Diseases of Immunity (Immunopathology)
Type II hypersensitivity ( Antibody-dependent type) Is mediated by antibodies directed against target antigens that are fixed on the surface of cells or other tissue components. The antigen may be endogenous as normal molecules in the cell membrane or may be exogenous like drugs, blood transfusion. The antibodies mediating this type of reaction are of IgG or IgM. Once these antibodies bind to the antigen at the cell membranesubsequent damage of the fixed antigen occurs by one of the following mechanism: A ) Complement-Dependent reaction: When antibody binds to an antigen at the cell surface it leads to complement activation and formation of membrane attack complex in the cell wall resulting in direct lysis of cell or cell coated with antibody and complement are phagocytozed ( opsonization which is phagocytosis of cells coated with antibodies). Circulating RBCs are most common antigens damaged by this mechanism.
Clinically, this reaction occurs in the following conditions Transfusion reaction: incompatible blood transfusion for either ABO or Rh incompatibility when RBCs from incompatible donor enter the recipient circulation, they become coated with antibodies directed against RBC antigen of the donor and are lysed.
Erythroblastosis fetalis: due to rhesus incompatibility between the fetus and mother. When fetus is Rh positive with Rh negative mother. Fetal RBCs (carrying D antigen which is foreign to the mother) enter maternal circulation in the last months of pregnancy or during delivery, the mother develop antibodies of IgG type ( become sensitized). During the second pregnancy these antibodies can cross the placenta and attack Rh antigen on fetal RBCs causing their lysis and development of hemolytic anemia and heart failure of the baby.
Pemphigus Vulgaris: a skin disorder characterized by formation of vesicles and bullae ( fluid filled cavities) due to formation of autoantibodies against desmosomal proteins that connect epidermal or squamous cells together resulting in loss of adhesion in between cells and formation of vesicles.
Pemphigus vulgaris: the blisters are large and rupture easily leaving shallow erosions
Pemphigus vulgaris: blister cavity lies above the basal layer which remains attached to the basement membraneAutoimmune Hemolytic Anemia, agranulocytosis and thrombocytopenia: auto antibodies directed against individual’s own blood components.Drug Reaction: the drug binds to the cell surface (most commonly RBCs) with production of antibodies against the drug resulting in lysis of RBCs and hemolytic anemia.
B) Antibody-Dependent Cell Mediated Cytotoxicity Involves killing of large antigens e.g. parasite and tumor cells without phagocytosis or complement activation but by cells that bears Fc receptors for Fc portion of IgG e.g. neutrophils, eosinophils, macrophages and NK cells.
In parasitic infestation, B-cell activation leads to production of IgE antibodies which bound to the parasite and to mast cells, eosinophils and macrophages through their Fc portion and the parasite is killed by cytokines derived from these cells.
C) Antibody-Mediated Cellular Dysfunction: Antibodies directed against cell surface receptors impair function without causing cell injury or inflammation e.g. In myasthenia gravis, antibodies against acetylcholine receptors in motor end plate of skeletal muscles are blocking antibodies interfere with action of acetylcholine at receptor binding site resulting in muscular weakness.
In Gravis disease, antibodies against thyroid-stimulating hormone receptor stimulate thyroid epithelial cells and result in hyperthyroidism.
Type III hypersensitivity ( Immune complex-mediated) Is mediated by deposition of antigen-antibody (immune) complexes followed by complement activation and accumulation of polymorph nuclear leukocytes.
Antigens may be exogenous e.g. bacteria and viruses or endogenous e.g. DNA and these immune complexes either form in the circulation (systemic) and then subsequently deposited in tissues or form and implanted locally at specific extra vascular sites e.g. kidney, joint, skin (localized) but the mechanism of tissue injury is the same.
Systemic Immune Complex Disease Pathogenesis Formation of antigen-antibody complexes, Deposition of immune complexes in various tissues thus initiating; An inflammatory reaction in various tissues and complement activation
If there is single exposure to the antigen, the lesion tend to be acute e.g. acute vasculities, acute post-streptococcal glomerulonephritis (streptococcal antigen) and acute serum sickness but repeated exposure to the same antigen leads to chronic disease e.g. systemic lupus erythematosus.
Acute serum sickness is the prototype of a systemic immune-complex disease. It was first described in human when foreign serum was administered for passive immunization ( e.g. horse antitetanus serum). Now it is uncommon and seen infrequently e.g. patient injected with horse antithymocyte globulin for treatment of aplastic anemia.
The first phase starts 5 days after injection of a foreign protein when specific antibodies ( IgG or IgM) are produced and form immune complexes with circulating antigen. In the second phase these circulating immune complexes are deposited in various tissues mainly kidney, heart, skin, serosal surfaces and basement membrane of blood vessels.
In the third phase: inflammatory reaction starts ( about 10 days after antigen administration). The deposition of immune complexes in tissue leads to activation of complement e.g. C3a which increases vascular permeability and are chemotactic factors for neutrophils. Neutrophils release inflammatory mediators free radicals and lysosomes which digest collagen and cause tissue damage.
Deposited immune complexes also induce platelet aggregation and activate Hageman factor leading to formation of microthrombi and local ischemia. IgG and IgM antibodies are the only type of immunoglobulin that are able to activate complement ( called complement fixing antibodies).
