Porcine reproductive and respiratory syndrome virus subverts repertoire development by proliferation of germline-encoded B cells of all isotypes bearing hydrophobic heavy chain CDR3.
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(H)A and D(H)B 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.
Butler
John E
JE
Department of Microbiology, University of Iowa Medical School, 51 Newton Road, Iowa City, IA 52242, USA. john-butler@uiowa.edu
Wertz
Nancy
N
Weber
Patrick
P
Lager
Kelly M
KM
D000818:Animals; D000831:Animals, Newborn; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000096:biosynthesis* / Q000235:genetics; D005854:Germ Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D057927:Hydrophobic and Hydrophilic Interactions; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D019318:Porcine Reproductive and Respiratory Syndrome / Q000276:immunology / Q000473:pathology; D019316:Porcine respiratory and reproductive syndrome virus / Q000276:immunology*; D011897:Random Allocation; D027041:Somatic Hypermutation, Immunoglobulin; D013552:Swine
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes