Immune System Part II PDF

Antigen Receptor Diversity Genes determine which specific antigens the immune system will recognize and defend against Encounter with antigen via receptors dictated by genetics dictates which T or B cells will proliferate, expand and attack Immune s...

Antigen Receptor Diversity Genes determine which specific antigens the immune system will recognize and defend against Encounter with antigen via receptors dictated by genetics dictates which T or B cells will proliferate, expand and attack Immune system comprises billions of different types of antigen- specific receptors these billions are generated from ~25,000 genes billions can be generated from thousands because of a process called VDJ gene rearrangement stitching together portions of gene segments to make many different combinations somatic recombination  Antigen Presenting Cells: APCs Cells that engulf antigens and present antigen fragments on their surface for recognition naïve T cells can only recognize antigens presented on MHC molecules Three major APCs: Dendritic cells: most powerful APC Macrophage long extensions for very efficient phagocytosis upon antigen internalization they home to lymphatics to present Macrophages can activate T cells often present antigen to T cells to activate T cells to produce macrophage-activating chemicals -> activated macrophages B cells Dendritic Cell B Cell do NOT activate T cells present antigen to T helper (TH) cells to support their own activation Clonal Selection of B cells Activation of B cells happens when matching antigen binds to the B cell receptor (a membrane-bound antibody) Antigen (Ag)-antibody (Ab) binding leads to receptor- mediated endocytosis Activated cells will become one of two types: plasma cells: antibody factories can secrete ~2000 Abs/sec active for 4-5 days Abs will enter circulation and bind to complimentary Ag, marking them for destruction memory cells: long-lived can mount a very fast immune response if they encounter the same antigen  Primary vs Secondary Humoral Responses Primary Humoral Response Secondary Humoral Response first exposure to an Ag re-exposure to the same Ag lag of 3-6 days: B cell faster, more prolonged, proliferation and more effective differentiation to plasma memory cells are already on cell ‘alert’ Ab levels peak ~ 10 days, within 2-3 days Ab then decline concentration climbs: antibody titer Ab levels can remain elevated for weeks – months Active vs Passive Humoral Immunity  General Antibody Structure Fab Region Fc Region Each Ab has TWO Ab-binding sites: can bind 2 of each identical Ag Stem Region (Fc) determines the Ab class (discussed on next slide(s) effector region determine what cells (and chemicals) can recognize the Ab dictates functions that will contribute to eliminating the Ag Antibody Classes (MADGE) Ab classes have different characteristics, biological roles and locations throughout body A single B cell can switch from producing one Ab class to another, producing 2+ different classes of the same specificity  Mechanisms of Ab Action Abs do NOT Destroy Ag Directly Neutralization simplest defensive mechanism Abs block specific sites on viruses or bacterial toxins Prevents binding to receptors on tissue cells Phagocytes eventually destroy the Ag-Ab complex Agglutination Clumping/lattice formation caused by 2 binding arms of Ab IgM are powerful agglutinators: 10 binding sites Precipitation Soluble antigens are cross-linked Large complexes come out of solution Complement protein complexes activated/formation of MAC cell lysis enhancement of inflammatory response promotion of phagocytosis  Antibodies as Diagnostics, Research Tools & Pharmaceuticals Hybridomas: B cells fused to tumor cells are ‘immortal’ in culture and will produce Abs Monoclonal Abs (mAb): purified Ab preparations specific for one Ag/epitope and from one B-cell clone Drug names that end in ‘mab’ are based on monoclonal Abs  T Cell Maturation and Function Memory cells will be long-lived and play roles in future encounters with the same antigen CD4+ T cells usually CD8+ T cells usually become TH (or become Tc and sometimes Treg) and destroy cells help to direct the harboring foreign immune response antigen MHC Proteins and Antigen Presentation T cell Activation is a Two-Step Process It takes TWO signals to activate a T cell: 1. Antigen binding in the context of MHC antigen presentation 2. Co-stimulatory signals other molecules on APCs interacting with molecules on T cells If a T cell binds Ab but doesn’t receive a costimulatory signal: cell enters a state of non-responsiveness known as anergy.  T cell Subtypes & Functions T cell Subtype Functionality TH: Helper T cells ‘Board of Directors’ for the immune system; without TH, no adaptive response develops T H1 stimulate inflammation, macrophage activation, Tc development T H2 mainly defend against parasitic worms and extracellular pathogens B cell dependent responses and Ab formation TH17 cells that release IL-17; support mucosal barriers TC: Cytotoxic T cells only T cell type that can directly attack and kill other cells main targets are virus-infected cells and cancer cells Treg: Regulatory T cells dampen to turn down/shut down immune response  Cytokines Chemical Messengers of the Immune System  TC Killing Mechanisms NK cells kill in a similar manner to cytotoxic T cells, but NK cells do NOT look for antigen presented on MHC. look for signs of cellular abnormality: lack of MHC, increase in expression of other molecules  Organ Transplants Four categories: Limitations to organ transplants autograft: tissue is transplanted from one location of NK cells, macrophages, T cells and antibodies from the body to another in the same person recipient will act to destroy the grafted (foreign, isograft: tissue donated to a patient from a genetically non-self) tissue identical individual Numerous antigens/molecules are interrogated to very rare determine donor/recipient compatibility only example is tissue donation from one identical ABO and other blood antigens twin to another MHC antigens allograft: tissue transplanted from an individual who is not genetically identical to a patient but is from the Post-transplant same species immunosuppressive therapy most frequent type of transplant corticosteroids to hold down inflammation therapeutically the most successful anti-proliferative drugs xenograft: tissue donation from a different species immunosuppressant drugs rarely practical therapeutically ex: valve replacements (recently: pig kidney successfully transplanted to human) Homeostatic Imbalances: Immunodeficiencies & Autoimmune Diseases SCID: severe combined immunodeficiency syndromes A few examples of autoimmune conditions: congenital Rheumatoid arthritis: joint destruction various genetic defects produce deficits in B and T cells Myasthenia gravis: communication between skeletal and Treatments include HSC transplant, possible genetic nerves engineering Multiple Sclerosis: destruction of myelin sheath Grave’s disease: thyroid disorder HIV/AIDS: Acquired Immune Deficiency Syndrome Type I diabetes: destruction of insulin-producing cells cripples immune function by depleting/interfering with Systemic Lupus Erythematosus: systemic attacks that TH cell activities particularly target kidneys, heart, lungs, and skin death is often from overwhelming infection or cancer Glomerulonephritis: damages kidney’s filtration ~33M people live with HIV/AIDS worldwide membranes Treatments: fusion inhibitors prevent virus from entering host Treatment options focus primarily on immunosuppression cells but more targeted approaches include: integrase inhibitors prevent incorporation of viral blocking cytokine activity genetic material into host’s DNA blocking co-stimulatory molecules that are required for reverse transcriptase and protease inhibitors block immune cell activation enzymatic activities needed for viral replication No cure/vaccine is available, but prophylactics exist  Failure of Self-Tolerance Why do autoimmune diseases happen? lymphocytes are educated to recognize self vs non-self self-reactive cells get destroyed weakly self-reactive lymphocytes may survive the culling in some poorly understood cases, co-stimulatory signals may go awry TREG cells may not activate appropriately to inhibit responses Possible triggers for auto-immune reactions Molecular mimicry: a foreign antigen resembles a self-antigen and gets attacked as collateral damage rheumatic fever: antibodies produced during a streptococcal infection react with antigens of the heart, joints and kidneys Type I diabetes is believed to be caused by viral infection that resembles antigens found on insulin- producing cells Neo-antigens: new self-antigens appear gene mutations that cause new/modified proteins to be expressed on cell membranes changes in structure of a self-antigen due to a hapten or infection  Hypersensitivities Immune system damages tissues while responding to a perceived threat Three types categorized by (1) timecourse and (2) whether antibodies or T cell are involved 1. Immediate Hypersensitivities: AKA allergies Sensitization: asymptomatic first encounter with antigen (allergen) IgE is the driving antibody response Histamine release by mast cells and basophils propagates reaction upon second and subsequent allergen exposures dilation of blood vessels and increased permeability underlie many of the common allergy symptoms: runny nose, watery eyes, reddened skin inhaled allergen in bronchioles causes smooth muscle to contract, constricting air flow in GI tract, allergens can induce cramping, vomiting, or diarrhea Anaphylactic shock is a systemic response to allergen allergen enters bloodstream mechanism is essentially same as local responses but mast cells and basophils are activated system-wide EpiPen (epinephrine) will reverse histamine-mediated effects  Developmental Aspects of Immune System Early weeks of gestation: stem cells of the immune system originate in the liver and spleen Early life to adulthood: bone marrow becomes primary source of immune cells Newborn’s immune system depends heavily on antibodies (TH2-type immunity) TH1 system must be educated and strengthened by interactions with both harmful and harmless antigens If such antigen exposure does NOT occur, TH2 may remain prominent and allergies are likely to develop Extrinsic factors (in addition to antigen exposure) that affect immune system development nervous system: (psychoneuroimmunology): how depression, emotional stress and grief can impair immune function diet: certain dietary components (ex: Vitamin D) may play a key role in infection and autoimmunity In old(er) age: efficiency begins to wane thymus atrophies red bone marrow is replaced by yellow (fat) incidence of cancer, immune deficiencies, and autoimmunity go up  Hypersensitivities, cont. 2. Subacute Hypersensitivities 3. Delayed hypersensitivities Abs involved are IgG and IgM rather than IgE Caused by T cells vs Abs onset of response is slower (1-3 hrs) takes ~1-3 days to manifest reaction lasts longer (10-15 hrs) inflammation and tissue damage result from Two types of subacute hypersensititivities cytokine-induced macrophages and sometime Tc. cytotoxic (type II) reactions: Abs bind to Ag on ex: contact dermatitis cells of the body and stimulate phagocytosis and/or lysis mismatched blood transfusion immune-complex (type III) hypersensitivities: insoluble Ag-Ab complexes form and neutrophil-lead inflammation damages local tissues often a result of a persistent infection or autoimmune disease state