BBI Introduction.docx

**Introduction to the Immune System** - Our Bodies way to protect itself from threats and potential threats - The period when a cell type is developing and differentiating is usually a period where it is vulnerable and an opportunity for clinical intervention - Can make some inferen...

**Introduction to the Immune System** - Our Bodies way to protect itself from threats and potential threats - The period when a cell type is developing and differentiating is usually a period where it is vulnerable and an opportunity for clinical intervention - Can make some inferences between two cell types that come from a common starting cell - Pathogens: foreign bodies to our own human existence; they are living - Fungi, bacteria, viruses, parasites - Development: - Start as an embryo with embryonic tissues wrapped around a yolk sac - In yolk sac are multipotential hematopoietic stem cells (hemocytoblast) - Bound to be blood cells, but many different types - Once there is an embryonic liver, they migrate there - When there, differentiate into two main types - Common Myeloid Progenitor - Differentiates into: - Megakaryocytes: create thrombocytes (clotting) - Erythrocytes: red blood cells - Leukocytes: all other cells, white blood cells - Mast Cells: create histamines - Myeloblasts: phagocytes -\> innate immune system, 1^st^ defense - Basophil - Neutrophil - Eosinophil - Monocyte - Dendritic Cells - Macrophage - Common Lymphoid Progenitor - Natural Killer Cell: large granular lymphocyte - Is also a phagocyte - Small Lymphocyte: Adaptive Immune System - T Lymphocyte - B Lymphocyte - Plasma Cell - Dendritic Cell (two different types of dendritic cells; one from myeloid and one from lymphoid) - All cells eventually migrate to tissues all over the body - There are not really two different separate systems; more like two different strategies, where some cells are more active in one system or the other - Innate Immune System: non-specific defense against pathogens; faster - Born with; more intuitive; localized - Evolved to have receptors for very common pathogens - Can also detect a non self-cell and engulf/kill it quickly - Phagocytes: have receptors for common pathogens - Macrophages: - Engulf cells - Lysosomes break down the cell and find an antigen from the pathogen - Present an antigen as a beacon for other immune cells - Release cytokines: umbrella term for all signals between immune cells - Bind to receptors for the cytokine on other cells - Kind of like the immune version of a neurotransmitter present in the brain - Some create a scaffold for other immune cells to find the infections/wound/damage when concentration of cytokine increases - Some also widen or restrict blood vessels - This can allow more blood cells to get to site or can isolate it to prevent spreading - Widen to allow blood cells in then constrict quickly; this generates heat to prevent pathogens from surviving at a higher temperature (designed only to survive at body temp) - Dendritic Cells: - Really good at presenting antigens because they have lots of processes with greater surface area - Ingest pathogen - Break down pathogen via lysosomes - Release cytokines - Neutrophils: - Cluster around area of infection - They are attracted to site via scaffolding from cytokine - Commit apoptosis instead of engulfing pathogen - Programmed cell suicide - Causes release of lysosomes to break down pathogen - Releases pus - Natural Killer Cells (NK): - Cytotoxicity: cell death - Kill self-cells that have been infected by virus or tumor cells - Detects stressed self-cells and bore holes in cell using perforin; this induces apoptosis in self-cell - Also can kill pathogens, but there primary function is stressed self-cells - Release cytokines - Blood Vessel: lined with endothelial cells - Contain red and white blood cells - White blood cells circulate in blood vessel and monitor for signals -chemoattractants - Rolls along endothelial cells; adheres - Squeezes through two endothelial cells and out of blood stream to do its job - Transmigration - Running alongside the vasculature is the lymphatic system: - There to catch fluid that "leaks" out of blood vessel and push it back into the vein to prevent continuous emptying of blood vessel and dropping of pressure - Extravasation: leakage of vesicant fluid out of a blood vessel into surrounding tissue - Lymph Vessels: tubes that carry lymph through the body to lymph nodes and back to veins - Lymph: blood, cell, and tissue fluid; can include white blood cells, signals, proteins - The signal our body gets about what's going on systemically - Lymphoid Organs: - Primary: central lymphoid organs; where maturation and development of lymphocytes