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Immunology Week 10 (Flipped Class; 3 Videos (Sex, Drugs, and HIV: Lets get…

- - - - Types
        
        Malignant: due to DNA alterations due to a variety of causes (chemical, physical, infections, etc.)
        
        Cancer-inducing genes (when altered)
        
        Tumor suppressor genes (loss of function)
        
        Apoptosis genes (loss of function or control)
        
        Proto-oncogenes (loss of control)
        
        Benign
      - Caused by cells that have lost control of the cell cycle: a single initially modified tumor cell multiplies to form a mass of tumor cells (a lozalized benign tumor) which invade the basal lamina and metastasize into blood vessels
      - Antigens
        
        Tumor-specific: unique to tumor cells, do not occur on normal cells in the body
        
        Tumor-associated: not unique to tumor cells, variant forms of normal genes, temporal displacement of gene expression, high expression of low level proteins
      - MHC Class l pathways
        
        Oncofetal peptide results from the inappropriate expression of the embryonic gene (TAA)
        
        The normal protein is overexpressed (TAA)
        
        Mutation causes MHC Class l to present an altered peptide
      - Tumors of the immune system
        
        Lymphomas: solid tumors within lymphoid tissue, typically in bone marrow, lymph nodes, or thymus
        
        Leukemias: proliferate as single cells, detected as increased cell numbers in blood or lymph fluid (doesn't actually form a mass), and can be in cells from either lymphoid or myeloid lineages
    - - Immunoediting
        
        Anti-tumor responses select for toughest cells
        
        3 phases: elimination, equilibrium, and escape
        
        Elimination: attacking the cells that can be targeted
        
        Equilibrium: state of balance between destruction and the surviva of "best" cells
        
        Escape: most aggressive or leas immunogenic cells thrive and spread
        
        Tumor cells might become less immunogenic because of things like reduced MHC expression, altered MHC genes, reduced expression of NK activating ligands, altered cell death receptors, or poor costimulatory signals
        
        Protects against and promotes tumor growth
      - Tumor specific Igs
        
        Sometimes block CTL access (bc cell is coated with Igs - Ig-mediated cytotoxicity)
        
        Ig-Ag complexes can block Fc receptors (ie on NK cells)
      - Tumor specific CTLs
        
        Issue is that many tumors down-regulate MHC. Something that allows tumors to grow has low MHC expression
      - NK cells and Macroghages (Other innate cells)
        
        Can carry out ADCC
        
        Not restricted by MHC molecules
        
        NK scan the surface of cells for necessary surface molecules, rely on inhibitory and activating signals.
    - - Increases cellular stress signals, which can increase mutation rates # - snowball effect
      - Inflammation is pro-angiogenic (increases blood vessel growth, allows for greater tumor-cell invasion into surrounding tissues)
      - Growth factors/cytokines released by cells often induce proliferation - snowball effect
    - - Monoclonal Igs: Because we have Ags on these cells, if we can identify them then we can use monoclonal Igs to tag them or just to engage our own immune system. Fell off the radar: using Igs fused with glass beads
      - Cytokines: Cytokines are so complex and would definitely cause side effects
      - Drugs (chemotherapy, hormonal, molecular inhibitors): chemotherapy stops the cell cycle and turns things down, antagonists/blockers/inhibitors reduces signalling
      - Cell based
      - Therapeutic Vaccines: Therapeutic vaccines involve putting an actual cell into you. Taking out dendritic cells, exposing them and sensitizing them to Ags, and putting them back into you.
  - - - Small particles allowed in by invitation only (Blood-brain barrier)
      - Ags surveyed from outside only (T cells sampled CSF)
    - - Drain CSF into neck lymphatics
      - Demonstrates a connection b/w the immune privileged brain and the overall immune system #
    - - Sensory Systems
      - Behaviour
      - Neurodegenerative disease
      - Cognition
        
        Proinflammatory signals from macrophages inhibit a protein important in learning and memory
        
        IL-4 from CD4+ T cells reduce the signals from macrophages and increase cognition
        
        Stress of learning vs. stress from infection
      - Injury repair: cytokines and mediators promoting would healing and resolution of inflammation
- - - - Severity ranges from mild to fatal
      - Loosely categorized as affecting innate or adaptive responses (50/50 between humoral and cell mediated)
      - Nature of immune defect determines which pathogens are most dangerous
      - Due to genetic or developmental defects (signal transduction or cell communication are most common). Often passed down and the deficiencies are related to the pathways that are affected
      - Consequences depend on the severity of disruption and specific component involved
      - Types
        
        Combined: usually affects both B and T cells. Disrupts adaptive immunity (ie SCID, BLS)
        
