lecture 14, immune system II

the adaptive immune system

1. active immunity

2. passive immunity

active immunity

• natural

  • complete immune response occurs following a natural encounter with an antigen

    • ex. a cold

  • you do everything

  • day to day inoculation

• artificial

  • complete immune response happens following exposure to an antigen artificially

    • ex. vaccine

passive immunity

• natural

  • mother to child transmission of antibodies

    • ex, IgG transmission across the placenta, IgA transmission via breast milk (baby doesn’t know how to make it)

• artificial

  • injection of premade antibodies to help neutralize infectious material

    • ex. post-exposure to rhabdovirus

• you were given it

major histocompatibility complex

• two types

  • different in each person

    • responsible for transplant rejection

1. MHC I: embedded in the plasma membrane of all nucleated cells in the body

   • every nucleated cell has this (RBC wont)

   • characteristic of you

2. MHC II: embedded in the plasma membrane of antigen presenting cells

   • only antigen presenting cells

   • macrophage would have both (antigen resenting and nucleated)

b lymphocytes

• naïve B lymphocytes (haven’t been stimulated yet) develop into antibody secreting cells

  • antibody=immunoglobin (both proteins)

    • Ab=Ig

  • antibody is inserted into plasma membrane

    • when specific antigen binds, B cell is activated

  • each b lymphocyte is responsible for antibody production against a single epitope

    • develops into a clonal population of cells once exposed to antigen (consequence of mitotic division)

    • clonal population consists of

      • a large fraction of plasma cells

        • short lived effectors that actively secrete antibody

      • small fraction of memory cells (some saved for later, could be years)

        • long lived cells that are important for future exposure to antigen

antibodies consist of

• two identical heavy chains

• two identical light chains

each b lymphocyte produces an antibody specific to only one antigen

• unique F_ab fragment

  • variable segment of the antibody

  • two per antibody

constant region-Fc region

• five different classes

  • IgA

  • IgG

  • IgD

  • IgE

  • IgM

IgM

• pentamer (2×5=10)

• first to be secreted in response to antigen

  • primary immune response

    • class switching leads to the production of a different Fc variety

• always first every time

• really good against one type

IgA

• dimer (2×2=4)

• secreted at mucosal sites

• important in neutralization of pathogens that are able to move past mucosal membranes

• released in breast milk, digestive tract, respiratory tract, reproductive tract

IgG

• monomer (present in blood and tissue)

• ∼75% of plasma antibody

• crosses the placenta (how they come up with vaccine schedule for babies) born in sterile sac

• involved in secondary antibody response

• spray into nasal → IgA

• flu shot → IgG

IgE

• monomer

• important for destruction of parasites

• also released in response to allergens

• can bind to mast cells leading to degranulation

• FcIgE receptor on basophil → for allergen allows to bind to allergen and causes degranulation of HIS

IgD

• monomer

• located on the surface of B lymphocytes (sits on surface)

• unknown function

• advertisement

antibody functions

• works to:

  1. agglutinate antigens

     • behave like a mop

     • pick up 2 antigens at once (minimum)

     • stops what foreign material was going to do

  2. opsonize foreign material

     • enhances phagocytosis

     • Fc region lets it talk to other immune cells

     • trusted sources

  3. neutralize antigen

     • prevents infection/spread of infectious material/toxin activity

  4. cytotoxicity (antibody dependent cytotoxicity → starts to attack you)

     • when bound to antigen, antibody Fc (trusted source so the body thinks its ok to kill) region binds to NK cells, mast cells

       • triggers calcium entry into cell causing degranulation

         • destroys antigen

       • mast cells specifically have Fc IgE receptors

         • important for the inflammatory response

  5. complement activation

     • leads to the formation of MAC attack complex and antigen destruction (antibody can be first hit)

antibody response

• work to neutralized exogenous antigen (outside cell, ECF, ISF, plasma) (humoral, antibody)

  • bacteria, toxins, viral particles (anything that is foreign from outside)

  • secreted from activated plasma cells (effector cells)

  • ex. B cells bind and internalizes antigen

    • antigen is digested and trafficked to the cell surface atop MHCII

      • antigen is presented

    • T helper cells come along and bind antigen-MCHII complex

      • Th cell releases cytokines that activate B lymphocyte to proliferate and begin secreting antibodies