occurs - Bone Marrow - Thymus: right over heart - Secondary: where lymphocytes end up initiating adaptive immune response - Tonsils - Adenoids - Lymph Nodes - Spleen - Appendix - Peyer's Patches: - Lymph nodes in gut - Lymph streams through lymphoid organs where lymphocytes are present to receive signals - Acquired/Adaptive Immune Response: generate new defense responses against new pathogen; patrol whole body - B Cells: originate in stem cells in the bone marrow and mature - Job is to develop antibodies (immunoglobins) \[go by ig\_\_\_\] - Perfectly specific for one type of antigen for on type of pathogen - Small proteins that circulate throughout blood and bind to specific pathogens - Shaped like Y with two protein chains - Light (variable) protein chain on arms: antigen binding region - Different for each specific antigen - Heavy (constant) protein chain on stalk: receptor binding region - The same on all B cells for a class - Rearrangement of B cell DNA allows for a limitless variety of antibodies - Kind of like a combination lock; keeps trying out new combinations of nucleotides -\> spewing trial antibodies specific for antigen - If not correct, undergoes apoptosis - New B cells keep trying combinations until correct antibody is generated - Once signal is received that it is correct, differentiates into plasma cell - Somatic hypermutation: can mutate DNA in cell while alive - Antigen driven activation of naïve B cells leads to differentiation of plasma cells and memory B cells - Each produces antibodies with one specific light chain - In absence of antigen induced activation -\> apoptosis - T Cells: originate in bone marrow, mature in thymus - Helper T Cells: necessary for B cell learning which antibody to secrete - Occurs because of cytokines that the helper T cell secretes - Communication between the helper T cells and B cells allows for B cell to understand whether correct antibody was produced or whether incorrect and should undergo apoptosis - Killer T Cells: similar to natural killer cells - Skip B cells and start looking for infected self-cells that match the antigen presenting cells (APCs) - APCs help killer T cells identify the infected cells via the antigen and activate the T cells - Examples: dendritic cells, macrophages; also self-cells can be APCs - Secrete perforins or deliver enzyme packages to infected cells - Major Histocompatibility Complex (MHC): proteins on APCs that hold out the antigen to be identified by the T Cells; this determines whether Helper or Killer T Cell - MHC I Molecules: on all human cells - Present an antigen that has been created inside the cell -\> endogenous - Proteins made by an infected cell when the virus takes over the machinery - Proteins made by a tumor cell - T Cell recognizes MHC I protein complex and differentiates into Killer T Cell, to go look for similarly infected self-cells - MHC II Molecules: only on immune cells - Present an antigen that are from an external cell that has been broken down -\> exogenous - In an immune cell after a macrophage has digested the pathogen; T Cell recognizes the MHC II protein complex and differentiates into Helper T Cell. Helper T Cell then can recruit B Cells to produce antibodies to address circulating pathogen - Autoimmune Diseases: disorders where the immune system backfires, causing the immune system to attack healthy self-tissue - B Cells start erroneously producing antibodies - Normal Safety Precaution: If a B Cell starts producing MHC I like antibodies they undergo apoptosis, as this would cause antibodies to start attacking healthy self-cells - This disfunctions in autoimmune diseases - Multiple Sclerosis (MS): produce antibodies against oligodendrocytes and Schwann cells which produce myelin necessary for neural efficiency and preventing cross talk -\> neurodegeneration - Paraneoplastic Syndrome: is metastatic cancer; when antibodies that are supposedly for attacking tumor cells, accidently attack the healthy self-tissue that the tumor started out as or a different section of healthy self-tissue - Example: someone who had metastatic breast cancer, experiences balance issues due to attack in brain tissue - Pediatric Autoimmune Neuropsychiatric Disease Associated with Streptococcus (PANDAS): childhood form of OCD; antibodies erroneously attack the basal ganglia (regulating habit formation and repetitive movements), originally a strep diagnosis caused antibodies to be produced - Strep is a very old so the body is very good at creating mass amounts of antibodies to attack the infections, but the strep bacteria can also look similar to self-tissue causing accidental cross damage - Myasthenea Gravis: antibodies erroneously attack the neuromuscular