        B-cell: depressed production of one of more Ig isotypes
        
        Disruptions to Innate Response: may also impact adaptive responses (ie CAM disruption)
        
        Complement: Relatively common; occur in the various steps/pathways
        
        Disruption in immune regulation; can manifest as autoimmunity (ie mutation in the AIRE gene
      - Severe Combined Immunodeficiency (SCID): Can be characterized by a very low number of circulation lymphocytes, failure to mount T cell mediated responses, and no developed thymus. #
        
        Common cause: deficit of IL-2 receptor
        
        Results in severe and recurrent infections
        
        Infants suffer from chronic diarrhea, pneumonia, skin, mouth and throat lesions, and various opportunistic infections
        
        Usually fatal in early years of life
        
        Treatment
        
        Future: gene therapy to repair leukocytes (halted to do recent adverse effects)
        
        Present: bone marrow transplants
        
        Past: confinement to sterile environment (bubble boy)
      - Treatments (Replacement Therapies)
        
        Replacement of a missing Cell Type or Lineage: Bone marrow or hematopoietic Stem Cell transplantation
        
        Replacement of missing or defective Gene: Gene therapy (some problems w/ inducing leukemia in trials)
        
        Replacement of Missing Proteins: passive Ig, recombinant proteins
    - - HIV/AIDS
        
        Stereotypes: Homosexual males, drug addicts, poor, Africa, Stupid people
        
        : A retrovirus that spreads mainly by sexual contact, by passage of bodily fluids, and from mother to infant. Human Immunodeficiency Virus 1 (HIV-1)
        
        Has 2 RNA genomes and a reverse transcriptase (RT).
        
        Evades system by using decoys by putting molecules on it's surface that resemble host molecules
        
        Infection DETAILS
        
        CD4 cells: the receptor being used
        Chemokine receptor (not shown): that will bind to the cell, engage the membrane and enter
        RNA and Reverse transcriptase: some will become the double stranded and move in, some of it will stay in the cytoplasm.
        
        - Once you have the provirus you can hijack the machinery of the cell.
        
        Plugs the provirus right in the location where transcription will occur
        
        That will be used to make the new versions of the virus.*
        
        Provirus also used for dormancy
        
        Depletion of CD4+ T cells #
        
        Blood: reaches steady state
        
        Lymph Nodes + GI Tract
        
        Infection of lymph via dendritic cells
        
        Swollen lymph nodes, fever, and sometimes rashes
        
        Destruction continues during chronic stage
        
        Infection usually not noticed until opportunistic infections occur
        
        Death caused by...
        
        Fungal infections (...
        
        Cancer (cervical, lymphoma, viral induced)
        
        Yeast Infections (usually first sign)
        
        Parasitic infections (severe wasting induced)
        
        Frequent viral infections (HSV...
        
        Bacterial infections (TB...
        
        ..., Pneumonia)
        
        Gradual loss of immune function
        
        Asymptomatic Phase: lengthy (possibly years), gradual decrease in CD4+ T cells and an increase in viral load #
        
        AIDS: crash in CD4+ T Cell numbers, high HIV blood levels
        
        Acute Phase: spike in HIV blood levels that are eventually brought (mostly) under control by anti-HIV Igs
        
        In the blue, the opposite is happening: decreased cell count, viral load increases, opportunistic infections, where a lot of people realize that they have HIV.
        
        Infection Outline: transmission and affected cells
        
        Vagnial/anal intercourse
        
        Receipt of infected blood/blood products
        
        Passage of HIV from mother to infant
        
        Dendritic cells (--> to CD4+ T cells) through passing
        
        Treatment
        
        Anti-retroviral drugs
        
        * Must be careful not to accidentally target normal cell processes
        
        Mechanisms
        
        Prevents virus from fusing with and entering a cell
        
        Interferes with reverse transcription
        
        Blocks viral protease needed for construction of new virions
        
        visualization of targeting
        
        HAART
        
        Uses a combination of drugs with different mechanisms (to block different mutation pathways). Used to be MANY but today has been reduced to 1 or 2 pills
        
        Very effective, can lead to deplete loads below limits of detection (Undetectable)
        
        Can also be used prophylactically in high-risk groups
        
        Highly Active Antiretroviral Therapy
        
        NO vaccines available b/c of difficulties
        
        HIV has a rapid mutation rate
        
        Killed HIV does not retain antigenicity
        
        Most vaccines allow low level infection (that doesn't work with HIV)
        
        There is no suitable animal model for testing
        
        Until recently had no natural immunity to mimc (Reverse vaccinology being used to determine useful target Ags)