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Immuno Review Sheet Renee Prater, 11/14/2008 Dear MSI’s, It has been a real honor and pleasure working with such a bright and enthusiastic class. Many of you have asked for a review sheet to try to pull immunology together and help with studying for final exams. I have compiled some of the information that I feel is most important (below) and it has turned out to be LONG and still not totally complete. I am posting this today so that you have time to review this before you leave for T-day break. If you see parts of this that can be improved, please let me know ASAP and I will revise and repost a new version so that the class can benefit the most from a review document. I couldn’t possibly put everything in here, so please go back and review all course material (and of course lecture material from Dr. Z, A, and R) so that you are adequately prepared for the final, and please let me know how I can modify this so that you have the best possible material to be successful on the immuno final and beyond. Thank you so much for your attention, enthusiasm, and patience. Happy Thanksgiving and best wishes for your continued success! You are amazing student doctors! Renee P. Lecture #1 Introduction to Immunity Definitions: Acute phase proteins: serum proteins produced by the liver, whose levels increase during infection or inflammatory reactions. Adaptive immune system: recently evolved system of immune responses mediated by T and B lymphocytes. Immune responses by these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during development and throughout the life of the organism. Additional cells of the adaptive immune system include various types of antigenpresenting cells. Adhesion molecules: cell surface molecules involved in the binding of cells to extracellular matrix or to neighboring cells, where the principal function is adhesion rather than cell activation. Allergen: an agent (pollen, dust, animal dander) that causes IgE-mediated hypersensitivity reactions. Antibody: B cell-produced molecules encoded by genes that rearrange during B cell development consisting of immunoglobulin heavy and light chains that together form the central component of the B cell receptor for antigen. Antibody can exist as B cell surface antigen-recognition molecules or as secreted molecules in plasma and other body fluids. Antigens: foreign or self-molecules that are recognized by the adaptive and innate immune systems resulting in immune cell triggering, T cell activation and/or B cell antibody production. Antigen receptors: the lymphocyte receptors for antigens including the T cell receptor (TCR) and surface immunoglobulin on B cells which acts as the B cell’s antigen receptor (BCR). Antigen presentation: process by which certain cells in the body (antigen presenting cells or APC, including macrophages, dendritic cells, B cells, etc) express antigen on their cell surface (MHC class II) in a form recognizable by lymphocytes. Lymphocyte binding to class II MHC stimulates lymphocytes to be active, proliferate, and secrete cytokines to activate other parts of the immune system. APCs are in skin, in lymph nodes, and in other organs. Once APCs phagocytose pathogens, they migrate through lymph vessels to a nearby lymph node to interact with T cells and help to activate CMI and humoral immunity. Apoptosis: the process of programmed cell death whereby signaling through various death receptors on the surface of cells (e.g., TNF receptors, CD95) leads to a signaling cascade that involves activation of the caspase family of molecules and leads to DNA cleavage and cell death. Apoptosis, which does not lead to induction of inordinate inflammation, is to be contrasted with cell necrosis, which does lead to induction of inflammatory responses. B lymphocytes: bone marrow-derived or bursal-equivalent lymphocytes that express surface immunoglobulin (the B cell receptor for antigen), and secrete specific antibody after interaction with antigen. B cell receptor for antigen: complex of surface molecules that rearrange during postnatal B cell development, made up of surface immunoglobulin (g) and associated Ig alpha-beta chain molecules that recognize nominal antigen via Ig heavy and light chain variable regions, and signal the B cell to terminally differentiate to make antigen-specific antibody. Basophil: the least commonly seen polymorphonuclear leukocyte in circulation that stains with basic dyes (dark bluish purple granules in the cytoplasm) and has an important role in control of inflammation, such as release of histamine and proteases such as elastase. Basophils are also an important source of IL-4, which is an important cytokine in the TH2 pathway and humoral immunity. Basophils are often associated with allergic reactions, and they have receptors for IgE on their cell surface. IgE binding activates basophils. Bradykinin: a vasoactive peptide that is the most important mediator of the kinin system, and causes pain and leaky vessels in acute inflammation. Cell-mediated immunity: immune reactions that are mediated by cells rather than by antibody or other humoral factors. CMI involves T H1 activation of TC, which are important in fighting intracellular pathogens. Chemokines: cytokines that bind to G protein-linked receptors and are chemotactic and have cell-activating properties. Complement: cascading series of plasma enzymes and effector proteins whose function is to lyse pathogens and/or target them to be phagocytosed by neutrophils and monocyte/macrophage lineage cells of the reticuloendothelial system. Individual complement proteins, that are produced by the liver and normally circulate independently and in inactive form, come together in the complement cascade to form the membrane attack complex (MAC) that lyses infected cells or pathogens. By-products of the complement system are used as chemokines, or as opsonins. Co-stimulatory molecules: molecules of antigen-presenting cells that lead to T cell activation when bound by ligands on activated T cells. Cytokines: Soluble proteins that interact with specific cellular receptors that are involved in the regulation of the growth and activation of immune cells and mediate normal and pathologic inflammatory and immune responses. Dendritic cells: myeloid and/or lymphoid lineage antigen-presenting cells of the adaptive immune system. Immature dendritic cells, or dendritic cell precursors, are key components of the innate immune system by responding to infections with production of high levels of cytokines. Dendritic cells are key initiators both of innate immune responses via cytokine production and of adaptive immune responses via presentation of antigen to T lymphocytes. Endothelial cells: cells that line blood vessels and lymphatic vessels. When damaged, they release tissue factors that activate inflammation immunity. Eosinophils: relatively uncommonly found polymorphonuclear leukocyte that contains cytoplasmic granules that stain with acidic dyes (orange-red) and are particularly involved in reactions against parasitic worms and in some hypersensitivity reactions. Flow cytometry: analysis of cell populations that are in suspension, and can be identified and sorted (FACS) based on cell size and surface markers. Germinal centers: an area of secondary lymphoid tissue where B cells differentiate and undergo antibody class switching (that is, B cells first produce IgM early in an infection, then switch to another type of immunoglobulin, usually IgG, in a more established infection. You can tell how long a person has been infected with an organism by looking at their ratio of IgM to IgG). Granulocytes: