A Quantitative Assessment of TRB CDR3-CMV Antigen Chemical Interactions Distinguishes Schizophrenia Patients from Control Patients
Anthony Sun1, Rachel Eakins2, Etienne Gozlan1, Andrea Chobrutskiy3, Boris Chobrutskiy4, George Blanck1
1Department of Molecular Medicine, University of South Florida, Morsani College of Medicine, 2University of Maryland School of Medicine, 3Department of Pediatrics, 4Department of Internal Medicine, Oregon Health and Science University Hospital
Objective:

This study explores the immunological relationship between schizophrenia and cytomegalovirus (CMV) by analyzing chemical complementarity between T-cell receptor beta complementarity-determining region 3s (TRB CDR3s) and CMV antigens in schizophrenia patients and control patients.

Background:

Schizophrenia is a destructive and stigmatized disease with poorly understood etiology. Although its cause is unknown, previous research has suggested both genetic and environmental risk factors. One such factor is CMV infection. Further understanding of this relationship could support improvements in schizophrenia diagnosis and treatment.

Design/Methods:

TRB recombination reads were recovered from blood sample exome files (phs000473) that included schizophrenia cases and controls. TRB CDR3 amino-acid sequences from 223 schizophrenia cases and 357 controls were inputted into the Adaptive Match webtool (adaptivematch.com) to be analyzed with CMV antigen amino-acid sequences. The webtool calculated chemical complementarity scores (CSs) for the TRB CDR3s and CMV antigens based on hydrophobic interactions (Hydro CSs), electrostatic interactions (Electrostatic CSs), and a combination of the two (Combo CSs). These scores were then averaged and compared.

Results:

Five previously identified CMV protein antigens were analyzed: UL40, pp65, IE1, IE2, and UL29. These were analyzed as full-length proteins and as randomly subdivided fragments. In total, this amounted to 43 separate CMV antigens. In comparison to TRB CDR3s from control cases, TRB CDR3s from schizophrenia patients showed higher average Hydro CSs and Combo CSs to 43 out of 43 CMV antigens. Thus, TRB CDR3s from schizophrenia patients had higher chemical complementarity to CMV antigens than TRB CDR3s from control cases.

Conclusions:

These results are consistent with the idea that schizophrenia patients have a stronger immunological response to CMV infection than control cases, leading to increased chemical complementarity between their TRB CDR3s and CMV antigens. Further research could reveal whether this is indicative of an autoimmune mechanism in schizophrenia, and whether viral or immunosuppressive treatments could be effective therapies.

10.1212/WNL.0000000000208367
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