• endogenous (inside cell, antibody can’t help you, cell mediated)

antibody function

• cytokines produced by Th cells include (coordinated response):

  • interferon-y

    • activated macrophages (phagocytes)

  • interleukins

    • activate antibody production and Tc cells

    • activate eosinophils and mast cells

primary immune response

• occurs in response to the initial exposure to antigen

• slow production of low levels of antibody

• key result: memory produced (sit on shelf)

  • memory cells activated upon every subsequent exposure to antigen (why we vaccinate)

• 7-10 days

• first time you encounter specific epitode

• low and slow (IgM)

secondary immune response

• occurs in response to each subsequent antigen exposure

  • memory cell encounters antigen and completes clonal expansion

• results in rapid production of high levels of antibody

• memory cells are replenished

• swing into action

• see something again

• high and fast (antibody increase in 1-2 days)

cell mediated immunity

• mediated by cytotoxic T cells (toxic cells → kill cel)

  • responsible for destruction of abnormal cells

    • endogenous antigens

  • recognize antigen displayed on surface of MHCI

    • binds to MHCI-antigen complex and secrete perforins (pokes holes) and granzymes (kills)

      • granzyme enzymes enters the compromised cell via channels created by perforins

        • trigger apoptosis of cell

  • self-recognizing Tc cells are destroyed during development (find them and got rid of them)

immune response to bacterial invaders

• bacteria causes inflammatory response

  • also cause antibody production

  • complement activation

    • opsonization

    • mac attack (pore to allow cell to leak its content)

    • mast cell/ basophils degranulation

      • histamine release

        • vasodilation/increased vascular permeability

    • production of chemo-attractants (increase flow, increases immune cells)

      • recruits immune cells to match the foreign

    • phagocyte activation

      • non-encapsulated bugs only

immune response to viral invaders

• free viral particles will enter into host cells

  • infected host cells displays endogenous antigen with MHCI

    • activates cytotoxic T cells (destroy infected cell)

    • infected cell is destroyed → reservoir for viral production is eliminated

  • if previous exposure has taken place memory B cells are activated by virus

    • antibodies neutralize free virus preventing infection of host cells

    • antibody-virus complexes are phagocytosed by macrophages

      • viral antigens are presented with MHCII

        • activates Th cells

          • activated Th cells will activate Tc cells and B lymphocyte

      • macrophages produces interferon-a

        • sparks anti-viral response in uninfected host cells (important for inflammation)

          • minimize the number of new cells that may become infected

      • macrophage produced pro-inflammatory cytokines

type of vaccines

1. attenuated whole agent vaccines

2. inactivated whole agent vaccines

3. toxoids

4. subunit vaccines

5. conjugated vaccines

attenuated whole agent vaccines

• use weakened living microbes or weakened infectious virus

  • weakened because of an introduced mutation (makes it weak)

  • ex. virus that can enter host cell but cannot reproduce

  • exogenous → B cells will respond

• closely mimics an actual infection

  • stimulates a cell mediated response and an antibody mediated response (exo and endo)

• often confers life-long immunity

  • ex. MMR vaccine (measles, mumps, rubella)

guy has a gun, take gun away, still same guy, will just find another weapon

• BEST

• CON

  • the virus or bacterium may revert back to the original pathogenic form

  • can be very dangerous to immunocompromised patients (AIDS, cancer) and pregnant women

    • the organism may still be able to cause disease

inactive whole agent vaccines

• use whole agents that have been killed

  • ex. viruses-rabies, influenza, polio

• ex. bacteria- Vibrio cholera

• very safe

• take all out but looks the same outside

• not endogenous cant get into cell!!

toxoids

• inactivated toxins:

  • made from purified proteins (given to vaccinate people against the toxin)

  • “stand in” but cant act

• the immune response acts against the toxoid

  • stimulates the antibody mediated response only (exogenous)

  • usually requires a series of injections for full immunity

  • immunity does not last as long

  • ex. DPT vaccine (former) (diptheria, pertussis, tetanus) DTaP

    • required a booster shot every ten years

subunit vaccines

• contain purified components from viruses or bacteria (ex. show someone your eyes only → bits and pieces)

  • antigens most likely to induce an immune response

  • stimulates antibody mediated response only and memory (exogenous only)

  • ex. Streptococcus pneumoniae-purified capsular polysaccharide

    • pneumoshot: protects against pneumonia

  • ex. hepatitis B

    • viral coat proteins produced by genetically modified yeast (spike protein/capsid)

• EXTREMELY SAFE VACCINES: the disease causing agent is not present

conjugated vaccines

• a polysaccharide antigen is combined with a protein antigen-resulting in a stronger immune response in children

  • ex. Haemophilus influenza capsule combined with diphtheria toxoid

    • can induce an immune response in children as young as 2 months

    • make it big like this so inexperienced immune system notice it

mRNA vaccine

hypersensitivity

• also referred to as allergy

• an abnormal immune response (shouldn’t freak out over a peanut)

• immune response is mounted against allergen (would be there antigen/immunogen

• too sensitive

• 5 types

type 1 hypersensitivity

• this is referred to as an anaphylactic response

• the 1st encounter with the allergen causes B cells to differentiate into plasma and memory cells (nothing happens)

• the plasma cells make IgE which then binds to mast cells or basophils (seats self in the FcIgE spot)

• there are no apparent symptoms (at start)

type 1 hypersensitivity: 2nd encounter with the allergen

• IgE molecules bind to the antigen and mast cell or basophil releases histamine

• histamine triggers vasodilation: redness, swelling, and decreases blood pressure (decrease blood volume and increase vessel diameter) anaphylactic shock

  • mucous production: tears, runny nose

  • contraction of bronchial muscles: difficulty breathing (bronchoconstrictor with more Ca2+)

    • allergen binds and degranulates

treatments

• antihistamine

• epinephrine

• allergy shots

antihistamine

• this blocks the action of histamine

  • histamine is still produced but cannot trigger responses

  • works well for mild symptoms, example: hay fever

• stops it from causing problems

epinephrine

• used to treat anaphylactic shock (severe allergy)

• acts as a vasoconstrictor increasing blood pressure

• the effects last for 20-30 minuets

• this buys time to allow for administration of intravenous antihistamine

• epi-pen

allergy shots

• this is injected like a vaccine

• increasing doses of the antigen are given over 2 years

• this induces memory cells that produce IgG instead of IgE

• IgG will bind to and neutralize the antigen to presenting it from binding IgE

  • this prevents the release of histamine

type II hypersensitivity

• antibody dependent cytotoxicity

• activated by foreign antigenic cells

  • leads to phagocytosis and complement activation against the foreign cell

• ex. blood transfusion

  • ABO blood group system

    • antibodies bind to antigens on the surface of red blood cells

    • complement and phagocytes are activated leading to red blood cell agglutination and subsequent destruction

type II hypersensitivity: Rh factor

• this only occurs on the 2nd or subsequent pregnancy

• Rh is another surface antigen on red blood cells

• can occur when:

  • a child is produced between an Rh- woman and a Rh+ man

  • the child has a 50% chance of being Rh+

  • if this happens the mother can make antibodies against the Rh+ cells which can kill the baby after birth (when birth can cause for them to mix and be exposed → develop Rh factors)

• +=Rh

• -=no Rh

type III hypersensitivity

• this is immune complex formation

• it occurs when there are certain antibody to antigen ratios in the blood

• the antibody forms small complexes with the antigen which then get trapped in the membrane causing problems

• this also activate complement which in turn activates neutrophils to release enzymes

  • this can damage blood vessels

• sits in capillary wall. neutrophils called to region via Fc region → destruction scar tissue

type iv hypersensitivity

• this is delayed hypersensitivity

• it is the result of cell mediated response (cytotoxic T cells)

  • not antibody mediated

  • this causes a delay reaction 24-72 hours after contact

  • it results from the activation of memory T cells

  • ex. contact dermatitis: chemical reactions

    • abnormal looking skin cells

• how does it happen?

