage NO IMMUNOLOGICAL MEMORY (unlike adaptive immunity) |
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What are the functions of the normal microbiota?
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COMPETITION FOR NUTRIENTS
COMPETITION FOR RECEPTORS PRODUCTION OF ANTAGONISTS MAINTAINENCE OF LOW BUT CONSTANT EXPRESSION OF MHC II ON MACROPHAGES AND OTHER APC STIMULATION OF CROSS-PROTECTIVE ANTIBODIES e.g., THE CAPSULE OF E. coli K1 & N. meningitidis ARE IDENTICAL |
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EPITHELIAL DAMAGE:
RESULTS IN UP-REGULATION & RELEASE OF: |
INFLAMMATORY/IMMUNE REGULATION
IL-1α, IL1β,IL-6, IL-10, IL-33, TNF-α, TNF-β, LIF CHEMOTACTIC FACTORS IL-1α, IL1β, IL-3, IL-7, LIF, TGF-α TGF-β, PDGF,G-CSF, GM-CSF STRESS PROTEINS N.B. Components secreted from live, or liberated from dead or dying microorganisms trigger signaling receptors, also. |
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SIGNALING PATTERN-RECOGNITION RECEPTORS
PRESENT ON CELLS OF THE IMMUNE SYSTEM (PARTICULARLY PHAGOCYTES) AND SOMATIC CELLS |
TRANSMEMBRANE (cell surface & phagosome/lysosome membrane),
TOLL-LIKE RECEPTORS (~10 types): IMMUNE SYSTEM CELLS (PMN, DC, MO/MAC, B, T, NK & SOMATIC CELLS) CD14 (receptor for LPS and LBP): PMN/MAC CYTOSOL NLR FAMILY MEMBERS (nucleotide oligomerization domain-like receptor) NOD1 - NOD5 & CIITA (diaminopimilic acid - muramyldipeptide) ISD SENSOR (DNA) RIG-1/MDA5 (RNA helicases) sense viral RNA NALP1 - 14 (LPS, pore-forming toxins; type III and IV bacterial secretion systems) (NALP3 INVOLVED IN FORMATION & ACTIVATION OF INFLAMMASOMES – IL1β & IL-18) |
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ENDOCYTIC PATTERN-RECOGNITION RECEPTORS (PPRs)--- Transmembrane
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TRANSMEMBRANE
C-TYPE LECTIN FAMILY DECTIN-1 (β1-3 glucan) DC-SIGN (asialoglycoproteins) MANNOSE RECEPTOR GLUCAN RECEPTOR SCAVENGER RECEPTOR FAMILY Negatively charged macromolecules, including oxidized low-density lipoproteins, damaged or apoptotic cells, and pathogenic microorganisms N-FORMYL MET RECEPTORS FPR FPRL-1 COMPLEMENT RECEPTORS |
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ENDOCYTIC PATTERN-RECOGNITION RECEPTORS (PPRs)- Soluble
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SOLUBLE
MANNOSE-BINDING LECTIN C-REACTIVE PROTEIN [PHOSPHORYLCHOLINE/PHOSPHATIDYLETHANOLAMINE] LUNG SURFACTANT PROTEINS [SP-A & SP-D HAVE CARBOHYDRATE RECOGNITION DOMAINS[] COMPLEMENT COMPONENTS [C3b, C4b] |
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What does acute inflammation do?
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DELIVERS ADDITIONAL EFFECTOR MOLECULES AND CELLS TO THE SITE(S) OF INFECTION(S)
PROVIDES A PHYSICAL BARRIER TO PREVENT SPREAD OF INFECTION PROMOTES REPAIR OF INJURED TISSUE |
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HOW DOES A LIMITED NUMBER OF PRR WITH LOW SPECIFICITY RECOGNIZE DIVERSE CLASSES OF PATHOGENS AND ACTIVATE THE APPROPRIATE BRANCH OF THE ADAPTIVE IMMUNE SYSTEM?
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CO-OPERATIVE INTERATIONS BETWEEN SEVERAL PRR
USE OF DIFFERENT ADAPTOR MOLECULES USE OF DIFFERENT SIGNAL TRANSDUCTION PATHWAYS, e.g., NF-κB, IRF family, AP-1, ATF-2, etc. FORMATION OF INFLAMMASOMES |
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WHAT ARE THE OUTCOMES OF PRR LIGATION?
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RELEASE OF PRO-INFLAMMATORY CYTOKINES
RELEASE OF CHEMOKINES UPREGULATION/EXPRESSION OF MHC I & MHC II UPREGULATION/EXPRESSION OF CO-STIMULATORY MOLECULES UPREGULATION/EXPRESSION OF CELL ADHESION MOLECULES |
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What are some of the elements of an acute phase response?
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POSITIVE APRs
MAJOR: SERUM AMYLOID A & P, C-REACTIVE PROTEIN C’ COMPONENTS: C2, C3, C4, C5, C9, B, C1-INHIBITOR, C4 BINDING- PROTEIN COAGULATION PROTEINS: FIBRINOGEN, von WILLEBRAND FACTOR PROTEASE INHIBITORS: α1-ANTITRYPSIN, α1-NTICHYMOTRYPSIN, α2-ANTIPLASMIN METAL-BINDING PROTEINS: HAPTOGLOBIN, HAEMOPEXIN, CERULOPLASMIN, MnSOD |
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What are the different stages in response to an infection?
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What are the key features/ differences in barrier epithelia?
Aka. Skin Vs. Mucosa |
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What happens during phagocytosis? What are the different steps?
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What are the key features of the ADAPTIVE immune response?
