Drug-induced serum sickness

Principles to understand

• immune complex disease is mediated by IgG

• pattern of involvement

  • systemic

  • arteritis: antigen-antibody complexes precipitating on endothelial cells

  • arthritis: antigen-antibody complexes precipitating in joints

  • glomerulonephritis: capillary tufts, which are very leaky for fluid

  • skin rash: complexes come out of areas in the skin where there is sun exposure, because, after all, the erythema of sunburn is indicative of increased vascular permeability

• patterns of involvement when antigen is introduced intradermally, IV, or inhaled. it takes longer than an IgE-mediated reaction (type I hypersensitivity), say about 30 minutes to an hour

• this is not immediate hypersensitivity, but it is faster than T-cell-mediated hypersensitivity (type IV), so it is intermediate hypersensitivity. this time course distinguishes it

• pts may make antibodies to drugs that attach to cells or proteins and then these may form immune complexes

Facts about type III immune-mediated tissue damage

• immune reactant: IgG antibody

• antigen: soluble

• effector mechanism: complement; FcR+ cells

• examples: serum sickness, systemic lupus erythematosus (antigen is self-DNA or ribonuclear proteins)

Antibody-antigen ratio determines the amount of Ab-Ag precipitate

• precipitate grows to a maximum at an equivalence of antigen-antibody because this forms the largest lattice of antibody-antigen complexes

• if you have antigen excess, the antibodies don’t form a big lattice and hence tend to stay soluble

• if you have antibody excess, there isn’t enough antigen to crosslink it

• so, you don’t make as much of a precipitate on the two ends of the ratio, but you do make a lot if there is an equivalence of antigen and antibody

• this causes a very typical time course for this illness

Time course of type III hypersensitivity reactions

• intradermally-injected antigen in an immune individual with IgG antibody

• locally, there is immune-complex formation

• this leads to mast cell degranulation as well as activation of C5a, C3a, C4a

• this causes more cells to be attracted (C5a, C3a), increased vascular permeability (C3a), and increased mast cell degranulation (C3a)

• white cells come out and eat the antigen-antibody complexes locally and this stops the process if the complexes have not yet become systemic

• student question: what is the case if someone says that they have an allergy to bee stings? do they generally have a type I or type III hypersensitivity reaction? answer: IgE-mediated responses will show a welt in minutes. in either case, though, if the antigen is systemically absorbed, you will get vascular collapse regardless of whether it is high-titer IgG or high-titer IgE

Route of entry and sequelae

• intravenous: vasculitis, nephritis, arthritis. this is called serum sickness

• subcutaneous: Arthus reaction (wheal-and-flare); this describes the IgG response

• inhaled: farmer’s lung or silo filler’s lung, an asthma-like reaction

Rash

• looks pretty much the same as IgE-mediated allergy

Time course of serum sickness

• x-axis ticks are days, so two weeks are represented here

• foreign serum injection leads to formation of antigen-antibody complexes after a week

• you are sick as soon as these complexes start to form; this lasts through the blue triangle

• so it takes about a week to start, you are sick for several days, and then you are well (though you may have residual blood vessel, glomerular, joint damage)

• when might this happen clinically? we do give people monoclonal mouse antibodies for treatment of B-cell lymphoma, for example. these antibodies have mouse antigen-recognition site and carrier Fc

• this time course is absolutely typical for an IgG reaction by someone who hasn’t seen this antigen
  

Category: Pathology Notes