neutrophils, eosinophils, basophils. Granulomatous inflammation: macrophages, chronic inflammation. Often areas of granulomatous inflammation are ringed by small lymphocytes. HLA: human leukocyte antigen; human major histocompatibility complex (MHC). Innate immune system: ancient immune recognition system of host cells bearing germ line-encoded pattern recognition receptors (PRRs) that recognize pathogens and trigger a variety of mechanism of pathogen elimination. Cells of the innate immune system include natural killer (NK) cell lymphocytes, monocytes/macrophages, dendritic cells, neutrophils, basophils, eosinophils, tissue mast cells, and epithelial cells. Interferons: a group of molecules involving cell signaling between cells of the immune system, and used in protection against viral infections. Interleukins: a group of molecules involved in signaling between cells of the immune system. Large granular lymphocytes: lymphocytes of the innate immune system with azurophilic cytotoxic granules that have NK cell activity capable of killing foreign and host cells with little or no self MHC class I molecules. Macrophage: an important immune cell that is made in the bone marrow and circulates as a monocyte, then becomes a macrophage in tissue. Macrophages can act as APC, and are professional phagocytic cells that are very important in chronic inflammation. Natural killer cells: large granular lymphocytes that kill target cells that express little or no HLA class I molecules such as malignantly transformed cells and virally infected cells. NK cells express receptors that inhibit killer cell function when self-MHC class I is present. Neutrophils: polymorphonuclear leukocytes that are the most abundant in the blood, and perform phagocytosis and respiratory burst (increased oxidative metabolism) in acute inflammation. Opsonization: a process by which phagocytosis is facilitated by the deposition of opsonins (antibody or C3b) on the antigen. Pathogen-associated molecular patterns (PAMPs): invariant molecular structures expressed by large groups of microorganisms that are recognized by host cellular pattern recognition receptors in the mediation of innate immunity. Some examples of pamps include LPS or endotoxin, flagellin, hemagglutinin, teichoic acid, or unmethylated DNA (e.g., small sugars or proteins that are present on foreign material that is not present on host cells that can be recognized by members of innate immune system even without prior exposures) Pattern recognition receptors (PRRs): germ line-encoded receptors expressed by cells o the innate immune system that recognize pathogenassociated molecular patterns. Periarteriolar lymphoid sheath (PALS): accumulations of lymphoid tissue that constitutes the white pulp in the spleen. Plasma cell: a B cell that has differentiated to produce antibodies against a specific antigen. Primary lymphoid tissue: lymphoid organs where lymphocytes complete their initial maturation steps: including fetal liver, adult bone marrow, and thymus. Privileged sites: tissues that induce weak immune responses, or sites of the body that are partly shielded from graft rejection reactions; these include the testes, brain, fetus, and anterior chamber of the eye. Secondary lymphoid tissue: tissues that trap antigen and provide sites for mature lymphocytes to interact with that antigen, including lymph nodes, spleen, mucosal-associated lymphoid tissues, gut-associated lymphoid tissues, etc. T cells: thymus-derived lymphocytes that mediate adaptive cellular immune responses including T helper, T regulatory, and cytotoxic T lymphocyte effector cell functions. T cell receptor for antigen: complex of surface molecules that rearrange during postnatal T cell development made up of clonotypic T cell receptor (TCR) alpha and beta chains. The clonotypic TCR alpha and beta chains recognize peptide fragments of protein antigen physically bound in antigen-presenting cell MHC class I or II molecules to mediate effector functions. Tolerance: B and T cell nonresponsiveness to antigens that results from encounter with foreign or self antigens by B and T lymphocytes in the absence of expression of antigen-presenting cell costimulatory molecules. Tolerance to antigens may be induced and maintained by multiple mechanisms either centrally (in the thymus) or peripherally at sites throughout the peripheral immune system. Be able to list the body’s natural barriers to infection (such as on the skin: sweat glands produce sweat with high salt concentration, oil gland produce sebum with acid pH, stratified squamous epithelium sluffs off and takes potential pathogens with it, skin surface has commensal bacteria on it that occupies space and discourages pathogen growth, etc; digestive system has vomiting, diarrhea, peristalsis; urogenital system has commensal bacteria, etc). Understand that when you are exposed to a pathogen, either the immune system removes the pathogen and develops memory/resistance for future infection, or you suffer from chronic illness and either die or eventually become resistant to that organism and are able to clear the infection. Be able to list the major organs of the immune system, relatively where they are, what cells that normally reside there and what it looks like, whether they are a primary or secondary lymphoid organ, and what its function is in immunity. Know that the bone marrow has multipotential adult stem cells that may develop into red cells (erythrocytes), white cells (= leukocytes: neutrophils, monocyte/macrophages, basophils, eosinophils, mast cells, dendritic cells, lymphocytes - B and T, natural killer cells) and platelets (megakaryocytes). Know that innate immunity is an old system, can respond to antigens that it has never seen before because it recognizes common amino acid sequences that are present in a large number of pathogens, that it can respond rapidly, and that it is primarily phagocytic or killing in function. Also know that the innate immune system has no memory and activates the adaptive immune system by antigen presentation and production of cytokines. Know the cells of the innate immune system: monocyte/macrophage, dendritic cell, neutrophil, eosinophil, basophil, mast cell, NK cell (the only one that is from the lymphoid and not myeloid line). Know that the adaptive immune system is a newer system that is antigen specific, responds more slowly, and has memory. B cells and T cells are in adaptive immune system. Know the definition of the different chemicals the immune system uses to communicate between cells (cytokine is a general term of a chemical produced by a cell that influences the activity of another cell; a lymphokine is a cytokine that is produced by a lymphocyte; a monocyte is a cytokine that is produced by a monocyte/macrophage; a chemokine is a chemical produced, usually by innate immune system, to call other immune cells to the site of infection/inflammation by way of a chemical gradient – the chemokine concentration becomes greater in the tissue that is closest to the site of inflammation; interleukins are another chemical that leukocytes or white blood cells produce to talk to/activate/regulate each other; and finally interferons are chemicals that are produced that typically work to interfere with viral replication and also function in activation of CMI). Dendritic cells are innate immunity – sample environment to look for foreign antigens; if it finds a foreign antigen it phagocytoses, processes the antigen and puts the antigenic epitope on a class II MHC molecule to present to helper T cells (CD4 cells), to initate the adaptive immunity. If it is an intracellular pathogen it