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1) Antigen Specificity - flexibility of responses, bacteria and parasites are treated differently
2) Diversity - a whole repertoire of immune cells will participate in the response 3) Self-Regulation - will turn off when infection is over 4) Immunologic Memory - will remember infections to mount better/faster response next time |
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How do immune cells communicate to one another? (There are 2 big ways)
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1) Receptor-Ligand Interactions - In this example, the T cell is recognizing an antigen being presented by a dendritic cell. The TCR - T cell receptor for antigen - is reading the antigen held by the MHC II. The adhesion CD4 is holding the cells
together to allow the interaction. The TCR also interacts with the CD3 to signal the T cell to become activated. 2) Communication by Soluble Proteins (Cytokines) - they are hormone-like signals that bind to receptors on the surface of cells and change gene expression to alter activity. This leads to differentiation, proliferation, activation/inactivation, or migration (chemokines) to where antigens have been spotted and are being destroyed. |
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define innate vs adaptive immunity
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Innate - second line of defense, non-specific, no memory, based
in reading general danger signals and uses inflammation heavily Adaptive - third line of defense, antigen specific, diversity of response, has memory, self-regulating |
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describe how antigen and lymphocytes find one another
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Antigen is connected with lymphocytes via antigen-presenting
cells (APCs) which present pieces of the digested infecting agent on the cell surface with MHC II receptors. They travel to lymph nodes to find a lymphocyte that will recognize the antigen |
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describe how antigen receptors are used by T and B lymphocytes
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Using the MHC II-bound antigen, the lymphocyte will bind. T
lymphocytes will differentiate based on environment and the infection. B lymphocytes will synthesize and release antigen specific antibodies, which can trigger a complement cascade |
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Which Immune cell (from lymphoid lineage) LACKS ANTIGEN SPECIFIC RECEPTORS? What type of Immunity does it help in?
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NATURAL KILLER CELLS
-innate immunity |
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Which immune cells are a key link between innate and adaptive immune systems? How do they do this/ what is their role?
Which lineage do they derive from? |
DENDRITIC CELLS
1. recognize PAMS with PRR 2. (immature DC) Phagocytize 3. (mature DC) antigen presentation 4. activates T cells BOTH lymphoid and myleoid lineage (mostly myleoid) |
They generally reside in the sub mucosa of:
the alimentary canal, the genitourinary tract, the respiratory tract, and the dermis in the skin — these are the areas where pathogens will first enter the body, and so dendritic cells are able to encounter antigens early, endocytose them, and present them in order to activate the adaptive immune response through T cells. In this way it is a bridge between innate and adaptive immunity, instructing naïve T cells. You DO need to activate CD4 helper T cells (of any non-Treg type) to further activate the adaptive immune system—this is why dendritic cells are crucial. So, there are two critical steps in the immune response: 1. inflammation to recruit APCs and 2. APC contact with naïve helper T-cells. |
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Where can macrophages be found? What are they derived from? Where do you find the following macrophages:
Stem cells Monocytes Residential and recirculationg macrophages Kupffer Cells Aveolar Macrophages Splenic macrophages mesangial macrophages A cells |
Stem cells- bone marrow
Monocytes- blood Residential and recirculationg macrophages- Lymph nodes Kupffer Cells- liver Aveolar Macrophages- lungs Splenic macrophages- spleen mesangial macrophages- kidney A cells- synovial joints |
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Which cells are mostly small and inactive? How could you tell with a light microscope?
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Lymphocytes
evidence of fxn inactivity: condensed chromatin, HUGE nucleus, small cytoplasm, lack of rough ER |
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Where do B cells get educated?
Describe the location and stages of B cell maturation |
In the first phase of development, progenitor B cells in the bone marrow rearrange their immunoglobulin genes. This phase is independent of antigen but is dependent on interactions with bone marrow stromal cells (first panels). It ends in an immature B cell that carries an antigen receptor in the form of cell-surface IgM and can now interact with antigens in its environment. Immature B cells that are strongly stimulated by antigen at this stage either die or are inactivated in a process of negative selection, thus removing many self-reactive B cells from the repertoire (second panels). In the third phase of development, the surviving immature B cells emerge into the periphery and mature to express IgD as well as IgM. They can now be activated by encounter with their specific foreign antigen in a peripheral lymphoid organ (third panels). Activated B cells proliferate, and differentiate into antibody-secreting plasma cells and long-lived memory cells (fourth panels).
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Where do T cells get educated?
Describe the location and stages of T cell maturation. |
T-cell precursors migrate from the bone marrow to the thymus, where the T-cell receptor genes are rearranged (first panels); α:β T-cell receptors that are compatible with self-MHC molecules transmit a survival signal on interacting with thymic epithelium, leading to positive selection of the cells that bear them. Self-reactive receptors transmit a signal that leads to cell death, and cells bearing them are removed from the repertoire in a process of negative selection (second panels). T cells that survive selection mature and leave the thymus to circulate in the periphery; they repeatedly leave the blood to migrate through the peripheral lymphoid organs, where they may encounter their specific foreign antigen and become activated (third panels). Activation leads to clonal expansion and differentiation into effector T cells. These are attracted to sites of infection, where they can kill infected cells or activate macrophages (fourth panels); others are attracted into B-cell areas, where they help to activate an antibody response (not shown).
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If you do a WBC count what would you see? What would you see the most of? Why would it be helpful to do a WBC count?
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Segmented (mature) neutrophils and lymphoctyes have largest % of total WBC.
Different subtypes can become elevated in infections, and this is why a differential is important for clinical diagnosis. |
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Out of the leukocytes, which lymphoctyes are there and which are most common in blood?
