Immuno Type II, III & IV Hypersen (15, 16)

• abnormal antibody directed against a target organ causes destruction of the target cell/organ by complement mediated lysis or ADCC
• complement mediated lysis: Ig attached to target cell, binds complement which punches holes in cell membrane, effectively killing the cell
• ADCC: NK cell finds/attaches to the Fc portion of the antibody & kills cell by pumping into it perforin & granzyme
• antibody (Ig) = 'guided missile' into target cell

• neutrophils
• when antibody binds to a target cell, neutrophils can ALSO bind to the antibodies & phagocytose said target cell

• Autoimmune hemolytic anemia
• Autoimmune thrombocytopenia
• Goodpastures syndrome
• Hyperacute graft rejection
• Anti-receptor antibody diseases (eg. Myasthenia gravis, Grave’s disease)

• immune cells will recognize coated cells (or pathogens) using their Fc RECEPTORS, which bind to the Fc region of antibodies
• engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell:
• phagocytes: phagocytose
• mast cells & neutrophils: degranulate
• NK cells: release cytokines and cytotoxic molecules to destroy its target

• autoantibodies are made against RBCs
• RBCs are destroyed by activation of complement resulting in hemolysis or by macrophage phagocytosis
• more common in women

• autoantibodies are made against platelets
• platelets bound with IgG are removed from the circulation by macrophages in the spleen and liver
• symptoms = little red spots all over skin (purpuric spots) + bruising; low platelet count

• autoantibodies are made against glomerular & alveolar basement membranes - made against same protein in both basement membranes
• may affect kidneys AND lungs; clinical features include glomerulonephritis and hemoptysis (spitting up blood)

• pre-formed antibodies are made against antigens on transplanted tissue (graft)
• activation of complement triggers the blood clotting cascade, leading to ischemia + loss of the graft within minutes to hours of transplantation
• (also a type I hypersensitivity reaction - b/c immediate)

diseases where antibody is made against a receptor on the surface of a cell (eg. Myasthenia gravis & Grave’s disease)

• an autoantibody is made to the acetylcholine receptor (AChR) on muscle cells
• said Ig binds to the receptor & BLOCKS binding of acetylcholine (an NT) --> as result there can be no muscle activation
• additionally, the autoantibody induces complement activation, resulting in damage to the muscle end-plate detroying AChRs as the disease progresses; also the muscle cell itself phagocytoses the antibody-receptor complex, destroying AChRs
• 

• an autoantibody to the receptor for thyroid-stimulating hormone (TSH) on cells of the thyroid
• its binding causes constant stimulation of the thyroid, & therefore unending overproduction of the thyroid hormones T3 & T4
• cure: remove 3/4ths of thyroid

an autoantibody is made against the adrenal gland

• antigen-antibody immune complexes are trapped in the small vessels of the body, particularly in the skin, kidney, & joints
• binding of complement to the Ig triggers an inflammatory reaction; the creation of C3a and C5a chemotactically attract neutrophils
• neutrophils degranulate in the vessel wall releasing powerful lysosomal enzymes that serve to degrade the immune complex
• however it simultaneously damages the vessel walls (vasculitis)
• in the meantime as well, complement levels drop as they're being distracted by these immune complexes
• 

animals with NO polymorphs (aka neutrophils)

• autoantibodies are made against your own DNA (antigen = DNA); called antinuclear antibodies (ANA)
• immune complexes (antigen-antibody complexes) deposit in many tissues and affect many organ systems (skin, joints, serosal surfaces, kidneys, & CNS)
• classic example of immune-complex disease

• occurs after a person is infected by streptococcus bacteria [sore throat]
• they make anti-streptococcal antibody, which combines with streptococcal antigen (immune complex) & gets stuck/deposits mainly in the glomerular capillary wall of the kidneys

• caused by antibodies made against contents of foreign serum from another animal (eg. a horse)
• typically induced following therapy with large doses of foreign antibodies (eg. monoclonal mouse antibodies or horse serum antitoxins to cure snake bites)
• immune complexes deposit in various tissues, especially in arteries, joints, & renal glomeruli

• when an antibody is made against a drug
• they may combine with the drug forming immune complexes that can deposit in vessel walls producing vasculitis
• *NOTE: penicillin & its derivatives may also cause acute allergic reactions (Type l), immune complex reactions (Type lll) OR delayed hypersensitivity reactions (Type lV)

• a localized, not circulatory, type III hypersensitivity reaction
• happens when antigen is introduced into an individual who already has pre-formed antibodies against that antigen
• immune complexes at the site where antigen was introduced attract neutrophils & produce inflammation (after about 6-8 hours)
• eg. tetanus booster or hypersensitivity pneumonitis (Farmer’s Lung or Bird Fancier's Disease)

• when tetanus toxin is given in the form of a shot booster to a person who already has tetanus antibodies, the area of injection may get sore, red & inflamed as a result of immune complexes in the arm attracting neutrophils & such
• example of Arthus reaction/localized immune complex disease/type II hypersensitivity reaction (6-8 hours to form)

• inflammation of the alveoli within the lung caused by a type III (immune complex) hypersensitivity reaction to inhaled organic dusts
• an X-ray looks like there's a 'snow storm' in the lungs
• eg. Farmer’s Lung, Bird Fancier's Disease

• occurs in farmers turning hay because organisms called actinomycetes are present in mouldy hay
• repeated inhalation of these organisms stimulates systemic IgG antibody production
• further inhalation produces immune complexes in the lung and an Arthus (localized) reaction
• LATE there is infiltration by T-cells with cytokine production and further inflammation
• *therefore this is a mixture of Type III and a Type IV hypersensitivity reactions

• Type III: antibody, antigen, polymorphs (neutrophils), complement AND
• Type IV: T CELLS