is presented to helper 1 T cells, and through release of interferon-gamma, the helper 1 T cell upregulates cell-mediated (or cytotoxic) immunity (via the work of cytotoxic T cells, or CD8 cells). If the pathogen is extracellular, then the helper 2 cells are upregulated via interleukin 4, which primarily upregulates humoral immunity (production of immunoglobulins by B cells that are transformed into plasma cells). Remember that macrophages and dendritic cells are not the only antigen presenting cells: B cells can also be antigen presenting cells. Remember that antibodies are specific to one particular antigen or epitope – this is usually a protein, usually is about 10 amino acids long, and the antigen and antibody fit together very specifically like a lock and key. Remember that antibodies have a constant region and a variable region that is antigen-specific. When B lymphocytes are mature and just being activated, they first produce IgM, and then they undergo isotype or class switching and become full-fledged plasma cells, which then produce IgG. Remember that IgA is the doublet that is found primarily at the mucosal surfaces, and guards against pathogens gaining entry into the body. Remember that IgE is usually associated with allergy. Cytotoxic T cells kill infected or cancerous cells with the use of their cytoplasmic granules – perforin pokes holes in the infected/cancer cell membrane; granzyme forces that infected or tumor cell to undergo apoptosis. Remember that APC are the few cells in the body that can make class II MHC molecules. They use this receptor to present antigen to the helper T cells. In contrast, nearly all cells (except red blood cells) have MHC class I antigens. If that cell is infected, it can put the antigenic part of the pathogen that is infecting it onto a class I MHC molecule, and target it for destruction by a cytotoxic T cell before it infects another neighboring cell. However, remember that healthy cells that have degraded part of itself or another “self” cell can also present self proteins on class I MHC. The cytotoxic (CD8) T cell has been trained in the thymus (positive and negative selection) to only become activated and start killing if that protein on the MHC class I receptor is foreign. If it is a self protein the Tc cell shouldn’t do anything. IF it DOES start killing cells, then that Tc cell is considered “autoreactive”, and suggests that there is autoimmunity. Recognize that the immune system is a very intricate system – has a lot of checks and balances that need to keep it in check so that there is not excessive immune stimulation (autoimmunity), or insufficient immune stimulation (cancer and infectious disease). Know that the complement system consists of a series of soluble proteins in the blood that come together in acute inflammation to do the following: chemotaxis, opsonization, and membrane attack complex. Make sure you know the factors that act as opsonins, as chemotactic agents, and that are encompassed in the MAC (Dr. Zed lecture). Be familiar with a few of the more common diseases associated with primary immune deficiency (born with it – genetic deficiency like SCID, etc), and secondary immune deficiency (drug or chemical or malnutrition or chronic disease caused) such as AIDS; also be familiar with the concept of autoimmunity and a few of the more common autoimmune diseases (lupus, rheumatoid arthritis, diabetes). Also know that immune cells can become cancerous and cause either solid or circulating neoplasms. Lecture #2 Inflammation, Wound Healing, Cytokines Inflammation is the response of vascularized tissue to injury. The purposes of inflammation are: 1. Clean up dead cells, bacteria and other pathogens. 2. Deliver inflammatory cells and fluids that contain clotting proteins, chemokines, complement proteins, etc. to the area of injury. 3. Deliver growth factors that help to heal the injured tissue. Know that acute inflammation occurs when vascular tissues are injured. There is a release of phospholipids from the injured cell membranes, which causes the arachidonic acid cascade (inflammation, pain); also there is a release of histamine from mast cells and basophils that cause increased vascular permeability, leakage of plasma and inflammatory cells to the area of injury. Know that in acute inflammation the first step is cleaning up the debris, and the second step is wound healing. In acute inflammation, usually neutrophils respond first, then macrophages. Know that mature neutrophils have segmented nuclei (like string of sausages) and the less mature form that comes out of the bone marrow in acute inflammation, to keep up with the demand when the mature neutrophils are running low is called a band because the diameter of its nucleus is roughly equal all the way around. You should see the most segmented neutrophils, then fewer bands, then even fewer less mature neutrophils, and this is called an orderly left shift in acute inflammation. If an avascular tissue is injured, it is slower to heal because it depends on the nearby vascularized tissue to help with the inflammatory process. Five cardinal signs of inflammation: 1. Heat – due to vasodilation caused by histamine and seratonin, released by mast cells and basophils. 2. Redness – also due to vasodilation caused by histamine. 3. Swelling – caused by edema fluid from leaky vessels – increased vascular permeability is caused by histamine and serotonin. 4. Pain – caused by kinin system which is activated by tissue injury. 5. Loss of function. Know the 5 cardinal signs of inflammation are primarily due to the tissue damage and the resulting vasodilation and fluid and cell exudation. When tissues are damaged, endothelial cells, macrophages, and neutrophils release proteins that cause mast cell degranulation and histamine release, which causes vasodilation (actually to be more precise, dilation of venules to deliver cells and proteins to the area of injury, and constriction of arterioles to help stop bleeding). Cells of the innate immune system (macrophages, natural killer cells, etc) recognize PAMPS on bacteria (such as hemagglutinin on influenza virus, flagellin on flagellated bacteria, teichoic acid on G+ bacteria, LPS on G- bacteria, and unmethylated DNA, which is foreign to host cells) and bind the PAMPS with their Toll-like receptors. This helps to upregulate both innate and adaptive immunity. Proteins that are helpful in acute inflammation: antibodies to activate the classical complement cascade and for opsonization; complement proteins for MAC and for opsonization and chemotaxis, kinins for vasodilation and pain, and the clotting or coagulation cascade to help stop the bleeding, which is usually accompanied by the fibrinolysis cascade, which breaks down excess fibrin to prevent thrombus formation and potential thromboembolism. TPA is example. Cells that are helpful in acute inflammation: neutrophils (purulent or pus inflammation), lymphocytes (more chronic inflammation along with macrophages), and eosinophils (allergy or parasitic infection). Remember the acute phase proteins are released by the liver in acute inflammation, and they include C reactive protein, coagulation proteins, complement proteins, etc. Remember the inflammatory cytokines: IL-1, 2, 6, and 8, and TNF alpha and IFN gamma. Remember that IL-4 is related to upregulation of humoral immunity. Chemokines are cytokines (proteins made by immune cells) that attract other immune cells by a concentration gradient to the site of inflammation. Antibodies can serve two functions: opsonins (attach to antigens to make them easier to phagocytose or eliminate) and neutralizing antibodies (bind to