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Distribution of lymphocytes in peripheral blood. It can be seen that CD4+ T cells are most numerous followed by CD8+ T cells, B cells and LGL (Large Granular Lymphocytes) aka NK cells (Natural Killer cells).
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Looking only at lymphocytes located in the blood, about 85% are T cells (combined CD4 and CD8 populations), about 10% are NK cells (the slides also call them LGL cells), and about 15% are B cells.
*The reason you see fewer B cells is that they spend little time in the blood and are mostly located in secondary lymphoid system* |
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Where do circulating lymphocytes encounter antigens?
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In the lymph node, where does the lymph enter? Where does it exit? What areas have intense B cell proliferation (2ndy lymphoid follices)? What immune cells mostly make up the Paracortex area?
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The diagram above shows a lymph node in longitudinal section. A lymph node consists of an outermost cortex and an inner medulla. The cortex is composed of an outer cortex of B cells organized into lymphoid follicles, and deep, or para-cortical, areas made up mainly of T cells and dendritic cells. When an immune response is under way, some of the follicles contain central areas of intense B-cell proliferation called germinal centers and are known as secondary lymphoid follicles. These reactions are very dramatic, but eventually die out as senescent germinal centers. Lymph draining from the extracellular spaces of the body carries antigens in phagocytic dendritic cells and phagocytic macrophages from the tissues to the lymph node via the afferent lymphatics. These migrate directly from the sinuses into the cellular parts of the node. Lymph leaves by the efferent lymphatics in the medulla. The medulla consists of strings of macrophages and antibody-secreting plasma cells known as the medullary cords. Naive lymphocytes enter the node from the bloodstream through specialized post-capillary venules (not shown) and leave with the lymph through the efferent lymphatic. The light micrograph shows a transverse section through a lymph node, with prominent follicles containing germinal centers.
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The AFFERENT lymphatic vessel is where dendritic cells enter carrying pathogen that they have taken up in the periphery, displaying antigen from the pathogen on their surface so that they will activate naïve T lymphocytes.
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When you are sick, what is causing this to happen in a lymph node?
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Intense B cell proliferation in the lymph node (in the germinal centers) accounts for the swelling.
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The spleen and lymph have a lot in common (both structure and fxn). Name some things they have in common...
Most importantly what is the KEY DIFFERENCE between the LYMPH NODE and SPLEEN? |
Spleen has no lymphatic supply or drainage. Only BLOOD supply and drainage.
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The schematic at top left shows that the spleen consists of red pulp (pink areas), which is a site of red blood cell destruction, interspersed with the lymphoid white pulp. An enlargement of a small section of a human spleen (top right) shows the arrangement of discrete areas of white pulp (yellow and blue) around central arterioles. Most of the white pulp is shown in transverse section, with two portions in longitudinal section. The bottom two schematics show enlargements of a transverse section (lower center) and longitudinal section (lower right) of white pulp. Surrounding the central arteriole is the periarteriolar lymphoid sheath (PALS), made up of T cells. Lymphocytes and antigen-loaded dendritic cells come together here. The follicles consist mainly of B cells; in secondary follicles a germinal center is surrounded by a B-cell corona. The follicles are surrounded by a so-called marginal zone of lymphocytes. In each area of white pulp, blood carrying both lymphocytes and antigen flows from a trabecular artery into a central arteriole. From this arteriole smaller blood vessels fan out, eventually terminating in a specialized zone in the human spleen called the perifollicular zone (PFZ), which surrounds each marginal zone. Cells and antigen then pass into the white pulp through open blood-filled spaces in the perifollicular zone. The light micrograph at bottom left shows a transverse section of white pulp of human spleen immunostained for mature B cells. Both follicle and PALS are surrounded by the perifollicular zone. The follicular arteriole emerges in the PALS (arrowhead at bottom), traverses the follicle, goes through the marginal zone and opens into the perifollicular zone (upper arrowheads). Co, follicular B-cell corona; GC, germinal center; MZ, marginal zone; RP, red pulp; arrowheads, central arteriole.
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What are the only types of cells that can activate naive T-lymphocytes (tolerant and have not yet been activated by antigen)?
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The ANTIGEN PRESENTING CELLS (APC)
1.) Mature dendritic cells are found in lymphoid tissues and are derived from immature tissue dendritic cells that interact with many distinct types of pathogens 2.) Macrophages are specialized to internalize extracellular pathogens, especially after they have been coated with antibody, and to present their antigens. 3.) B cells have antigen-specific receptors that enable them to internalize large amounts of specific antigen, process it, and present it. |
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What is unique about the lymphatic system of Peyer's Patches?
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no afferent lymphatics (can drain cells with lymph, but can't supply)
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What are hallmarks of activated lymphocytes (effector T and B cells)? What would this look like under a microscope?
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large amount of cytoplasm, the nucleus with prominent nucleoli, abundant mitochondria, and the presence of rough endoplasmic reticulum, all hallmarks of active cells. The rough endoplasmic reticulum is especially prominent in plasma cells (effector B cells), which are synthesizing and secreting very large amounts of protein in the form of antibody.
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What are these?
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CLUSTER OF DIFFERENTIATION
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Which cells is the general that dictates what type of cells we will need for an immune attack? How does it signal this?
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DENDRITIC CELLS signals DIFFERENTIATION of naive T cells via cytokines!
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Differentiation into different effector CD4+ T cell lineages, T helper (Th) 1, Th2, Th17, and T regulatory (Treg) cells is initiated through an interaction of dendritic cells with uncommitted (naïve) CD4+ T helper cells (Thp). The effector cell types are characterized by their synthesis of specific cytokines and their immuno-regulatory functions, as indicated on the right. The differentiation along different lineages involves different cytokines and the activation of distinct signaling cascades and transcription factors that result in the induction of additional cyto/chemokines and cyto/chemokine receptors, which may be part of positive and negative feedback loops. These cytokines and transcription factors may favor one cell lineage, while inhibiting another.
