Philipp Dettmer: Immune

Proteins:

• made from chains of amino acids
• shape determines function, what it attracts/repels, how they interact (biological pathways)
• DNA is instructions to make them (genes), around 1%. Rest is regulating which are built when and how many
  • first, special proteins read the DNA, convert them to mRNA
  • mRNA is translocated to ribosome, where mRNA is read and translated into amino acids that are assembled
  • those amino acid chains fold into specific shapes

Cells have receptors, communicate by releasing cytokines (proteins carrying information). When a cell notices a cytokine with its receptor, it triggers pathways inside the cell changing gene expression and therefore behavior of the cell.

Antigen: protein piece recognized by the immune system

Immune system has two parts: Innate and Adaptive

Innate system:

• active at birth
• Macrophage: eat dead cells and enemies, dissolves them
  • in intenstines, do not release cytokines that would call in Neutrophils and cause inflammation
• Neutrophil:
  • eat enemies, throw granules at enemies that rip them apart
  • NET: uses own DNA to trap bacteria or viruses
• Cause inflammation: if cells are dying unnaturally, releasing chemicals causing inflammation – fluid enters area, bringing complement proteins
• Release Pyrogens: cause fever, which slows down reproduction of viruses and bacteria. Because our cells are more complex, they work more efficiently in fever.

Complement:

• over thirty types
• maims enemies, activates immune cells and guides them
• passively generated unlike cytokines
• C3:
  • C3b: has to find a victim, to which it attaches and changes shape. It can then grab other complement proteins, change their shape, and merge with them. This quickly activates large number of complement. Then they change shape again, construct Membrane Attack Complex: new complement broteins anchor themsleves in bacteria surface, and rip a hole.
  • C3a: similar to cytokine, alarm signal to immune cells
• membranes of cells and bacteria are negatively charged; complement is positive, so they allow phagocytes to attach to bacteria (opsonization)

Lymphatic system

• covers the whole body
• main job is to transport blood cells and other things back into circulation (lymph). While doing that, it picks up other things too (e.g. bacteria)
• Spleen: filters and recycles old blood cells, stores emergency reserve of blood and platelets. Can respond quickly with IgM antibodies
• Tonsils: contain Microfold Cells that sample things coming into the body
• Peyer’s patches: gut lymph node with microfold cells

Monocytes: reinforcement cells, can transform into Macrophages and Dendritic Cells

Dendritic Cells:

• basically everywhere, deliver context to Adaptive Immune System
• sample what’s going on at infection site and bring it to lymph nodes
• activate Helper T Cells, which help at infection site and activate B Cells and Killer T Cells
• cross-present: sample virus antigens, present some in their MHC I molecules, activating Killer T Cells
• also search for autoreactive T cells, and disable them

Adaptive system:

• takes a few years to develop
• takes gene segments, randomly combines them and removes/adds parts to create many different receptors
• T Cells trained in Thymus, B cells in bone marrow
• T Cell has one specfic receptor, able to recognize one specific antigen (and can connect to a few more)
• Thymus makes sure that immune cells do not recognize self as other:
  • Test that T Cells can make working receptors
  • Test that T Cells are really good at recognizing receptors of cells they need to work it
  • Test that T Cells cannot recognize main proteins inside the body
    • Inside Thymus, cells can make proteins that are usually only made in other organs and hormones
    • if they can, this is autoimmune reaction. But for a full reaction, needs MHC to bind to self-antigen efficiently (genetic bad luck), and an infection that provokes Innate system to activate them.
• Thymus stops working over time

Helper T Cells:

• recognize antigen if it’s presented in MHC class II molecule, gets activated
  • only antigen-presenting cells have MHC II: Dendritic, Macrophages, B cells
  • makes sure they don’t get activated by accident by something just floating around
• in Lymph Node begins cloning itself quickly
• follow cytokines to site of infection
• stimulate Innate Immune System (keep Macrophages alive)
• after infection, most kill themselves, some become Memory Helper T Cells
  • Tissue-Resident Memory T Cells: at the site of infection
  • Effector Memory T Cells: patrol lymphatic system and blood
  • Central Memory T Cells: remain in lymph nodes, when activated produce new Effector T Cells

Killer T Cells:

• depend on MHC I to get activated
• have to be activated by Dendritic Cell and then by activated Helper T Cell
• insert signal into infected cell for apoptosis