  • small chemicals interact with the skin proteins to from antigen

  • this causes a change in skin cells

  • the cell mediated immune response acts against foreign or abnormal cells

  • targets a localized area of the skin

  • cytotoxic T cells destroy skin cells: causes red, itchy, swollen skin

ONLY CELL MEDIATED

type IV hypersensitivity: poison ivy

• first contact: limited response occur and there is no resulting dermatitis

  • memory T cells are produced

  • second contact: memory T cells differentiate into activated cytotoxic T cells

    • causes contact dermatitis → look like abnormal skin cells

transplantation

• tissue or organ rejection

• involved both the antibody mediated response and the cell mediated response to foreign cells

  • both type II (start making antibodies MHC I) and type IV hypersensitivities

  • treatment: drugs that suppress the immune response (make person at risk for other infections)

  • cyclosporine, prednisone

  • since the immune system is suppressed transplant patients are very susceptible to infection

  • as a result these patients must be kept in isolation

• graft vs host disease:

  • cytotoxic T cells from the donor tissue see the host’s body as foreign and attack

    • in the organ leftover Ct will start to attack host, your cytotoxic T will attack organ too

  • cyclosporine is used to suppress the immune response in order to prevent this attack

immunodeficiency disorders

• results due to inadequate immune system (don’t have enough)

• there two types:

  1. congenital (inherited) immunodeficiency - present at birth

  2. acquired immune deficiency

congenital (inherited) immunodeficiency - present at birth

• ex, serve combined immunodeficiency disease (SCID)

  • non-functional T and B cells: no type of adaptive immunity is present

  • allows for severe infections to develop

acquired immune deficiency

• ex. acquired immunodeficiency syndrome (AIDS)

  • this is the last stage of HIV infection

• HIV infects and subsequently kills Y helper cells, macrophages and dendritic cells (lose function)

  • the patient is extremely susceptible to infection: both the antibody: both the antibody and the cell mediated immune responses are impaired

    • opportunistic infection

    • attack with viral spike protein

human immunodeficiency virus

• HIV

• spikes enable HIV to attach to and penetrate the host cell

• viral DNA can integrate into host cell chromosomes as provirus

• RNA → reverse transcriptase → DNA (hides HIV in DNA)

• the virus remained latent here for a long time

  • this shelters the virus from the immune system

  • the virus may also cause active infection

  • new viruses produce bud out from the host cell

• HIV is an enveloped virus

antigenic changes in HIV

• HIV genome is highly susceptible to mutation

• antigens change: helps the virus to invade to the immune system

• reverse transcriptase (highly error prone)

two major groups of HIV viruses (with many sub-groups of each):

• HIV-1: most common HIV virus worldwide (gets there faster)

• HIV-2: found in western Africa: slower progression of disease

stages of HIV infection

1. category A: early stage

   • often asymptomatic but may cause flu like symptoms, swollen lymph nodes

   • when you first get infected

   • asymptomatic

2. category B: middle stage

   • may be asymptomatic

   • may lead to increased infection: example-yeast infections of the throat, mouth or vagina (TH infected are dying)

   • persistent diarrhea

   • shingles → reactivation of virus of chicken pox

   • HIV is reproducing but is killed and thus controlled by the immune system

     • HIV resides mostly in the lymph

   • this stage can last 10-20 years

3. category C: late stage

   • clinical AIDS defined by a decrease in T helper cells < 200 cells TH per mmm3 blood

   • persistent infections occur

   • ex. yeast infections of esophagus, bronchi, and lungs

   • kaposi’s sarcoma: rare herpes virus prevalent in AIDs patients

   • high prevalence of pneumonia, tuberculosis, etc. in these patients

HIV transmission

• direct or indirect contact with infected bodily fluids

1. blood

   • contact with infected blood

   • ex. needle sharing, need stick at hospital (occupational hazard)

   • blood has 1000-100000 viruses/mL

   • 1:4 infected blood exposure result in infection

2. semen/vaginal secretions

   • contact through unprotected sex

   • semen has 10-50 viruses/mL

   • 1:1000 unprotected sexual encounters result in infection (if you have lesions it can be more prone)

3. mother to child

   • this form of transmission either occur during pregnancy, at birth or via breast milk

autoimmune disease

• this is when the body mounts an immune response against itself (turns on itself)

  • this can occur in response to an infection or it can genetic (inherited)

1. rheumatoid arthritis

   • IgM, IgG and complement act against collagen in the joints (holds you together)

   • causes chronic inflammation

2. lupus

   • antibodies produced to chromatin which is a complex of protein, DNA and RNA

   • the chromatin-antibody complexes accumulate in the joints, kidneys and blood vessels (like type III hypersensitivity)

3. multiple sclerosis

   • T cells and macrophages attack myelin sheath covering neurons (insulating so don’t get ions everywhere)

   • symptoms range from mild fatigue to severe paralysis

   • this may triggered with Epstein-Barr virus (hard to spread impulses quickly because ions are going everywhere)