juncture -\> neuromuscular function degeneration - Sickness Behavior: Immune-CNS interactions; behaviors exhibited by everyone no matter the type or the intensity of the sickness - Maybe there is an immune component to psychological disorders, as at times similar behaviors are exhibited - Anhedonia (don't enjoy the things we normally do), lethargy, social withdrawal - Sounds like MDD - Fever: immunologic response to an infection in order to kill the pathogen - Generated by the hypothalamus as signaled by cytokines as it resets the body's set point to be higher - Anorexia (not nervosa): decreases iron, as some bacteria thrive off of iron, in order to weaken them - Temporarily a little anemic - Social Withdrawal/Anhedonia: encourages isolation to prevent spreading infection; conserve energy - Proinflammatory Cytokines IL-1 and IL-6 produced by T Cells and macrophages - Also produced by resident immune cells in the brain; microglia and astrocytes - Travel to the brain and signal neurons in different regions, including the hippocampus and hypothalamus - Thus cognitive function and mood are changed due to different firing of neurons in the hippocampus - Thus temperature regulation and motivation for feeding and drinking are changed due to different firing of neurons in the hypothalamus - How the Immune System and Nervous System communicate to produce different behavior 1. Direct activation of cytokine receptors all over neurons a. Receptors are bound by IL-1 b. Ex. if IL-1 receptor is bound at the same time as an NMDAR receptor is bound by glutamate, intracellular cascade of interactions occurs causing a change in the cell's gene transcription and different proteins are produced (different outcome if both are activated instead of just NMDAR alone) 2. Direct activation of neurotransmitter receptors c. Immune cells have neurotransmitter receptors on their surface d. Active neurons can also signal microglia (immune cells in the brain) through NT reception e. NTs are also in the periphery (less so) which can influence immune cells in the periphery 3. Indirectly through microglia (mainly) and astrocytes (less so) f. The immune cells in the brain when activated by cytokines can express antigen through MHC II g. Can perform phagocytosis h. Microglia are really macrophage that have colonized the brain i. Astrocytes can perform immune functions but are not true immune cells - Pathway Implicated in Psychoneuroimmunology: - IFN-α \[pro-inflammatory cytokine; similar to IL-1 and IL-6\] activate **microglia** to produce IDO (indoleamine) \[also active in astrocytes and neurons\] by binding to receptor on microglia - IDO (enzyme) shunts tryptophan metabolism pathway \[which normally is a precursor to serotonin and melatonin\] - Tryptophan is instead converted to kynurenine - Kynurenine is converted into quinolinic acid - Quinolinic acid is an NMDA agonist; it binds to the receptor and activates it like glutamate - NMDA glutamate receptor is important in integrating information and causing intracellular activity, important for neural plasticity - A lot of NMDA activity can cause more neural plasticity and vice vera - Too much NMDA activity can cause neurons to get excited to death (excitotoxicity) - **Astrocytes** are usually activated by a different set of cytokines, anti-inflammatory cytokines. Usually acting to balance out the pro-inflammatory cytokines - Ex. IL-10 - When astrocyte activated by these cytokines, IDO is produced by the astrocyte - IDO still causes tryptophan to convert kynurenine - But kynurenine is converted into kynurenic acid - Kynurenic acid is an antagonist of NMDA receptor - Does the same thing to NMDA receptor that ketamine does - IMPORTANT BALANCE - In depression we often see too much NMDA activity - Increase of quinolinic acid in the CNS - Ketamine has been used as a treatment for depression - In schizophrenia we often see too little NMDA activity - Increase of kynurenic acid in the CNS - Ketamine given to a non-depressed individual produces symptom similar to schizophrenia - Pathway Specified Further in the Neuron: - Immune response in periphery - Inflammatory cytokines bind to cytokine receptors on microglia in the CNS - Microglia produces IDO, causing tryptophan conversion - In order for IDO to be produced in microglia, increases the production of COX~2~ \[blocked every time you take ibuprofen, which prevents PGE~2~ production\] - COX~2~ is an enzyme that is necessary for the production of PGE~2~, which then induces the tryptophan pathway described previously - Tryptophan is only converted into serotonin and melatonin in neurons, not in microglia and astrocytes - Neurons don't produce IDO, they take it up from microglia and astrocytes