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Which type of cells do all elements of the immune system arise from?
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PLURIPOTENT HEMATOPETIC STEM CELLS
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These pluripotent cells divide to produce two types of stem cells. A common lymphoid progenitor gives rise to the lymphoid lineage (blue background) of white blood cells or leukocytes— the natural killer (NK) cells and the T and B lymphocytes. A common myeloid progenitor gives rise to the myeloid lineage (pink and yellow backgrounds), which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. T and B lymphocytes are distinguished from the other leukocytes by the possession of antigen receptors, and from each other by their sites of differentiation—the thymus and bone marrow, respectively. After encounter with antigen, B cells differentiate into antibody-secreting plasma cells, while T cells differentiate into effector T cells with a variety of functions. Unlike T and B cells, NK cells lack antigen specificity. The remaining leukocytes are the monocytes, the dendritic cells, and the neutrophils, eosinophils, and basophils. The last three of these circulate in the blood and are termed granulocytes, because of the cytoplasmic granules whose staining gives these cells a distinctive appearance in blood smears, or polymorphonuclear leukocytes, because of their irregularly shaped nuclei. Immature dendritic cells (yellow background) are phagocytic cells that enter the tissues; they mature after they have encountered a potential pathogen. The common lymphoid progenitor also gives rise to a minor subpopulation of dendritic cells, but for simplicity this developmental pathway has not been illustrated. However, as there are more common myeloid progenitor cells than there are common lymphoid progenitors, the majority of the dendritic cells in the body develop from common myeloid progenitors. Monocytes enter tissues, where they differentiate into phagocytic macrophages. The precursor cell that gives rise to mast cells is still unknown. Mast cells also enter tissues and complete their maturation there.
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Which cells are of myeloid orgin? Which are involved in innate immunity? Adaptive Immunity? Which ones phagocytize? Which ones are APC? Which ones are primarily secretory cells?
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MACROPHAGE, DENDRITIC CELLS, NEUTROPHILS, BASOPHILS, MAST CELLS, EOSINOPHILS
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Cells of the myeloid lineage perform various important functions in the immune response. A photomicrograph of each cell type is shown in the center panels. Macrophages and neutrophils are primarily phagocytic cells that engulf pathogens and destroy them in intracellular vesicles, a function they perform in both innate and adaptive immune responses. Dendritic cells are phagocytic when they are immature and can take up pathogens; after maturing, they function as specialized cells that present pathogen antigens to T lymphocytes in a form they can recognize, thus activating T lymphocytes and initiating adaptive immune responses. Macrophages can also present antigens to T lymphocytes and can activate them. The other myeloid cells are primarily secretory cells that release the contents of their prominent granules upon activation via antibody during an adaptive immune response. Eosinophils are thought to be involved in attacking large antibody-coated parasites such as worms; basophils are also thought to be involved in antiparasite immunity. Mast cells are tissue cells that trigger a local inflammatory response to antigen by releasing substances that act on local blood vessels. Mast cells, eosinophils, and basophils are also important in allergic responses.
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Which immune cell (from lymphoid lineage) is part of the INNATE immune system? They also LACK ANTIGEN SPECIFIC RECEPTORS, unlike other lymphocytes....
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What are Cytokines?
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Instructional molecules of immune system!!
Cytokines are small proteins, or instructive molecules, which tell of their cells what to do. They are the signals to hematopoietic stem cells that induce them to irreversibly differentiate into specialized immune cells, losing their potentiality as you go along and committing themselves to a certain development pathway. |
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What are chemokines?
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GPS system of immune system!!!
Chemokines also signal to other cells, but they are specifically chemoattractive and tell cells where to go. |
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What are cell adhesion molecules? Why are they important?
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cell adhesion molecules work like “homing devices” to direct cells within the body.
**In the bone marrow a combination of chemokines and cell adhesion molecules retain cells inside until they are mature enough to leave. |
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What are the two biggest barriers (aka portals of entry if you are a pathogen)? Which one is easiest to get in to and why?
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Skin and Mucosa
Mucosa are thin + absorptive and must allow passages of air/ food. |
When a pathogen enters the body, it tends to take the path of least resistance. Because the mucosa are easier to pass into than the skin, the secondary lymphoid tissues tend to be organized by the major mucosal openings, often in rings such as WALDEYER' S RING (around the mouth, includes tonsils and adenoids).
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Which four properties largely determine Immunogenicty (how able the substance is at provoking an immune response against it)?
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1. Foreigness: the greater the phylogenetic distance between two species the greater the antigenic disparity
2. Molecular size: generally > 100 kDa; molecules < 5-10 kDa are poor immunogens 3. Chemical composition & heterogeneity: primary, secondary, tertiary & quaternary organization contribute to immunogenicity 4. Aromatic a.a. (tyrosine/phenylalanine) enhance immunogenicity |
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MHC proteins are expressed by all mammals. What is the name for MHC in humans?
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HUMAN LEUKOCYTE ANTIGENS or HLA molecules
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Which MHC class and HLA are expressed on the cell surface of ALL NUCLEATED CELLS?
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MHC Class 1
(HLA-A, HLA-B, HLA-C) |
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Which immune cell interacts with the (nucleated) cells expressing Class 1 MHC?
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CD8+
Cytotoxic T Cells |
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Which MHC class/ HLA molecules are expressed on the surface of cells in the immune system?
(i.e. B-cells, DC, macrophages, activated T-cells, etc.) |
MHC class II molecules
HLA-DR HLA-DQ HLA-DP |
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Which immune cells specifically interact with cells expressing class II MHC?