antigens to prevent them from entering and infecting a cell). The most important opsonins are C3b and IgG. Be able to describe each type of leukocyte as far as their cytoplasmic and nuclear features, and know what each one does: Neutrophil: pale granular cytoplasm, segmented nucleus, does phagocytosis and respiratory burst (releases reactive oxygen and nitrogen to kill pathogens). Eosinophil: bright red staining granular cytoplasm, segmented or bilobed nucleus, is associated with allergic and parasitic inflammation. Monocyte: larger, pale blue “ground glass” cytoplasm, kidney bean-shaped nucleus, does phagocytosis and releases cytokines; tissue form is macrophage. Lymphocyte: small round cell with scant blue cytoplasm and round nucleus. Functions to kill infected cells (Tc) or make antibodies (B cell/plasma cell) or help the humoral and CMI systems (Th). Mast cells: larger cell, pinkish-purple granular cytoplasm, releases histamine in acute inflammation. Remember the types of inflammation and the cells/characteristics that accompany them: granulomatous (macrophage), fibrinous (in serous cavities), purulent/suppurative (neutrophil), serous (blisters – fluid), and ulcerative (large defect in mucosa or epithelium). Know the basic steps in leukocyte extravasation, or the sequence by which neutrophils leave the vessels and enter the tissues (margination to the endothelial surface, rolling, tight adhesion, diapedesis/extravasation, etc): 1. Margination 2. Rolling 3. Adhesion to endothelium 4. Diapedesis/extravasation/transmigration (synonyms) 5. Chemotaxis 6. Leukocyte activation 7. Phagocytosis Leukocyte deficiencies: 1. Bone marrow is not producing enough 2. Stress/corticosteroids/absence of adhesion molecules prevents margination and extravasation of neutrophils into tissue 3. Neutrophil can’t phagocytose foreign material 4. Neutrophil can’t digest phagocytosed material in phagolysosome 5. Phagocyte can’t release reactive oxygen species Remember that chronic inflammation is a pathologic condition (as compared to acute inflammation which is actually HELPFUL to the body). Know that chronic inflammation is generally pathologic, and results when the infection/inflammation cannot be cleared by acute inflammation. Chronic inflammation typically has macrophages in the center, and small lymphocytes ringing the area of inflammation. Make SURE not to confuse granulomatous tissue, or granulomas, with GRANULATION tissue, which is a mixture of new blood vessels and collagen-forming fibroblasts, that are important in healing. Examples of chronic inflammatory stimuli are things that are difficult for the body to break down such as silica from old breast implants, asbestos, tuberculosis or other larger organisms, suture material, etc. Macrophages can have several appearances: foamy, epithelioid, multinucleated. In wound healing, the major steps in healing are inflammation, proliferation, and remodeling, and these three steps usually overlap. Proliferative phase entails fibroplasia (fibroblasts make type III collagen, which is a scaffold for new blood vessel formation and for cell migration into the area; this is later replaced with type I collagen that is stronger, and is aligned along tension lines. Fibroblasts commit apoptosis at the end of wound healing. Special fibroblasts called myofibroblasts help with wound contraction, and then also commit apoptosis after wound healing is complete. Epithelialization is the process of the epithelial cells regrowing over an area of injury. If the injury is superficial, then the basal epithelial cells that reside just above the basement membrane, can repopulate the epithelial surface. However if the defect went below the basement membrane and into the dermis, then the new epithelial cells have to grow into the defect from the healthy peripheral tissues. First intention healing is when there was a small, usually clean defect (such as a surgical cut), where the distance between the two healthy sides is short, and wound healing is fast and does not leave a bad scar. First intention healing is when the two sides of the wound are closely apposed, as with suturing or stapling; these wounds tend to heal more quickly and leave a smaller scar. In contrast, second intention healing is where there is a larger or irregular defect such as an ulcer or a large abrasion, and so there is a larger distance that has to be covered in order to heal the defect. This usually results in a longer healing time, incomplete repair of the defect, and leaves a permanent, larger scar. Remember the steps in wound healing: inflammation, neovascularization (new vessels), fibrosis, remodeling. Remember that once the inflammation is subsiding, growth factors like transforming growth factor (TGF) further suppress the immune system and encourage wound healing. Remember examples of dysregulated wound healing: keloid, hypertrophic scar. In contrast, second intention healing is when there was a large, wide defect such as an ulcer or large abrasion. Review factors that retard wound healing such as concurrent disease, age, malnutrition, etc. Be able to recognize signs of pathologic wound healing such as dehiscence, keloid, excessive contracture, and dystrophic calcification. Know what an abscess is (collection of neutrophils/pus that is surrounded by a tough fibrous capsule). It is difficult for antibiotics to penetrate abscesses, Lecture #5 Cellular Interactions in Immunity (you may find that some of the information in the rest of the lectures has already been covered above in the prior lectures’ reviews) Adenoids are pharyngeal or nasopharyngeal tonsils, secondary lymphoid organs, and if they are enlarged they can obstruct the nasal passages and disrupt breathing. Surgery is adenoidectomy. Tonsils are secondary immune organ in the oropharynx that sample for pathogens coming in through the nose and mouth. Tonsils have crypts, and contain mainly lymphocytes and macrophages. Increased macs or neutrophils is tonsillitis, and may require antibiotic or surgical therapy. Tonsil has stratified squamous epithelium (vs. adenoid which has ciliated respiratory epithelium) because there is more trauma from food going past the tonsils. Thymus is the primary lymphoid organ that “schools” immature T cells from the bone marrow in positive (being able to bind antigens with high affinity) and negative (won’t respond to self proteins) selection. Those that fail this schooling are removed by apoptosis. Those that succeed can leave the thymus and go to secondary lymphoid organs or circulate in the blood. Remember that autoimmunity results if those that fail negative selection are permitted to leave the thymus. Lymph node filters lymph, which is fluid/plasma that has escaped the vasculature and needs to re-enter the venous system. The lymph vessels are open ended in the tissue and have a series of lymph nodes (secondary lymphoid organs) in a chain along the vessel that looks for pathogens in the lymph. If pathogens are found the B and T cells in the lymph nodes are activated to fight the infection. There are also a few macrophages in normal lymph nodes, but increased numbers of macs or increased numbers of neutrophils means inflammation and is called lymphadenitis. Lymph nodes can also be used to see if cancer has spread from a primary tissue through the lymphatic system and beyond. These nodes are called sentinal nodes (like with breast cancer). Also remember that lymph fluid is pumped by skeletal muscle contraction, since it is not directly connected to the heart. Lymph vessels also have one-way valves to discourage back flow. If there is excess lymph production, or if there is a problem with