A 34-year-old woman with end-stage kidney disease secondary to IgA nephropathy is undergoing kidney transplant from an unrelated living donor. The patient receives induction immunosuppression with a rabbit antithymocyte globulin-based regimen immediately prior to the procedure. The surgery is performed without complications, and maintenance immunosuppressive therapy is begun. Ten days later, the patient experiences high fevers, generalized pruritic rash, and pain, redness, and swelling of the bilateral metacarpophalangeal joints, wrists, and knees. The erythrocyte sedimentation rate is elevated. Arthrocentesis of the involved joint yields synovial fluid with neutrophilic leukocytosis; there are no crystals and no bacteria on Gram stain. Which of the following is most likely responsible for the increased synovial membrane permeability in this patient?

Question

A 34-year-old woman with end-stage kidney disease secondary to IgA nephropathy is undergoing kidney transplant from an unrelated living donor.  The patient receives induction immunosuppression with a rabbit antithymocyte globulin-based regimen immediately prior to the procedure.  The surgery is performed without complications, and maintenance immunosuppressive therapy is begun.  Ten days later, the patient experiences high fevers, generalized pruritic rash, and pain, redness, and swelling of the bilateral metacarpophalangeal joints, wrists, and knees.  The erythrocyte sedimentation rate is elevated.  Arthrocentesis of the involved joint yields synovial fluid with neutrophilic leukocytosis; there are no crystals and no bacteria on Gram stain.  Which of the following is most likely responsible for the increased synovial membrane permeability in this patient?

Quizplus · Accepted Answer

This patient received rabbit antithymocyte globulin and subsequently developed manifestations (eg, high fever, pruritic rash, joint pain/swelling) of serum sickness, an immune complex-mediated, type III hypersensitivity reaction that occurs 7-10 days after exposure to foreign protein in medication or vaccination. The underlying pathophysiology is as follows: Foreign proteins from the medication are processed by antigen-presenting cells and displayed on major histocompatibility complex class II molecules (MHCII). Patrolling CD4 cells bind the antigen-MHCII, undergo activation, and stimulate B cells to form plasma cells that secrete high-affinity IgG. The IgG binds the foreign proteins in the medication, thereby generating immune complexes (ICs). When large quantities of ICs are rapidly formed, they aggregate and deposit in the skin and joints. Deposited ICs activate the classical complement cascade. Although this generates the opsonizing protein C3b, which allows the IC to be cleared by phagocytic cells using the C3b receptor (Choice A), it also generates the highly inflammatory anaphylatoxins C3a and C5a. C3a and C5a are potent chemoattractants that dramatically increase phagocyte recruitment (eg, neutrophils, macrophages) to areas of IC deposition due to effects on the vasculature (eg, vasodilation, increased permeability) and immune cells (eg, increased adhesion molecule expression). This leads to development of local (eg, skin rash, joint pain/effusion, neutrophilic joint effusion) and systemic (eg, high fever, elevated erythrocyte sedimentation rate) inflammatory manifestations that resolve spontaneously over a few days as the ICs are processed/removed by phagocytes. (Choice C) IL-5 is a cytokine produced by activated CD4 cells and mast cells. It stimulates B cells to proliferate and generate IgA. It does not play a significant role in neutrophil recruitment to areas of IC deposition. (Choice D) N-formylated peptides are chemoattractants released by damaged host cells and pathogens. Although they recruit neutrophils to areas of active infection, they are not the primary driver in serum sickness; in serum sickness, most of the inflammatory response is mediated by C3a and C5a. (Choice E) RANTES is a chemokine that recruits T cells, eosinophils, and basophils to areas of inflammation. It is not a strong neutrophil chemoattractant and is not a significant by-product of the classical complement cascade activation. Educational objective: Serum sickness is an immune complex-mediated, type III hypersensitivity reaction that occurs when immune complexes deposit in skin and joints and activate the classical complement cascade. This generates the highly inflammatory anaphylatoxins C3a and C5a, leading to skin rash, joint arthralgia/arthritis, and high fever.

A 34-Year-Old Woman with End-Stage Kidney Disease Secondary to IgA