(i.e. B-cells, DC, macrophages, activated T-cells, etc.) aka other immune cells and professional antigen presenting cells. |
CD4+ T Lymphocytes
Helper T cells (only once expressed are the cells visible to the helper T cell) |
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What are some similarities and differences between the protein structures of MHC I and MHC II protein structure?
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Similar
+hetero diamers +protien binding cleft (pbc) +platform inserted in cell membrane MHC I - (3 alpha 1 beta). pbc is two alpha units...(a1+a2) MHC II -(2 alpha 2 beta). pbc is beta1 and alpha1 unit. |
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How would you describe the quaternary structure of the MHC (class I +II) binding cleft holding a peptide.... in terms of food?
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HOT DOG BUN! Yummy!!
2 alpha helixes, and beta sheet floor |
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How would you describe the quaternary structure of the MHC (class I +II) binding cleft holding a peptide.... in terms of food? What is the length of the peptide displayed by MHC?
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HOT DOG BUN! Yummy!!
2 alpha helixes, and beta sheet floor |
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Class I MHC is essentially a healthy check up on the nucleated cells in the body by the CD8+ T cells of body. How does this work? How could a tumor cell be detected?
Hint-- where are class 1 MHC molecules assembled? |
1. Each MHC I molecule BINDS to peptide floating around (during normal protien assembly/ degredation) while in ER when the MHC I is first synthesized.
2. Then stabilizes and travels to golgi. 3. then MHC displayed on surface on cell. If there is something funky going on (ie. cancer or viral infection) the CD8+ cells detects the funky peptide on the surface and destroys it. |
Targeted into the endoplasmic reticulum by an N-terminal signal (leader) peptide, the 2 polypeptide chains of each class I molecule assemble in the ER. At the time of assembly when the two chains (alpha and b2m) are associating and folding into their native conformation, they pick up a peptide, about 10 or so amino acids long, found within the ER. Each newly synthesized class I molecule picks up a single peptide. This stabilizes the MHC molecule and it moves through the Golgi to the cell surface where it displays the peptide. It is estimated that about 2000 different peptides can be picked up by MHC class I molecules as they head for the cell surface. These peptides are derived from the normal degradation of cellular proteins or may derive from a pathogen.
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Class II MHC on the surface of immune cells (i.e. antigen presenting cells like DC and macrophages) show helper T cells some extracellular peptide they ate... (could be either normal degraded peptides or pathogen or vaccine.) What special equipment does the MHC II need so that is can properly find the correct extracellular peptide?
Hint—What do we need to make sure that the MHC II ends up at the right place at the right time with the extracellular peptide, and not a peptide from inside ER like in class 1 assembly? |
INVARIANT CHAIN
class II molecules associate with this third polypeptide chain in the ER, the invariant chain. 1. Invariant chain blocks the class II peptide binding site when MHC synthesized in ER AND targets the class II molecules to the ENDOCYTIC pathway. 2. In ENDOSOME MHCII BINDS to extracellular peptide that was degraded by macrophage or w/e 3. Stabilized, then appears on surface of immune cell (TA –DA Antigen presentation!! to the CD4+ T Cell helper. CD4+ will not recognize peptide all by itself on its own. Must be presented by MHC II. |
Class II molecules also bind peptides; however, they bind peptides in a different cellular compartment than the class I molecules. The class II molecules associate with a third
polypeptide chain in the ER, the invariant chain. This chain blocks the class II peptide binding site and targets the class II molecules to the endocytic pathway. Once in this pathway, used by cells for bringing in material from the cell surface or external environment of the cell, the invariant chain is removed and the class II molecules are free to bind peptides. These peptides are derived from the normal degradation of cellular proteins or may derive from something foreign (eg pathogen, vaccine). Once stabilized by bound peptides, the class II molecules move to the cell surface where they are available to interact with T ymphocytes. |
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There are many alleles/ variants present for the MHC complex gene ( aka POLYMORPHISIM). We can have mendialian like inheritance of genes. Why is this? Which chromosome is this MHC gene complex located on?
How big is it (how many bp)? |
Chromosome 6
the MHC genes (including I and II HLA) are all clustered together on chromosome 6. MHC 4 million BP large |
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When the HLA alpha chain genes are all localized on a single chromosome (and there are SOOOO many phenotypes ), the set of HLA genes are inherited as a ________.
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HAPLOTYPE-
all HLA genes located and inherited together on a single copy of chromosome 6. **since there are so many alleles, it is probably extremely rare for two people to have the exact same type unless they are siblins (1 in 4) chance |
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What kind of expression do MHC molecules have?
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CODOMINANT
both alleles from mom and dad are expressed. |
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Most genes have very limited number of alleles (i.e. histones are pretty much the same gene for everybody). How the heck is there so much diversity in humans for the HLA? What is the point? When would it be useful?
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ZOMBIE VIRUS OUTBREAK
a.k.a. diversity alters peptide binding site. This diversity is important in protecting the human population as a whole from pathogens |
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So what do these peptide motifs look like?
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It is estimated that only about 1 in 1000 to 1 in 10,000 random peptides has the motif enabling it to bind to a specific MHC molecule. The specific amino acids that form the “motif” (e.g., hydrophobic amino acid at position 2 and an aliphatic amino acid at position 9) are the amino acids whose side chains anchor the peptide into pockets in the bottom and
sides of the MHC binding site. |
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So... we have all these MHC displaying on cell surface? How often do they change (both MHCI and MHC II)?
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CONTINUOUSLY. Very dynamic display of peptides!!