drainage, then you get edema. Spleen is secondary lymphoid organ that has red pulp (which destroys old red cells and is a storage for additional blood in case of acute hemorrhage), and white pulp, which is the immune component of the organ. The white pulp tends to concentrate around vessels as periarterial lymphoid sheaths (PALs) to look for antigens in the blood. Peyer’s patch is large oval lymph tissues (secondary lymphoid organ) in the digestive system, mostly in the ileum. Peyer’s patches contain high concentrations of B lymphocytes that make IgA to protect the mucosal surface from invading lumenal pathogens. Appendix is blind ended tube near junction of small and large intestine that contains lymphoid material (secondary lymphoid organ). Inflammation is appendicitis, and is considered a medical emergency if it ruptures. Bone marrow is primary lymphoid organ that makes hematopoietic cells, and schools the B cells in positive and negative selection, as the T cells are schooled in the thymus. In acute inflammation, the bone marrow increases production of neutrophils, then monocytes and lymphocytes, to keep up with the demands of the infection/inflammation. Endocytosis can be divided into pinocytosis (engulfing fluid, drinking) and phagocytosis (engulfing solid particles, eating). Lecture #6 Tolerance and Programmed Cell Death Remember that with APC/helper T cell interaction (CD4) the APC has the MHC class II with processed antigen on it, and the T cell has T cell receptor and coreceptor (CD4) for specific binding; the purpose of this is to activate helper T cell and initiate adaptive immunity. The infected cell presents foreign antigen on class I MHC molecule to cytotoxic T cell receptor with co-receptor (CD8) for specific binding. The purpose of this is for the T cell to kill the infected cell. Regulatory T cells, or suppressor T cells, downregulate the immune system at the end of the inflammatory process, and do so either by inducing apoptosis or by other methods. Usually T cell suppression is encouraged by presence of growth hormones like TGF that signal when inflammation is winding down and healing is beginning. Another signal for immunity to quiet down is when there is no co-stimulation of antigen presenting cells, so they stop producing inflammatory cytokines and there is less activation of lymphocytes. When cells are poorly activated, they become anergic and die. Remember that a few of the T cells and B cells remain after the immune stimulation is over; these are memory cells that are antigen specific and will respond more quickly the next time the body encounters that pathogen. Immune suppression can be inborn (primary) or acquired by disease, drugs, etc. Allergy is basically an over-enthusiastic response to a pathogen. Autoimmunity is an inappropriate response against self proteins. Lecture #7. Defense against Microbes Pathogen can cause disease in an otherwise healthy person; an opportunistic infection is where a commensal (normally harmless) organism takes advantage of someone who is immunocompromised, and causes disease, where it could not cause disease in an immunocompetent individual. Remember the four major plasma enzyme systems and what they do: Complement: membrane attack complex, opsonin, chemotaxis Coagulation: blood clots Fibrinolysis: breaks down clots, makes FDPs Kinin: vasodilation, blood pressure, pain – bradykinin Know the function of these mediators in acute inflammation: prostaglandin, complement, bradykinin. histamine, Gram positive bacteria have peptidoglycan which is polysaccharide capsule which prevents complement lysis and is poorly immunogenic (need conjugate vaccine to prevent this infection). Teichoic acid is immunogenic. Gram negative bacteria have thin peptidoglycan layer so susceptible to complement; have lipopolysaccharide or endotoxin to help fend off the immune cells, but LPS is immunogenic. Extracellular pathogens are killed by antibody neutralization, opsonization and CMI, and complement. Intracellular pathogens are killed primarily by cell mediated immunity. Those intracellular pathogens like mycobacterium that have ways to evade immune system (have a lot of lipid in the cell wall – mycolic acid - and can prevent phagosome from binding with lysosome for bacterial destruction). But cell wall also has proteins in it that are immunogenic so can be killed by CMI. Spirochete bacteria are extracellular so killed by humoral immunity. No cell wall, just few proteins on cell membrane that are immunogenic. Viruses are all obligate intracellular pathogens, so are killed primarily by CMI. They can escape immune system destruction by antigenic drift (changing a single codon in their DNA over time) or antigenic shift (changing a whole sequence of codons in their DNA over time). That way the immune has to start over and build up new immunity against that changed virus, because the memory cells won’t recognize after antigenic variation. Fungal infections usually occur in immunocompromised patients. Several are intracellular (CMI), most are extracellular (humoral). Most parasites are big (either single celled protozoa or multicelled parasites). Mainly humoral immunity, eosinophils, IgE. Lecture #8. Major Histocompatibility Gene Complex T cell receptor for antigen only interacts with antigen when the antigen is bound on the APC cell surface and it is bound to an MHC molecule. If APC phagocytoses a foreign pathogen, processes it, and puts the antigen up on the cell surface on a class II MHC molecule then a helper T cell will bind and become activated. Helper T cells responding to an intracellular antigen will differentiate into Th1, with stimulation from interferon gamma, and will initiate CMI. If the helper T cell is responding to an extracellular antigen, then it will differentiate into a Th2 then it will be further activated by IL-4 and will initiate humoral immunity. If the APC or any other nucleated cell becomes infected with that pathogen and needs to die before the infection spreads to other cells, it puts that antigen up on the cell surface in association with MHC class I. A cytotoxic T cell recognizes and kills that cell (CMI). If the APC or other nucleated cell has degraded old worn out cellular components and presents THAT self protein on MHC class I, the T cell should recognize that as self and ignore it. If that T cell becomes activated, that is autoimmunity. B cells can also be APCs. Remember that when they are mature B cells and are activated they produce IgM. Then they undergo isotype switching and start to make IgG when they are full fledged plasma cells. Clonal expansion is the rapid multiplication of activated T cells to more effectively fight the infection. Of all the cells in a particular clone, they all recognize the same antigen. Although there may be many sets of clones against one pathogen, as bacteria, viruses, parasites, etc have many epitopes that the immune system can consider as immunogenic. MHC class III is actually part of complement, not a receptor that presents antigen. The reason that each one of our MHCs are different (polymorphism) is an evolutionary protection: if we all have varying susceptibilities and resistance to different diseases by having polymorphic MHCs then at least a segment of the population should be able to survive most of the infections that we might encounter. But the reason transplants fail without immunosuppression is because our MHCs are so polymorphic and we consider each other’s as foreign and reject it. Lecture #9: Primary Immune Deficiency Primary immune deficiency is rare, and is usually associated with antibody (B cell, humoral immunity) deficiency. Primary and