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United States Department of Agriculture

Agricultural Research Service

Research Project: SWINE VIRAL DISEASES PATHOGENESIS AND IMMUNOLOGY Title: Porcine reproductive and respiratory syndrome virus (PRRSV) subverts normal development of adaptive immunity by proliferation of germline-encoded B cells with hydrophobic HCDR3

Authors
item Butler, John - UNIVERSITY OF IOWA
item Weber, P - UNIVERSITY OF IOWA
item Wertz, N - UNIVERSITY OF IOWA
item Lager, Kelly

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 10, 2007
Publication Date: February 15, 2008
Citation: Butler, J.E., Wertz, N., Weber, P., Lager, K.M. 2008. Porcine reproductive and respiratory syndrome virus subverts repertoire development by proliferation of germline-encoded B Cells of all isotypes bearing hydrophobic heavy chain CDR3. Journal of Immunology. 180(4):2347-2356.

Interpretive Summary: Porcine reproductive and respiratory syndrome (PRRS) is the number one disease concern of the U.S. swine industry. It is caused by the PRRS virus (PRRSV). PRRSV vaccines are commercially available for use in control of this disease; however, they do not fully cross-protect vaccinated swine against all PRRSV strains. Why vaccines do not fully cross-protect is not understood and this phenomenon is one focus of research at the National Animal Disease Center. Animal studies involving germ-free pigs have been conducted to study the direct effect of PRRSV on a pig's immune response to this virus. This paper extends our findings that PRRSV can modulate the host response by diverting the specific antibody response. This diversion takes energy away from the development of a protective response, presumably, the diversion is an advantage to the virus since it delays the pig's specific immune response against the virus. Another research focus is to identify the properties of the virus that cause this diversion to occur. The anticipated goal of this work will be to understand the biology of the virus to an extent where specific mutations can be made that disable the diversionary tactics of PRRSV resulting in the improvement of vaccines.

Technical Abstract: Isolator piglets infected with porcine reproductive and respiratory syndrome virus (PRRSV) develop severe hypergammaglobulinemia, lymph node adenopathy and autoimmune disease. The expanded B cell clones in this disease are unusual in bearing hydrophobic HCDR3 regions and these are disseminated to most all lymphoid tissues. In this study we show by spectratypic and clonal analysis 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. More than 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; all of these in germline configuration. Both DHA and DHB in reading frame three are exclusively used and encode a minimal tri-peptide motif containing three hydrophobic amino acids (Leu, Val, Iso) or any two plus alanine. Thus PRRSV targets a subpopulation of pre-immune B cells with a hydrophobic motif in HCDR3 for expansion and differentiation in an apparent non-adaptive, T cell and antigen-independent manner. Immunoglobulins secreted by these cells are not virus specific and presumably account for the hypergammaglobulinemia and the Ig aggregates and autoantibodies seen in PIPs. This process may subvert or delay normal development of protective adaptive immunity thereby prolonging infectivity and permitting a greater period for spread of the disease.

Last Modified: 8/22/2014
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