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DO NOT F*** THIS UP VERY IMPORTANT!!!
Name at least 4 differences between Class I MHC and Class II MHC molecules. |
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WTF is a TCR? Where can I find one? What are the elements? What does it detect?
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TCR NEVER secreted!
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The TCR is always found inserted in the T cell surface; it is never secreted. The receptor has 2 polypeptide chains, called alpha and beta. The two chains are disulfide bonded. The TCR is expressed in a complex with CD3 on the T cell surface. CD3 helps move the TCR to the cell surface and aids in TCR signaling.
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WTF is a TCR? Where can I find one? What are the elements? What does it detect?
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TCR NEVER secreted!
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The TCR is always found inserted in the T cell surface; it is never secreted. The receptor has 2 polypeptide chains, called alpha and beta. The two chains are disulfide bonded. The TCR is expressed in a complex with CD3 on the T cell surface. CD3 helps move the TCR to the cell surface and aids in TCR signaling.
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What kinds of peptides can be displayed/ bound/ presented by MHC molecules? What happens when an MHC presents a self-peptide? Why?
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Hopefully NOTHING happens with a self peptide!!!
Why??*** USUALLY SELF PEPTIDES ARE IGNORED BECAUSE T CELLS WITH TCR TO SELF ARE NEGATIVELY SELECTED IN THE THYMUS** We don't want an auto immune rxn (autoreactive T cell) to form an attack on our own cells. We educate cells in thymus so precisely this doesn't happen. |
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Which cell is the bouncer for the body? What type of immune cell rolls around and plays a role in surveillance as the body's mall cop? What activates it?
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THE T CELL!
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T cells survey MHC-peptide complexes on cell surfaces. Many MHC molecules on the cell will be carrying self peptides so the T cells will ignore them. If the T cell carries a TCR specific for a peptide from a pathogen found on the cell surface, it will stop and become activated.
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Does TCR bind to both MHC Classes?
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Yes, but TCR really suck at both binding AND producing a signal (low binding affinity and short cytoplasmic tails)... sure, they can identify a peptide motif, but need a lot of extra help from other molecules to adhere and activate.
CD8+ (cytotoxic T cells) interact with MHC I CD4+ (helper T cells) interact with MHC II |
The affinity of TCR for its ligand (MHC-peptide) is low and the TCR cytoplasmic tails are not designed for signaling. Thus the TCR needs both adhesion and signaling assistance from other molecules such as CD3, CD4 (binds MHC class II), CD8 (binds MHC class I).
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What type of receptor is this? What type of cell will you find this on?
Bonus:: How many different copies of this SAME (clonally unique receptor) cover the surface of this cell? |
T- Cell Receptor (TCR)
Each T cell expresses about 30,000 copies of a single clonally unique receptor (ie all have same MHC-peptide binding site). |
Comparison of the amino acid sequences
of TCRs from many different T cells shows that the first N-terminal approximately 100 amino acids are variable and the remainder are conserved. The combination of alpha variable region and beta variable region form the antigenMHC recognition site. Each T cell expresses about 30,000 copies of a single clonally unique receptor (ie all have same MHC-peptide binding site). |
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The TCR binding is specific for two things.... What two elements are needed in order for recognition to occur?
Bonus** So why is there still a problem with transplanted tissues? |
DUAL RECOGNITION
Each TCR is specific for a particular MHC-peptide complex, exhibiting specificity for both: 1.) ANTIGENIC PEPTIDE (ag restricted) and 2.) MHC (MHC restricted). |
Minor problem though in transplants........
TCRs can recognize more than one MHC/peptide complex as long as they appear physically and chemically identical. So an antigen specific TCR from a transplant recipient can recognize a foreign MHC holding a self peptide on the transplanted tissue causing allorecognition and tissue rejection. |
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How good is the fit between TCR and antigen peptide on the MHC?
Also... What is another fancy name for T-Cell Receptors (TCR)? |
Complementary “Fit”
With COMPLEMENTARITY DETERMINING REGIONS (CDRs) aka TCRs TCR= CDR The fit is not very tight... which is good because we don't want TCR to it to bind too tightly to MHC anyways... |
The variable regions of the TCR interact with some but not all amino acid side chains in the peptide bound in the antigen binding groove of an MHC molecule as well as the MHC molecule itself.
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How is large and diverse repertoire of TCR Ag/ MHC binding sites generated?
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-Recognize large and diverse repertoire of
antigenic fragments - Recognize limited set of self MHC molecules |
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When is this library of TCRs available for immune response generated made?
What action causes the T cell to proliferate? |
this diversity of TCR made even BEFORE exposure to antigen ever happens (similar to Ig rearrangement)
ONLY EXPOSURE TO MHC/AG COMPLEX WILL ACTIVATE PROLIFERATION OF T CELL. T CELL WILL NOT RECOGNIZE IF JUST ANTIGEN ALONE. NEEDS MHC ANTIGEN PRESENTATION!!!!!! |
The library of TCRs available for an immune response is generated prior to exposure to antigen. As
hematopoietic stem cells mature in the thymus, the TCR genes rearrange to form functional TCR loci, synthesizing cell surface receptors (TCR). The mechanism is very similar to Ig gene rearrangement. Once out roaming around, exposure to MHC-antigenic peptide complexes selects those TCRs that are specific for those complexes and these T cells begin proliferating. |
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When does this occur? Where does this occur? What cell type does this occur in?
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PLUREPOTENT STEM CELL (or common lymphoid progenitor) IN BONE MARROW.
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When does this rearrangement happen? In which organ? In which cell?