Pathology When immune complexes are deposited in blood vessels the pathologic lesion is called vasculitis while their deposition in the glomeruli is called glomerulonephritis and in the joint is called arthritis
Vasculitis : deposition of immune complexes in basement membrane of blood vessels causes increased vascular permeability leading to protein deposition and necrosis in the vessel wall ( acute necrotizing vasculitis). The necrotic wall takes an eosinophilic appearance called fibrinoid necrosis, and immune complexes can be detected in the vessel wall by electron microscopy and by immunofleurescence.
The deposition of immune complexes in an artery is called vasculitis with circumferential bright pink area of fibrinoid necrosis with protein infiltration & inflammation
Acute glomerulonephritis: the immune complexes are deposited in the glomerular basement membrane leading to basement membrane thickening and leukocyte infiltration in the glomeruli. Systemic lupus erythematosus: is a chronic form of systemic immune complex disease in which autoantibodies are formed against self antigens e.g. nuclear or cytoplasmic parts of cells in different tissues with formation of immune complexes mainly in skin, kidney, joints, heart, and serosal surfaces.
IgG antibodies detected in granular pattern by immunoflourescence
Local Immune Complex Disease (Arthus Reaction): Arthus reaction is defined as a localized area of tissue necrosis resulting from acute immune complex vasculitis. It occurs after injection of an antigen into the skin of a previously immunized individual ( antibodies to that antigen are already present in the circulation),so immune complexes are formed during diffusion of that antigen through the vascular wall (in situ or local formation of immune complexes) which then become deposited at the site of injection and produce the same inflammatory reaction, complement activation and histological appearance of systemic immune complex disease. The site of injection develops severe edema, hemorrhage and ulceration.
Type IV Hypersensitivity ( Cell-Mediated ): Is mediated by specifically sensitized T lymphocytes ( without antibodies) It is subdivided into two types: Delayed Type Hypersensitivity: mediated by CD4+ T lymphocytes Direct Cell Cytotoxicity: mediated by CD8+ T lymphocytes
Delayed type hypersensitivity Classically seen in tuberculin reaction and granulomatous inflammation in response to T.B., fungi , transplant rejection and tumor immunity. Pathogenesis: The sequence of events in DTH begins with the first exposure of the individual to tubercle bacilli. CD4+ lymphocytes recognize peptide antigen of tubercle bacilli in association with class II antigens on the surface of dendritic cells (antigen presenting cells).
Once CD4+ T lymphocytes recognize the antigen, it become sensitized with formation of TH1 type lymphocytes that develop memory cells and remain in the circulation for years.On subsequent exposure to the same antigen, memory cells respond to the presented antigen on antigen presenting cells and become activated and secrete cytokines mainly TNF, IL-2 and IFN-ɣ . IL-2 causes proliferation of T cells that have accumulated at the site of delayed type reaction.
INF-ɣ is a potent activator of macrophages, it attract macrophages at the site of reaction from blood monocytes. Activated macrophages become large, flat and eosinophilic ( called epithelioid cells) , some of these epithelioid cells under the influence of INF-ɣ fuse and form multinucleated giant cells. Epithelioid cells become surrounded by a collar of lymphocytes and fibroblasts and called granuloma and the pattern is called granulomatous inflammation.
Epithelioid cells produce potent products ( proteases and oxide radicals) that are able to kill or neutralize mycobacteria and prevent dissemination of bacilli. Loss of CD4+ T cells due to e.g. HIV infection, the ability of individual to respond against intracellular pathogens like mycobacteria is markedly impaired so mycobacteria are engulfed by macrophages but are not killed or inactivated and granuloma do not form leading to dissemination of tubercle bacilli.
The granuloma is composed of localized collection of epithelioid cells surrounded by lymphocytes with langhans type giant cell.
Tuberculin Reaction: This reaction is found in individuals already sensitized to tubercle bacilli by a previous infection ( a previous exposure of individual to tubercle bacilli with formation of sensitized CD4+ T lymphocytes and memory cells). Tuberculin is a protein extract of tubercle bacilli and within 8-12 hours of subcutaneous injection of tuberculin, a local area of erythema develops reaching its peak of 1-2 cm within 24-48 hours and then subsight gradually.
In this reaction, memory cells recognize tuberculin on surface of antigen presenting cells and secrete cytokines like IL-2 and INF-ɣ and causes accumulation of lymphocytes and macrophages in the perivascular area with local increase in vascular permeability leading to tissue indurations and local edema
Tuberculin reaction is used to screen population for individuals who have prior exposure to tuberculosis and therefore have circulating memory cells, so immunosuppression or loss of CD4+ T lymphocyte e.g., due to HIV infection leads to negative tuberculin test even in the presence of severe infection.
T – Cell- Mediated CytotoxicityIs mediated by CD8+ T cells ( cytotoxic T lymphocytes). These cells are main defensive mechanism against viral infection, tumor cells and transplant rejection.Class I MHC molecules bind to intracellular viral particles and form a complex presented to CD8+ T cells, these cells once activated it secrete mediators e.g. perforin that cause lysis or apoptosis of virally infected cells before viral replication ( the same mechanism acts against tumor cells and transplanted cells)