title: Human autoantibodies specific for neurotrophin receptors TrkA, TrkB, and TrkC protect against lethal Trypanosoma cruzi infection in mice.
abstract: Patients with Chagas' disease remain asymptomatic for many years, presumably by keeping the etiological agent Trypanosoma cruzi in check through protective immunity against. Recently, we found that T. cruzi uses TrkA, a receptor tyrosine kinase responsive to neurotrophin nerve growth factor in vertebrate nervous systems, to invade cells. We also found that TrkA, TrkB, and TrkC, but not T. cruzi, are targets of specific autoantibodies present in the sera of patients with chronic Chagas' disease. Here we show that TrkA-, TrkB-, and TrkC-specific autoantibodies isolated from the sera of four individuals with chronic indeterminate (asymptomatic) Chagas' disease potently blocked invasion of Trk-bearing neuronal PC12 cells, neuroglial astrocytes, enteroglial cells, and Schwann cells and Trk-expressing non-neural smooth muscle and dendritic cells. However, these autoantibodies did not inhibit T. cruzi invasion of mutant PC12 cells lacking TrkA or of normal cells lacking Trk receptors, suggesting that autoantibodies interfered with parasite/Trk cross talk to access the intracellular milieu. Passive immunization of susceptible and resistant mouse strains with very small doses of these autoantibodies reduced parasitemia and transferred resistance to an otherwise lethal trypanosome infection. Hence, this exquisitely sensitive and unique regulatory immunity against the host (instead of parasite) could benefit infected individuals by blocking cellular invasion of the obligatory intracellular pathogen, resulting in attenuation of tissue infection and clinical manifestations. Such action is contrary to the horror autotoxicus frequently associated with microbe-related autoimmune responses.
authors.affiliation: Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.forename: Joseph
authors.initials: J
authors.lastname: Alroy
authors.forename: Alejandro O
authors.initials: AO
authors.lastname: Luquetti
authors.forename: Mercio
authors.initials: M
authors.lastname: PereiraPerrin
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D014355:Chagas Disease / Q000097:blood / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D006801:Humans; D007116:Immunization, Passive; D007249:Inflammation / Q000276:immunology; D051379:Mice; D016716:PC12 Cells; D018512:Parasitemia / Q000276:immunology; D017434:Protein Structure, Tertiary; D051381:Rats; D020917:Receptor, trkA / Q000097:blood / Q000737:chemistry / Q000276:immunology; D020813:Receptor, trkB / Q000097:blood / Q000737:chemistry / Q000276:immunology; D020812:Receptor, trkC / Q000097:blood / Q000737:chemistry / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000097:blood / Q000737:chemistry / Q000276:immunology*; D016019:Survival Analysis; D014349:Trypanosoma cruzi / Q000472:pathogenicity / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D017475:Receptors, Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC