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Type II hypersensitivity occurs when IgG or IgM antibodies bind to antigens on cell surfaces, leading to cell destruction through complement activation, FcγR-mediated ADCC by NK cells and macrophages, or antibody-dependent cellular phagocytosis. Examples include Graves' disease (antibodies to TSH receptor), hemolytic transfusion reactions (ABO incompatibility), and drug-induced hemolytic anemia (when drugs act as haptens). The target cell damage is proportional to antibody titer and complement availability.
Compare destruction mechanisms: complement-mediated (MAC formation), ADCC (FcγR-NK interaction), and ADCP (FcγR-macrophage). Use hemolytic transfusion reactions as a prototypic example.
You already know that different antibody isotypes — IgG, IgM, IgA, IgE — have distinct effector functions determined by their Fc regions. Type II hypersensitivity is what happens when IgG or IgM antibodies bind to antigens that are fixed on cell surfaces rather than floating freely in solution. Instead of neutralizing a soluble toxin or opsonizing a microbe, the antibody marks a host cell (or a cell carrying surface-bound foreign antigen) for destruction. The damage is directed, specific, and proportional to how much antibody is present and which effector pathways it activates.
There are three principal destruction mechanisms, and understanding which one dominates in a given disease is clinically important. First, complement-mediated lysis: IgM or IgG bound to a cell surface activates the classical complement pathway, culminating in membrane attack complex (MAC) formation that punches holes in the target cell. This is the dominant mechanism in acute hemolytic transfusion reactions, where preformed anti-A or anti-B IgM antibodies bind to mismatched red blood cells and trigger rapid complement activation, causing massive intravascular hemolysis within minutes. Second, antibody-dependent cell-mediated cytotoxicity (ADCC): NK cells and macrophages bearing Fcγ receptors recognize the Fc portion of IgG coating the target cell and release cytotoxic granules or reactive oxygen species to kill it — no complement required. Third, antibody-dependent cellular phagocytosis (ADCP): macrophages engulf and digest antibody-coated cells via Fcγ receptor-mediated phagocytosis, which is how opsonized red blood cells are cleared in the spleen during autoimmune hemolytic anemia.
What makes Type II hypersensitivity particularly important is that the target antigen doesn't have to be foreign. In autoimmune diseases, the immune system produces antibodies against self-antigens on the body's own cells. In Graves' disease, antibodies bind the TSH receptor on thyroid cells — but instead of destroying the cell, they mimic TSH and stimulate the receptor, causing hyperthyroidism. In myasthenia gravis, antibodies bind acetylcholine receptors at the neuromuscular junction, blocking neurotransmitter binding and causing muscle weakness. These examples show that Type II reactions aren't limited to cell killing: antibodies can also activate or block receptor function, depending on what they bind and how.
A useful way to distinguish Type II from other hypersensitivities is by where the antigen sits. In Type I (immediate hypersensitivity), IgE on mast cells binds soluble allergens. In Type III (immune complex), antibodies bind soluble antigens that form circulating complexes depositing in tissues. In Type II, the antigen is fixed — attached to a cell membrane or extracellular matrix. This fixed location means the immune response is targeted to specific tissues rather than causing widespread inflammation, which is why Type II diseases tend to affect particular organs: red blood cells in hemolytic anemia, the thyroid in Graves' disease, the neuromuscular junction in myasthenia gravis. The clinical presentation follows directly from which cell surface the offending antibody recognizes.