• delayed-type hypersensitivity (DTH) or Type IV reactions are mediated by T cells & activated macrophages
• the mechanisms of DTH are the same as those for cell-mediated immunity however in delayed hypersensitivity, the result is tissue damage
• T cells release inappropriately large amounts of cytokines in response to an antigen --> cytokines recruit & activate effector cells (mainly macrophages) which cause local tissue damage

• similar to other hypersensitivity reactions, sensitization is REQUIRED to generate DTH
• during sensitization, APCs (particularly dendritic cells) process the antigen and present it to TH1 cells
• sensitization activates and expands the number of antigen-specific TH1 cells that can cause a DTH reaction if re-exposure to the antigen occurs

• during the effector phase, T cells (antigen-specific TH1 cells) produce cytokines that recruit & activate macrophages + other inflammatory cells
• accumulation of inflammatory cells causes local tissue damage
• DTH reactions also involve CD8+ T cells which cause tissue damage via cell-mediated cytotoxicity

• skin inflammation that occurs when a foreign substance touches your skin causing irritation
• example of delayed hypersensitivity

• urushiol in poison ivy
• cosmetics
• foreign chemicals
• latex/rubber
• metals (eg. nickel, zinc reacting with skin proteins) in jewelry
• p-Phenyl diamine in hair dyes
• Neomycin in topical ointments

• Cytokine and Chemokine Production
• Endothelial Cell Activation
• Macrophage Activation
• Killing by Cytotoxic T Lymphocytes (CD8+)

• IL-2: promotes T cell proliferation
• IFNγ: activates macrophages
• IL-1 & TNF: upregulates adhesion molecules on endothelial cells

• endothelial cells undergo changes to facilitate infiltration of leukocytes into the site of inflammation
• they increase their number of adhesion molecules on their surface
• they change their shape to facilitate extravasation of leukocytes
• they secrete IL-8, a chemokine which attractants leukocytes

• INFγ + other T cell-derived cytokines stimulate new or increased gene transcription that up-regulates most macrophage functions
• increased phagocytosis and killing
• increased oxygen consumption
• increased expression of surface molecules (MHC molecules, Fc receptors, + adhesion molecules)
• increased secretion of monocyte/macrophage-derived cytokines (eg. IL-1, TNF, & IL-6)

• IL-1, TNF, & IL-6 increase the inflammatory response and may produce tissue destruction
• LATER they contribute to fibrosis or scarring due to the fibrogenic effect of some cytokines
• may also instigate granuloma formation (individual clusters/nodules of macrophages)

• is antigen-specific
• requires cell contact
• induces apoptosis of target cells by activating enzymes IN target cells that digest the cell’s own DNA, as well as the action of perforin & granzymes

• target --> T cell
• LFA3 --> CD2
• ICAM --> LFA1
• MHC Class 1 --> CD8

• a commonly performed procedure used to identify the nature of the antigen causing contact dermatitis
• a solution of the suspected antigen is spread on the skin and covered by an occlusive dressing
• appearance of an area of induration & erythema within three days indicates sensitivity

• 2-5 days
• this is because memory cells have to be TURNED ON in order to elicit a reaction
• why a patch test is usually read after ~48 hours

• tuberculin skin test
• chronic infections (eg. Viral hepatitis)
• chronic bacterial diseases (eg. TB, syphilis, leprosy)
• chronic fungal infections (eg. Candidiasis)
• parasitic diseases (eg. Leishmaniasis)
• in many chronic conditions it is the immune response that causes the damage & disease manifestation

• TB screening test that determines whether a person has been exposed to tuberculosis before; if positive 2-5 days later is a type of DTH reaction
• tuberculosis protein purified protein derivative (PPD) is injected into the skin of an individual
• if the person has had a previous cell-mediated immune response to M. tuberculosis, the site of injection becomes raised & red (erythema & induration) --> due to memory T cells reacting with/destroying the injected toxins

primarily mononuclear cells of the monocyte-macrophage series along with a few lymphocytes

• Arthus, or immune complex reaction (type III)
• they are NOT characteristic of a delayed hypersensitivity reaction (type IV)

• vaccine given to individuals born in other countries against tuberculosis
• if given this vaccine, a person will have memory T-cells that can produce a positive tuberculin skin test

• 1. Intracellular Bacteria (tuberculosis)
• 2. Large Viruses (pox & herpes)
• 3. Fungi (candida albicans, pneumocystis)
• 4. Parasites (toxoplasma)
• these infections are what immunocompromised people get (HIV, transplant receivers)
• [intense bacterial infection = lacking complement]

• Insulin-Dependent Diabetes Mellitus (IDDM)
• Rheumatoid Arthritis
• Multiple Sclerosis
• Crohn’s Disease
• Psoriasis
• Celiac Disease
• All of these diseases are primarily caused by T- cell attack
• this may be followed by secondary auto-antibody production

• a form of inflammation that MAY follow acute inflammation OR may start as a low grade response to certain microorganisms, inanimate materials, or autoantigens
• occurs when polymorphs of an acute inflammation response can't get rid of whatever is causing the inflammation, so lymphocytes & macrophages move into the site to try & take care of it --> chronic
• present during Tuberculosis, Leprosy, Fungal infections, Silicosis, & Rheumatoid arthritis

• lymphocytes, macrophages, & plasma cells
• there are NO polymorphs, antibody OR complement
• what results is tissue destruction, fibrosis, & scar formation

• when macrophages - in certain cases of chronic inflammation - collect in layers surrounding the problematical material (silica, or TB, etc)
• and fuse, forming giant cells
• structure = layers of macrophages surrounding a central core

because the bacteria somehow prevent lysosomes from fusing with the phagocytic vesicles