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Porcine Reproductive and Respiratory Syndrome Virus Subverts Repertoire Development by Proliferation of Germline-Encoded B Cells of All Isotypes Bearing Hydrophobic Heavy Chain CDR3¹

John E. Butler^2,*, Nancy Wertz^*, Patrick Weber^* and Kelly M. Lager

^* Department of Microbiology, University of Iowa Medical School, Iowa City, IA 52242; and National Animal Disease Center, Ames, IA 50010

Isolator piglets infected with porcine reproductive and respiratory syndrome virus (PRRSV), which is related to the lactate dehydrogenase-elevating virus of mice, develop severe hypergammaglobulinemia, lymph node adenopathy, and autoimmune disease. Many of the polyclonally activated B cell clones bear hydrophobic H chain CDR3s (HCDR3s) and are disseminated to most lymphoid tissues. We show in this study that B cells with identical hydrophobic HCDR3s are expressed with all major isotypes in PRRSV-infected piglets (PIPs), explaining why PRRSV-induced hypergammaglobulinemia is seen in all major isotypes. Up to one-third of randomly selected VDJ clones from the respiratory tract of PIPs have hydrophobic HCDR3s exclusively bearing VDJ rearrangements with CDR1, CDR2, and nearly intact DH segments in germline configuration. These HCDR3s are long and D_HA and D_HB are exclusively used in reading frame 3. A minimal tripeptide motif containing three hydrophobic amino acids (Leu, Val, and Ile) or any two plus alanine is common to this hydrophobic patch. We propose that PRRSV infection causes generalized Ag-independent B cell activation and hypergammaglobulinemia with biased expansion of a subpopulation of the preimmune repertoire with hydrophobic binding sites that normally disappears during Ag-driven repertoire diversification. Elevated Ig levels in PIP cannot be explained as antiviral Abs; some Igs can account for autoantibodies to dsDNA and Golgi, whereas those with hydrophobic binding sites may account for the Ig aggregates seen in PIPs and lactate dehydrogenase-elevating virus-infected mice. This diversion from normal repertoire development may explain the delayed immune response to PRRSV.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant 05-174 from the National Pork Board and U.S. Department of Agriculture Agricultural Research Service Cooperative Agreement 58-3625-4-155.

² Address correspondence and reprint requests to Dr. John E. Butler, University of Iowa, Department of Microbiology, 51 Newton Road, Iowa City, IA 52242. E-mail address: john-butler{at}uiowa.edu

³ Abbreviations used in this paper: PRRS, porcine reproductive and respiratory syndrome; BAL, bronchoalveolar lavage; BSAg, B cell superantigen; dpi, days postinoculation; HCDR3, H chain CDR3; H.I., hydropathicity index; IIP, SIV-infected piglets; LDV, lactate dehydrogenase-elevating virus; PCV-2, porcine circovirus-2; PIC, parasite-infected conventional pigs; PIP, PRRSV-infected piglets; pnt, polynucleotide; PRRSV, PRRS virus; RF, reading frame; SHM, somatic hypermutation; SIV, swine influenza virus.