acquired (secondary) immune deficiency often present with similar clinical signs: recurrent infections and infections with low-virulence organisms (opportunistic infections). Severe combined immunodeficiency (SCID) occurs when both cell-mediated and humoral immunity are both impaired – either an absolute lack of B and T cells, or B and T cells that are physically present, but are dysfunctional. For example, SCID can occur with a MHC class II deficiency, which impairs antigen presentation, and therefore would impair both arms of the adaptive immune system. You never want to give a modified live vaccine to a SCID patient. Kids may be born with an inborn error of B cell production or function. But more commonly, we may see a transient inability of babies to produce immunoglobulins. Often they grow out of this and so no treatment is necessary. If you have a deficiency of IgA, you are at greater risk of developing respiratory or gastrointestinal infections, because IgA works at the mucosal surface to reduce infections that cross mucosal barriers. Problems with neutrophils may include lack of production or maturation of neutrophils in the bone marrow, improper formation of cytoplasmic granules that may reduce the ability of the neutrophils to perform respiratory burst, or problem with neutrophil extravasation from the blood vessels, which may be due to improper adhesion to the endothelium or inability to squeeze through the leaky endothelial spaces to enter the tissue. Lecture #10: Acquired Disorders of Immune Deficiency Acquired immune deficiency is rarer than primary immune deficiency. Some of the causes of acquired immunodeficiency are malnutrition, aging, chemical or drug exposures (including alcohol), and concurrent diseases. Malnutrition may include protein, vitamin, or other micronutrient deficiency. Alcoholics often look like malnutrition patients as far as their immunodeficiency diseases, and malnutrition can affect all parts of the immune system (innate, adaptive, complement, etc). Often we don’t see acquired immunodeficiency associated with disease because there are so many redundancies in the immune system that if one arm is not working properly, other parts of the immune system will make up for that deficit. Lecture #11: Immunopathology of AIDS HIV is retrovirus, caused predominantly by HIV-1 in developing and first world countries (HIV-2 is endemic in Africa but is less virulent than HIV-1). HIV is transmitted sexually in blood and semen and through breast milk. Not thought to be spread by saliva (kissing), or by mosquitoes. Don’t worry about learning the statistics that are in this lecture for my test – I just gave you rough estimates of the incidence of AIDS in this country and the world to give you an idea the severity of the problem. What I would like you take away from this is that HIV is not under control, and the incidence is growing in the older population, and in minorities such as African Americans and Hispanics. Remember that HIV is preventable and is influenced by societal, cultural, and economic factors. HIV was thought to originate as a zoonotic disease, transferred from chimpanzees to man in Africa in the late 1970’s, and was identified when physicians saw an increased incidence of weird diseases (pneumocystis, Kaposi’s sarcoma, etc). HIV predominantly affects CD4 (helper) T lymphocytes, although it also affects many other cells in the immune system, and throughout the body. Know the non-specific physicochemical barriers that normally protect you from HIV infection (skin properties, secretions, acute phase proteins, etc). Neutrophils are typically normal in early HIV infection, and can be protective even in late-stage disease if the body keeps producing neutrophils. But if HIV affects neutrophil production or maturation in the bone marrow and you get neutropenia, then the neutrophils will not be able to protect against HIV infection. (this is an example of how if one arm of the immune system, e.g., CD4 lymphocytes, are not working properly, the immune system has redundancies, e.g., innate immune cells such as neutrophils, that can help to overcome problems with another arm of the immune system. But when BOTH are non-functional, the patient suffers overt clinical signs such as increased susceptibility to secondary disease). Over ½ of AIDS patients have neutropenia, and many more who are not neutropenic still have dysfunctional neutrophils that further increase susceptibility to secondary infections. AIDS patients with neutropenia tend to be more highly susceptible to strep and aspergillus infections. HIV is also associated with problems with macrophages (so decreased antigen presentation, and decreased phagocytosis), problems with NK cells, and problems with complement system. Lecture #12 Immunologic Testing CBC – complete blood cell count. Slide must be monolayer, and count white cells in multiples of 100, calculate % of each white cell. Increased neutrophils (neutrophilia) means inflammation (or stress). Increased band neutrophils means early active inflammation (left shift). Eosinophilia allergy or parasitic infection. Monocytosis usually means established or chronic inflammation. In biochemical blood profile, look at amount of protein. If hyperproteinemia, do serum protein electrophoresis (separate mixture of proteins based on their surface electrical charge). A peak is albumin, B peak is acute phase proteins (complement, coagulation proteins, C reactive protein, etc), C peak is IgM (early infection, D peak is IgG (more established infection - >96 hrs approximately). Ways to detect antigen: agglutination – use monoclonal antibodies into a patient sample that has particulate/solid antigens. Immune complexes get “glued” together – agglutinate – into a clump you can see visually (can’t see individual antigen-antibody immune complexes). Precipitation uses monoclonal antibodies to find soluble antigens in solution. Enzyme linked immunosorbant assay – ELISA – coat bottom of well with monoclonal antibody, then add patient sample, then “sandwich” the antigen in with another layer of antibody that is labeled with something you can see (chromogen). Immunochemistry – put monoclonal antibody on a fixed piece of patient tissue that has been sliced thinly. Antigen- antibody complex lights up. Immunoelectrophoresis – first separate antigens in patient sample using electrical charge, then put antibody on the side and the antigen and the antibody migrate towards each other. Where they meet there is a line of immune complexes. Western blotting separates antigens by molecular weight (size) then you can add antibody and the immune complex lights up. Affinity chromatography uses antibody-coated latex beads in a column – dump the patient sample with suspect antigen into the column, the antigen that matches that antibody sticks to the antibody and bead and the rest washes away. You can also detect the RNA of a protein (antigen) by studying the RNA of a patient sample that may contain the antigen. This is called PCR. Epitope mapping is a way to determine which antigens on the surface of a pathogen would be most immunogenic. Those can be put into a vaccine. Detection of antibodies – either add the specific antigen to find that antibody, or make a monoclonal antibody against the ANTIBODY of interest (remember antibodies are proteins so you can make an antibody to another antibody – called anti-IgG, for example, or secondary antibody). Agglutination – same principle if you are looking for an antibody in a patient sample that is attached to something solid (like an RBC), either add the antigen or an antibody against the antibody and they all stick