Diseases of Immunity study notes 1 General - Type I hypersensitivity - havoc resulting from IgE and mast-cell degranulation - Type II - antibodies attack cells, causing cell death by complement fixation or phagocytosis - Type III - antigen-antibody complexes precipitates and cause the damage - Type IV - havoc wrought by specifically-sensitized T-cells; classic delayed hypersensitivity - harm by macrophages, no antibody involved; cell-mediatd toxicity - individual cells assasinated by T-CTL, without other harm, may be antibody-dependent or independent - Type V - antibody binds to cells and causes them to malfunction, though they are not killed Cells of the immune system - T lymphocytes - have passed through the thymus; predominant throughout lymph nodes except around germinal centers; make up the white pulp; 80% of circulating lymphocytes are T-cells; T-helper cells activate B and other T cells; one subclass of the T cell is the effector cell of type IV hypersensitivity, which conttrols cell-mediated immunity; T supressor cells tell other B and T cells it's time to stop whatever they are doing; T inducer cells tell other T cells to become helpers or supressors; T cytolytic cels attach to and kill cells bearing whatever antigen against which they are specifically programmed and sensitized ( may be CD4 or CD8) - B lymphocytes - when activated produce freely circulating immunoglobulins; predominate in the follicles of the lymph nodes and are more common than T-cells in hte red pulp of the spleen and in the marrow; in the germinal centers, antigen-antibody complexes are presented to baby B-cells by the dendritic follicular cells, these will be the ones that produce IgG; around 15% of circulating lymphocytes are B-cells; they have surface immunoglobin, Fc receptors, and C3b receptors; B cells become plasma cells when activated - natural killer lymphocytes - have cytoplasmic granules; capable of lysing some tumor cells without anything being specially sensitized - mononuclear phagocytes - all of the reticuloendothelial system throughout the body; wnadering macrophages and microglia are monocytes from the peripheral blood that have entered the tissues, as were fixed phagocytes; a subclass of these called the dendritic and langerhans cells seem to be the best antigen processors and the poorest effector phagocytes; essential to the immune response; busy macrophages modulate the activity of the other cells by secreting soluble factors such as Il-1 and TNF-alpha; also macrophages are effector cells when summoned by T-cells or activated complement; can become epithelioid cells of granulomas to wall off other things - mast cells and basophils - rich in vasoactive substances; release histamine righ away, leukotreine later; effects on blood vessels, smooth muscle, gastric parietal cells - neutrophils - 1/2000 people, chronic granulomatous disease, where the neutrophils cannot produce peroxide to kill staphylococci, and epithelioid macrophages take over Immunoglobulins and complement - IgM are pentamers, cold-reactive, appear early, can fix complement; IgG are monomers, warm-reactive, and appear later (come from B cells with good memories); IgA tend to be found on mucosal surfaces; IgD is a receptor on a B cell; IgE sticks by its Fc portion to basophils and mast cells - idiotypes are specific recognition sequences that make a perticular antibody unique; the complement cascade when activated increases vascular permeability, summons polys and monos, and punches holes in membranes Cytokines - interleukin-1 - a monokine by macrophages that are phagocytotic or hurting, causes T-cells to multiply; also causes acute phase reaction, catabolism of muscle in acute illness, recruits macrophages for granuloma formation, and is largely responsible for the increase in circulating neutrophils - interleukin-2 - T cell growth factor; a lymphokine from activated T4+ cells which promotes the division of other T-cells; experimental in cancer therapy; levels are extremely elevated in chronic fatigue syndrome - interferons - some produced by T-cells, interfere with viruses and have a huge variety of other activities - alpha interferon - treatment for hairy cell leukemia; being used against chronic hepatitis B; administration causes a flu-like syndrome; can cause severe fatigue or insanity - gamma interferon - principle substance that makes macrophages angry and form granulomas, and the substance that causes macrophages to express Ia antigen - tumor necrosis factor - monokine and a closely-related lymphokine tandem homologous gene products that mediate a wide range of tissue injuries; thalidomide selectively inhibits alpha-TNF production - transforming growth factor B - three isoforms which apparently turn down most aspects of chronic inflammation; mice bron without the first isoform die of widespread chronic inflammation Type I immune injury in human disease - result of antigen binding to IgE on the surface of mast cellsand basophils; they instantly degranulate and release active substances into the surrounding tissue - IgE protects us against worms - some people make more IgE than others, and these are the people with allergies - once induced, IgE binds to mast cells and basophils; the person is now allergetic to the particular allergen - histamine from mast cells makes vessels leaky, causes bronchial smooth muscle to contract, and casues the gastric parietal cells to churn out acid - mast cells also release eosinophil chemotactic factor of anaphylaxis and neutrophil chemotactic factor - leukotreines C4, D4, and E4 are secondary mediators produced after the first round - they are archidonic acid metabolites, the SRS of anaphylaxis - local anaphylaxis - more often a nuisance than a real danger - urticaria - analogous to the wheel and flare effect of histamine in acute inflammation - an itchy mosquito bite - angioedema - similar to urticaria, but a whole organ is involved; it often results in C1-esterase inhibitor deficiency - allergic rhinitis - hay fever - sneezing and itchy conjunctiva due to exposure to airborne allergens - allergic bronchial asthma - bronchoconstriction following inhalation of an allergen - generalized anaphylaxis - a life-threatening emergency in which seconds count - commonest clinicla setting ins penicillin injection; if patient survives the initial extreme drop in blood pressure, then all the small airways clamp shut; mainstream treatment is epinephrine - chocolate, strawberries, and codeine release histamine non-immunologically in everyone - hypersensitivity as a cause of functional or idiopathic illness - atopic dermatitis (eczema); most cases due to food allergy - an unknown percentage of people suffer from malaise, fatigue, behavior problems, and functional headaches; these patients usually respond well to treatment of allergy Type II immune injury in human disease - in this type of hypersensitivity, antibodies attach to antigens on the surface of a cell, and then something injurs or destroys the cell - what can destroy an antibody-coated cell? - C9. at the end of the complement cascade, is cytolytic; complement fixing antibodies attaching to a cell are likely to wreck it; cells with protruding Fc portions of IgG or coated with activated C3 bits are tasty to polys and mononuclear phagocytes - better established is T-helper cell-mediated (type IV variant) cytotoxicity (Hashimoto's disease) - transfusion reactions - ABO incompatibility usually involves ready-made, complement-fixing IgM; Rh incompatibility usually involves IgG - in hemolytic disease of the newborn, the mother has become sensitized to one of the father's red cell antigens which she does not share; if isoantibody is IgG, it can cross the placenta; - autoimmune hemolytic anemias result from the body's making antibodies against its own red cell antigens - some people make antibodies against their own platelets, which are destroyed in the RE system - in paroxysmal cold hemoglobinuria, the antibody against the red cells is an IgM active only in the cold - in Goodpasture's disease, the body makes antibodies against the basement membranes of the glomeruli and lungs; holes get punched in the vessels, and fibrin and blood fill and ruin the nephrons and alveoli - some chronic autoimmune diseases feature antibodies against the cells that are being destroyed; these include juvenile onset diabetes mellitus, lymphocytic thyroiditis, autoimmune adrenocortical insufficiency, hypophysitis, parathyroiditis, and others - some have antibodies against neutrophils Type III injury in human disease - this sort of tissue injury is mediated by antigen-antibody complexes - if there is a great excess of either antigen or of antibody, mixtures of the two are readily soluble and easily disposed of by the body - the complexes form huge lattices; usually get deposited around the body, typically in the walls of blood vessels; C9 punches holes in healthy membranes; process takes several hours to develop following exposure to hte antigen, but it can last for years - model for localized immune-complex mediated tissue injury is the arthus reaction, in which immune complexes form in situ - in membranous glomerulopathy, antibodies complex with an antigen that is distributed at regular intervals along the gloerular basement membrane; immune complexes appear as a regular series of bumps - in other conditions, circulating immune complexes deposit in various other tissues, and they re what gets injured - in organic pneumoconioses, the problem is a pulmonary vasculitis due to type II hypersensitivity - in systemic lupus erythematous, the patient makes antibodies against many of her own tissue proteins and nucleic acids; antigen-antibody complexes are deposited in hte glomeruli, pleura, pericardium, synovium, skin, and elsewhere - when many or all vessels are involved with a severe type III hypersensitivity reaction, the classic desciption is serum sickness Type IV immune injury in human disease - in type IV, special T helper cells (Td) programmed to recognize a particular altered self antigen, are stimulated; object is to destroy every cell bearing the altered self antigen - great for ridding the body of virally infected cells, cells harboring intracelular parasites, and perhaps tumor cells - in coordination with the class II MHC of the dendritic macrophage that presents it - the stimulated Td cell signals to other T-cells and macrophages, telling them that it is time for a type IV hypersensitivity reaction - Td cell produces interferon - the now stimulated T-CTL cell specialized for killing cells bearing a particular antigen will attack when it encounters that antigen in association with the class I MHC - angry macrophages are the ones that become epithelioid cells; these will eat whatever they can - the model for type IV hypersensitivity is the tuberculin skin test - lack of effective Td function occurs in some diseases and is called anergy - poison ivy, rash from a nickel watch band, or rash from neomycin ointment - in viral hepatits, the viruses may not really do the liver cells any harm, but they express their antigens on the liver cell membranes - spontaneous regression of pigment nevi and malignant melanomas is attributed to type IV hypersensitivity Type V immune injury in human disease - includes stimulatory hypersensitivity - these are disorders in which autoantibodies do not destroy the cells or molecules to which they bind, but cause them to malfunction - circulating anticoagulants are antibodies against a coagulation factor (usually VIII or prothrombin activator) - these occur in lupus erythematosus and in hemophiliacs to whom the factor VIII they inject is a foreign protein - classic pernicious anemia is due to an autoantibody which binds to intrinsic factor, rendering it unable to carry vitamin B12 through the ileal mucosa - a few cases of insulin-resistant diabetes mellitus are caused by autoantibodies that tie up insulin receptors - in Grave's disease, antibodies against hTSH receptors of the thyroid bind and stimulate the receptor; the result is marked hyperthyroidism Transplant rejection - T cells do most of the rejecting; the most antigenic cells of the graft are the lymphocytes and donor macrophages - hyperacute reaction happens when the patient gets a allograft and already has antibodies against it; pattern of type III immunity - acute rejection is mediated by T cells and is basically done by cell-mediated immunity - chronic rejection - usual in old allografts; mostly you will see fibrosis of the organ and dense fibrous narrowing of the arterial lumens Graft vs Host disease - when bone marrow or some other organ containing T cells is transplanted into an immune-disabled patient, T cells in the graft attack tehe foreign histocompatability antigens of the recipient - NK cells may be responsible in humans, and lymphocytes are observed attached to epithelial cells - acute graft vs host disease may occur 20-100 days following a transplant, even if HLA antigens appear identical - chronic graft vs host disease occurs after 100 days and is characterized by more widespread involvement of epithelial surfaces and a more dense chronic inflammatory infiltrate; a scleroderma like syndrome can develop