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TCR ALPHA CHAIN REARRANGEMENT IN THYMUS
1. Occurs as the LYMPHOID STEM CELL matures into a T CELL in the THYMUS, 2.) the alpha chain locus undergoes a PERMANENT DNA rearrangement in which 1 V segment is spliced next to 1 J segment at random. 3.) This functional locus is then transcribed, RNA processed to yield mRNA and an alpha chain polypeptide synthesized. |
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The beta locus of the T-Cell receptor (TCR) has a similar
organization and undergoes a similar DNA rearrangement process as does the alpha chain locus.What is the main DIFFERENCE between the beta chain and alpha chain locus on germline?? Similarities? |
Beta had V + D + J
aplha has V + J (similar to B cell light and heavy chain germlines...) Both germlines are found in cells that are NOT T CELLS. |
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In what ways are the TCR genes similar to Ig genes? WHAT IS A BIG ONE THAT MAKES THEM DIFFERENT???
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Similarity to Ig Genes:
Mechanisms to Generate Many Amino Acid Sequences in the CDRs Both have: Multiple gene segments (V/D/J) V-D-J combinatorial diversity Junctional diversity Alpha / beta combinations BUT just one thing TCRs have is: NO SOMATIC MUTATION!!! (unlike those crafty Ig in B cells) |
In contrast to Ig,
there is NO SOMATIC MUTATION. WHYY??? this might be that mutation might result in loss of MHC molecule binding so function might be too readily damaged by mutation. Many TCR antigen/MHC recognition sites are created by random use of the multiple TCR gene segments, junctional diversity as V and J are joined (or V-D-J). A T cell rearranges both alpha and beta loci to encode a unique 2 chain receptor. |
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So exactly how many different binding site are possible with Ig and TCR?
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The bottom line is that the immune system can potentially synthesize millions of TCR and antibody molecules, each with a unique antigen binding site. Basically, we should be able to respond to any antigen we encounter in our life time with this repertoire. Of course, the receptors available at any one time are limited by the number of
circulating T and B cells. |
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How does the MHC - TCR interaction play a role in the clinic?
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Differences in the ability to display specific peptides to T lymphocytes among individuals expressing
different HLA alleles may cause differences in immune responsiveness and have implications in the design of peptide-based vaccines. Specific HLA alleles are associated with disease resistance or susceptibility. Differences in HLA alleles expressed by patient and organ donor can cause unwanted immune responses in transplantation. Some virally-infected or tumor cells lose HLA class I expression. During an ongoing immune response, these HLA-negative cells become invisible to T lymphocytes and are no longer targeted by T cells for destruction. Evaluation of the TCR and Ig gene rearrangements is used in diagnosis. Since each T cell undergoes a unique rearrangement of alpha chain and beta chain genes during development, these rearrangements can be used as a marker for that T cell. They can, for example, be used to determine if T cell proliferation is derived from a single T cell (monoclonal response) or from many T cells (polyclonal response). The state of the TCR locus (rearranged or not) can be used to stage T cell tumors. Staging is used, in part, to classify diseases such as acute vs chronic leukemia. In some T cells, the DNA rearrangement process occurs aberrantly resulting in incorrect gene At any one time, diversity present in one person is much less splicing. Genes normally inactive can become activated by splicing them into the TCR locus. This has been implicated in some T cell tumors and these aberrant translocations can serve as a marker for specific diseases . All of the above is also true for B cells and the Ig loci (e.g., Philadelphia chromosome). |
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What are the antigen receptors in the immune system?
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Humoral and Cell- Mediated
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Describe 3 ways in which T cell receptors are similar to immunoglobulins?
3 ways they differ? |
dude, you tell me.
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WHAT IS COMPLEMENT & WHAT DOES IT DO?
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COMPLEMENT IS…
A system of plasma proteins some of which are inactive proteases activated by cleavage (termed zymogens) A triggered enzyme cascade with downstream amplification - cf coagulation system Components are cleaved into 2 pieces ‘b’ (binding - BIG); ‘a’ (soluble mediator – small) |
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What are the six things that complement can do?
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Augments or complements:
1. Phagocytosis via opsonization 2. Inflammation via chemotactic factors, etc. 3. Kills microorganisms & host cells (pathological) 4. B cells activation and maturation 5. Immune complex removal 6. T cell modulation |
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What is complement?
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COMPLEMENT IS…
A system of plasma proteins some of which are inactive proteases activated by cleavage (termed zymogens) A triggered enzyme cascade with downstream amplification - cf coagulation system Components are cleaved into 2 pieces ‘b’ (binding - BIG); ‘a’ (soluble mediator – small) |
The complement system was discovered in the late 1890s and was given its name by Paul Ehrlich as ‘something in the blood that complements, or assists, immune cells’. It is now realized that the complement system plays important roles in both innate and adaptive immunity. The complement system is a multi-component enzyme cascade that terminates in the formation of a membrane attack complex (MAC) which creates a ring or pore in the envelope of microorganisms or the membrane of cells. Along the route the cascade generates chemotactic factors, ‘handles’ (opsonins) that allow phagocytes to grasp pathogens, a disposal system for antigen-antibody complexes and stimulation of T and B lymphocytes.
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WHAT CLASSES OF ANTIBODY ACTIVE COMPLEMENT, AND WHY?
COMPLEMENT DOESN’T FUNCTION AT MUCOSAL SURFACES – WHY NOT? |
One of the most important defense factors is the integrity of the barrier epithelia and the activation of complement is strongly proinflammatory and tissue destructive. Thus, IgA is a non-inflammatory antibody that does not activate complement. Also, external secretions such as saliva, tears, etc., are anti-complementary, i.e., they do not allow complement activation.
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What is the only real difference between the mannose binding lectinpathway and the classical complement pathways?