together and agglutinate into a clump you can see. You can also detect soluble antibodies in solution using precipitation. You can also do ELISA by coating the bottom of the well either with the antigen, or more commonly, with a secondary antibody against the antibody you are interested in finding. Then you “sandwich” the antibody you are trying to find with more secondary antibody that is labeled with something you can see. Immunoelectrophoresis: put patient sample with mixture of antibodies in, apply electric current to separate antibodies, then add either antigen or secondary antibody on the sides. When they diffuse towards each other and meet in the area of equal concentration, there is a line. Western blot is where you separate a mixture of antibodies by molecular weight. You can also detect immune complexes by ELISA or fluorescence. Immune complexes that the macrophages can’t eat will deposit in vessels, kidney, joints. Monoclonal antibodies are made by injecting antigen into a lab animal and letting their immune system make the antibody to that specific antigen. Then you bleed the animal and purify the particular antibody. Monoclonal antibodies can be used both to diagnose antigens or antibodies, or can also be used therapeutically to neutralize antigens or toxins (botulism, tetanus, rabies, snake venom). You can separate white cells from blood using buoyancy or flow cytometry/cell sorting to test the function of each group of white cells. Remember: neutrophils phagocytose and produce reactive oxygen/nitrogen species. monocytes/macrophages phagocytose and produce cytokines lymphocytes proliferate and produce cytokines. So you can test those functions to see if the cells are working properly. We also have animal models of many human immunologic diseases, to study about them so that we can better understand the disease in humans. Lecture #13: Vaccination and Immunotherapy Know difference between passive and active immunization. Passive immunization is directly transferring antibodies from one person to another – natural – through placenta or breast milk (IgG) – remember neonatal gut has specific receptors for Ig, that are lost within the first few months. Or injected to counteract toxin or virus – ex. botulism, tetanus, rabies, snake venom. Active vaccination means injecting small amounts of the antigen and encouraging the body’s own immune system to make its own antibodies against that antigen. You give most childhood vaccines after 2 months when: baby’s immune system can respond and when mom’s antibodies are lower so that they don’t just bind to and neutralize the vaccine antigen. Most vaccines are given in shots (parenterally) – to stimulate IgG. Others are given intranasally to stimulate IgA and mucosal immunity. Modified live vaccines – live whole virus that is less virulent but still encourages strong and long-lasting immunity. May have contaminants and you have to be careful of storing the vaccine properly so that it doesn’t die and become less effective. Killed vaccines have heat or chemical denatured whole pathogens. Less effective vaccines so often multiple doses are needed. Also often adjuvants or immune stimulants are needed to make the vaccine more effective. Some can be given to pregnant women, unlike MLV vaccines. Toxoids are inactivated toxic compounds that are immunogenic. They are not the organism themselves. Recombinant subunit vaccines are made from only the immunogenic parts of the organism, not the whole organism itself. May use epitope mapping to develop. Conjugate vaccines are made against a normally non-immunogenic part of the organism, such as the polysaccharide capsule of the Gram positive bacterium. The sugar is conjugated to a protein which is immunogenic. Then eventually the immune system not only recognizes the protein but also the sugar as immunogenic and then can respond to just the sugar if a future infection occurs. Recombinant vector vaccine – take nonvirulent virus and add the immunogenic DNA part of the vaccine. DNA vaccine – inject DNA and immune system mounts an immune response against the DNA. There are some controversies with vaccination Parasitic vaccines are difficult to develop, but parasites have many many epitopes because they are big. Immunopharmacology – use upregulation or downregulation of immune system rather than drugs to treat disease. Used in cancer and in infectious diseases. Immune suppression can be used, especially in transplant biology. Lectures #18 and 19: Transplantation and Transplant Rejection During development and early postnatal life, the body learns to recognize self from non-self. One of the most polymorphic molecules our body makes is the MHC molecule, and this is why transplantation biology is so difficult. The easiest tissues to transplant are those that have the fewest antigens on them, and ones that are relatively avascular. So… corneal transplants and red blood cell transfusions were among the earliest successful transplants. Have an idea which organs can be transplanted, and which ones can come from living donors (e.g., lung, liver, skin, kidney, etc) and which ones can be autologous transplants (e.g., skin in burn victims, bone marrow stem cells in patients with cancer, etc.) Know the terms autograft, syngraft or isograft, allograft, and xenograft. Know the difference between transplant rejection (donor immune system rejecting the transplanted tissue) and graft vs. host disease (where lymphocytes within the transplanted tissue attack the immunosuppressed host). Know the different types of tissue typing methods (serologic, mixed leukocyte reactions, and genotyping), and which one is fastest and most precise, to minimize graft rejection (that would be genotyping), and in which instances tissue typing would be helpful or not helpful (e.g., cornea –no need to cross match because it is an avascular tissue and is not likely to be rejected; no time to cross match in a life-saving transplant such as heart or liver – you just have to really immunosuppress those patients for life; but in instances when you have time, like in a bone marrow transplant, there are good reasons to try to take the time to match, to reduce the incidence of graft rejection or graft vs. host disease). Be able to explain the idea of xenogeneic transplantation, and the positive and negative aspects of this technique (e.g., positive is that we can use pig or other animal body parts to transplant into people which will help to reduce the number of people who die every year waiting for a transplant; but negative is that the tissue may harbor zoonotic disease, which could be devastating when transplanted into an immunosuppressed transplant patient). Know the immune privileged sites of the body (anterior chamber of the eye, hair follicles, brain, testes and fetus). Be able to explain the significance of an Rh- mom and an Rh+ dad, and an Rh+ baby, and how that scenario might negatively impact the second child because the mom’s body would have made antibodies against Rh and those antibodies could attack the second baby. Be able to define first and second set rejection, and know what hyperacute (preexisting antibodies), acute (CMI), and chronic rejection (both humoral and CMI, happens over months to years) terms mean and their significance to the patient. Know that once chronic rejection has occurred, immunosuppression will not help because the damage is already done. Know those proinflammatory cytokines that are so important: IL-1, 2, 6, 8, IFNgamma, and TNF-alpha. Lecture #20 Transfusion Reactions The definition of blood transfusion is transfer of blood or blood products from one person’s circulation to another’s. Transfusion