Circulating antigen-antibody complexes deposit in tissues (kidney, skin, joints) and activate complement, recruiting leukocytes and causing inflammation. Serum sickness from foreign proteins (antibiotics, antivenom) or autoimmune conditions (lupus) exemplify immune complex disease; C3 deposition on glomeruli causes proliferative GN.
You have already studied the four types of hypersensitivity reactions. Immune complex disease is the mechanism behind Type III hypersensitivity — and the key to understanding it is recognizing that the damage here is not caused by the antibody attacking host tissue directly (that is Type II), but by the antibody-antigen complex being deposited *in* tissue after forming in the bloodstream. It is collateral damage: the immune system cannot cleanly clear the complex, and in trying to do so, destroys the tissue it lands in.
Here is the sequence: antigen (a foreign protein, drug hapten, or self-antigen in autoimmunity) circulates in blood and binds circulating IgG or IgM antibodies. Normally, complement and phagocytes clear these immune complexes quickly. But when complexes are formed in large amounts, at a particular size, or in a host with impaired clearance, they persist in circulation and begin depositing in vessel walls and filtration organs. The glomeruli of the kidney, the synovium of joints, and small dermal capillaries are particularly vulnerable because blood is filtered or slowed through these structures under pressure, physically trapping the complexes.
Once deposited, immune complexes activate the complement cascade through the classical pathway — the same cascade you already know, now triggered not by a pathogen surface but by the Fc regions of antibodies in the complex. Complement activation generates C3a and C5a (anaphylatoxins), which recruit neutrophils and increase vascular permeability. Neutrophils attempt to phagocytize the complexes but cannot — the complexes are embedded in the basement membrane — so neutrophils release their granule contents (proteases, reactive oxygen species) extracellularly, damaging the surrounding tissue. The result is vasculitis, glomerulonephritis, and arthritis — the classic triad of serum sickness.
Serum sickness is the prototypical example: days after exposure to a foreign protein (antivenom, monoclonal antibodies, certain antibiotics), patients develop fever, rash, joint pain, and sometimes kidney involvement. The delay (7–14 days) reflects the time needed to mount an antibody response to the foreign antigen — only after antibodies are generated do complexes form and deposit. In contrast, lupus nephritis represents chronic immune complex disease: auto-antibodies against nuclear antigens (anti-dsDNA) form complexes that deposit in glomeruli over years, with C3 staining on biopsy as the pathological signature. Understanding that the same immune complex mechanism drives both acute serum sickness and chronic lupus nephritis shows how pathophysiology generalizes: the antigen changes, but the mechanism is identical.