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The mannose-binding lectin pathway differs from the classical pathway only by the fact that the mannose-binding lectin pathway is initiated by the mannose-binding lectin and not C1. However, comparison of the two components shows that they are remarkably similar to one another. They both are heterotrimers that look like a bunch of daffodils. Beyond this the two pathways are identical.
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Which complement protiens (4) help with Membrane attack complex (MAC) assembly?
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The Membrane Attack Complex (MAC) is composed of a complex of four complement components (C5b, C6, C7, and C8) that bind to the outer surface of the cell membrane, and many copies of a fifth component (C9) that hook up to one another, forming a ring in the membrane. The ring structure formed by C9 creates a pore in the membrane that allows free diffusion of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive.
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The Membrane Attack Complex (MAC) is composed of a complex of four complement components (C5b, C6, C7, and C8) that bind to the outer surface of the cell membrane, and many copies of a fifth component (C9) that hook up to one another, forming a ring in the membrane. The ring structure formed by C9 creates a pore in the membrane that allows free diffusion of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive.
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What are the different sources of grafts (4)?
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1. AUTOGRAFT- self
2. SYNGENIC GRAFT (ISOGRAFT) - genetically identical (monozygotic twin, within inbred mouse strain) 4. ALLOGENIC GRAFT -genetically different, same species a.)Related - blood relatives share some genes through descent b.) Unrelated 4. XENOGRAFT: different species |
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In Ig (immunoglobulins), in the VARIABLE domain of both the light & heavy chains:
where in the Beta-barrel do we find the HYPERvariable segments of amino acids? What about the framework regions? Hint**Which part of the anti-parallel Beta barrel forms the PARATOPE? |
IN THE LOOPS!!
Framework everything else. The hypervariable regions lie in the LOOPS of the folded structure. |
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Describe the lifestyle of the B cell in 4 simple steps.
DON'T FORGET TO TELL ME THE LOCATIONS... |
1. GENERATION in the bone marrow (germline stem cell- gene rearrangement)
2. NEGATIVE SELECTION in the bone marrow 3. MIGRATION to peripheral lymph (if they pass the test) [possibly bind antigen... and then...] 4. PROLIFERATION in bone marrow and lymphoid tissue (plasma cells+ memory cells) 4. |
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Where can the steps of the Ig (B-cells) gene rearrangement can get f*&% up? What does this eventually lead to?
Which chain rearranges first: light chain or heavy chain? |
Heavy chain genes rearranged first.
If it gets messed up, CELL LOSS... boo hoo |
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All of the interactions in the thymus are ________ interactions. (We need the T-cell receptor to bind self- MHC, but not with a death grip.)
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WEAK
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When T cells are in the early stage, they express both CD4 and CD8 receptor.
Then the first MHC interaction determines the CD receptor that it keeps... so... Class I --> Cytotoxic T cells (CD8) Class II --> Helper T cells (CD4) |
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How do we know why the thymus is crucial for T- cell development?
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Only ___% of both B and T cells created ever make it out to the peripheral as mature cells. The rest that didn't pass through the (-/+) selection are "gobbled up" after apoptosis by _______.
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1-2%
MACROPHAGES |
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How come you can get any T-cells out of the thymus at all when you have both negative and positive selection going on at the same time?
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Why does it take so damn long (7-10 days) to get an immune response from the adaptive system? (humurol response)
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Because of this....
Clonal selection |
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What did Dr. Cole call the "Red+ yellow+ green lego blocks" of the immune system.
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This is your tool kit for making all sorts of paratope combinations.
all remaining DNA is thrown away |
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How are these like the B cells in bone marrow?
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Ramdomly changing these receptors
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AUTOIMMUNE diseases arise when autoreactive B and T cells escape deletion and regulatory mechanisms in our body.
Thankfully, this doesn't happen too often. How does the immune system protect from attacking itself? (6 types)- Where do they happen? Hint- What can happens thymus + bone marrow? Blood brain barrier and peripheral organs? in 2dary lymph tissue? In 2nry lymph tissue AND sites of inflammation? |
because our body has many mechanisms we have to deal with autoreactive cells called...
LAYERS OF SELF TOLERANCE: 1. CENTRAL TOLERANCE-- occurs in the primary lymphoid tissue (thymus and bone marrow), where autoreactive B and T cells are deleted. If cells escape this first layer, they can be acted upon in the periphery (layers 2-6). 2. ANTIGEN SEGREGATION-- refers to the sequestering of antigens from the immune system in “immunologically privileged” sites, where B and T cells can’t get to them. 3. PERIPHERAL ANERGY-- results from the delivery of signal 1 without signal 2 (co-stimulation), rendering the T cell anergic. 4. REGULATORY CELLS-- suppress unwanted immune responses via cytokines and intercellular signals. 5. CYTOKINE DEVIATION-- is the polarization towards the Th2 helper T cells (via cytokines), which have anti-inflammatory effects. 6. CLONAL EXHAUSTION-- results from the lack of antigen to activate T cells (via presentation by dendritic cells), driving the T cells to apoptosis. This also occurs when CTLA-4 is secreted by T cells, competes with CD28 for B7 binding, and shuts off clonal expansion of T cells. |
Immune system wants to keep the largest amount of diversity possible, so it is willing to risk releasing some autoreactive cells....
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What do you call it when your body is your own worst enemy? And the immune system kicks the living sh*t out of you?
What factors can cause this to happen? Which gender does it affect more? |
Cause every now and then you have AUTO-IMMUNITY...
Both GENETIC FACTORS (HLA alleles, TCR repetoire, and cytokine polymorphisims) and ENVIRONMENTAL INFECTION/EXPOSURE MORE FEMALES have it |
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