can be used to treat hemorrhage from trauma, infection, or bleeding disorders, or to replenish red cells due to increased red cell destruction, as with hemolytic anemia, or if there is inadequate production of red cells in the bone marrow. Red cells have fewer antigens on their surface than nucleated cells (remember they DON’T have MHC class I or II on their surface, and that is the protein that is the most polymorphic, and causes the most problems with rejection of transplanted tissue), so therefore, it is easier to match people for blood transfusion than it is to match someone for an organ transplant. The major antigens on red cells are A, B, and Rh factor (there are also minor red cell antigens that I am not going to hold you responsible for this test). So, if you are A (e.g., AA or AO), you have A antigens on your red cells, and your body makes anti-B antibodies, and you can receive A or O blood. If you are B (e.g., BB or BO), you have B antigens on your red cells and your body makes anti-A antigens, and you can receive B or O blood. If you are AB, you have A and B antigens on your red cells and you can receive A, B, AB, or O blood (universal recipient) If you are O, you don’t have A or B antigens on your red cells and you can ONLY receive O blood (universal donor). Rhesus (Rh factor) is the second most significant blood antigen (protein) that is on the surface of red cells of most people (more common to be Rh+ than Rh-). Refer back to lecture 18-19 review notes for explanation about Rh factor in pregnancy. Know that the test we use to cross match blood for compatibility in a transfusion is agglutination. Also remember that when we do transfusions, we usually only transfuse red cells (or platelet-rich plasma) because these cells do not have nuclei, and therefore do not have MHC class I or II on them, so are less likely to cause an immune reaction. We hardly ever transfuse white cells because of the problem with immune reaction. Be able to recognize the signs of an acute hemolytic reaction: fever, chills, flushing (acute phase response), cardiovascular signs such as tachycardia, hypo- or hypertension, nausea, and burning or bleeding at the IV site). Know that the mechanism behind this is IgM antibody against donor antigens due to donor-recipient incompatibility. If you take a sample of that patient’s blood, you will see red plasma (hemoglobin from lysed red cells). You may also see hemoglobin in the urine, which is harmful to the renal tubular epithelial cells. Know what transfusion-related acute lung injury is (immune complexes that deposit in vascular bed of lung tissue and cause an inflammatory reaction, plasma leakage, and pulmonary edema). Be able to list some of the more common transfusion-related infectious diseases, such as hepatitis, HIV, cytomegalovirus, west nile virus, and other rare ones. Lecture #22: Systemic Sclerosis, Sjögren’s Syndrome Scleroderma is a chronic immune disease that results in edema, endothelial targeting, perivascular accumulation of T cells, release of proinflammatory cytokines, and ultimately fibrosis (collagen deposition) in the skin (esp hands). Thought to be triggered by cytomegalovirus (CMV) or exposure to organic solvents, or microchimerism. First you get swelling (edema), then skin becomes thick and hard (fibrosis). Often you get flexion contractures because of tight skin. Blood vessels also look mottled because of the perivascular lymphocytic cuffing and telangiectasis. Remember that 90% of scleroderma patients also get Raynaud’s phenomenon (vasospasm in fingers and toes that causes them to turn blue). Systemic sclerosis is multisystemic scleroderma – affects musculoskeletal system (joint pain, arthritis, myopathy), pulmonary system (dyspnea, nonproductive cough, interstitial fibrosis in lower lung lobes, pulmonary hypertension), GI (GERD, dysphagia, malabsorption and bacterial overgrowth, and colitis) and renal systems (due to hypertension, microangiopathic hemolytic anemia). Remember CREST syndrome (calcinosis, Raynaud’s syndrome, esophageal dysmotility, sclerodactyly, and telangiectasis). Diagnosis of systemic sclerosis is by demonstration of antibodies. Sjögren’s syndrome is autoimmune disorder where autoimmune CD4 T cells attack moisture-producing glands that produce tears and saliva (affects eyes, mouth, throat especially, but also affects kidney, GI, vessels, etc) Tests: anti-nuclear antibody and rheumatoid factor tests. Treatment: symptomatic and immunosuppressive. Lecture #23 and 24: Autoimmune Disease, Lupus, Rheumatoid Arthritis Be able to list the major factors involved in autoimmunity, such as genetic predisposition (mostly in MHC molecules), molecular mimicry, dysregulation of cytokines or hormones, defective T cells, and pre-existing defects in the target organs. Know that systemic lupus erythematosus (SLE or lupus) is called the great imitator. It is a multsystemic autoimmune disease that is thought to be a type III hypersensitivity reaction, and can be triggered by UV radiation, infectious agents such as bacteria or viruses, or chemicals such as drugs (antidepressants, antibiotics). Symptoms of lupus include general malaise, malar skin rash, musculoskeletal joint pain, anemia and other blood abnormalities, various cardiovascular, nervous, and pulmonary problems, as well as renal – membranous glomerulonephritis. Be familiar with the 11 criteria for lupus, and know that 4 of them must be minimally present for the diagnosis of lupus. Know about some of the more organ specific autoimmune diseases such as Hashimoto’s thyroiditis as a cause of hypothyroidism in women more than men. Know that there are genetic, environmental, and immune causes for this disorder, and know the symptoms and diagnosis as well as treatment. Autoimmune diabetes mellitus is a reaction to self-islet cells. Often misdiagnosed as type 2 diabetes but it is actually loss of cells that produce insulin, not insulin resistance like with type 2 diabetes. Diagnosis is with low c-peptide levels, and treatment is symptomatic (insulin replacement). Myasthenia gravis is an autoimmune disorder that affects skeletal muscle cells (actually against acetylcholine receptors at the post-synaptic junction). Diagnosis is identification of autoantibodies at the post-synaptic junction as well as strength tests. Treatment is immunosuppression and cholinesterase inhibitors (which prolong the action of acetylcholine at the post-synaptic junction). Rheumatoid arthritis (RA) is a systemic autoimmune disorder that affects middleaged females more than males. There is a genetic predisposition. It usually presents as a polyarthritis, synovitis, and erosion of the joint surface. Some of the most characteristic lesions of RA are ulnar deviation, bouttonniere deformity, swan neck deformity, and z-thumb deformity. You can often also see a rheumatoid nodule around the elbow, or over other bony prominences. RA often occurs after an infection with EBV, CMV, parvo, or rubella. T cells interact with self-antigen and deposit immune complexes in the small vessels in the joint (synovium) that causes chronic synovitis that is perpetuated by TNFalpha. Long-term effects are joint destruction. RA can be differentiated from osteoarthritis by the way the symptoms present: typically RA is worst in the morning, before the patient gets moving. In contrast, osteoarthritis, which is a disease of wear and tear of the joint, usually gets worse after exercise. Know how to diagnose and treat RA (rheumatoid factor, radiography, etc to diagnose, and treatment is with anti-inflammatory agents, DMARDS, anti-TNF antibodies, physical therapy, and last resort joint replacement).