Regulatory T Cells: can reduce effectiveness of Adaptive system, shut down inflammation

Natural Killer Cells:

• hunt cells infected by viruses and cancer cells
• kill any cells that have no MHC class I molecules. all have them, except red blood cells

Plasmocytoid Dendritic Cells:

• scan for signs of viruses
• if they find, they release extreme amounts of interferons cytokines
  • shut down protein production in cell
  • stimulate cells to make more MHC class I
    • most diverse genes of human species – that’s why organ transplantation is a problem

B Cells

• produce antibodies: B cell receptors
• have to be activated by both Innate and Adaptive
• sit in lymph nodes, take antigens from lymph
• if complement is attached to pathogens, confirms that there is a real danger
• activated T Cell needs to find activated B Cell, both need to recognize the same antigen
• turns into Plasma Cell, producing antibodies:
  • two pincers, each able to grab a specific antigen, and the middle which can connect to immune cells
  • able to activate complement system
  • start with IgM antibodies, but can be changed by Helper T Cell
  • types:
    • IgM: majority produced, five antibodies merged together. Can clump together viruses well.
    • IgG:
      • good at opsonizing, unable to activate complement system later
      • can pass from mother to child in placenta
      • takes longest to decay
    • IgA: most abundant, cleanup mechanism for mucosa, can pass through epithelial cells. Can’t activate complement, which would mean inflammation (not good for mucosa like gut). Pass from mother to child in milk.
    • IgE: originally served to protect against parasites like worms, also responsible for allergic shock. Produced normally in skin, lungs, intestines
      • when a parasite recognized first time close to surface, IgE produced, priming Mast Cells. when encountered second time, Mast Cells attack.
• some become memory cells:
  • Long-Lived Plasma Cells: stay in bone marrow and constantly produce antibodies
  • Memory B Cells: settle down in lymph nodes, wait for antigens and then immediately start as Plasma Cells

Intestinal mucosa structure

• first layer: mucus with antibodies, defensins, other defense proteins
• epithelial cells: one cell thick. Scan own insides and if it realizes it is infected, release cytokines
• Lamina Propria: Macrophages, B Cells, Dendritic Cells

Virus:

• mostly just hull with some genetic code and proteins
• abuse receptors, can transfer genetic material in victim and starat producing virus
• viruses bud from the cell, using its membrane, or dissolve it
• multiply and mutate very quickly
• harder to detect because it has no metabolism
• retrovirus: intrudes and merges with genetic code
• cytokine type interferons:

Antibiotics: compounds that normally microbes use to kill other microbes:

• Penicillium: interrupts cell wall construction. Our cells do not have cells walls (except bacteria in gut, which is why antibiotics can ruin the gut microbiome)
• Tetracycline: inhibits bacterial ribosomes

Drugs are molecules that connect to specific shape of a part of enemy that’s not present in a human body

Vaccination:

• make a weak version of pathogen. Especially good with viruses, because they are simple and easier to control
• Live vaccine: has to be stored correctly so weak pathogens don’t die
• Inactivated vaccine: use dead pathogens and chemicals that highly activate immune system
• Subunit vaccine: use only certain parts (antigens), so they can be recognized by T and B cells

Allergies:

• antigens = allergens. Short piece of protein that can be recognized by Adaptive immune cells and antibodies
• Mast Cells:
  • carry histamine, causes rapid and massive inflammation
  • have receptors that attach to IgE antibodies
• on first encounter, IgE may be produced, and Mast Cells attach to them
• on second exposure, the IgE on Mast Cell connects to the allergens, and Mast Cells degranulate: release all chemicals including histamine.
  • release cytokines that all in Baophils
• Basophil: has IgE receptors that they charge after first exposure, keep up allergic reaction
• Eosinophil: activate later, prolong allergic reaction

Cancer:

• genetic code constantly mutates a bit, these damages accumulate
• you can increase chances of cancer by damaging your DNA (smoking, drinking, being obese which produces inflammatory cytokines, contact with carcinogens)
  • nicotine slows down immune system, including Natural Killer Cells, which are one of main countermeasures against cancer
• needs 3 key mutations:
  1. in oncogenes: monitoring growth and proliferation. Originally useful in embryo growth
  2. In genes responsible for fixing broken genetic code (tumor suppressor genes)
  3. In genes that cause apoptosis.